When should we offer antenatal sequencing for urinary tract malformations? A systematic review, cohort study and meta-analysis.

OBJECTIVE: Determine the incremental yield of prenatal exome sequencing (PES) over chromosome microarray (CMA) and/or karyotype for urinary tract malformations (UTMs). METHOD: A prospective cohort study encompassing data from the English Genomic Medicine Service North Thames Laboratory Hub for fetuses with bilateral echogenic kidneys (BEKs) was combined with data from a systematic review. MEDLINE, EMBASE, Web of Science, MedRxiv and GreyLit were searched from 01/2010-02/2023 for studies reporting on the yield of PES over CMA or karyotype in fetuses with UTMs. Pooled incremental yield was determined using a random effects model. PROSPERO CRD42023364544. RESULTS: Fourteen studies (410 cases) were included. The incremental yield for multisystem UTMs, any isolated UTMs, and BEKs was 31% [95% CI, 18%-46%; I2  = 78%], 16% [95% CI, 6%-26%; I2  = 80%] and 51% [95% CI, 27%-75%; I2  = 34%]. The most common clinical diseases and syndromes identified, based on the variant genes detected, were Bardet-Biedl syndrome (BBS genes), dominant and recessive polycystic kidney diseases (PKD1, PKD2 and PKHD1) and renal cysts and diabetes syndrome (HNF1B). CONCLUSION: There was a notable incremental genetic diagnostic yield when PES was applied to multisystem UTMs and BEKs. There was a modest incremental yield when this technique was used for UTMs other than BEKs.

Use of Postpartum Hemorrhage Checklist during Vaginal Deliveries: A Quality Improvement Study.

OBJECTIVE: Postpartum hemorrhage (PPH) protocols improve patient safety and reduce utilization of blood products; however, few data exist on sustainability of PPH checklist use, how use affects care delivery, and variation of use among patient subgroups. This study aimed to (1) examine compliance with PPH checklist use during vaginal deliveries, (2) evaluate whether checklist use varied by patient and/or care team characteristics, and (3) evaluate whether checklist use was associated with increased use of recommended medications/interventions. STUDY DESIGN: This was a quality improvement study performed from April 2021 through June 2023. A multidisciplinary team developed a revised PPH checklist and used quality improvement methodology to increase checklist use following vaginal birth. Data were collected from medical records and clinician survey. Control charts were generated to track checklist use and evaluate special cause variation. Chi-square tests and logistic regression were used to evaluate variation in medications/interventions and across subgroups. RESULTS: During the study period, there were 342 cases of PPH at the time of vaginal birth. The checklist was used in 67% of PPH cases during the 20-month period after implementation in a setting where no checklist was previously being used. We found no statistically significant differences in checklist use by patient or health care team characteristics. Use of tranexamic acid, carboprost, and misoprostol were significantly associated with checklist use. CONCLUSION: This study demonstrated successful implementation of a checklist protocol where no checklist was previously being used, with sustained use in an average of 67% of PPH cases over 20 months. Checklist use was consistent across subgroups and was associated with higher use of interventions shown to lower blood loss. KEY POINTS: · Our study showed sustainability of PPH checklist use over a 20-month period.. · PPH checklist use was associated with increased use of interventions known to reduce blood loss.. · Checklist was used consistently across patient subgroups; may help address inequities in obstetric outcomes..

An automated, electronic, client-centred results delivery system saves time and improves workflow.

Background Traditional result notification methods, such as telephone calls, return visits and individualised emails or Short Message Service (SMS) texts, can be time consuming and may not align with client preference. We conducted a cross-sectional survey of our clients that showed that many clients prefer negative results by SMS or email, with the option to call or attend in person for positive results. Methods: We developed an innovative result-robot module in the electronic medical record that reads the electronic result and, using predefined algorithms, determines which SMS or email result template to send to the client. Results and Conclusion: Delivering automated negative results resulted in a 41% decrease in the number of clients calling for their results, demonstrating a significant efficiency gain.

Gender differences in driving under the influence (DUI) program client characteristics: Implications for treatment delivery.

The purpose of this descriptive study was to examine gender differences in the characteristics of clients in a large Driving Under the Influence (DUI) program in Southern California. We analyzed secondary de-identified data from a large DUI program for the years 2009-2014 (n = 19,619). Sociodemographic characteristics, measures of physical and mental comorbidity, and alcohol use severity measures were compared for male and female clients. Women averaged 32.85 years of age (SD = 10.70), while men were slightly older at 34.2 years (SD = 11.19). Females comprised an increasingly greater percentage of the client population over the time period studied (27.6%-30.7%). In a multivariable model, compared to male clients, females were more likely to be White non-Hispanic, not currently married, and younger. Women were more likely than men to report anxiety, depression, and a history of domestic violence. Blood alcohol content at arrest and measures of hazardous drinking did not differ significantly by gender. Results suggested that gender-specific DUI programs might be useful.

Feto-maternal indicators of cardiac dysfunction as a justification for the cardiac origins for pre-eclampsia.

While the pathophysiology of pre-eclampsia has been postulated as being secondary to placental dysfunction, a cardiac origin has more recently been proposed. Although an association between fetal congenital cardiovascular disease and pre-eclampsia has been demonstrated, no precise pathophysiologic mechanism for this association has been described. This review highlights the current biophysical (including echocardiography and Doppler indices) and biochemical (including proteomic, metabolomic and genetic/transcriptomic) markers of cardiac dysfunction that have been investigated in maternal and fetal cardiac disease and their overlap with predictors of pre-eclampsia.   Common pathways of inflammatory and anti-angiogenesis imbalance, endothelial damage, and oxidative stress have been demonstrated in both cardiovascular disease and pre-eclampsia and further investigation into these pathways could help to elucidate the common pathophysiologic mechanisms linking these disorders.

Building High-Performance Team Dynamics for Rapid Response Events in a US Tertiary Hospital: A Quality Improvement Model for Sustainable Process Change.

Hospital rapid response systems are designed to reduce unmet patient needs and prevent clinical deterioration. Rapid response teams are the principal component of a rapid response system and require teamwork to function optimally; poor communication among team members can result in substandard patient care. The authors describe a process for developing and implementing standardized communication and a teamwork structure for rapid response events (RREs) at a large academic hospital. The multidisciplinary team developed a project charter and key driver diagram, developed a "communication bundle," used quality improvement methodology, monitored adherence to the changes, and reported these data to key stakeholders on a weekly basis. By project end, the team met the goal of having 70% or more of adult RREs include the use of the "communication bundle." The balancing measure demonstrated that the introduction of a formalized communication framework did not significantly increase the duration of RREs.

Voluntary commitments made by the world's largest companies focus on recycling and packaging over other actions to address the plastics crisis.

Plastic pollution has caused significant environmental and health challenges. Corporations that contribute to the make, use, and distribution of plastics can play a vital role in addressing global plastic pollution and many are committing to voluntary pledges. However, the extent to which corporation voluntary commitments are helping solve the problem remains underexplored. Here we develop a novel typology to characterize voluntary commitments to reduce plastic pollution made between 2015-2020 by 974 companies including the top 300 of the Fortune Global. We find that 72% of these companies have made commitments to reduce plastic pollution. About 67% of companies participating in voluntary environmental programs (VEPs) and 17% of non-VEPs participants made measurable and timebound commitments. However, rather than tackle virgin plastics, most companies target general plastics and frequently emphasize end-of-life controls with a primary focus on recycling. Growing commitments on plastic pollution are made by large and important companies, but significantly more efforts beyond plastic recycling are required to effectively address plastic pollution challenges.

Modulation of PPARalpha expression and inflammatory interleukin-6 production by chronic glucose increases monocyte/endothelial adhesion.

OBJECTIVE: We have previously reported increased monocyte adhesion to human aortic endothelial cells (HAECs) cultured in 25 mmol/L glucose (HG) compared with normal glucose (NG) (5.5 mmol/L). In this study, we explored mechanisms that contribute to increased monocyte adhesion by elevated glucose. METHODS AND RESULTS: We found that HAECs cultured in HG have increased production of the chemokine interleukin-6 (IL-6). We examined whether IL-6 directly modulated monocyte adhesion to EC. Inhibition of IL-6 using a neutralizing antibody significantly reduced glucose-mediated monocyte adhesion by 50%, and addition of IL-6 directly to human EC stimulated monocyte adhesion. PPARalpha has been reported to negatively regulate expression of IL-6 in vascular cells, so we examined PPARalpha-associated signaling in EC. A known PPARalpha agonist, Wy14,643, prevented glucose-mediated IL-6 production by EC and reduced glucose-mediated monocyte adhesion by 40%. HG-cultured HAEC had a 50% reduction in expression of PPARalpha compared with control EC. Primary aortic EC isolated from PPARalpha knockout (KO) mice showed increased monocyte adhesion compared with EC isolated from control mice. PPARalpha KO EC also had increased production of IL-6. Finally, we measured IL-6 levels in diabetic db/db mice and found significant 6-fold elevations in IL-6 levels in db/db EC. CONCLUSIONS: These data indicate that IL-6 production is increased in diabetes and contributes to early vascular inflammatory changes. PPARalpha protects EC from glucose-mediated monocyte adhesion, in part through regulation of IL-6 production.

Evaluation of a nurse-care management system to improve outcomes in patients with complicated diabetes.

OBJECTIVE: This study evaluated the efficacy of a nurse-care management system designed to improve outcomes in patients with complicated diabetes. RESEARCH DESIGN AND METHODS: In this randomized controlled trial that took place at Kaiser Permanente Medical Center in Santa Clara, CA, 169 patients with longstanding diabetes, one or more major medical comorbid conditions, and HbA(lc) >10% received a special intervention (n = 84) or usual medical care (n = 85) for 1 year. Patients met with a nurse-care manager to establish individual outcome goals, attended group sessions once a week for up to 4 weeks, and received telephone calls to manage medications and self-care activities. HbA(lc), LDL, HDL, and total cholesterol, triglycerides, fasting glucose, systolic and diastolic blood pressure, BMI, and psychosocial factors were measured at baseline and 1 year later. Annualized physician visits were determined for the year before and during the study. RESULTS: At 1 year, the mean reductions in HbA(lc), total cholesterol, and LDL cholesterol were significantly greater for the intervention group compared with the usual care group. Significantly more patients in the intervention group met the goals for HbA(1c) (<7.5%) than patients in usual care (42.6 vs. 24.6%, P < 0.03, chi(2)). There were no significant differences in any of the psychosocial variables or in physician visits. CONCLUSIONS: A nurse-care management program can significantly improve some medical outcomes in patients with complicated diabetes without increasing physician visits.

Shared medical appointments to screen for geriatric syndromes: preliminary data from a quality improvement initiative.

Older adults are at greater risk of developing conditions that affect health outcomes, quality of life, and costs of care. Screening for geriatric conditions such as memory loss, fall risk, and depression may contribute to the prevention of adverse physical and mental comorbidities, unnecessary hospitalizations, and premature nursing home admissions. Because screening is not consistently performed in primary care settings, a shared medical appointment (SMA) program was developed to fill this gap in care. The goals of the program were to improve early identification of at-risk individuals and ensure appropriate follow-up for memory loss, fall risk, and depression; facilitate discussion about prevention, diagnosis, and treatment of these conditions; implement strategies to reduce risks for these conditions; and increase access to screening and expand preventive health services for older adults. Between August 2011 and May 2013, 136 individuals aged 60 and older participated in the program. Three case studies highlighting the psychosocial and physiological findings of participation in the program are presented. Preliminary data suggest that SMAs are an effective model of regularly screening at-risk older adults that augments primary care practice by facilitating early detection and referral for syndromes that may otherwise be missed or delayed.

Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia.

Nelarabine is the prodrug of 9-beta-arabinofuranosylguanine (ara-G) and is therapeutically classified as a purine nucleoside analog. Nelarabine is converted to ara-G by adenosine deaminase and transported into cells by a nucleoside transporter. Ara-G is subsequently phosphorylated to ara-G triphosphate (ara-GTP), thereby initiating the therapeutic effect by inhibiting DNA synthesis. Nelarabine has been extensively studied in regards to its pharmacokinetics, and the data have demonstrated that ara-GTP preferentially accumulates in malignant T-cells. Clinical responses to nelarabine have been demonstrated in various T-cell malignancies and appear to correlate with a relatively high intracellular concentration of ara-GTP compared to nonresponders. Therefore, this unique drug feature of nelarabine accounts for clinical utilization in treating adult and pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Neuropathy is the most predominant adverse effect associated with nelarabine and the incidence correlates with the dose administered. Myelosuppression has been observed, with thrombocytopenia and neutropenia as the most common hematologic complications. This article reviews the pharmacology, mechanism of action, and pharmacokinetic properties of nelarabine, as well as nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies. The toxicity profile, dosage, and administration, and areas of ongoing and future research, are also presented.

Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice.

Atherosclerosis is a major complication of diabetes. Up to 16 weeks of age, the db/db mouse is insulin-resistant and hyperglycemic and is a good model of Type 2 diabetes. After approximately 16 weeks of age, the mice develop pancreatic beta cell failure that can progress to a Type 1 diabetes phenotype. We have previously shown that glucose increases production of endothelial 12/15 lipoxygenase (12/15LO) products in vitro. In young 10-week-old Type 2 diabetic db/db mice, we found significant elevations in levels of urinary 12/15LO products, 12S-hydroxyeicosatetraenoic acid (12S-HETE) and 13S-hydroxyoctadecaenoic acid (13S-HODE) in vivo compared with C57BLKS/J mice. Using isolated primary aortic endothelial cells (ECs) from db/db mice and WEHI78/24 mouse monocyte cells in static adhesion assays, we found increased WEHI monocyte adhesion to db/db ECs (14 +/- 2 monocytes/field for db/db ECs versus 4 +/- 1 monocytes/field for C57BLKS/J ECs, p < 0.002). Thus, ECs from db/db mice appear to be "pre-activated" to bind monocytes. Analysis of db/db ECs revealed a 2-fold elevation in 12/15LO protein compared with C57BLKS/J EC. To determine that 12/15LO products were responsible for the increased monocyte adhesion observed with db/db ECs, we inhibited expression of murine 12/15LO using either an adenovirus expressing a ribozyme to 12/15LO (AdRZ) or with the 12/15LO inhibitor cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate. Treatment of db/db ECs for 48 h with AdRZ or 4 h with 10 microm cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate significantly reduced monocyte adhesion to db/db endothelium (p < 0.009). Thus, inhibition of the murine 12/15LO in db/db mice significantly reduced monocyte/endothelial interactions. We also found that adhesion of monocytes to diabetic db/db ECs was mediated by interactions of alpha4beta1 integrin on monocytes with endothelial vascular cell adhesion molecule 1 and connecting segment 1 fibronectin and interactions of beta2 integrins with endothelial intercellular adhesion molecule 1. In summary, regulation of the 12/15LO pathway is important for mediating early vascular changes in diabetes. Modulation of the 12/15LO pathway in the vessel wall may provide therapeutic benefit for early vascular inflammatory events in diabetes.

Application of a nurse-managed inpatient smoking cessation program.

This study reports on the effectiveness of a nurse case-managed smoking cessation program for general hospitalized patients that was continued for 3 years after clinical trials were completed. Patients admitted to the hospital who smoked were offered a smoking cessation program during their hospitalization. The program included physician advice, bedside education and counseling with a nurse specially trained in smoking cessation techniques, take-home materials (videotape, workbook, and relaxation audiotape), nicotine replacement therapy if requested or indicated, and four nurse-initiated post-discharge telephone counseling calls. Of the 2091 patients identified as smokers, 52% enrolled in the program, 18% wanted to quit on their own, 20% did not want to quit, and 10% were ineligible. The 12-month self-reported cessation rate (7-day point prevalence) was 35% if patients lost to follow-up were considered smokers, 49% if not. Patients hospitalized for cancer, cardiovascular, or pulmonary reasons were most likely to participate and had the highest self-reported cessation rates (63%, 57%, and 46%, respectively). This nurse-managed smoking cessation intervention was effective when it was put into standard hospital practice outside of its originating randomized clinical trial structure. The program, relatively inexpensive to deliver, appears to be acceptable to the majority of smokers who are hospitalized, resulted in high 1-year cessation rates, and can be extended to hospital employees and their families, work-sites, and communities on a cost-recovery basis.

Glucose regulates interleukin-8 production in aortic endothelial cells through activation of the p38 mitogen-activated protein kinase pathway in diabetes.

We have shown that chronic elevated glucose (25 mm) increases monocyte adhesion to human aortic endothelial cells (EC). This increased adhesion is mediated primarily through induction of interleukin (IL)-8 via activation of the transcription factor AP-1 (Srinivasan, S., Yeh, M., Danziger, E. C., Hatley, M. E., Riggan, A. E., Leitinger, N., Berliner, J. A., and Hedrick, C. C. (2003) Circ. Res. 92, 371-377). In the current study, we identified the elements in the AP-1 transcriptional complex that are activated by glucose. These elements include c-Jun, c-Fos, and Fra-1. AP-1 is activated by cellular oxidative stress, and we have reported significant production of ROS by high glucose-cultured cells. We examined signaling pathways upstream of AP-1 in EC that lead to AP-1 activation by HG. EC cultured in 25 mm glucose had a 2-fold increase in p38 phosphorylation compared with control normal glucose-cultured EC. Inhibition of the p38 pathway using 5 microm SB203580 significantly reduced glucose-mediated IL-8 mRNA production by 60%. Furthermore, blocking p38 pathway activation using a dominant-negative p38 construct significantly reduced glucose-mediated monocyte adhesion by 50%. Thus, glucose-stimulated monocyte adhesion is primarily regulated through phosphorylation of p38 with subsequent activation of AP-1, leading to IL-8 production. To study this pathway in the setting of diabetes, we used the db/db mouse. P38 phosphorylation was increased in diabetic db/db mice compared with control mice. We found a dramatic elevation in plasma levels of KC, the mouse ortholog of IL-8 in diabetic db/db mice (1800 +/- 100 pg/ml KC in db/db versus 300 +/- 75 pg/ml in C57BL/6J control mice, p < 0.0001). Inhibition of the p38 pathway in diabetic db/db mice significantly reduced monocyte adhesion by 50%. Taken together, these data indicate that chronic elevated glucose in diabetes activates the p38 MAP kinase pathway to increase inflammatory IL-8 gene induction and monocyte/endothelial adhesion.

12/15-Lipoxygenase activity mediates inflammatory monocyte/endothelial interactions and atherosclerosis in vivo.

We have shown that the 12/15-lipoxygenase (12/15-LO) product 12S-hydroxyeicosatetraenoic acid increases monocyte adhesion to human endothelial cells (EC) in vitro. Recent studies have implicated 12/15-LO in mediating atherosclerosis in mice. We generated transgenic mice on a C57BL/6J (B6) background that modestly overexpressed the murine 12/15-LO gene (designated LOTG). LOTG mice had 2.5-fold elevations in levels of 12S-hydroxyeicosatetraenoic acid and a 2-fold increase in expression of 12/15-LO protein in vivo. These mice developed spontaneous aortic fatty streak lesions on a chow diet. Thus, we examined effects of 12/15-LO expression on early events leading to atherosclerosis in these mice. We found that, under basal unstimulated conditions, LOTG EC bound more monocytes than B6 control EC (18 +/- 2 versus 7 +/- 1 monocytes/field, respectively; p < 0.0001). Inhibition of 12/15-LO activity in LOTG EC using a 12/15-LO ribozyme completely blocked monocyte adhesion in LOTG mice. Thus, 12/15-LO activity is required for monocyte/EC adhesion in the vessel wall. Expression of ICAM-1 in aortic endothelia of LOTG mice was increased severalfold. VCAM-1 expression was not changed. In a series of blocking studies, antibodies to alpha(4) and beta(2) integrins in WEHI monocytes blocked monocyte adhesion to both LOTG and B6 control EC. Inhibition of ICAM-1, VCAM-1, and connecting segment-1 fibronectin in EC significantly reduced adhesion of WEHI monocytes to LOTG EC. In summary, these data indicate that EC from LOTG mice are "pre-activated" to bind monocytes. Monocyte adhesion in LOTG mice is mediated through beta(2) integrin and ICAM-1 interactions as well as through VLA-4 and connecting segment-1 fibronectin/VCAM-1 interactions. Thus, 12/15-LO mediates monocyte/EC interactions in the vessel wall in atherogenesis at least in part through molecular regulation of expression of endothelial adhesion molecules.