Newborn survival: a multi-country analysis of a decade of change

Neonatal deaths account for 40% of global under-five mortality and are ever more important if we are to achieve the Millennium Development Goal 4 (MDG 4) on child survival. We applied a results framework to evaluate global and national changes for neonatal mortality rates (NMR), healthy behaviours, intervention coverage, health system change, and inputs including funding, while considering contextual changes. The average annual rate of reduction of NMR globally accelerated between 2000 and 2010 (2.1% per year) compared with the 1990s, but was slower than the reduction in mortality of children aged 1-59 months (2.9% per year) and maternal mortality (4.2% per year). Regional variation of NMR change ranged from 3.0% per year in developed countries to 1.5% per year in sub-Saharan Africa. Some countries have made remarkable progress despite major challenges. Our statistical analysis identifies inter-country predictors of NMR reduction including high baseline NMR, and changes in income or fertility. Changes in intervention or package coverage did not appear to be important predictors in any region, but coverage data are lacking for several neonatal-specific interventions. Mortality due to neonatal infection deaths, notably tetanus, decreased, and deaths from complications of preterm birth are increasingly important. Official development assistance for maternal, newborn and child health doubled from 2003 to 2008, yet by 2008 only 6% of this aid mentioned newborns, and a mere 0.1% (US$4.56m) exclusively targeted newborn care. The amount of newborn survival data and the evidence based increased, as did recognition in donor funding. Over this decade, NMR reduction seems more related to change in context, such as socio-economic factors, than to increasing intervention coverage. High impact cost-effective interventions hold great potential to save newborn lives especially in the highest burden countries. Accelerating progress requires data-driven investments and addressing context-specific implementation realitie

Differential regulation of NF-κB activation and function by topoisomerase II inhibitors

BACKGROUND: While many common chemotherapeutic drugs and other inducers of DNA-damage result in both NF-κB nuclear translocation and DNA-binding, we have previously observed that, depending on the precise stimulus, there is great diversity of the function of NF-κB. In particular, we found that treatment of U-2 OS osteosarcoma cells with the anthracycine daunorubicin or with ultraviolet (UV-C) light resulted in a form of NF-κB that repressed rather than induced NF-κB reporter plasmids and the expression of specific anti-apoptotic genes. Anthracyclines such as daunorubicin can induce DNA-damage though inhibiting topoisomerase II, intercalating with DNA and undergoing redox cycling to produce oxygen free radicals. In this study we have investigated other anthracyclines, doxorubicin and aclarubicin, as well as the anthracenedione mitoxantrone together with the topoisomerase II inhibitor ICRF-193, which all possess differing characteristics, to determine which of these features is specifically required to induce both NF-κB DNA-binding and transcriptional repression in U-2 OS cells. RESULTS: The use of mitoxantrone, which does not undergo redox cycling, and the reducing agent epigallocatechingallate (EGCG) demonstrated that oxygen free radical production is not required for induction of NF-κB DNA-binding and transcriptional repression by these agents and UV-C. In addition, the use of aclarubicin, which does not directly inhibit topoisomerase II and ICRF-193, which inhibits topoisomerase II but does not intercalate into DNA, demonstrated that topoisomerase II inhibition is not sufficient to induce the repressor form of NF-κB. CONCLUSION: Induction of NF-κB DNA-binding and transcriptional repression by topoisomerase II inhibitors was found to correlate with an ability to intercalate into DNA. Although data from our and other laboratories indicates that topoisomerase II inhibition and oxygen free radicals do regulate NF-κB, they are not required for the particular ability of NF-κB to repress rather than activate transcription. Together with our previous data, these results demonstrate that the nature of the NF-κB response is context dependent. In a clinical setting such effects could profoundly influence the response to chemotherapy and suggest that new methods of analyzing NF-κB function could have both diagnostic and prognostic value

Prevalence and outcomes of pregnancies in women living with HIV over a 20-year period: The EuroSIDA study, 1996 to 2015

OBJECTIVE: To evaluate time trends in pregnancies and pregnancy outcomes among women living with HIV in Europe. DESIGN: European multicentre prospective cohort study. METHODS: EuroSIDA has collected annual cross-sectional audits of pregnancies between 1996 and 2015. Pregnancy data were extracted and described. Odds of pregnancy were modelled, adjusting for potential confounders using logistic regression with generalised estimating equations. RESULTS: Of 5535 women aged 16 to <50 years, 4217 (76.2%) had pregnancy information available, and 912 (21.6%) reported 1315 pregnancies. The proportions with at least one pregnancy were 28.1% (321/1143) in East, 24.5% (146/596) in North, 19.8% (140/706) in West/Central, 19.3% (110/569) in Central East and 16.2% (195/1203) in South Europe. Overall 319 pregnancies (24.3%) occurred in 1996-2002, 576 (43.8%) in 2003-2009 and 420 (31.9%) in 2010-2015. After adjustment, the odds of pregnancy were lower in 1996-2002, in South, Central East and East compared to West/Central Europe, in older women, those with low CD4 counts or with prior AIDS, and higher in those with a previous pregnancy or who were HCV positive.Outcomes were reported for 999 pregnancies in 1996-2014, with 690 live births (69.1%), seven stillbirths (0.7%), 103 spontaneous (10.3%) and 199 medical abortions (19.9%). CONCLUSIONS: Around 20% of women in EuroSIDA reported a pregnancy, with most pregnancies after 2002, when more effective antiretroviral therapy became available. Substantial differences were seen between European regions. Further surveillance of pregnancies and outcomes among women living with HIV is warranted to ensure equal access to care

Two Nuclear Localization Signals in USP1 Mediate Nuclear Import of the USP1/UAF1 Complex

The human deubiquitinase USP1 plays important roles in cancer-related processes, such as the DNA damage response, and the maintenance of the undifferentiated state of osteosarcoma cells. USP1 deubiquitinase activity is critically regulated by its interaction with the WD40 repeat-containing protein UAF1. Inhibiting the function of the USP1/UAF1 complex sensitizes cancer cells to chemotherapy, suggesting that this complex is a relevant anticancer target. Intriguingly, whereas UAF1 has been reported to locate in the cytoplasm, USP1 is a nuclear protein, although the sequence motifs that mediate its nuclear import have not been functionally characterized. Here, we identify two nuclear localization signals (NLSs) in USP1 and show that these NLSs mediate the nuclear import of the USP1/UAF1 complex. Using a cellular relocation assay based on these results, we map the UAF1-binding site to a highly conserved 100 amino acid motif in USP1. Our data support a model in which USP1 and UAF1 form a complex in the cytoplasm that subsequently translocates to the nucleus through import mediated by USP1 NLSs. Importantly, our findings have practical implications for the development of USP1-directed therapies. First, the UAF1-interacting region of USP1 identified here might be targeted to disrupt the USP1/UAF1 interaction with therapeutic purposes. On the other hand, we describe a cellular relocation assay that can be easily implemented in a high throughput setting to search for drugs that may dissociate the USP1/UAF1 complex

Instructor feedback versus no instructor feedback on performance in a laparoscopic virtual reality simulator: a randomized educational trial

<p>Abstract</p> <p>Background</p> <p>Several studies have found a positive effect on the learning curve as well as the improvement of basic psychomotor skills in the operating room after virtual reality training. Despite this, the majority of surgical and gynecological departments encounter hurdles when implementing this form of training. This is mainly due to lack of knowledge concerning the time and human resources needed to train novice surgeons to an adequate level. The purpose of this trial is to investigate the impact of instructor feedback regarding time, repetitions and self-perception when training complex operational tasks on a virtual reality simulator.</p> <p>Methods/Design</p> <p>The study population consists of medical students on their 4^thto 6^thyear without prior laparoscopic experience. The study is conducted in a skills laboratory at a centralized university hospital. Based on a sample size estimation 98 participants will be randomized to an intervention group or a control group. Both groups have to achieve a predefined proficiency level when conducting a laparoscopic salpingectomy using a surgical virtual reality simulator. The intervention group receives standardized instructor feedback of 10 to 12 min a maximum of three times. The control group receives no instructor feedback. Both groups receive the automated feedback generated by the virtual reality simulator. The study follows the CONSORT Statement for randomized trials. Main outcome measures are time and repetitions to reach the predefined proficiency level on the simulator. We include focus on potential sex differences, computer gaming experience and self-perception.</p> <p>Discussion</p> <p>The findings will contribute to a better understanding of optimal training methods in surgical education.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01497782">NCT01497782</a></p

Classification of the height and flexibility of the medial longitudinal arch of the foot

<p>Abstract</p> <p>Background</p> <p>The risk of developing injuries during standing work may vary between persons with different foot types. High arched and low arched feet, as well as rigid and flexible feet, are considered to have different injury profiles, while those with normal arches may sustain fewer injuries. However, the cut-off values for maximum values (subtalar position during weight-bearing) and range of motion (ROM) values (difference between subtalar neutral and subtalar resting position in a weight-bearing condition) for the medial longitudinal arch (MLA) are largely unknown. The purpose of this study was to identify cut-off values for maximum values and ROM of the MLA of the foot during static tests and to identify factors influencing foot posture.</p> <p>Methods</p> <p>The participants consisted of 254 volunteers from Central and Northern Denmark (198 m/56 f; age 39.0 ± 11.7 years; BMI 27.3 ± 4.7 kg/m²). Navicular height (NH), longitudinal arch angle (LAA) and Feiss line (FL) were measured for either the left or the right foot in a subtalar neutral position and subtalar resting position. Maximum values and ROM were calculated for each test. The 95% and 68% prediction intervals were used as cut-off limits. Multiple regression analysis was used to detect influencing factors on foot posture.</p> <p>Results</p> <p>The 68% cut-off values for maximum MLA values and MLA ROM for NH were 3.6 to 5.5 cm and 0.6 to 1.8 cm, respectively, without taking into account the influence of other variables. Normal maximum LAA values were between 131 and 152° and normal LAA ROM was between -1 and 13°. Normal maximum FL values were between -2.6 and -1.2 cm and normal FL ROM was between -0.1 and 0.9 cm. Results from the multivariate linear regression revealed an association between foot size with FL, LAA, and navicular drop.</p> <p>Conclusions</p> <p>The cut-off values presented in this study can be used to categorize people performing standing work into groups of different foot arch types. The results of this study are important for investigating a possible link between arch height and arch movement and the development of injuries.</p