Considerations for the development of guidance on dose level selection for developmental and reproductive toxicity studies.

In 2022, the European Chemicals Agency issued advice on the selection of high dose levels for developmental and reproductive toxicity (DART) studies indicating that the highest dose tested should aim to induce clear evidence of reproductive toxicity without excessive toxicity and severe suffering in parental animals. In addition, a recent publication advocated that a 10% decrease in body weight gain should be replaced with a 10% decrease in bodyweight as a criterion for dose adequacy. Experts from the European Centre for Ecotoxicology and Toxicology of Chemicals evaluated these recent developments and their potential impact on study outcomes and interpretation and identified that the advice was not aligned with OECD test guidelines or with humane endpoints guidance. Furthermore, data analysis from DART studies indicated that a 10% decrease in maternal body weight during gestation equates to a 25% decrease in body weight gain, which differs from the consensus of experts at a 2010 ILSI/HESI workshop. Dose selection should be based on a biological approach that considers a range of other factors. Excessive dose levels that cause frank toxicity and overwhelm homeostasis should be avoided as they can give rise to effects that are not relevant to human health assessments.

Evaluation of a telemedicine pilot program for the provision of HIV pre-exposure prophylaxis in the Southeastern United States.

Pre-exposure prophylaxis (PrEP) is a daily regimen that reduces the risk of acquiring HIV by up to 97%. There is limited information on the use of telehealth to provide PrEP in a program aimed toward the primary prevention of HIV. This was a 6-month telePrEP feasibility study that assessed process measures, clinical outcomes and patient satisfaction. Descriptive statistics and Chi-square analysis were used to evaluate measures and outcomes from the start to the end of the study. Twenty patients enrolled, and 80% completed the study. Participants were cisgender males (100%) with an average age of 35.6 years, white (95%), and were college graduates or higher (55%). The majority (75%) had very high comfort with video calls before the program. Self-reported adherence to PrEP medication remained high throughout the program (60%-70%). Without this program 31.2% of participants were unlikely to have received PrEP. For obtaining PrEP 56.3% preferred telemedicine only, and 31.2% preferred a combination of telemedicine and in-person office visits. PrEP is an effective method of preventing HIV infection for those at high risk. Our program shows that telemedicine can be useful to expand access to medication for patients at high risk.

Proactive Electronic Visits for Smoking Cessation and Chronic Obstructive Pulmonary Disease Screening in Primary Care: Randomized Controlled Trial of Feasibility, Acceptability, and Efficacy.

BACKGROUND: Most smokers with chronic obstructive pulmonary disease (COPD) have not yet been diagnosed, a statistic that has remained unchanged for over two decades. A dual-focused telehealth intervention that promotes smoking cessation, while also facilitating COPD screening, could help address national priorities to improve the diagnosis, prevention, treatment, and management of COPD. The purpose of this study was to preliminarily evaluate an integrated asynchronous smoking cessation and COPD screening e-visit (electronic visit) that could be delivered proactively to adult smokers at risk for COPD, who are treated within primary care. OBJECTIVE: The aims of this study were (1) to examine e-visit feasibility and acceptability, particularly as compared to in-lab diagnostic pulmonary function testing (PFT), and (2) to examine the efficacy of smoking cessation e-visits relative to treatment as usual (TAU), all within primary care. METHODS: In a randomized clinical trial, 125 primary care patients who smoke were randomized 2:1 to receive either proactive e-visits or TAU. Participants randomized to the e-visit condition were screened for COPD symptoms via the COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE). Those with scores ≥2 were invited to complete both home spirometry and in-lab PFTs, in addition to two smoking cessation e-visits. Smoking cessation e-visits assessed smoking history and motivation to quit and included completion of an algorithm to determine the best Food and Drug Administration-approved cessation medication to prescribe. Primary outcomes included measures related to (1) e-visit acceptability, feasibility, and treatment metrics; (2) smoking cessation outcomes (cessation medication use, 24-hour quit attempts, smoking reduction ≥50%, self-reported abstinence, and biochemically confirmed abstinence); and (3) COPD screening outcomes. RESULTS: Of 85 participants assigned to the e-visits, 64 (75.3%) were invited to complete home spirometry and in-lab PFTs based on CAPTURE. Among those eligible for spirometry, 76.6% (49/64) completed home spirometry, and 35.9% (23/64) completed in-lab PFTs. At 1 month, all cessation outcomes favored the e-visit, with a significant effect for cessation medication use (odds ratio [OR]=3.22). At 3 months, all cessation outcomes except for 24-hour quit attempts favored the e-visit, with significant effects for cessation medication use (OR=3.96) and smoking reduction (OR=3.09). CONCLUSIONS: A proactive, asynchronous e-visit for smoking cessation and COPD screening may offer a feasible, efficacious approach for broad interventions within primary care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04155073; https://clinicaltrials.gov/ct2/show/NCT04155073.

Preventive Care Utilization by Patients Who Use Virtual Urgent Care.

Introduction: The use of direct to patient (DTP) telemedicine for common acute conditions is widespread. It provides certain advantages over in-person visits, but has led to concerns about fragmentation of care. It is unknown whether use of DTP telemedicine decreases use of primary care services in a way that leads to missed preventive screenings and immunizations. Methods: Virtual urgent care (VUC) is a DTP telemedicine service to treat common acute conditions. All VUC encounters completed at an academic health system from July 2018 to December 2019 were evaluated and analyzed in 2020. Only patients established with primary care (at least one primary care visit in the same year as VUC encounter) were included. Specific preventive screenings (breast cancer, gonorrhea/chlamydia, and cervical cancer) and immunizations (tetanus and influenza) were characterized as up to date based on national guidelines. Chi-squares and multivariate logistic regressions were used to assess receipt of screenings and immunizations. Regressions included VUC and primary care utilization and demographic factors. Results: Patients evaluated (N = 1025) were mostly 25-50 years old (69.7%), women (81.8%), and white (74.9%). More than half (56.5%) had only used VUC once. In multivariate analyses, VUC utilization was not negatively associated with any of the preventive services evaluated, whereas primary care utilization was associated with receipt of both immunizations and gonorrhea/chlamydia screening. Conclusions: Higher VUC utilization is not negatively associated with receipt of preventive services, as long as a primary care relationship is established. VUC may provide a useful method of encouraging receipt of preventive services, especially for younger patients.

STochastic Optical Reconstruction Microscopy (STORM) reveals the nanoscale organization of pathological aggregates in human brain.

AIMS: Histological analysis of brain tissue samples provides valuable information about the pathological processes leading to common neurodegenerative disorders. In this context, the development of novel high-resolution imaging approaches is a current challenge in neuroscience. METHODS: To this end, we used a recent super-resolution imaging technique called STochastic Optical Reconstruction Microscopy (STORM) to analyse human brain sections. We combined STORM cell imaging protocols with neuropathological techniques to image cryopreserved brain samples from control subjects and patients with neurodegenerative diseases. RESULTS: This approach allowed us to perform 2D-, 3D- and two-colour-STORM in neocortex, white matter and brainstem samples. STORM proved to be particularly effective at visualizing the organization of dense protein inclusions and we imaged with a <50 nm resolution pathological aggregates within the central nervous system of patients with Alzheimer's disease, Parkinson's disease, Lewy body dementia and fronto-temporal lobar degeneration. Aggregated Aß branches appeared reticulated and cross-linked in the extracellular matrix, with widths from 60 to 240 nm. Intraneuronal Tau and TDP-43 inclusions were denser, with a honeycomb pattern in the soma and a filamentous organization in the axons. Finally, STORM imaging of α-synuclein pathology revealed the internal organization of Lewy bodies that could not be observed by conventional fluorescence microscopy. CONCLUSIONS: STORM imaging of human brain samples opens further gates to a more comprehensive understanding of common neurological disorders. The convenience of this technique should open a straightforward extension of its application for super-resolution imaging of the human brain, with promising avenues to current challenges in neuroscience.

A Telehealth Initiative to Overcome Health Care Barriers for People Experiencing Homelessness.

People experiencing homelessness (PEH) encounter barriers to health care, increasing their vulnerability to illness, hospitalization, and death. Telehealth can improve access to health care, but its use in PEH has been insufficiently evaluated. Needs assessment surveys completed by clients at an urban drop-in center for PEH (n = 63) showed mental (58.7%) and physical (52.4%) health challenges were common, as was emergency department (ED) use (75.9%, n = 54). Surveys collected after in-person and telehealth clinical visits showed patient satisfaction was >90% for both visit types (n = 125, 44.0% telehealth and 56.0% in person). Without access to telehealth visits, 29.1% of patients would have gone to the ED and 38.2% would not have gotten care. Providers (n = 93, 69.6% telehealth and 30.4% in person) were more likely to agree/strongly agree they made a positive impact on patients' health through telehealth (92.2%) than in person (71.4%) (p = 0.019). Telehealth is a feasible and potentially cost-effective method to increase access to health care and reduce health outcome disparities in PEH.

Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation.

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.

Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias.

The development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathological responses in MPNs suggests a need for development of better therapies for JAK kinase-dependent malignancies. Here, we demonstrate that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells.

Moodivate: A self-help behavioral activation mobile app for utilization in primary care-Development and clinical considerations.

Depressive symptoms are highly prevalent and are associated with considerable functional impairment, significant public health costs, and heightened mortality risk. Individuals experiencing impairment due to depressive symptomatology are most likely to report their symptoms to a primary care provider. As such, national guidelines highlight the need to assess and effectively treat depression via primary care. Despite these guidelines, the dissemination of evidence-based psychotherapy via primary care is limited, likely due to both provider- and patient-level treatment barriers. Mobile health (mHealth) technologies are promising for addressing these barriers and for promoting uptake of evidence-based depression treatment. Among evidence-based psychotherapies for depression, brief Behavioral Activation Treatment for Depression (BATD) has shown great promise and is particularly amenable to mHealth delivery. Herein, we discuss the development of a BATD mobile application, Moodivate, that was developed in order to disseminate BATD via primary care. This paper focuses on description of (1) rationale for Moodivate treatment development, (2) Moodivate treatment components, (3) ongoing clinical trial evaluation of Moodivate, and (4) clinical considerations for incorporating Moodivate into clinical practice.

Blast injury of the ear by massive explosion: a review of 41 cases.

BACKGROUND: Blast injuries in modern warfare are common, and the ear is often affected as it is an effective pressure transducer. This study aimed to evaluate military blast injuries of the ear. METHODS: From May 2002 to October 2014, all patients referred to two military hospitals near Paris, France following exposure to massive explosions were analysed. RESULTS: Among the 41 patients (82 ears), 36 of them reported tinnitus, 25 hearing loss, 14 earache and 8 vertigo. It was noted that 44% of the patients had tympanic membrane perforations and that this was bilateral in two-thirds of the cases. The hearing loss in 29% of the cases was pure sensorineural, in 55% it was mixed and in 15% it was a pure conductive hearing loss. There was no correlation between the impact of middle ear lesions and the severity of the inner ear injury. Three patients had a pharyngolaryngeal blast injury detected on the battlefield associated with blast lung injury, but only two of them had tympanic perforations. Nine tympanoplasty procedures were performed, of which 44% succeeded in sealing the perforation. CONCLUSIONS: Blast injuries of the ear are characterised by significant functional signs and are not correlated to otoscopic examinations. Sensorineural hearing loss is almost immediately final. When deciding on initial management, the status of the tympanic membrane does not provide any information about the risk of a primary blast injury of the lung; laryngeal nasofibroscopy seems a more relevant screening test.

Integrated cell and process engineering for improved transient production of a "difficult-to-express" fusion protein by CHO cells.

Based on an optimized electroporation protocol, we designed a rapid, milliliter-scale diagnostic transient production assay to identify limitations in the ability of Chinese hamster ovary (CHO) cells to produce a model "difficult-to-express" homodimeric Fc-fusion protein, Sp35Fc, that exhibited very low volumetric titer and intracellular formation of disulfide-bonded oligomeric aggregates post-transfection. As expression of Sp35Fc induced an unfolded protein response in transfected host cells, we utilized the transient assay to compare, in parallel, multiple functionally diverse strategies to engineer intracellular processing of Sp35Fc in order to increase production and reduce aggregation as two discrete design objectives. Specifically, we compared the effect of (i) co-expression of ER-resident molecular chaperones (BiP, PDI, CypB) or active forms of UPR transactivators (ATF6c, XBP1s) at varying recombinant gene load, (ii) addition of small molecules known to act as chemical chaperones (PBA, DMSO, glycerol, betaine, TMAO) or modulate UPR signaling (PERK inhibitor GSK2606414) at varying concentration, (iii) a reduction in culture temperature to 32°C. Using this information, we designed a biphasic, Sp35Fc-specific transient manufacturing process mediated by lipofection that utilized CypB co-expression at an optimal Sp35Fc:CypB gene ratio of 5:1 to initially maximize transfected cell proliferation, followed by addition of a combination of PBA (0.5 mM) and glycerol (1% v/v) at the onset of stationary phase to maximize cell specific production and eliminate Sp35Fc aggregation. Using this optimal, engineered process transient Sp35Fc production was significantly increased sixfold over a 12 day production process with no evidence of disulfide-bonded aggregates. Finally, transient production in clonally derived sub-populations (derived from parental CHO host) screened for a heritably improved capability to produce Sp35Fc was also significantly improved by the optimized process, showing that protein-specific cell/process engineering can provide a solution that exceeds the limits of genetic/functional diversity within heterogeneous host cell populations. .

Quantile regression in environmental health: Early life lead exposure and end-of-grade exams.

Conditional means regression, including ordinary least squares (OLS), provides an incomplete picture of exposure-response relationships particularly if the primary interest resides in the tail ends of the distribution of the outcome. Quantile regression (QR) offers an alternative methodological approach in which the influence of independent covariates on the outcome can be specified at any location along the distribution of the outcome. We implemented QR to examine heterogeneity in the influence of early childhood lead exposure on reading and math standardized fourth grade tests. In children from two urban school districts (n=1,076), lead exposure was associated with an 18.00 point decrease (95% CI: -48.72, -3.32) at the 10th quantile of reading scores, and a 7.50 point decrease (95% CI: -15.58, 2.07) at the 90th quantile. Wald tests indicated significant heterogeneity of the coefficients across the distribution of quantiles. Math scores did not show heterogeneity of coefficients, but there was a significant difference in the lead effect at the 10th (ß=-17.00, 95% CI: -32.13, -3.27) versus 90th (ß=-4.50, 95% CI: -10.55, 4.50) quantiles. Our results indicate that lead exposure has a greater effect for children in the lower tail of exam scores, a result that is masked by conditional means approaches.

Discrepancies in cardiovascular disease risk calculation affect aspirin use recommendations in patients with diabetes.

OBJECTIVES: Aspirin is recommended for cardiovascular disease (CVD) prevention in patients who are at high risk for CVD. The objective of this study was to compare agreement between two American Diabetes Association-endorsed CVD risk calculators in identifying candidates for aspirin therapy. METHODS: Adult patients with diabetes mellitus (n = 238) were studied for 1 year in a family medicine clinic. Risk scores were calculated based on the United Kingdom Prospective Diabetes Study Risk Engine and the Atherosclerosis Risk in Communities Coronary Heart Disease Risk Calculator. Analyses included χ(2), κ scores, and logistic regressions. RESULTS: The Atherosclerosis Risk in Communities Coronary Heart Disease Risk Calculator identified 50.4% of patients as high risk versus 23.5% by the United Kingdom Prospective Diabetes Study Risk Engine. κ score for agreement identifying high-risk status was 0.3642. Among patients at high risk, African Americans (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.24-0.86) and those with uncontrolled diabetes (OR 0.30, 95% CI 0.16-0.56) had lower odds of disagreement, whereas nonsmokers had higher odds (OR 2.98, 95% CI 1.57-5.69). Among patients at low risk, women (OR 3.83, 95% CI 1.64-8.91), African Americans (OR 5.96, 95% CI 3.07-11.59), and those with high high-density lipoprotein (OR 2.82, 95% CI 1.48-5.37) showed greater odds of disagreement. CONCLUSIONS: Improved risk assessment methods are needed to identify patients with diabetes mellitus who benefit from aspirin for the primary prevention of CVD. Prospective trials are needed to provide additional evidence for aspirin use in this population.

Predictions of tissue concentrations of myclobutanil, oxyfluorfen, and pronamide in rat and human after oral exposures via GastroPlusTM physiologically based pharmacokinetic modelling.

Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals. This study addresses the absence of PBPK-type data for myclobutanil, oxyfluorfen, and pronamide by generating in vitro data for key input PBPK parameters (Caco-2 permeability, rat plasma binding, rat blood to plasma ratio, and rat liver microsomal half-life), followed by generation of PBPK models for these three chemicals via the GastroPlusTM software. Incorporating these experimental input parameters into PBPK models, the prediction accuracy of plasma AUC (area under curve) was significantly improved. Validation against rat oral administration data demonstrated substantial enhancement. Steady-state plasma concentrations (Css) of pronamide aligned well with published data using measured PBPK parameters. Following validation, parent-based tissue concentrations for these agrochemicals were predicted in humans and rats after single or 30-day repeat exposure of 10 mg/kg/day. These predicted concentrations contribute valuable information for future human toxicity risk assessments of these agrochemicals.

Early lead exposure (<3 years old) prospectively predicts fourth grade school suspension in Milwaukee, Wisconsin (USA).

School suspensions are associated with negative student outcomes. Environmental lead exposure increases hyperactivity and sensory defensiveness, two traits likely to increase classroom misbehavior and subsequent discipline. Childhood Blood Lead Level (BLL) test results categorized urban fourth graders as exposed (2687; lifetime max BLL 10-20 µg/dL) or unexposed (1076; no lifetime BLL ≥5 µg/dL). Exposed children were over twice as likely as unexposed children to be suspended (OR=2.66, 95% CI=[2.12, 3.32]), controlling for covariates. African American children were more likely to be suspended than white children, but lead exposure explained 23% of the racial discipline gap. These results suggest that different rates of environmental lead exposure may contribute to the racial discipline gap.

A zebrafish model for hepatoerythropoietic porphyria.

Defects in the enzymes involved in the haem biosynthetic pathway can lead to a group of human diseases known as the porphyrias. yquem (yqe(tp61)) is a zebrafish mutant with a photosensitive porphyria syndrome. Here we show that the porphyric phenotype is due to an inherited homozygous mutation in the gene encoding uroporphyrinogen decarboxylase (UROD); a homozygous deficiency of this enzyme causes hepatoerythropoietic porphyria (HEP) in humans. The zebrafish mutant represents the first genetically 'accurate' animal model of HEP, and should be useful for studying the pathogenesis of UROD deficiency and evaluating gene therapy vectors. We rescued the mutant phenotype by transient and germline expression of the wild-type allele.

Dissection of gastric homeostasis in vivo facilitates permanent capture of isthmus-like stem cells in vitro.

The glandular stomach is composed of two regenerative compartments termed corpus and antrum, and our understanding of the transcriptional networks that maintain these tissues is incomplete. Here we show that cell types with equivalent functional roles in the corpus and antrum share similar transcriptional states including the poorly characterized stem cells of the isthmus region. To further study the isthmus, we developed a monolayer two-dimensional (2D) culture system that is continually maintained by Wnt-responsive isthmus-like cells capable of differentiating into several gastric cell types. Importantly, 2D cultures can be converted into conventional three-dimensional organoids, modelling the plasticity of gastric epithelial cells in vivo. Finally, we utilized the 2D culture system to show that Sox2 is both necessary and sufficient to generate enterochromaffin cells. Together, our data provide important insights into gastric homeostasis, establish a tractable culture system to capture isthmus cells and uncover a role for Sox2 in enterochromaffin cells.

Rationale, design, and protocol for a hybrid type 1 effectiveness-implementation trial of a proactive smoking cessation electronic visit for scalable delivery via primary care: the E-STOP trial.

BACKGROUND: Cigarette smoking remains the leading cause of preventable disease and death in the United States. Primary care offers an ideal setting to reach adults who smoke cigarettes and improve uptake of evidence-based cessation treatment. Although U.S. Preventive Services Task Force Guidelines recommend the 5As model (Ask, Advise, Assess, Assist, Arrange) in primary care, there are many barriers to its implementation. Automated, comprehensive, and proactive tools are needed to overcome barriers. Our team developed and preliminarily evaluated a proactive electronic visit (e-visit) delivered via the Electronic Health Record patient portal to facilitate evidence-based smoking cessation treatment uptake in primary care, with promising initial feasibility and efficacy. This paper describes the rationale, design, and protocol for an ongoing Hybrid Type I effectiveness-implementation trial that will simultaneously assess effectiveness of the e-visit intervention for smoking cessation as well as implementation potential across diverse primary care settings. METHODS: The primary aim of this remote five-year study is to examine the effectiveness of the e-visit intervention vs. treatment as usual (TAU) for smoking cessation via a clinic-randomized clinical trial. Adults who smoke cigarettes are recruited across 18 primary care clinics. Clinics are stratified based on their number of primary care providers and randomized 2:1 to either e-visit or TAU. An initial baseline e-visit gathers information about patient smoking history and motivation to quit, and a clinical decision support algorithm determines the best evidence-based cessation treatment to prescribe. E-visit recommendations are evaluated by a patient's own provider, and a one-month follow-up e-visit assesses cessation progress. Main outcomes include: (1) cessation treatment utilization (medication, psychosocial cessation counseling), (2) reduction in cigarettes per day, and (3) biochemically verified 7-day point prevalence abstinence (PPA) at six-months. We hypothesize that patients randomized to the e-visit condition will have better cessation outcomes (vs. TAU). A secondary aim evaluates e-visit implementation potential at patient, provider, and organizational levels using a mixed-methods approach. Implementation outcomes include acceptability, adoption, fidelity, implementation cost, penetration, and sustainability. DISCUSSION: This asynchronous, proactive e-visit intervention could provide substantial benefits for patients, providers, and primary care practices and has potential to widely improve reach of evidence-based cessation treatment. TRIAL REGISTRATION: NCT05493254.

Impact of EHR-based clinical decision support on adherence to guidelines for patients on NSAIDs: a randomized controlled trial.

PURPOSE: Electronic health records (EHRs) with clinical decision support hold promise for improving quality of care, but their impact on management of chronic conditions has been mixed. This study examined the impact of EHR-based clinical decision support on adherence to guidelines for reducing gastrointestinal complications in primary care patients on nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: This randomized controlled trial was conducted in a national network of primary care offices using an EHR and focused on patients taking traditional NSAIDs who had factors associated with a high risk for gastrointestinal complications (a history of peptic ulcer disease; concomitant use of anticoagulants, anti-platelet medications [including aspirin], or corticosteroids; or an age of 75 years or older). The offices were randomized to receive EHR-based guidelines and alerts for high-risk patients on NSAIDs, or usual care. The primary outcome was the proportion of patients who received guideline-concordant care during the 1-year study period (June 2007-June 2008), defined as having their traditional NSAID discontinued (including a switch to a lower-risk medication), having a gastroprotective medication coprescribed, or both. RESULTS: Participants included 27 offices with 119 clinicians and 5,234 high-risk patients. Intervention patients were more likely than usual care patients to receive guideline-concordant care (25.4% vs 22.4%, adjusted odds ratio = 1.19; 95% confidence interval, 1.01-1.42). For individual high-risk groups, patients on low-dose aspirin were more likely to receive guideline-concordant care with the intervention vs usual care (25.0% vs 20.8%, adjusted odds ratio = 1.30; 95% confidence interval, 1.04-1.62), but there was no significant difference for patients in other high-risk groups. CONCLUSIONS: This study showed only a small impact of EHR-based clinical decision support for high-risk patients on NSAIDs in primary care offices. These results add to the growing literature about the complexity of EHR-based clinical decision support for improving quality of care.

Urinary lead level and colonization by antibiotic resistant bacteria: Evidence from a population-based study.

BACKGROUND: Infection by antibiotic resistant bacteria (ARB) is a global health crisis and asymptomatic colonization increases risk of infection. Nonhuman studies have linked heavy metal exposure to the selection of ARB; however, few epidemiologic studies have examined this relationship. This study analyzes the association between urinary lead level and colonization by ARB in a nonclinical human population. METHODS: Data came from the Survey of the Health of Wisconsin 2016-2017, and its ancillary Wisconsin Microbiome Study. Urinary lead levels, adjusted for creatinine, were used to assess exposure. ARB included methicillin resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), fluoroquinolone resistant Gram-negative bacilli (RGNB), and Clostridium difficile (C. diff), from skin, nose, and mouth swabs, and saliva and stool samples. Logistic regression, adjusted for covariates, was used to evaluate associations between Pb and ARB. Secondary analysis investigated Pb resistance from ARB isolates. RESULTS: Among 695 participants, 239 (34%) tested positive for ARB. Geometric mean urinary Pb (unadjusted) was 0.286 µg/L (95% confidence intervals [CI] = 0.263, 0.312) for ARB negative participants and 0.323 µg/L (95% CI = 0.287, 0.363) for ARB positive participants. Models adjusted for demographics, diet, and antibiotic use showed elevated odds of positive colonization for those in the 95th percentile (vs. below) of Pb exposure (odds ratio [OR] = 2.05, 95% CI = 0.95, 4.44), and associations were highest in urban residents (OR = 2.85, 95% CI = 1.07, 7.59). RGNB isolates were most resistant to Pb. DISCUSSION: These novel results suggest that Pb exposure is associated with increased colonization by ARB, and that RGNB are particularly resistant to Pb.