Thioredoxin-interacting protein (TxNIP) is up-regulated by high glucose and is associated with oxidative stress. It has been implicated in hyperglycemia-induced β-cell dysfunction and apoptosis. As ...high glucose and oxidative stress mediate diabetic nephropathy (DN), the contribution of TxNIP was investigated in renal mesangial cell reactive oxygen species (ROS) generation and collagen synthesis. To determine the role of TxNIP, mouse mesangial cells (MC) cultured from wild-type C3H and TxNIP-deficient Hcb-19 mice were incubated in HG. Confocal microscopy was used to measure total and mitochondrial ROS production (DCF and MitoSOX) and collagen IV. Trx and NADPH oxidase activities were assayed and NADPH oxidase isoforms, Nox2 and Nox4, and antioxidant enzymes were determined by immunoblotting. C3H MC exposed to HG elicited a significant increase in cellular and mitochondrial ROS as well as Nox4 protein expression and NADPH oxidase activation, whereas Hcb-19 MC showed no response. Trx activity was attenuated by HG only in C3H MC. These defects in Hcb-19 MC were not due to increased antioxidant enzymes or scavenging of ROS, but associated with decreased ROS generation. Adenovirus-mediated overexpression of TxNIP in Hcb-19 MC and TxNIP knockdown with siRNA in C3H confirmed the specific role of TxNIP. Collagen IV accumulation in HG was markedly reduced in Hcb-19 cells. TxNIP is a critical component of the HG-ROS signaling pathway, required for the induction of mitochondrial and total cell ROS and the NADPH oxidase isoform, Nox4. TxNIP is a potential target to prevent DN.
Background: Thioredoxin-interacting protein (TxNIP) is up-regulated by high glucose (HG), inhibits the antioxidant, thioredoxin, and thereby is implicated in oxidative stress.
Results: TxNIP deficiency protects mesangial cells from HG-induced oxidative stress and increased collagen by blocking mitochondrial glucose metabolism, NADPH oxidase, and Nox4.
Conclusion: TxNIP controls ROS generation by regulating the TCA cycle versus glycolytic glucose flux.
Significance: Inhibition of TxNIP is a promising approach to treat glucose toxicity.
Chronic exposure to high glucose leads to diabetic nephropathy characterized by increased mesangial matrix protein (e.g., collagen) accumulation. Altered cell signaling and gene expression ...accompanied by oxidative stress have been documented. The contribution of the tyrosine kinase, c-Src (Src), which is sensitive to oxidative stress, was examined. Cultured rat mesangial cells were exposed to high glucose (25 mmol/L) in the presence and absence of Src inhibitors (PP2, SU6656), Src small interfering RNA (siRNA), and the tumor necrosis factor-α-converting enzyme (TACE) inhibitor, TAPI-2. Src was investigated in vivo by administration of PP2 to streptozotocin (STZ)-induced diabetic DBA2/J mice. High glucose stimulated Src, TACE, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2, p38), and collagen IV accumulation in mesangial cells. PP2 and SU6656 blocked high glucose-stimulated phosphorylation of Src Tyr-416, EGFR, and MAPKs. These inhibitors and Src knockdown by siRNA, as well as TAPI-2, also abrogated high glucose-induced phosphorylation of these targets and collagen IV accumulation. In STZ-diabetic mice, albuminuria, increased Src pTyr-416, TACE activation, ERK and EGFR phosphorylation, glomerular collagen accumulation, and podocyte loss were inhibited by PP2. These data indicate a role for Src in a high glucose-Src-TACE-heparin-binding epidermal growth factor-EGFR-MAPK-signaling pathway to collagen accumulation. Thus, Src may provide a novel therapeutic target for diabetic nephropathy.
We determined whether implementing the Pediatric Emergency Care Applied Research Network (PECARN) traumatic brain injury (TBI) prediction rules and providing risks of clinically important TBIs ...(ciTBIs) with computerized clinical decision support (CDS) reduces computed tomography (CT) use for children with minor head trauma.
Nonrandomized trial with concurrent controls at 5 pediatric emergency departments (PEDs) and 8 general EDs (GEDs) between November 2011 and June 2014. Patients were <18 years old with minor blunt head trauma. Intervention sites received CDS with CT recommendations and risks of ciTBI, both for patients at very low risk of ciTBI (no Pediatric Emergency Care Applied Research Network rule factors) and those not at very low risk. The primary outcome was the rate of CT, analyzed by site, controlling for time trend.
We analyzed 16 635 intervention and 2394 control patients. Adjusted for time trends, CT rates decreased significantly (
< .05) but modestly (2.3%-3.7%) at 2 of 4 intervention PEDs for children at very low risk. The other 2 PEDs had small (0.8%-1.5%) nonsignificant decreases. CT rates did not decrease consistently at the intervention GEDs, with low baseline CT rates (2.1%-4.0%) in those at very low risk. The control PED had little change in CT use in similar children (from 1.6% to 2.9%); the control GED showed a decrease in the CT rate (from 7.1% to 2.6%). For all children with minor head trauma, intervention sites had small decreases in CT rates (1.7%-6.2%).
The implementation of TBI prediction rules and provision of risks of ciTBIs by using CDS was associated with modest, safe, but variable decreases in CT use. However, some secular trends were also noted.
The Women's Health Needs Study (WHNS) collected information on the health characteristics, needs, and experiences, including female genital mutilation (FGM) experiences, attitudes, and beliefs, of ...women aged 18 to 49 years who were born, or whose mothers were born, in a country where FGM is prevalent living in the US. The purpose of this paper is to describe the WHNS design, methods, strengths and limitations, as well as select demographic and health-related characteristics of participants.
We conducted a cross-sectional survey from November 2020 -June 2021 in four US metropolitan areas, using a hybrid venue-based sampling (VBS) and respondent-driven sampling (RDS) approach to identify women for recruitment.
Of 1,132 participants, 395 were recruited via VBS and 737 RDS. Most were born, or their mothers were born, in either a West African country (Burkina Faso, Guinea, Mali, Mauritania, Sierra Leone, The Gambia) (39.0%) or Ethiopia (30.7%). More than a third were aged 30-39 years (37.5%) with a majority who immigrated at ages ≥13 years (86.6%) and had lived in the United States for ≥5 years (68.9%). Medicaid was the top health insurer (52.5%), followed by private health insurance (30.5%); 17% of participants had no insurance. Nearly half of women reported 1-2 healthcare visits within the past 12 months (47.7%). One in seven did not get needed health care due to cost (14.8%). Over half have ever used contraception (52.1%) to delay or avoid pregnancy and 76.9% had their last pelvic and/or Papanicolaou (pap) exam within the past 3 years. More than half experienced FGM (55.0%). Nearly all women believed that FGM should be stopped (92.0%).
The VBS/RDS approach enabled recruitment of a diverse study population. WHNS advances research related to the health characteristics, needs, and experiences of women living in the US from countries where FGM is prevalent.
Failure to prevent stroke in patients with atrial fibrillation (AF) has become increasingly important for patient safety and quality of care. ...we conducted a multicenter, outpatient clinic, ...retrospective cohort analysis using data abstracted through our electronic health record between March 2013 and March 2014. Clinical characteristics, CHA2DS2-VASc (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category), and HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INRs, Elderly, Drugs or alcohol) scores, guideline adherence, and 90-day outcomes (all-cause mortality, stroke, systemic embolic events, and bleeding) were determined by a web-based decision support tool.
Zika virus is primarily transmitted through mosquito bites. Because Zika virus infection during pregnancy can cause serious birth defects, reproductive-aged women need protection from Zika virus ...infection. This report describes Zika virus prevention behaviors among women aged 18–49 years and assesses whether pregnancy status and healthcare provider counseling increases Zika virus prevention behaviors.
A population-based cell phone survey of women aged 18–49 years living in Puerto Rico was conducted in July–November 2016. Data were analyzed in 2018–2019. Prevalence estimates and 95% CIs were calculated for Zika virus prevention behaviors. Adjusted prevalence ratios were estimated to examine the association of pregnancy status with healthcare provider counseling on Zika virus prevention behaviors, controlling for age, education, and health insurance status.
Most women reported using screens on open doors/windows (87.7%) and eliminating standing water in/around their homes (92.3%). Other Zika virus prevention behaviors were less common (<33%). In adjusted analysis, pregnant women were more likely than women not at risk for unintended pregnancy to report using mosquito repellent every/most days (adjusted prevalence ratio=1.44, 95% CI=1.13, 1.85). Healthcare provider counseling was associated with receiving professional spraying/larvicide treatment (adjusted prevalence ratio=1.42, 95% CI=1.17, 1.74), sleeping under a bed net (adjusted prevalence ratio=2.37, 95% CI=1.33, 4.24), using mosquito repellent (adjusted prevalence ratio=1.57, 95% CI=1.40, 1.77), and wearing long sleeves/pants (adjusted prevalence ratio=1.32, 95% CI=1.12, 1.55).
Receipt of healthcare provider counseling was more consistently associated with Zika virus prevention behaviors than pregnancy status. Healthcare provider counseling is an important strategy for increasing the uptake of Zika virus prevention behaviors among women aged 18–49 years.
Here we present the case of a patient that suffered a cardiac arrest due to pulmonary embolus. The patient was resuscitated using extracorporeal membrane oxygenation and treated with ...ultrasound-accelerated catheter-directed thrombolysis during support on extracorporeal membrane oxygenation, with an excellent outcome. This case demonstrates that the use of extracorporeal membrane oxygenation and ultrasound-accelerated catheter-directed thrombolysis can be highly effective for managing select patients with pulmonary embolus and cardiac arrest.
Abstract Objective Implement and perform pilot testing of web-based clinical decision support services using a novel framework for creating and managing clinical knowledge in a distributed fashion ...using the cloud. The pilot sought to (1) develop and test connectivity to an external clinical decision support (CDS) service, (2) assess the exchange of data to and knowledge from the external CDS service, and (3) capture lessons to guide expansion to more practice sites and users. Materials and methods The Clinical Decision Support Consortium created a repository of shared CDS knowledge for managing hypertension, diabetes, and coronary artery disease in a community cloud hosted by Partners HealthCare. A limited data set for primary care patients at a separate health system was securely transmitted to a CDS rules engine hosted in the cloud. Preventive care reminders triggered by the limited data set were returned for display to clinician end users for review and display. During a pilot study, we (1) monitored connectivity and system performance, (2) studied the exchange of data and decision support reminders between the two health systems, and (3) captured lessons. Results During the six month pilot study, there were 1339 patient encounters in which information was successfully exchanged. Preventive care reminders were displayed during 57% of patient visits, most often reminding physicians to monitor blood pressure for hypertensive patients (29%) and order eye exams for patients with diabetes (28%). Lessons learned were grouped into five themes: performance, governance, semantic interoperability, ongoing adjustments, and usability. Discussion Remote, asynchronous cloud-based decision support performed reasonably well, although issues concerning governance, semantic interoperability, and usability remain key challenges for successful adoption and use of cloud-based CDS that will require collaboration between biomedical informatics and computer science disciplines. Conclusion Decision support in the cloud is feasible and may be a reasonable path toward achieving better support of clinical decision-making across the widest range of health care providers.
To determine the effect of providing risk estimates of clinically important traumatic brain injuries and management recommendations on emergency department (ED) outcomes for children with isolated ...intermediate Pediatric Emergency Care Applied Research Network clinically important traumatic brain injury risk factors.
This was a secondary analysis of a nonrandomized clinical trial with concurrent controls, conducted at 5 pediatric and 8 general EDs between November 2011 and June 2014, enrolling patients younger than 18 years who had minor blunt head trauma. After a baseline period, intervention sites received electronic clinical decision support providing patient-level clinically important traumatic brain injury risk estimates and management recommendations. The following primary outcomes in patients with one intermediate Pediatric Emergency Care Applied Research Network risk factor were compared before and after clinical decision support: proportion of ED computed tomography (CT) scans, adjusted for age, time trend, and site; and prevalence of clinically important traumatic brain injuries.
The risk of clinically important traumatic brain injuries was known for 3,859 children with isolated findings (1,711 at intervention sites before clinical decision support, 1,702 at intervention sites after clinical decision support, and 446 at control sites). In this group, pooled CT proportion decreased from 24.2% to 21.6% after clinical decision support (odds ratio 0.86; 95% confidence interval 0.73 to 1.01). Decreases in CT use were noted across intervention EDs, but not in controls. The pooled adjusted odds ratio for CT use after clinical decision support was 0.73 (95% confidence interval 0.60 to 0.88). Among the entire cohort, clinically important traumatic brain injury was diagnosed at the index ED visit for 37 of 37 (100%) patients before clinical decision support and 32 of 33 patients (97.0%) after clinical decision support.
Providing specific risks of clinically important traumatic brain injury through electronic clinical decision support was associated with a modest and safe decrease in ED CT use for children at nonnegligible risk of clinically important traumatic brain injuries.
Achieving maternal mortality reduction as a development goal remains a major challenge in most low-resource countries. Saving Mothers, Giving Life (SMGL) is a multi-partner initiative designed to ...reduce maternal mortality rapidly in high mortality settings through community and facility evidence-based interventions and district-wide health systems strengthening that could reduce delays to appropriate obstetric care.
An evaluation employing multiple studies and data collection methods was used to compare baseline maternal outcomes to those during Year 1 in SMGL pilot districts in Uganda and Zambia. Studies include health facility assessments, pregnancy outcome monitoring, enhanced maternal mortality detection in facilities, and population-based investigation of community maternal deaths. Population-based evaluation used standard approaches and comparable indicators to measure outcome and impact, and to allow comparison of the SMGL implementation in unique country contexts.
The evaluation found a 30% reduction in the population-based maternal mortality ratio (MMR) in Uganda during Year 1, from 452 to 316 per 100,000 live births. The MMR in health facilities declined by 35% in each country (from 534 to 345 in Uganda and from 310 to 202 in Zambia). The institutional delivery rate increased by 62% in Uganda and 35% in Zambia. The number of facilities providing emergency obstetric and newborn care (EmONC) rose from 10 to 25 in Uganda and from 7 to 11 in Zambia. Partial EmONC care became available in many more low and mid-level facilities. Cesarean section rates for all births increased by 23% in Uganda and 15% in Zambia. The proportion of women with childbirth complications delivered in EmONC facilities rose by 25% in Uganda and 23% in Zambia. Facility case fatality rates fell from 2.6 to 2.0% in Uganda and 3.1 to 2.0% in Zambia.
Maternal mortality ratios fell significantly in one year in Uganda and Zambia following the introduction of the SMGL model. This model employed a comprehensive district system strengthening approach. The lessons learned from SMGL can inform policymakers and program managers in other low and middle income settings where similar approaches could be utilized to rapidly reduce preventable maternal deaths.
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