Counting on birth registration: mixed-methods research in two EN-BIRTH study hospitals in Tanzania.

BACKGROUND: Birth registration marks a child's right to identity and is the first step to establishing citizenship and access to services. At the population level, birth registration data can inform effective programming and planning. In Tanzania, almost two-thirds of births are in health facilities, yet only 26% of children under 5 years have their births registered. Our mixed-methods research explores the gap between hospital birth and birth registration in Dar es Salaam, Tanzania. METHODS: The study was conducted in the two Tanzanian hospital sites of the Every Newborn-Birth Indicators Research Tracking in Hospitals (EN-BIRTH) multi-country study (July 2017-2018). We described the business processes for birth notification and registration and collected quantitative data from women's exit surveys after giving birth (n = 8038). We conducted in-depth interviews (n = 21) to identify barriers and enablers to birth registration among four groups of participants: women who recently gave birth, women waiting for a birth certificate at Temeke Hospital, hospital employees, and stakeholders involved in the national birth registration process. We synthesized findings to identify opportunities to improve birth registration. RESULTS: Standard national birth registration procedures were followed at Muhimbili Hospital; families received birth notification and were advised to obtain a birth certificate from the Registration, Insolvency, and Trusteeship Agency (RITA) after 2 months, for a fee. A pilot programme to improve birth registration coverage included Temeke Hospital; hand-written birth certificates were issued free of charge on a return hospital visit after 42 days. Among 2500 women exit-surveyed at Muhimbili Hospital, 96.3% reported receiving a birth notification form and nearly half misunderstood this to be a birth certificate. Of the 5538 women interviewed at Temeke Hospital, 33.0% reported receiving any documentation confirming the birth of their child. In-depth interview respondents perceived birth registration to be important but considered both the standard and pilot processes in Tanzania complex, burdensome and costly to both families and health workers. CONCLUSION: Birth registration coverage in Tanzania could be improved by further streamlining between health facilities, where most babies are born, and the civil registry. Families and health workers need support to navigate processes to register every child

Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors

Strategies to induce p53 activation in wtp53-retaining tumors carry high potential in cancer therapy. Nutlin, a potent highly selective MDM2 inhibitor, induces non-genotoxic p53 activation. Although Nutlin shows promise in promoting cell death in hematopoietic malignancies, a major roadblock is that most solid cancers do not undergo apoptosis but merely reversible growth arrest. p53 inhibition by unopposed MDMX is one major cause for apoptosis resistance to Nutlin. The Hsp90 chaperone is ubiquitously activated in cancer cells and supports oncogenic survival pathways, many of which antagonize p53. The Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) is known to induce p53-dependent apoptosis. We show here that in multiple difficult-to-kill solid tumor cells 17AAG modulates several critical components that synergize with Nutlin-activated p53 signaling to convert Nutlin's transient cytostatic response into a cytotoxic killing response in vitro and in xenografts. Combined with Nutlin, 17AAG destabilizes MDMX, reduces MDM2, induces PUMA and inhibits oncogenic survival pathways, such as PI3K/AKT, which counteract p53 signaling at multiple levels. Mechanistically, 17AAG interferes with the repressive MDMX–p53 axis by inducing robust MDMX degradation, thereby markedly increasing p53 transcription compared with Nutlin alone. To our knowledge Nutlin+17AAG represents the first effective pharmacologic knockdown of MDMX. Our study identifies 17AAG as a promising synthetic lethal partner for a more efficient Nutlin-based therapy

Sampling the Solution Space in Genome-Scale Metabolic Networks Reveals Transcriptional Regulation in Key Enzymes

Genome-scale metabolic models are available for an increasing number of organisms and can be used to define the region of feasible metabolic flux distributions. In this work we use as constraints a small set of experimental metabolic fluxes, which reduces the region of feasible metabolic states. Once the region of feasible flux distributions has been defined, a set of possible flux distributions is obtained by random sampling and the averages and standard deviations for each of the metabolic fluxes in the genome-scale model are calculated. These values allow estimation of the significance of change for each reaction rate between different conditions and comparison of it with the significance of change in gene transcription for the corresponding enzymes. The comparison of flux change and gene expression allows identification of enzymes showing a significant correlation between flux change and expression change (transcriptional regulation) as well as reactions whose flux change is likely to be driven only by changes in the metabolite concentrations (metabolic regulation). The changes due to growth on four different carbon sources and as a consequence of five gene deletions were analyzed for Saccharomyces cerevisiae. The enzymes with transcriptional regulation showed enrichment in certain transcription factors. This has not been previously reported. The information provided by the presented method could guide the discovery of new metabolic engineering strategies or the identification of drug targets for treatment of metabolic diseases

An integrated network visualization framework towards metabolic engineering applications

Background Over the last years, several methods for the phenotype simulation of microorganisms, under specified genetic and environmental conditions have been proposed, in the context of Metabolic Engineering (ME). These methods provided insight on the functioning of microbial metabolism and played a key role in the design of genetic modifications that can lead to strains of industrial interest. On the other hand, in the context of Systems Biology research, biological network visualization has reinforced its role as a core tool in understanding biological processes. However, it has been scarcely used to foster ME related methods, in spite of the acknowledged potential. Results In this work, an open-source software that aims to fill the gap between ME and metabolic network visualization is proposed, in the form of a plugin to the OptFlux ME platform. The framework is based on an abstract layer, where the network is represented as a bipartite graph containing minimal information about the underlying entities and their desired relative placement. The framework provides input/output support for networks specified in standard formats, such as XGMML, SBGN or SBML, providing a connection to genome-scale metabolic models. An user-interface makes it possible to edit, manipulate and query nodes in the network, providing tools to visualize diverse effects, including visual filters and aspect changing (e.g. colors, shapes and sizes). These tools are particularly interesting for ME, since they allow overlaying phenotype simulation results or elementary flux modes over the networks. Conclusions The framework and its source code are freely available, together with documentation and other resources, being illustrated with well documented case studies.This work is partially funded by ERDF - European Regional Development Fund through the COMPETE Programme (operational programme for competitiveness) and by National Funds through the FCT (Portuguese Foundation for Science and Technology) within project ref. COMPETE FCOMP-01-0124-FEDER-015079 and the FCT Strategic Project PEst-OE/EQB/LA0023/2013. The work of PV is funded by PhD grant ref. SFRH/BDE/51442/2011

Differential orientation effect in the neural response to interacting biological motion of two agents

<p>Abstract</p> <p>Background</p> <p>A recent behavioral study demonstrated that the meaningful interaction of two agents enhances the detection sensitivity of biological motion (BM), however, it remains unclear when and how the 'interaction' information of two agents is represented in our neural system. To clarify this point, we used magnetoencephalography and introduced a novel experimental technique to extract a neuromagnetic response relating to two-agent BM perception. We then investigated how this response was modulated by the interaction of two agents. In the present experiment, we presented two kinds of visual stimuli (interacting and non-interacting BM) with two orientations (upright and inverted).</p> <p>Results</p> <p>We found a neuromagnetic response in the bilateral occipitotemporal region, on average 300 – 400 ms after the onset of a two-agent BM stimulus. This result showed that interhemispheric differences were apparent for the peak amplitudes. For the left hemisphere, the orientation effect was manifest when the two agents were made to interact, and the interaction effect was manifest when the stimulus was inverted. In the right hemisphere, the main effects of both orientation and interaction were significant, suggesting that the peak amplitude was attenuated when the visual stimulus was inverted or made to interact.</p> <p>Conclusion</p> <p>These results demonstrate that the 'interaction' information of two agents can affect the neural activities in the bilateral occipitotemporal region, on average 300 – 400 ms after the onset of a two-agent BM stimulus, however, the modulation was different between hemispheres: the left hemisphere is more concerned with dynamics, whereas the right hemisphere is more concerned with form information.</p

Improved precision on the experimental E0 decay branching ratio of the Hoyle state

Stellar carbon synthesis occurs exclusively via the $3\alpha$ process, in which three $\alpha$ particles fuse to form $^{12}$C in the excited Hoyle state, followed by electromagnetic decay to the ground state. The Hoyle state is above the $\alpha$ threshold, and the rate of stellar carbon production depends on the radiative width of this state. The radiative width cannot be measured directly, and must instead be deduced by combining three separately measured quantities. One of these quantities is the $E0$ decay branching ratio of the Hoyle state, and the current $10$\% uncertainty on the radiative width stems mainly from the uncertainty on this ratio. The $E0$ branching ratio was deduced from a series of pair conversion measurements of the $E0$ and $E2$ transitions depopulating the $0^+_2$ Hoyle state and $2^+_1$ state in $^{12}$C, respectively. The excited states were populated by the $^{12}$C$(p,p^\prime)$ reaction at 10.5 MeV beam energy, and the pairs were detected with the electron-positron pair spectrometer, Super-e, at the Australian National University. The deduced branching ratio required knowledge of the proton population of the two states, as well as the alignment of the $2^+_1$ state in the reaction. For this purpose, proton scattering and $\gamma$-ray angular distribution experiments were also performed. An $E0$ branching ratio of $\Gamma^{E0}_{\pi}/\Gamma=8.2(5)\times10^{-6}$ was deduced in the current work, and an adopted value of $\Gamma^{E0}_{\pi}/\Gamma=7.6(4)\times10^{-6}$ is recommended based on a weighted average of previous literature values and the new result. The new recommended value for the $E0$ branching ratio is about 14% larger than the previous adopted value of $\Gamma^{E0}_{\pi}/\Gamma=6.7(6)\times10^{-6}$, while the uncertainty has been reduced from 9% to 5%.Comment: Accepted for publication as a Regular Article in Phys. Rev. C on July 29 202

On the Mechanism of Action of SJ-172550 in Inhibiting the Interaction of MDM4 and p53

SJ-172550 (1) was previously discovered in a biochemical high throughput screen for inhibitors of the interaction of MDMX and p53 and characterized as a reversible inhibitor (J. Biol. Chem. 2010; 285∶10786). Further study of the biochemical mode of action of 1 has shown that it acts through a complicated mechanism in which the compound forms a covalent but reversible complex with MDMX and locks MDMX into a conformation that is unable to bind p53. The relative stability of this complex is influenced by many factors including the reducing potential of the media, the presence of aggregates, and other factors that influence the conformational stability of the protein. This complex mechanism of action hinders the further development of compound 1 as a selective MDMX inhibitor

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

The impact of gender and parenthood on physicians' careers - professional and personal situation seven years after graduation

BACKGROUND: The profile of the medical profession is changing in regard to feminization, attitudes towards the profession, and the lifestyle aspirations of young physicians. The issues addressed in this study are the careers of female and male physicians seven years after graduation and the impact of parenthood on career development. METHODS: Data reported originates from the fifth assessment (T5) of the prospective SwissMedCareer Study, beginning in 2001 (T1). At T5 in 2009, 579 residents (81.4% of the initial sample at T1) participated in the questionnaire survey. They were asked about occupational factors, career-related factors including specialty choice and workplace, work-life balance and life satisfaction. The impact of gender and parenthood on the continuous variables was investigated by means of multivariate and univariate analyses of variance; categorical variables were analyzed using Chi-square tests. RESULTS: Female physicians, especially those with children, have lower rates of employment and show lower values in terms of career success and career support experiences than male physicians. In addition, parenthood has a negative impact on these career factors. In terms of work-life balance aspired to, female doctors are less career-oriented and are more inclined to consider part-time work or to continue their professional career following a break to bring up a family. Parenthood means less career-orientation and more part-time orientation. As regards life satisfaction, females show higher levels of satisfaction overall, especially where friends, leisure activities, and income are concerned. Compared to their male colleagues, female physicians are less advanced in their specialty qualification, are less prone to choosing prestigious surgical fields, have a mentor less often, more often work at small hospitals or in private practice, aspire less often to senior hospital or academic positions and consider part-time work more often. Any negative impact on career path and advancement is exacerbated by parenthood, especially as far as women are concerned. CONCLUSION: The results of the present study reflect socially-rooted gender role stereotypes. Taking into account the feminization of medicine, special attention needs to be paid to female physicians, especially those with children. At an early stage of their career, they should be advised to be more proactive in seeking mentoring and career-planning opportunities. If gender equity in terms of career chances is to be achieved, special career-support measures will have to be provided, such as mentoring programs, role models, flexitime and flexible career structures