Primary care physician referral practices regarding BRCA1/2 genetic counseling in a major health system.

PURPOSE: The United States Preventive Services Task Force recommends primary care physicians refer patients at high risk for BRCA1/2 mutations to genetic testing when appropriate. The objective of our study was to describe referrals for BRCA1/2 testing in a large integrated health system and to assess factors associated with referral. METHODS: This retrospective cohort study includes female patients between 18 and 50 years who had a primary care visit in the Cleveland Clinic Health System between 2010 and 2019. We used multivariable logistic regression to estimate differences in the odds of a woman being referred for BRCA1/2 testing by patient factors and referring physician specialty. We also assessed variation in referrals by physicians. RESULTS: Among 279,568 women, 5% were high risk. Of those, 22% were referred for testing. Black patients were significantly less likely to be referred than white patients (aOR 0.87; 95% CI 0.77, 0.98) and Jewish patients were more likely to be referred than non-Jewish patients (aOR 2.13; 95% CI 1.68, 2.70). Patients primarily managed by OB/GYN were significantly more likely to be referred than those cared for via Internal/Family Medicine (aOR 1.45; 95% CI 1.30, 1.61). Less than a quarter of primary care physicians ever referred a patient for testing. CONCLUSION: The majority of primary care patients at high risk for a BRCA1/2 mutation were not referred for testing, and over a decade, most physicians never referred a single patient. Internal/Family Medicine physicians, in particular, need support in identifying and referring women who could benefit from testing.

Patient Perspectives on Self-Monitoring of Blood Glucose When not Using Insulin: a Cross-sectional Survey.

BACKGROUND: Professional societies have recommended against use of self-monitoring blood glucose (SMBG) in non-insulin-treated type 2 diabetes (NITT2D) to control blood sugar levels, but patients are still monitoring. OBJECTIVE: To understand patients' motivation to monitor their blood sugar, and whether they would stop if their physician suggested it. DESIGN: Cross-sectional in-person and electronic survey conducted between 2018 and 2020. PARTICIPANTS: Adults with type 2 diabetes not using insulin who self-monitor their blood sugar. MAIN MEASURES: The survey included questions about frequency and reason for using SMBG, and the impact of SMBG on quality of life and worry. It also asked, "If your doctor said you could stop checking your blood sugar, would you?" We categorized patients based on whether they would stop. To identify the characteristics independently associated with desire to stop SMBG, we performed a logistic regression using backward stepwise selection. KEY RESULTS: We received 458 responses. The common reasons for using SMBG included the doctor wanted the patient to check (67%), desire to see the number (65%), and desire to see if their medications were working (61%). Forty-eight percent of respondents stated that using SMBG reduced their worry about their diabetes and 61% said it increased their quality of life. Fifty percent would stop using SMBG if given permission. In the regression model, respondents who said that they check their blood sugar levels because "I was told to" were more likely to want to stop (AOR: 1.69, 95%CI: 1.11, 2.58). Those that used SMBG due to habit and to understand their diabetes better had lower odds of wanting to stop (AOR: 0.33, 95%CI: 0.18-0.62; AOR: 0.60, 95%CI: 0.39-0.93, respectively). CONCLUSIONS: Primary care physicians should discuss patients' reasons for using SMBG and offer them the option of discontinuing.

Change in Physician Burnout between 2013 and 2020 in a Major Health System.

OBJECTIVE: Assessing changes in physician burnout over time can offer insight into the causes of burnout. Existing studies are limited by using different samples of physicians at each time point. Our objective was to assess changes in burnout between 2013-2014 and 2019-2020 overall and within a cohort of physicians who took the survey twice. METHODS: This is a longitudinal cohort and cross-sectional study of physicians in a major health system. They were administered the Maslach Burnout Inventory in 2013-2014 and 2019-2020. We separately assessed differences in odds of burnout and its subscales in 2013-2014 and 2019-2020 by physician characteristics and clinical time. We then assessed differences in the odds of reporting burnout and its subscales in 2019-2020 compared with 2013-2014 overall and by physician sex, race, and change in clinical full-time employment. RESULTS: There were 1220 respondents in 2013-2014, 503 in 2019-2020, and 149 who responded at both time points. Burnout increased from 35% to 56%. Compared with 2013-2014, physicians had 2.39 higher odds (95% confidence interval [CI] 1.92-2.98) of burnout in 2019-2020, and this change in burnout was significantly more pronounced for female versus male physicians (odds ratio 1.80; 95% CI 1.57-1.80). Compared with White physicians, non-White physicians had significantly lower odds of burnout at both time points, but their odds increased significantly more over time (odds ratio 1.36; 95% CI 1.05-1.57). CONCLUSIONS: We found a substantial increase in burnout over time, which was particularly pronounced for non-White and female physicians. Assessment over time is essential for understanding problematic trajectories of burnout that may be obscured by cross-sectional studies.

RSV attenuates epithelial cell restitution by inhibiting actin cytoskeleton-dependent cell migration.

The airway epithelium's ability to repair itself after injury, known as epithelial restitution, is an essential mechanism enabling the respiratory tract's normal functions. Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections worldwide. We sought to determine whether RSV delays the airway epithelium wound repair process both in vitro and in vivo. We found that RSV infection attenuated epithelial cell migration, a step in wound repair, promoted stress fiber formation, and mediated assembly of large focal adhesions. Inhibition of Rho-associated kinase, a master regulator of actin function, reversed these effects. There was increased RhoA and phospho-myosin light chain 2 following RSV infection. In vivo, mice were intraperitoneally inoculated with naphthalene to induce lung injury, followed by RSV infection. RSV infection delayed reepithelialization. There were increased concentrations of phospho-myosin light chain 2 in day 7 naphthalene + RSV animals, which normalized by day 14. This study suggests a key mechanism by which RSV infection delays wound healing.

Titanium dioxide nanoparticles exaggerate respiratory syncytial virus-induced airway epithelial barrier dysfunction.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children worldwide. While most develop a mild, self-limiting illness, some develop severe acute lower respiratory infection and persistent airway disease. Exposure to ambient particulate matter has been linked to asthma, bronchitis, and viral infection in multiple epidemiological studies. We hypothesized that coexposure to nanoparticles worsens RSV-induced airway epithelial barrier dysfunction. Bronchial epithelial cells were incubated with titanium dioxide nanoparticles (TiO2-NP) or a combination of TiO2-NP and RSV. Structure and function of epithelial cell barrier were analyzed. Viral titer and the role of reactive oxygen species (ROS) generation were evaluated. In vivo, mice were intranasally incubated with TiO2-NP, RSV, or a combination. Lungs and bronchoalveolar lavage (BAL) fluid were harvested for analysis of airway inflammation and apical junctional complex (AJC) disruption. RSV-induced AJC disruption was amplified by TiO2-NP. Nanoparticle exposure increased viral infection in epithelial cells. TiO2-NP induced generation of ROS, and pretreatment with antioxidant, N-acetylcysteine, reversed said barrier dysfunction. In vivo, RSV-induced injury and AJC disruption were augmented in the lungs of mice given TiO2-NP. Airway inflammation was exacerbated, as evidenced by increased white blood cell infiltration into the BAL, along with exaggeration of peribronchial inflammation and AJC disruption. These data demonstrate that TiO2-NP exposure exacerbates RSV-induced AJC dysfunction and increases inflammation by mechanisms involving generation of ROS. Further studies are required to determine whether NP exposure plays a role in the health disparities of asthma and other lung diseases, and why some children experience more severe airway disease with RSV infection.

Disruption of the airway epithelial barrier in a murine model of respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is a major cause of hospitalization for infants and young children worldwide. RSV is known to infect epithelial cells and increase the permeability of model airway epithelial monolayers in vitro. We hypothesized that RSV infection also induces airway barrier dysfunction in vivo. C57BL/6 mice were intranasally inoculated with RSV, and on day 4 post-inoculation were examined for viral replication, lung inflammation, and barrier integrity as well as the structure and molecular composition of epithelial junctions. In parallel, primary mouse tracheal epithelial cells (mTEC) were cultured for in vitro studies. RSV-infected mice lost weight and showed significant peribronchial inflammation compared with noninfected controls and UV-inactivated RSV-inoculated animals. RSV infection increased the permeability of the airway epithelial barrier and altered the molecular composition of epithelial tight junctions. The observed RSV-induced barrier disruption was accompanied by decreased expression of several tight-junction proteins and accumulation of cleaved extracellular fragments of E-cadherin in bronchoalveolar lavage and mTEC supernatants. Similarly, in vitro RSV infection of mTEC monolayers resulted in enhanced permeability and disruption of tight-junction structure. Furthermore, incubation of mTEC monolayers with a recombinant fragment of E-cadherin caused tight-junction disassembly. Taken together, these data indicate that RSV infection leads to airway barrier dysfunction in vivo, mediated by either decreased expression or cleavage of junctional proteins. Our observations provide further insights into the pathophysiology of RSV infection and provide a rationale for development of barrier-protecting agents to alleviate the pathogenic effects of RSV infection.

IFN-γ, IL-17A, or zonulin rapidly increase the permeability of the blood-brain and small intestinal epithelial barriers: Relevance for neuro-inflammatory diseases.

Breakdown of the blood-brain barrier (BBB) precedes lesion formation in the brains of multiple sclerosis (MS) patients. Since recent data implicate disruption of the small intestinal epithelial barrier (IEB) in the pathogenesis of MS, we hypothesized that the increased permeability of the BBB and IEB are mechanistically linked. Zonulin, a protein produced by small intestine epithelium, can rapidly increase small intestinal permeability. Zonulin blood levels are elevated in MS, but it is unknown whether zonulin can also disrupt the BBB. Increased production of IL-17A and IFN-γ has been implicated in the pathogenesis of MS, epilepsy, and stroke, and these cytokines impact BBB integrity after 24 h. We here report that primary human brain microvascular endothelial cells expressed the EGFR and PAR2 receptors necessary to respond to zonulin, and that zonulin increased BBB permeability to a 40 kDa dextran tracer within 1 h. Moreover, both IL-17A and IFN-γ also rapidly increased BBB and IEB permeability. By using confocal microscopy, we found that exposure of the IEB to zonulin, IFN-γ, or IL-17A in vitro rapidly modified the localization of the TJ proteins, ZO-1, claudin-5, and occludin. TJ disassembly was accompanied by marked depolymerization of the peri-junctional F-actin cytoskeleton. Our data indicate that IFN-γ, IL-17A, or zonulin can increase the permeability of the IEB and BBB rapidly in vitro, by modifying TJs and the underlying actin cytoskeleton. These observations may help clarify how the gut-brain axis mediates the pathogenesis of neuro-inflammatory diseases.

The effect of hematocrit on in vitro bilirubin photoalteration.

BACKGROUND: Phototherapy using light in the spectral range of 410-500 nm, which overlaps the absorption of bilirubin, is the common treatment for neonatal hyperbilirubinemia. Hemoglobin (Hb) absorbs light strongly throughout this same range and thus can compete with bilirubin for this light and consequently reduce the efficacy of phototherapy. Here, we determined the effect of hematocrit (Hct) on in vitro bilirubin photoalteration using narrow-band blue (450 nm) light-emitting diodes (LEDs). METHODS: Suspensions with Hcts from 0 to 80% and 16 ± 1 mg/dl bilirubin were prepared by mixing red blood cells (RBCs), bilirubin (30 mg/dl) in 4% human serum albumin, and normal saline. Aliquots of each suspension were exposed to blue light at equal irradiances. Before and after 60 min of exposure, bilirubin levels in supernatants (n = 46) were measured using a diazo-dye method. RESULTS: Bilirubin photoalteration steeply decreased by ~60% as Hct increased from 0 to 10%. Over the clinically relevant range of 30-70% Hct, the decrease was significant, but less drastic, exhibiting a quasi-linear dependence on Hct. CONCLUSION: Bilirubin photoalteration under blue light in vitro is significantly reduced as Hct increases. Clinical studies are warranted to confirm these in vitro observations that Hct can affect the efficacy of phototherapy.

Informed Decision Making for Anticoagulation Therapy for Atrial Fibrillation.

BACKGROUND: Patients with atrial fibrillation (AF) must decide between warfarin and direct oral anticoagulants (DOACs), a decision involving important tradeoffs. Our objective was to understand whether physicians engage patients in informed decision making for anticoagulants. DESIGN: We performed an analysis of recorded conversations between physicians and anticoagulation-naïve patients in the Verilogue Point-of-Practice database. We assessed the presence of 7 elements of informed decision making, as well as a discussion of financial costs. RESULTS: Of 37 encounters with 21 physicians, 92% resulted in a DOAC prescription and 8% resulted in a warfarin prescription. Seventy percent met criteria for discussion of pros and cons, 70% for discussion of the alternatives, 43% presented the decision, 30% included an assessment of patient understanding, 22% included an explanation of the patient's role in decision making, 22% included an assessment of patient preferences, and 19% included a discussion of uncertainty. Two encounters (5%) included all 7 elements and 9 (24%) included none. Physicians discussed treatment costs with patients in 43% of encounters. LIMITATIONS: We assessed informed decision making in a single encounter. Physicians and patients may have had other discussions that were not captured in our data. CONCLUSIONS: Physicians often presented the alternatives but did not generally engage patients in informed decision making. The high rate of DOAC prescriptions is likely the result of physician preferences, as patient preferences were rarely assessed. IMPLICATIONS: Strategies to support physicians in engaging patients in informed decision making for anticoagulation are needed. HIGHLIGHTS: While physicians discussed the alternatives and presented pros and cons with patients, they rarely assessed patient preferences, explained the patient's role in decision making, or addressed uncertainty.The cost of treatment with DOACs versus warfarin was discussed by physicians in less than half of encounters, limiting patients' ability to make informed decisions for anticoagulation.Only 2 encounters (5%) fulfilled all 7 elements of informed decision making.

Patient and physician factors contributing to polypharmacy among older patients.

OBJECTIVE: Polypharmacy, or use of multiple medications, is associated with patient factors. Less is known regarding variation in polypharmacy by individual physicians. The objective of this study was to assess patient and physician factors associated with polypharmacy among older patients. METHODS: This is a cross-sectional study of patients aged ≥65 years with a primary care visit at Cleveland Clinic Health System in 2015 and their physicians. We collected patient demographics, comorbidities and current medications from the electronic health record, including potentially inappropriate medications (PIMs). We used mixed effects linear regression to estimate adjusted differences in the number of medications by patient factors. We generated adjusted prescribing rates for individual physicians and assessed differences in physician performance on quality measures by their prescribing rate. RESULTS: Our study included 44,570 patients who were prescribed an average of 6.8 medications (standard deviation: 4.0) by 701 physicians. Female sex, higher BMI, having Medicaid insurance, current or former smoking status, comorbidities and seeing a specialist were associated with number of medications. Age was not. Among 267 physicians who saw ≥20 study-eligible patients, the adjusted mean number of medications per patient ranged from 5.2 to 9.6. Compared to physicians who prescribed above the mean, lower prescribing physicians performed significantly better on medication reconciliation (p = .007) and hypertension control (p < .001) and prescribed fewer PIMs (p < .001). CONCLUSIONS: Individual physicians varied in their prescribing practices, even after adjusting for patient demographic and clinical characteristics. Interventions to reduce polypharmacy in older adults should target high prescribing physicians, as physician behavior is more actionable than patient factors.

Airway tight junctions as targets of viral infections.

The apical junctional complexes (AJCs) of airway epithelial cells are a key component of the innate immune system by creating barriers to pathogens, inhaled allergens, and environmental particles. AJCs form between adjacent cells and consist of tight junctions (TJs) and adherens junctions (AJs). Respiratory viruses have been shown to target various components of the AJCs, leading to airway epithelial barrier dysfunction by different mechanisms. Virus-induced epithelial permeability may allow for allergens and bacterial pathogens to subsequently invade. In this review, we discuss the pathophysiologic mechanisms leading to disruption of AJCs and the potential ensuing ramifications. We focus on the following viruses that affect the pulmonary system: respiratory syncytial virus, rhinovirus, influenza viruses, immunodeficiency virus, and other viruses such as coxsackievirus, adenovirus, coronaviruses, measles, parainfluenza virus, bocavirus, and vaccinia virus. Understanding the mechanisms by which viruses target the AJC and impair barrier function may help design therapeutic innovations to treat these infections.

Ligation of patent ductus arteriosus in very low birth weight premature infants.

BACKGROUND: Patent ductus arteriosus (PDA) is frequently encountered in premature infants. Optimal management of PDA remains undefined. We aim to assess the national trend for PDA ligation over 18 years and evaluate mortality and associated morbidities. METHODS: We used data from the National Inpatient Sample (NIS) and KID of the Healthcare Cost and Utilization Project (HCUP) from 1998 to 2015. All infants with gestational age 24-32 weeks and birth weight <1500 g were included. Patients with PDA were classified into two groups: those who did and did not receive surgical ligation. Associated mortality and morbidities were compared. RESULTS: A total of 429,900 neonatal admissions were identified. Of them, 149,473 (34.8%) infants had PDA. PDA-ligated infants were 27,364 (6.4%). PDA ligation was more likely in those with smaller gestational age and with birth weight <1000 g. A steady decline in PDA ligation was noticed since 2004. The mortality rate in PDA-ligated infants was less than in PDA-non-ligated infants (7.5% vs. 8.9%; OR = 0.82; 95% CI: 0.78-0.86; p < 0.001). However, the prevalence rates of pulmonary hemorrhage and necrotizing enterocolitis (NEC) were greater in PDA-ligated infants (OR = 1.58; 95% CI: 1.49-1.67; p < 0.001, and OR = 1.32; 95% CI: 1.26-1.38; p < 0.001, respectively). CONCLUSIONS: Ligation of PDA has been steadily declining since 2004. Despite higher morbidities, PDA-ligated infants had less mortality.

Ongoing developments in RSV prophylaxis: a clinician's analysis.

Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children worldwide. Lower respiratory tract infection due to RSV is one of the most common causes of hospitalization for infants, especially those born premature or with chronic lung or heart disease. Furthermore, RSV infection is an important cause of morbidity in adults, particularly in the elderly and immunocompromised individuals. The acute phase of this infection is often followed by episodes of wheezing that recur for months or years and usually lead to a physician diagnosis of asthma. RSV was discovered more than 50 years ago, and despite extensive research to identify pharmacological therapies, the most effective management of this infection remains supportive care. The trial of a formalin-inactivated RSV vaccine in the 1960s resulted in priming the severe illness upon natural infection. Currently, Palivizumab is the only available option for RSV prophylaxis, and because of restricted clinical benefits and high costs, it has been limited to a group of high-risk infants. There are several ongoing trials in preclinical, Phase-I, Phase-II, or Phase-III clinical stages for RSV vaccine development based on various strategies. Here we review the existing available prophylactic options, the current stages of RSV vaccine clinical trials, different strategies, and major hurdles in the development of an effective RSV vaccine.

cAMP-dependent activation of protein kinase A attenuates respiratory syncytial virus-induced human airway epithelial barrier disruption.

Airway epithelium forms a barrier to the outside world and has a crucial role in susceptibility to viral infections. Cyclic adenosine monophosphate (cAMP) is an important second messenger acting via two intracellular signaling molecules: protein kinase A (PKA) and the guanidine nucleotide exchange factor, Epac. We sought to investigate effects of increased cAMP level on the disruption of model airway epithelial barrier caused by RSV infection and the molecular mechanisms underlying cAMP actions. Human bronchial epithelial cells were infected with RSV-A2 and treated with either cAMP releasing agent, forskolin, or cAMP analogs. Structure and functions of the Apical Junctional Complex (AJC) were evaluated by measuring transepithelial electrical resistance and permeability to FITC-dextran, and determining localization of AJC proteins by confocal microscopy. Increased intracellular cAMP level significantly attenuated RSV-induced disassembly of AJC. These barrier-protective effects of cAMP were due to the activation of PKA signaling and did not involve Epac activity. Increased cAMP level reduced RSV-induced reorganization of the actin cytoskeleton, including apical accumulation of an essential actin-binding protein, cortactin, and inhibited expression of the RSV F protein. These barrier-protective and antiviral-function of cAMP signaling were evident even when cAMP level was increased after the onset of RSV infection. Taken together, our study demonstrates that cAMP/PKA signaling attenuated RSV-induced disruption of structure and functions of the model airway epithelial barrier by mechanisms involving the stabilization of epithelial junctions and inhibition of viral biogenesis. Improving our understanding of the mechanisms involved in RSV-induced epithelial dysfunction and viral pathogenesis will help to develop novel anti-viral therapeutic approaches.