Crude incidence in two-phase designs in the presence of competing risks.

BackgroundIn many studies, some information might not be available for the whole cohort, some covariates, or even the outcome, might be ascertained in selected subsamples. These studies are part of a broad category termed two-phase studies. Common examples include the nested case-control and the case-cohort designs. For two-phase studies, appropriate weighted survival estimates have been derived; however, no estimator of cumulative incidence accounting for competing events has been proposed. This is relevant in the presence of multiple types of events, where estimation of event type specific quantities are needed for evaluating outcome.MethodsWe develop a non parametric estimator of the cumulative incidence function of events accounting for possible competing events. It handles a general sampling design by weights derived from the sampling probabilities. The variance is derived from the influence function of the subdistribution hazard.ResultsThe proposed method shows good performance in simulations. It is applied to estimate the crude incidence of relapse in childhood acute lymphoblastic leukemia in groups defined by a genotype not available for everyone in a cohort of nearly 2000 patients, where death due to toxicity acted as a competing event. In a second example the aim was to estimate engagement in care of a cohort of HIV patients in resource limited setting, where for some patients the outcome itself was missing due to lost to follow-up. A sampling based approach was used to identify outcome in a subsample of lost patients and to obtain a valid estimate of connection to care.ConclusionsA valid estimator for cumulative incidence of events accounting for competing risks under a general sampling design from an infinite target population is derived

Pneumococcal carriage in sub-Saharan Africa--a systematic review.

BACKGROUND: Pneumococcal epidemiology varies geographically and few data are available from the African continent. We assess pneumococcal carriage from studies conducted in sub-Saharan Africa (sSA) before and after the pneumococcal conjugate vaccine (PCV) era. METHODS: A search for pneumococcal carriage studies published before 2012 was conducted to describe carriage in sSA. The review also describes pneumococcal serotypes and assesses the impact of vaccination on carriage in this region. RESULTS: Fifty-seven studies were included in this review with the majority (40.3%) from South Africa. There was considerable variability in the prevalence of carriage between studies (I-squared statistic = 99%). Carriage was higher in children and decreased with increasing age, 63.2% (95% CI: 55.6-70.8) in children less than 5 years, 42.6% (95% CI: 29.9-55.4) in children 5-15 years and 28.0% (95% CI: 19.0-37.0) in adults older than 15 years. There was no difference in the prevalence of carriage between males and females in 9/11 studies. Serotypes 19F, 6B, 6A, 14 and 23F were the five most common isolates. A meta-analysis of four randomized trials of PCV vaccination in children aged 9-24 months showed that carriage of vaccine type (VT) serotypes decreased with PCV vaccination; however, overall carriage remained the same because of a concomitant increase in non-vaccine type (NVT) serotypes. CONCLUSION: Pneumococcal carriage is generally high in the African continent, particularly in young children. The five most common serotypes in sSA are among the top seven serotypes that cause invasive pneumococcal disease in children globally. These serotypes are covered by the two PCVs recommended for routine childhood immunization by the WHO. The distribution of serotypes found in the nasopharynx is altered by PCV vaccination

Simultaneous quantification of 12 different nucleotides and nucleosides released from renal epithelium and in human urine samples using ion-pair reversed-phase HPLC

Nucleotides and nucleosides are not only involved in cellular metabolism but also act extracellularly via P1 and P2 receptors, to elicit a wide variety of physiological and pathophysiological responses through paracrine and autocrine signalling pathways. For the first time, we have used an ion-pair reversed-phase high-performance liquid chromatography ultraviolet (UV)-coupled method to rapidly and simultaneously quantify 12 different nucleotides and nucleosides (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, adenosine, uridine triphosphate, uridine diphosphate, uridine monophosphate, uridine, guanosine triphosphate, guanosine diphosphate, guanosine monophosphate, guanosine): (1) released from a mouse renal cell line (M1 cortical collecting duct) and (2) in human biological samples (i.e., urine). To facilitate analysis of urine samples, a solid-phase extraction step was incorporated (overall recovery rate ? 98 %). All samples were analyzed following injection (100 ?l) into a Synergi Polar-RP 80 Å (250 × 4.6 mm) reversed-phase column with a particle size of 10 ?m, protected with a guard column. A gradient elution profile was run with a mobile phase (phosphate buffer plus ion-pairing agent tetrabutylammonium hydrogen sulfate; pH 6) in 2-30 % acetonitrile (v/v) for 35 min (including equilibration time) at 1 ml min(-1) flow rate. Eluted compounds were detected by UV absorbance at 254 nm and quantified using standard curves for nucleotide and nucleoside mixtures of known concentration. Following validation (specificity, linearity, limits of detection and quantitation, system precision, accuracy, and intermediate precision parameters), this protocol was successfully and reproducibly used to quantify picomolar to nanomolar concentrations of nucleosides and nucleotides in isotonic and hypotonic cell buffers that transiently bathed M1 cells, and urine samples from normal subjects and overactive bladder patients

An Integrated-Photonics Optical-Frequency Synthesizer

Integrated-photonics microchips now enable a range of advanced functionalities for high-coherence applications such as data transmission, highly optimized physical sensors, and harnessing quantum states, but with cost, efficiency, and portability much beyond tabletop experiments. Through high-volume semiconductor processing built around advanced materials there exists an opportunity for integrated devices to impact applications cutting across disciplines of basic science and technology. Here we show how to synthesize the absolute frequency of a lightwave signal, using integrated photonics to implement lasers, system interconnects, and nonlinear frequency comb generation. The laser frequency output of our synthesizer is programmed by a microwave clock across 4 THz near 1550 nm with 1 Hz resolution and traceability to the SI second. This is accomplished with a heterogeneously integrated III/V-Si tunable laser, which is guided by dual dissipative-Kerr-soliton frequency combs fabricated on silicon chips. Through out-of-loop measurements of the phase-coherent, microwave-to-optical link, we verify that the fractional-frequency instability of the integrated photonics synthesizer matches the $7.0*10^{-13}$ reference-clock instability for a 1 second acquisition, and constrain any synthesis error to $7.7*10^{-15}$ while stepping the synthesizer across the telecommunication C band. Any application of an optical frequency source would be enabled by the precision optical synthesis presented here. Building on the ubiquitous capability in the microwave domain, our results demonstrate a first path to synthesis with integrated photonics, leveraging low-cost, low-power, and compact features that will be critical for its widespread use.Comment: 10 pages, 6 figure

The Citation Field of Evolutionary Economics

Evolutionary economics has developed into an academic field of its own, institutionalized around, amongst others, the Journal of Evolutionary Economics (JEE). This paper analyzes the way and extent to which evolutionary economics has become an interdisciplinary journal, as its aim was: a journal that is indispensable in the exchange of expert knowledge on topics and using approaches that relate naturally with it. Analyzing citation data for the relevant academic field for the Journal of Evolutionary Economics, we use insights from scientometrics and social network analysis to find that, indeed, the JEE is a central player in this interdisciplinary field aiming mostly at understanding technological and regional dynamics. It does not, however, link firmly with the natural sciences (including biology) nor to management sciences, entrepreneurship, and organization studies. Another journal that could be perceived to have evolutionary acumen, the Journal of Economic Issues, does relate to heterodox economics journals and is relatively more involved in discussing issues of firm and industry organization. The JEE seems most keen to develop theoretical insights

Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity

MDM2–MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2–MDMX–E2(UbcH5B)–ubiquitin complex, we designed MDM2 mutants that prevent E2–ubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53′s transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors

Knee joint kinetics in response to multiple three-dimensional printed, customised foot orthoses for the treatment of medial compartment knee osteoarthritis

The knee adduction moment is consistently used as a surrogate measure of medial compartment loading. Foot orthoses are designed to reduce knee adduction moment via lateral wedging. The 'dose' of wedging required to optimally unload the affected compartment is unknown and variable between individuals. This study explores a personalised approach via three-dimensional printed foot orthotics to assess the biomechanical response when two design variables are altered: orthotic length and lateral wedging. Foot orthoses were created for 10 individuals with symptomatic medial knee osteoarthritis and 10 controls. Computer-aided design software was used to design four full and four three-quarter-length foot orthoses per participant each with lateral posting of 0° 'neutral', 5° rearfoot, 10° rearfoot and 5° forefoot/10° rearfoot. Three-dimensional printers were used to manufacture all foot orthoses. Three-dimensional gait analyses were performed and selected knee kinetics were analysed: first peak knee adduction moment, second peak knee adduction moment, first knee flexion moment and knee adduction moment impulse. Full-length foot orthoses provided greater reductions in first peak knee adduction moment (p = 0.038), second peak knee adduction moment (p = 0.018) and knee adduction moment impulse (p = 0.022) compared to three-quarter-length foot orthoses. Dose effect of lateral wedging was found for first peak knee adduction moment (p < 0.001), second peak knee adduction moment (p < 0.001) and knee adduction moment impulse (p < 0.001) indicating greater unloading for higher wedging angles. Significant interaction effects were found for foot orthosis length and participant group in second peak knee adduction moment (p = 0.028) and knee adduction moment impulse (p = 0.036). Significant interaction effects were found between orthotic length and wedging condition for second peak knee adduction moment (p = 0.002). No significant changes in first knee flexion moment were found. Individual heterogeneous responses to foot orthosis conditions were observed for first peak knee adduction moment, second peak knee adduction moment and knee adduction moment impulse. Biomechanical response is highly variable with personalised foot orthoses. Findings indicate that the tailoring of a personalised intervention could provide an additional benefit over standard interventions and that a three-dimensional printing approach to foot orthosis manufacturing is a viable alternative to the standard methods.Full Tex

Second trimester inflammatory and metabolic markers in women delivering preterm with and without preeclampsia.

ObjectiveInflammatory and metabolic pathways are implicated in preterm birth and preeclampsia. However, studies rarely compare second trimester inflammatory and metabolic markers between women who deliver preterm with and without preeclampsia.Study designA sample of 129 women (43 with preeclampsia) with preterm delivery was obtained from an existing population-based birth cohort. Banked second trimester serum samples were assayed for 267 inflammatory and metabolic markers. Backwards-stepwise logistic regression models were used to calculate odds ratios.ResultsHigher 5-α-pregnan-3β,20α-diol disulfate, and lower 1-linoleoylglycerophosphoethanolamine and octadecanedioate, predicted increased odds of preeclampsia.ConclusionsAmong women with preterm births, those who developed preeclampsia differed with respect metabolic markers. These findings point to potential etiologic underpinnings for preeclampsia as a precursor to preterm birth

Networks in Archaeology: Phenomena, Abstraction, Representation

The application of method and theory from network science to archaeology has dramatically increased over the last decade. In this article, we document this growth over time, discuss several of the important concepts that are used in the application of network approaches to archaeology, and introduce the other articles in this special issue on networks in archaeology. We argue that the suitability and contribution of network science techniques within particular archaeological research contexts can be usefully explored by scrutinizing the past phenomena under study, how these are abstracted into concepts, and how these in turn are represented as network data. For this reason, each of the articles in this special issue is discussed in terms of the phenomena that they seek to address, the abstraction in terms of concepts that they use to study connectivity, and the representations of network data that they employ in their analyses. The approaches currently being used are diverse and interdisciplinary, which we think are evidence of a healthy exploratory stage in the application of network science in archaeology. To facilitate further innovation, application, and collaboration, we also provide a glossary of terms that are currently being used in network science and especially those in the applications to archaeological case studies

Combining PPI with qualitative research to engage ‘harder-to-reach’ populations: service user groups as co-applicants on a platform study for a trial

Abstract Background: Patient and public involvement (PPI) in all research studies is recommended from the earliest point and in as many stages as possible. Qualitative research is also recommended in the early stages of designing. complex intervention trials. Combining both together might enable inclusion of ‘harder-to-reach’ perspectives from the target population(s), particularly when the research is intended for their benefit. However, the interface between PPI and qualitative research has received little attention. Methods: In a multi-disciplinary, mixed methods study to inform the design of incentive trials for smoking cessation in pregnancy and breastfeeding, we combined PPI and qualitative research, with some overlap. Mother and baby groups from two geographically separate disadvantaged areas, with diverse experiences of the smoking and breastfeeding, but no training or previous involvement in research, were recruited as PPI research grant co-applicants. An iterative partnership approach facilitated involvement in research conduct and design across all project phases. Group PPI members were also invited to contribute to more formal qualitative data collection, as and when indicated by the research questions, and emerging analysis. Results: We engaged with ‘harder-to-reach’ women in mother and baby group settings, rather than in academic or home environments. These settings were relaxed and informal, which facilitated rapport-building, disclosures of unexpected information and maintained trust. 21 women participated in standard PPI activities: feedback on study protocols and documents; piloting questionnaires and interview schedules. PPI members voiced some different perspectives from those captured within the qualitative dataset. 19 participated in focused qualitative research. Novel aspects were audio recorded PPI discussions, which contributed qualitative data; first, to interpret systematic review findings and construct intervention vignettes for use in the qualitative research; second, to assist with recruitment to improve sample diversity in the formal qualitative dataset; and third, to translate theory and findings presented in a researcher generated logic model into a lay tool. This had face validity for potential trial participants and used the metaphor of a ladder. Conclusions: Combining and overlapping PPI and qualitative research added ‘harder-to-reach’ contributions, sample diversity, trust and engagement in creative approaches beyond what could be achieved through PPI or qualitative research alone. (350/350