Background:
Each year, nearly 300,000 women and 5 million fetuses or neonates die during childbirth or shortly thereafter, a burden concentrated disproportionately in low- and middle-income ...countries. Identifying women and their fetuses at risk for intrapartum-related morbidity and death could facilitate early intervention.
Methods:
The Limiting Adverse Birth Outcomes in Resource-Limited Settings (LABOR) Study is a multi-country, prospective, observational cohort designed to exhaustively document the course and outcomes of labor, delivery, and the immediate postpartum period in settings where adverse outcomes are frequent. The study is conducted at four hospitals across three countries in Ghana, India, and Zambia. We will enroll approximately 12,000 women at presentation to the hospital for delivery and follow them and their fetuses/newborns throughout their labor and delivery course, postpartum hospitalization, and up to 42 days thereafter. The co-primary outcomes are composites of maternal (death, hemorrhage, hypertensive disorders, infection) and fetal/neonatal adverse events (death, encephalopathy, sepsis) that may be attributed to the intrapartum period. The study collects extensive physiologic data through the use of physiologic sensors and employs medical scribes to document examination findings, diagnoses, medications, and other interventions in real time.
Discussion:
The goal of this research is to produce a large, sharable dataset that can be used to build statistical algorithms to prospectively stratify parturients according to their risk of adverse outcomes. We anticipate this research will inform the development of new tools to reduce peripartum morbidity and mortality in low-resource settings.
Pesticides and human health Blair, Aaron; Ritz, Beate; Wesseling, Catharina ...
Occupational and environmental medicine (London, England),
02/2015, Letnik:
72, Številka:
2
Journal Article
Recenzirano
...there has long been a concern about environmental and human consequences of widespread pesticide use.
Although cytokines play a pivotal role in the inflammatory responses that mediate the severity of acute renal failure (ARF), the importance of pro- and anti-inflammatory cytokine gene promoter ...polymorphisms has been unexplored.
We prospectively evaluated the relationship of single nucleotide polymorphism in the promoter region of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) to mortality in 61 patients with ARF requiring intermittent hemodialysis. Cytokine genotyping was performed on leukocytes using PCR techniques. Cox proportional-hazards regression analysis was used to explore these relationships.
The mean (±SD) APACHE II score was 24±7, MOF score 2±1, and 64% had sepsis. The TNF-α high producer genotype (−308 A-allele carrier) was associated with a higher risk of death after adjustment for the APACHE II score (HR=2.5;
P=0.04), and the IL-10 intermediate/high producer genotype (−1082 G-allele carrier) was associated with a lower risk of death after adjustment for the MOF score (HR=0.36;
P=0.03). Considering combinations of genotypes, the TNF-α high and IL-10 low producer genotype combination was associated with a ∼6-fold increased risk of death compared to the TNF-α-low and IL-10 intermediate/high producer genotype combination, after adjustment for either APACHE II (
P=0.004), MOF score (
P=0.004) or sepsis (
P=0.006).
TNF-α and IL-10 gene polymorphisms are related to the risk of death among patients with ARF who require dialysis. Larger studies are needed to confirm these relationships.
Enhanced recovery after surgery (ERAS) aims to improve surgical outcomes by integrating evidence-based practices across preoperative, intraoperative, and postoperative care. Data in electronic ...medical records (EMRs) provide insight on how ERAS is implemented and its impact on surgical outcomes. Because ERAS is a multimodal pathway provided by multiple physicians and health care providers over time, identifying ERAS cases in EMRs is not a trivial task. To better understand how EMRs can be used to study ERAS, we describe our experience with using current methodologies and the development and rationale of a new method for retrospectively identifying ERAS cases in EMRs.
Using EMR data from surgical departments at the University of North Carolina at Chapel Hill, we first identified ERAS cases using a protocol-based method, using basic information including the date of ERAS implementation, surgical procedure and date, and primary surgeon. We further examined two operational flags in the EMRs, a nursing order and a case request for OR order. Wide variation between the methods compelled us to consult with ERAS surgical staff and explore the EMRs to develop a more refined method for identifying ERAS cases.
We developed a two-step method, with the first step based on the protocol definition and the second step based on an ERAS-specific medication definition. To test our method, we randomly sampled 150 general, gynecological, and urologic surgeries performed between January 1, 2016 and March 30, 2017. Surgical cases were classified as ERAS or not using the protocol definition, nursing order, case request for OR order, and our two-step method. To assess the accuracy of each method, two independent reviewers assessed the charts to determine whether cases were ERAS.
Of the 150 charts reviewed, 74 were ERAS cases. The protocol only method and nursing order flag performed similarly, correctly identifying 74 percent and 73 percent of true ERAS cases, respectively. The case request for OR order flag performed less well, correctly identifying only 44 percent of the true ERAS cases. Our two-step method performed well, correctly identifying 98 percent of true ERAS cases.
ERAS pathways are complex, making study of them from EMRs difficult. Current strategies for doing so are relatively easy to implement, but unreliable. We have developed a reproducible and observable ERAS computational phenotype that identifies ERAS cases reliably. This is a step forward in using the richness of EMR data to study ERAS implementation, efficacy, and how they can contribute to surgical care improvement.
Vibrio harveyi regulates the expression of bioluminescence (lux) in response to cell density, a phenomenon known as quorum sensing. In V. harveyi, two independent quorum-sensing systems exist, and ...each produces, detects, and responds to a specific cell density-dependent autoinducer signal. The autoinducers are recognized by two-component hybrid sensor kinases called LuxN and LuxQ, and sensory information from both systems is transduced by a phosphorelay mechanism to the response regulator protein LuxO. Genetic evidence suggests that LuxO-phosphate negatively regulates the expression of luminescence at low cell density in the absence of autoinducers. At high cell density, interaction of the sensors with their cognate autoinducers results in dephosphorylation and inactivation of the LuxO repressor. In the present report, we show that LuxN and LuxQ channel sensory information to LuxO via a newly identified phosphorelay protein that we have named LuxU. LuxU shows sequence similarity to other described phosphorelay proteins, including BvgS, ArcB, and Ypd1. A critical His residue (His 58) of LuxU is required for phosphorelay function.
Current best practice in active surveillance involves the use of magnetic resonance imaging before a biopsy decision, enabling digital rectal examination and some biopsies to be avoided. The highest ...research priority in active surveillance for prostate cancer has been identified as the development of a dynamic, risk-adapted approach, according to an agreed framework, to reduce unnecessary testing and to maximise detection of disease that would benefit from treatment.
Active surveillance (AS) is recommended for low-risk and some intermediate-risk prostate cancer. Uptake and practice of AS vary significantly across different settings, as does the experience of surveillance—from which tests are offered, and to the levels of psychological support.
To explore the current best practice and determine the most important research priorities in AS for prostate cancer.
A formal consensus process was followed, with an international expert panel of purposively sampled participants across a range of health care professionals and researchers, and those with lived experience of prostate cancer. Statements regarding the practice of AS and potential research priorities spanning the patient journey from surveillance to initiating treatment were developed.
Panel members scored each statement on a Likert scale. The group median score and measure of consensus were presented to participants prior to discussion and rescoring at panel meetings. Current best practice and future research priorities were identified, agreed upon, and finally ranked by panel members.
There was consensus agreement that best practice includes the use of high-quality magnetic resonance imaging (MRI), which allows digital rectal examination (DRE) to be omitted, that repeat standard biopsy can be omitted when MRI and prostate-specific antigen (PSA) kinetics are stable, and that changes in PSA or DRE should prompt MRI ± biopsy rather than immediate active treatment. The highest ranked research priority was a dynamic, risk-adjusted AS approach, reducing testing for those at the least risk of progression. Improving the tests used in surveillance, ensuring equity of access and experience across different patients and settings, and improving information and communication between and within clinicians and patients were also high priorities. Limitations include the use of a limited number of panel members for practical reasons.
The current best practice in AS includes the use of high-quality MRI to avoid DRE and as the first assessment for changes in PSA, with omission of repeat standard biopsy when PSA and MRI are stable. Development of a robust, dynamic, risk-adapted approach to surveillance is the highest research priority in AS for prostate cancer.
A diverse group of experts in active surveillance, including a broad range of health care professionals and researchers and those with lived experience of prostate cancer, agreed that best practice includes the use of high-quality magnetic resonance imaging, which can allow digital rectal examination and some biopsies to be omitted. The highest research priority in active surveillance research was identified as the development of a dynamic, risk-adjusted approach.
The bioluminescent marine bacterium Vibrio harveyi controls light production using two parallel quorum‐sensing systems. V. harveyi produces two autoinducers (AI‐1 and AI‐2), which are recognized by ...cognate membrane‐bound two‐component hybrid sensor kinases called LuxN and LuxQ respectively. Under conditions of low cell density, in the absence of autoinducer, the hybrid sensors are kinases, and under conditions of high cell density, in the presence of autoinducer, the sensors are phosphatases. These activities allow LuxN and LuxQ to modulate the level of phosphorylation of the response regulator protein LuxO. LuxO, in turn, controls the transcription of the genes encoding luciferase. The phosphorelay protein LuxU is required for signalling to LuxO. In this report, we present a genetic analysis of the activities of the AI‐1 sensor LuxN. Point mutations and in frame deletions were constructed in luxN and recombined onto the chromosome of V. harveyi for in vivo phenotypic analysis. We show that the conserved histidine (H471) in the sensor kinase domain of LuxN is required for kinase activity but not for phosphatase activity. In contrast, the conserved aspartate (D771) in the response regulator domain of LuxN is required for both activities. Furthermore, the LuxN phosphatase activity is localized to the response regulator domain. Our results indicate that the LuxN kinase activity is regulated by the presence of AI‐1, whereas the LuxN phosphatase activity is constitutive. We also show that signalling from the two V. harveyi quorum‐sensing systems is not equivalent. AI‐1 and LuxN have a much greater effect on the level of LuxO phosphate and therefore Lux expression than do AI‐2 and LuxQ.
B-cell lymphomas are common malignancies in which transformed B cells enter the circulation, extravasate into tissues and form tumors in multiple organs. Lymphoma cells are thought to exit the ...vasculature and enter tissues through the same chemokine- and adhesion molecule-dependent mechanisms as normal B cells. We have previously shown that activation of the Rap GTPases, proteins that control cytoskeletal organization and integrin activation, is critical for chemokine-induced migration and adhesion in B-lymphoma cell lines. Using the A20 murine B-lymphoma cell line as a model, we now show that Rap activation is important for circulating lymphoma cells to enter tissues and form tumors in vivo. In vitro assays showed that Rap activation is required for A20 cells to efficiently adhere to vascular endothelial cells and undergo transendothelial migration. These findings suggest that Rap or its effectors could be novel targets for treating B-cell lymphomas.
Diatoms play a critical role in the oceans' carbon and silicon cycles; however, a mechanistic understanding of the biochemical processes that contribute to their ecological success remains elusive. ...Completion of the Thalassiosira pseudonana genome provided 'blueprints' for the potential biochemical machinery of diatoms, but offers only a limited insight into their biology under various environmental conditions. Using high-throughput shotgun proteomics, we identified a total of 1928 proteins expressed by T. pseudonana cultured under optimal growth conditions, enabling us to analyze this diatom's primary metabolic and biosynthetic pathways. Of the proteins identified, 70% are involved in cellular metabolism, while 11% are involved in the transport of molecules. We identified all of the enzymes involved in the urea cycle, thereby describing the complete pathway to convert ammonia to urea, along with urea transporters, and the urea-degrading enzyme urease. Although metabolic exchange between these pathways remains ambiguous, their constitutive presence suggests complex intracellular nitrogen recycling. In addition, all C(4) related enzymes for carbon fixation have been identified to be in abundance, with high protein sequence coverage. Quantification of mass spectra acquisitions demonstrated that the 20 most abundant proteins included an unexpectedly high expression of clathrin, which is the primary structural protein involved in endocytic transport. This result highlights a previously overlooked mechanism for the inter- and intra-cellular transport of nutrients and macromolecules in diatoms, potentially providing a missing link to organelle communication and metabolite exchange. Our results demonstrate the power of proteomics, and lay the groundwork for future comparative proteomic studies and directed analyses of specifically expressed proteins and biochemical pathways of oceanic diatoms.
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