Nicardipine or Nitroprusside for Postoperative Blood Pressure Control in Infants After Surgery for Congenital Heart Disease: Single-Center Retrospective Noninferiority and Cost Analysis, 2016-2020.

OBJECTIVES: Postoperative hypertension frequently occurs after surgery for congenital heart disease. Given safety concerns when using calcium channel blockers in infants along with the cost and side-effect profile of nitroprusside, we retrospectively assessed our experience of using nicardipine and nitroprusside for postoperative blood pressure control in infants who underwent surgery for congenital heart disease. We also investigated the cost difference between the medications. DESIGN: This study was a single-center retrospective, pre-post chart review of patients who had surgery for congenital heart disease between 2016 and 2020. The primary aim was a noninferiority comparison of achievement of blood pressure goal at 1-hour post-initiation of an antihypertensive agent. Secondary comparisons included achievement of blood pressure goal at 2 hours after medication initiation, Vasoactive-Inotropic Score (VIS), and blood transfusion, crystalloid volume, and calcium needs. SETTING: Academic quaternary-care center. PATIENTS: Infants under 1 year old who required treatment for hypertension with nitroprusside ( n = 71) or nicardipine ( n = 52) within 24 hours of surgery for congenital heart disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We failed to identify any difference in proportion of patients that achieved blood pressure control at 1-hour after medication initiation (nitroprusside 52% vs. nicardipine 54%; p = 0.86), with nicardipine noninferior to nitroprusside within a 15% margin. Of patients who did not achieve control at 1-hour post-medication initiation, receiving nicardipine was associated with blood pressure control at 2 hours post-medication initiation (79% vs. 38%; p = 0.003). We also failed to identify an association between antihypertensive types and mean VIS scores, blood transfusion volumes, crystalloid volumes, and quantities of calcium administered. Index cost of using nitroprusside was 16 times higher than using nicardipine, primarily due to difference in wholesale cost. CONCLUSIONS: In our experience of achieving blood pressure control in infants after surgery for congenital heart disease (2016-2020), antihypertensive treatment with nicardipine was noninferior to nitroprusside. Furthermore, nicardipine use was significantly less expensive than nitroprusside. Our contemporary practice is therefore to use nicardipine in preference to nitroprusside.

Predictive In Vitro-In Vivo Extrapolation for Time Dependent Inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 Using Pooled Human Hepatocytes, Human Liver Microsomes, and a Simple Mechanistic Static Model.

Inactivation of Cytochrome P450 (CYP450) enzymes can lead to significant increases in exposure of comedicants. The majority of reported in vitro to in vivo extrapolation (IVIVE) data have historically focused on CYP3A, leaving the assessment of other CYP isoforms insubstantial. To this end, the utility of human hepatocytes (HHEP) and human liver microsomes (HLM) to predict clinically relevant drug-drug interactions was investigated with a focus on CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Evaluation of IVIVE for CYP2B6 was limited to only weak inhibition. A search of the University of Washington Drug-Drug Interaction Database was conducted to identify a clinically relevant weak, moderate, and strong inhibitor for selective substrates of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, resulting in 18 inhibitors for in vitro characterization against 119 clinical interaction studies. Pooled human hepatocytes and HLM were preincubated with increasing concentrations of inhibitors for designated timepoints. Time dependent inhibition was detected in HLM for four moderate/strong inhibitors, suggesting that some optimization of incubation conditions (i.e., lower protein concentrations) is needed to capture weak inhibition. Clinical risk assessment was conducted by incorporating the in vitro derived kinetic parameters maximal rate of enzyme inactivation (min-1) (kinact) and concentration of inhibitor resulting in 50% of the maximum enzyme inactivation (KI) into static equations recommended by regulatory authorities. Significant overprediction was observed when applying the basic models recommended by regulatory agencies. Mechanistic static models, which consider the fraction of metabolism through the impacted enzyme, using the unbound hepatic inlet concentration lead to the best overall prediction accuracy with 92% and 85% of data from HHEPs and HLM, respectively, within twofold of the observed value. SIGNIFICANCE STATEMENT: Coupling time-dependent inactivation parameters derived from pooled human hepatocytes and human liver microsomes (HLM) with a mechanistic static model provides an easy and quantitatively accurate means to determine clinical drug-drug interaction risk from in vitro data. Optimization is needed to evaluate time-dependent inhibition (TDI) for weak and moderate inhibitors using HLM. Recommendations are made with respect to input parameters for in vitro to in vivo extrapolation (IVIVE) of TDI with non-CYP3A enzymes using available data from HLM and human hepatocytes.

An Innovative Approach to Remote Electronic Health Onboarding Record Education Amid a Global Pandemic.

The COVID-19 pandemic required social and physical distancing to reduce the spread of disease. The reduction in meeting sizes made it difficult to offer traditional in-person EHR training to new and transferring employees. This paper aims to share how one nurse educator team used an innovative approach to transition traditional EHR onboarding education to synchronous remote learning during the global pandemic. Participants in the remote learning course (n = 94) were compared with those who had previously completed the traditional course (n = 110). Postcourse evaluations for each group were comparable. Remote learning participants found the technology conducive to training and reported higher scores for locating and reviewing patient information than those in the traditional course. Providing remote EHR education is comparable with traditional classroom education. Remote learning provided a safe, effective way to onboard new staff during the pandemic.

The UroLift® System for lower urinary tract obstruction: patient selection for optimum clinical outcome.

INTRODUCTION: The minimally invasive UroLift® System procedure in moderate-to-severe benign prostate hyperplasia (BPH) refractory to medical treatment may be superior over other prostate procedures regarding its preserved sexual function post-operatively. We aimed to optimise patient selection criteria for the UroLift® System. MATERIAL AND METHODS: Fifty-one men that underwent UroLift® System surgery were retrospectively reviewed over >24 months. We evaluated the efficacy and safety of UroLift® System, pre-operatively and at three, six, 12, and 24 months post-operatively, assessing the International Prostate Symptom Score (IPPS), urinary flow rates (Qmax), post void residual (PVR) bladder scan volumes and the International Index of Erectile Function (IIEF). Adverse events were assessed by Clavien-Dindo Classification. RESULTS: The 51 men undergoing UroLift® System had a success rate of 92.2% over 2 years, with improvements in Qmax, IPSS and PVR. IIEF was preserved in all cases. Adverse events were Clavien-Dindo grade 1, most commonly mild-to-severe dysuria (19.6%), and resolved spontaneously. Four patients failed to improve. CONCLUSION: Patient-related selection criteria to optimise the UroLift® System clinical outcomes include age, Qmax, PVR urine, median lobe, PSA levels, prostate volume, IPSS and IIEF scores. The UroLift® System is safe and effective in moderate-to-severe BPH refractory to pharmacological treatments and avoids retrograde ejaculation.

Case Report: Focal Choroidal Excavation: Conversion from Conforming to Nonconforming in a Pregnant Female.

SIGNIFICANCE: Although rarely seen, clinicians should closely monitor patients, especially pregnant patients with focal choroidal excavation (FCE), as it can convert between subtypes and has been linked to pachychoroidal disease and potential for vision loss. PURPOSE: This study aimed to report a case of the conversion of conforming FCE to nonconforming FCE with spontaneous resolution in a pregnant female. CASE REPORT: A 35-year-old Indian woman presented with a slightly decreased vision in the right eye. The patient was 3 months pregnant at this visit. Her ocular history included stable conforming FCE in both eyes that was diagnosed 1 year earlier. Retinal pigmentary changes were noted in both eyes and consistent with previous examinations as being conforming FCEs in both eyes. Optical coherence tomography through the pigmented changes revealed FCE in the right eye with overlying serous fluid, with the left eye showing stable conforming FCE. She was diagnosed with a nonconforming FCE in the right eye secondary to her pregnancy. She was monitored with subsequent visits showing spontaneous resolution of the fluid and conversion back to a conforming FCE. CONCLUSIONS: This case highlights the conversion of a conforming FCE to a nonconforming FCE with spontaneous resolution in a pregnant female. Similarities are seen in terms of pathophysiology with central serous chorioretinopathy, a fellow pachychoroidal disease, which also has pregnancy as a risk factor. Risk factors in pregnant patients such as increased cortisol and increased ocular blood flow may play an important part in the pathophysiology of the conditions, as they both result in choroidal hyperpermeability. Frequent monitoring and follow-up times are suggested for the patients. Lifelong monitoring is also indicated, as reoccurrences have been reported. Further research is needed at this time to elucidate the exact etiology of FCE and conversions between conforming and nonconforming FCE.

Impact of Occlusal Intercuspal Angulation on the Quality of CAD/CAM Lithium Disilicate Crowns.

PURPOSE: Modification of intercuspal angulation (ICA) influences the amount of tooth structure removal, which may impact the retention and resistance form of the preparation. This study evaluated the impact of ICA on the marginal gap of CAD/CAM crowns and the influence that tooth structure removal, caused by variation of ICA, has on the resistance and retention form of the preparation. MATERIALS AND METHODS: Sixty ivorine molars were manufactured with various ICAs (100°, 110°, 120°, 140°, 160°, and 180°; 10 per group). The preparations were digitized using an intraoral scanner, and the crowns were designed using a design software. The designed crowns were then manufactured from lithium disilicate using a 3-axis milling machine, with the "detailed mode" selected for the manufacturing. The marginal gap of each crown was evaluated using a stereomicroscope at 20× magnification. Then, the marginal integrity and the resistance form of the preparation were assessed by tactile-visual evaluation, and they were given a categorical score. Crowns were then secured on their associated preparations using a temporary luting agent, and retention force was measured on a universal testing machine under tension with a 0.5 mm/min crosshead speed. Wilcoxon test followed by post-hoc tests (α = 0.05) were used to evaluate the impact of the ICA on the marginal gap and the retention form of the preparation. Fisher's exact test followed by post-hoc tests (α = 0.05) were used to assess the impact of the occlusal preparation design on the marginal integrity and the resistance form of the preparation. RESULTS: The marginal gap was significantly larger for ICA-180 preparations (72 µm), compared to the other groups (ICA-180 vs ICA-100, ICA-110, ICA-120, and ICA-160 p = 0.0001; ICA-180 vs. ICA-140 p = 0.0017). None of the crowns for ICA-180 preparations had clinically acceptable resistance form. Preparations with ICAs of 100°, 110°, and 120° had a significantly higher value of retention than the other groups (ICA-100 vs. ICA-120 p = 0.0119; ICA-100 vs. ICA-140, ICA-160, and ICA-180 p < 0.0001; ICA-110 vs. ICA-140, ICA-160, and ICA-180 p = 0.0001; ICA-120 vs. ICA-180 p = 0.0017). CONCLUSIONS: Crowns fabricated for preparations with various ICAs had clinically acceptable marginal adaptation. Variation in ICA impacts the loss of tooth structure. This loss of tooth structure may influence the resistance and retention form of the preparation.

RNA-Seq reveals the molecular mechanism of trapping and killing of root-knot nematodes by nematode-trapping fungi.

Nematode-trapping fungi are well known for their inherent potential to trap and kill nematodes using specialized trapping devices. However, the molecular mechanisms underlying the trapping and subsequent processes are still unclear. Therefore, in this study, we examined differential genes expression in two nematode-trapping fungi after baiting with nematode extracts. In Arthrobotrys conoides, 809 transcripts associated with diverse functions such as signal transduction, morphogenesis, stress response and peroxisomal proteins, proteases, chitinases and genes involved in the host-pathogen interaction showed differential expression with fold change (>±1.5 fold) in the presence of nematode extract with FDR (p-value < 0.001). G-proteins and mitogen activated protein kinases are considered crucial for signal transduction mechanism. Results of qRT-PCR of 20 genes further validated the sequencing data. Further, variations in gene expression among Duddingtonia flagrans and A. conoides showed septicity of nematode-trapping fungi for its host. The findings illustrate the molecular mechanism of fungal parasitism in A. conoides which may be helpful in developing a potential biocontrol agent against parasitic nematodes.

RVX-297- a novel BD2 selective inhibitor of BET bromodomains.

Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles. We report that RVX-297 preferentially binds to the BD2 domains of the BET bromodomain and Extra Terminal (BET) family of protein. We demonstrate the differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography, and describe the structural differences driving the BD2 selective binding of RVX-297. The isothermal titration calorimetry (ITC) data illustrate the related differential thermodynamics of binding of RVX-297 to single as well as dual BET bromodomains.

A Randomized Trial Evaluating Short-term Effectiveness of Overminus Lenses in Children 3 to 6 Years of Age with Intermittent Exotropia.

PURPOSE: To evaluate the short-term effectiveness of overminus spectacles in improving control of childhood intermittent exotropia (IXT). DESIGN: Randomized, clinical trial. PARTICIPANTS: A total of 58 children aged 3 to <7 years with IXT. Eligibility criteria included a distance control score of 2 or worse (mean of 3 measures during a single examination) on a scale of 0 (exophoria) to 5 (constant exotropia) and spherical equivalent refractive error between -6.00 diopters (D) and +1.00 D. METHODS: Children were randomly assigned to overminus spectacles (-2.50 D over cycloplegic refraction) or observation (non-overminus spectacles if needed or no spectacles) for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome was distance control score for each child (mean of 3 measures during a single examination) assessed by a masked examiner at 8 weeks. Outcome testing was conducted with children wearing their study spectacles or plano spectacles for the children in the observation group who did not need spectacles. The primary analysis compared mean 8-week distance control score between treatment groups using an analysis of covariance model that adjusted for baseline distance control, baseline near control, prestudy spectacle wear, and prior IXT treatment. Treatment side effects were evaluated using questionnaires completed by parents. RESULTS: At 8 weeks, mean distance control was better in the 27 children treated with overminus spectacles than in the 31 children who were observed without treatment (2.0 vs. 2.8 points, adjusted difference = -0.75 points favoring the overminus group; 2-sided 95% confidence interval, -1.42 to -0.07 points). Side effects of headaches, eyestrain, avoidance of near activities, and blur appeared similar between treatment groups. CONCLUSIONS: In a pilot randomized clinical trial, overminus spectacles improved distance control at 8 weeks in children aged 3 to <7 years with IXT. A larger and longer randomized trial is warranted to assess the effectiveness of overminus spectacles in treating IXT, particularly the effect on control after overminus treatment has been discontinued.

Progression of degenerative mitral stenosis: insights from a cohort of 254 patients.

BACKGROUND AND AIM OF THE STUDY: Degenerative mitral stenosis (DMS) is an increasingly common echocardiographic finding, yet the clinical and biological behavior and rate of progression of the condition are unknown. METHODS: A total of 254 patients was identified from the authors' echocardiographic database with DMS, defined as severe mitral annular calcification with extension into the mitral leaflets resulting in transmitral flow acceleration with a mean diastolic gradient of >2 mmHg in the absence of commissural fusion. Each patient required paired echocardiograms to have been recorded at least three months apart. Clinical, biochemical and pharmacological data were collected from each patient and related to the annualized rate of increase in mean diastolic mitral gradient and stenosis severity on a scale of 0 to 3. RESULTS: The characteristics of the patients were as follows: mean age 71 +/- 15 years; female gender 73%; and left ventricular ejection fraction 66 +/- 13%. Diabetes was present in 50% of patients, renal insufficiency in 40%, and coronary artery disease in 50%. Over a follow up period of 2.6 +/- 2.2 years, the mean gradient was increased by 0.8 +/- 2.4 mmHg (range: 0-15 mmHg) per year, while the stenosis grade was increased by 0.18 +/- 0.5 (range: 0-3) per year. The rate of progression was faster in patients with lesser degrees of stenosis (p = 0.01) and low serum albumen levels (p = 0.04), and slower in those receiving beta-blockers (p = 0.01). Milder stenosis, diabetes mellitus and lack of beta-blocker use were independent predictors of faster DMS progression. CONCLUSION: DMS progression is highly variable, but generally slow; its progression is accelerated in the presence of diabetes mellitus, but is retarded by beta-blocker use. DMS may be an active biological process offering potentially modifiable targets for intervention.

Enhancing type 2 diabetes treatment through digital plans of care - a randomized controlled trial: evaluation of change in patient reported outcome measures.

BACKGROUND: We investigated how a personalized care-planning software and linked mobile-app may aid people to self-manage their type 2 diabetes (T2D) more effectively. RESEARCH DESIGN AND METHODS: People with T2D and glycated hemoglobin (HbA1c) greater than 58 mmol/mol (7.5%) were randomized to either an intervention group receiving a personalized care plan, or the control group receiving usual care. Quality of life (QoL) was measured for both groups using validated questionnaires and one-on-one interviews with a subset of 12 participants from each group. RESULTS: QoL for the active treatment group increased, by their EQ -5D-5 L score increasing on average by 0.046, whereas it decreased for the control group on average by 0.009. The EQ Visual Analogue Score (VAS) of the intervention group also increased by 8.2%, whereas the control group had a reduction in EQ VAS score of 2.8% (p = 0.008 for difference). CONCLUSION: In this prospective RCT, the findings point to how the provision of personalized care plans can result in an improvement in individuals' self-rated QoL. This may lead to longer term health benefits.

Etiology impacts survival in patients with severe aortic regurgitation: results from a cohort of 756 patients.

BACKGROUND AND AIM OF THE STUDY: Severe aortic regurgitation (AR) is caused by a variety of mechanisms, which include the degenerative process, bicuspid aortic valve (BAV), aortic root dilation, endocarditis or a combination of these. Their frequency in a contemporary clinical series, and their impact on survival, are currently unknown. METHODS: The authors' echocardiographic database between 1993 and 2007 was screened for patients with severe AR, and yielded 756 patients. Detailed chart reviews were performed to acquire clinical and demographic data. Mortality data were obtained from the social security death index and analyzed as a function of the condition's etiology. RESULTS: The probable etiologies for AR were: degenerative in 29% of patients, BAV in 10%, aortic root pathology in 11%, endocarditis in 10%, and mixed or unclear mechanism in 40%. Survival was a function of the etiology (p < 0.0001), with degenerative mechanism having the worst prognosis and BAV the best. This differential impact on mortality remained significant after adjusting for age, gender, coronary artery disease, diabetes mellitus, renal insufficiency, left ventricular ejection fraction and aortic valve replacement, using the Cox regression model (p < 0.0001). CONCLUSION: Etiology has a significant independent impact on mortality in patients with severe AR, with the worst survival being seen in degenerative AR.

Standard Amblyopia Therapy in Adults with Longstanding Amblyopia Improves Visual Acuity and Contrast Sensitivity.

Purpose: Perceptual learning or dichoptic training may result in improved acuity in adult amblyopes. However, for amblyopic children (<18 years), most clinicians recommend standard part-time patching. The purpose of this study was to determine if standard amblyopia therapy results in an enhancement in vision in the amblyopic eye of adults. Patients and Methods: Fifteen amblyopes (20/30 or worse) were recruited and nine (age (SD) 32.9 (16.31)) with anisometropia or anisometropia and strabismus (ie, combined mechanism amblyopia) completed the study. Previous therapy did not exclude subjects. The subjects received a comprehensive eye exam and wore their best correction for at least four weeks prior to baseline testing. The non-amblyopic eye was patched for 2 hours per day (Amblyopia iNET training for 30 minutes and near/distance activities for 1.5 hours). The subjects had a baseline amblyopia evaluation followed by one visit per week for 12 weeks. At 12 weeks, the treatment was tapered off over one month and the subjects had a final amblyopia evaluation at 24 weeks. Contrast sensitivity was measured at baseline and 12 weeks with the Quick CSF system. Results: The subjects had a significant improvement in visual acuity across the weeks (p < 0.001). At baseline, weeks 12 and 24, the average logMAR acuities (SE) were 0.55 (0.09), 0.41 (0.08), and 0.38 (0.09), respectively. Weeks 4 to 24 were significantly different (p < 0.001) from baseline. The average acuity improvement over the 24 weeks was 1.7 logMAR lines. There was a significant increase in the area under the log contrast sensitivity function (p = 0.002) and its estimated acuity (p = 0.036) from baseline to 12 weeks. Conclusion: Standard amblyopia treatment can result in an improvement in visual acuity and contrast sensitivity in adults with longstanding anisometropic or combined mechanism amblyopia even if they had prior therapy.

Desolvation of BSA-ligand complexes measured using the quartz crystal microbalance and dual polarization interferometer.

By taking advantage of their unique difference in hydration sensitivity, we have shown that dual polarization interferometer (DPI) and quartz-crystal microbalance with dissipation monitoring (QCM-D) measurements can be used together to explore the degree of desolvation involved in the binding of small drug molecules to an immobilized bovine serum albumin film in real time. Results with DPI and QCM-D show significantly different mass values for three ligands of varying hydrophobicities that may be attributed to changes in the degree of hydration of the ligand-protein complexes in accordance with the physicochemical properties of the ligands. Furthermore, our data suggest that masses measured by QCM-D can be overwhelmed by changes in water content of ligand-protein, binary complexes, which has important consequences for future studies using mechanical resonators to study protein-binding events.

Slow rate of progression of grade 1 and 2+ aortic regurgitation.

BACKGROUND AND AIM OF THE STUDY: Although the progression of aortic stenosis has been well studied, the rate of progression of aortic regurgitation (AR) has not been definitively established. Further data would be valuable for clinical decision-making in patients with milder degrees of AR undergoing non-aortic valve cardiac surgery. Hence, this point was investigated in a large cohort of patients with grade 1 or 2+ AR. METHODS: The authors' echocardiographic database acquired between 1993 and 2007 was screened for patients with grade 1 or 2+ AR who had undergone follow up echocardiography at least one year later. The AR severity was graded as 1 to 4+, and any annual changes in AR grade were monitored. RESULTS: Among a total of 4,128 patients identified, 3,266 had grade 1+ AR and 862 had grade 2+ AR on the initial echocardiogram: the mean age was 67 +/- 15 years, and the duration of follow up was 4.2 +/- 2.7 years. Of those patients initially with grade 1+ AR, 95% showed no change in AR over a mean interval of 4.2 years, with an annual average increase in AR grade of 0.04. Of those patients initially with grade 2+ AR, 90% showed no change over this period, with an annual average increase in grade of 0.07. In the entire cohort, the AR progression correlated positively with age (p = 0.03), ventricular septal thickness (p < 0.0001), stroke distance (the time velocity integral of flow in the left ventricular outflow tract) (p = 0.0003), the presence of any degree of aortic stenosis (p = 0.01), and initial AR severity (p < 0.0001). CONCLUSION: The rate of AR progression is extremely slow, and prophylactic aortic valve replacement during non-aortic surgery may not be indicated in patients with grade 1 or 2+ AR in the absence of any higher risk for progression, such as grade 2+ AR combined with any degree of aortic stenosis and advanced age.

Part Three: A Brief Primer of Non-Insulin Treatments for Type 2 Diabetes Mellitus in Older People.

Diabetes is a heterogeneous condition that manifests differently in each patient. Fortunately, there are multiple different medication classes that can be used to help patients achieve their treatment goals. Diabetes is highly prevalent in older people, including patients who have been living with the condition for many years and those who are newly diagnosed. It is essential for senior care pharmacists to evaluate patient-specific goals, compelling indications, and risks and benefits of treatment. When evaluating therapy appropriateness, pharmacists must take into consideration the impact of medication therapy beyond glucose-lowering effects, including the overall impact on cardiovascular, renal, heart failure, and weight-related outcomes.

Combination of ZEN-3694 with CDK4/6 inhibitors reverses acquired resistance to CDK4/6 inhibitors in ER-positive breast cancer.

CDK4/6 inhibitors significantly prolong progression-free survival in patients with advanced hormone receptor-positive (HR+) HER2-negative breast cancer. Despite recent successes, patients acquire resistance, necessitating the development of additional novel therapeutic strategies. Bromodomain and extra-terminal domain (BET) proteins are key epigenetic regulators that interact with acetylated lysine (AcLys) residues of histones or transcription factors. BET proteins are directly involved in modulating estrogen receptor (ER) signaling and the cell cycle. Therefore, BET inhibitors can potentially offer new strategies in the treatment of advanced ER+ breast cancer. ZEN-3694 is an orally bioavailable small molecule BET inhibitor currently being evaluated in Phase 1/2 clinical trials (NCT03901469). To assess a potential combination strategy in a CDK4/6i resistant breast cancer population, we investigated the mechanism of action of ZEN-3694 combined with CDK4/6 inhibitors in the ER+ cell lines resistant to palbociclib or abemaciclib. Here, we describe that the combination of ZEN-3694 with CDK4/6i potently inhibits proliferation and induces apoptosis in CDK4/6i resistant cell lines. The resistance to both palbociclib and abemaciclib was associated with the strong upregulation of CDK6 and CCND1 protein levels, which was reversed by the ZEN-3694 treatment. Furthermore, RNAseq data and pathway analysis elucidated the combinatorial effects of ZEN-3694 with CDK4/6 inhibitors through significant downregulation of multiple pathways involved in cell cycle regulation, cellular growth, proliferation, apoptosis, inflammation, and cellular immune response. Our data indicate that ZEN-3694 has therapeutic potential in combination with CDK4/6 inhibitors in patients with advanced ER+ breast resistant to CDK4/6 inhibitors.

Validity of 1% Hormonal Receptor Positivity Cutoff by the ASCO/College of American Pathologists Guidelines at the Georgia Cancer Center.

PURPOSE: Treatment of breast cancer (BC) with borderline or low (1%-9%) estrogen and progesterone expression remains controversial, with recent data disputing ASCO/College of American Pathologists 2010 guidelines that lowered the threshold of receptor positivity from 10% to 1%. The objective of this retrospective study was to validate these guidelines at the Georgia Cancer Center with a high percentage of Black race. METHODS: All female patients with invasive BC diagnosed between 2005 and 2010 at the Georgia Cancer Center were chart reviewed up to an 11-year follow-up with data cutoff at 2016. We used Cox regression to explore survival among three hormonal status (HS) groups (< 1%, 1%-9%, and ≥ 10%) adjusting for all known BC clinicopathologic variables. Fisher's exact test was used to evaluate response to endocrine therapy (ET). RESULTS: Among 431 patients with mean age 59 years, 24.75% had HS < 1%, 17.5% HS 1%-9%, and 57.75% HS ≥ 10%. Race was 43.75% Black and 54% White. Disease stages were early (I-IIIA) in 84.4% and advanced (IIIB-IV) in 15.56%. Mortality in HS < 1% was significantly higher than that in HS ≥ 10% (hazard ratio [HR]: 1.8; 95% CI, 1.07 to 3.02), whereas no significant mortality difference between HS 1%-9% and HS ≥ 10% (HR: 1.05; 95% CI, 0.48 to 2.30) was observed. ET was protective, and treated patients had higher predicted survival than untreated patients in the 1%-9% group (HR: 0.10; 95% CI, 0.01 to 0.85). There was no significant mortality difference between ET-treated HS 1%-9% and ≥ 10% groups. CONCLUSION: One percent cutoff predicted superior survival on treatment with ET compared with the other groups, and HS as low as 1%-9% was equiprognostic to HS ≥ 10%. Whether other factors such as lymphovascular invasion, grade, and other parameters change the behavior of the 1%-9% HS group remains to be explored.

Study protocol for First Dental Steps Intervention: feasibility study of a health visitor led infant oral health improvement programme.

BACKGROUND: Dental caries in childhood is a burden on the daily lives of children and their families, and associated with poor oral health in adulthood. In England, dental caries is the most common reason for young children to be admitted to hospital. It is believed that most tooth extractions (due to decay) for children aged 10 years and under, could be avoided with improved prevention and early management. National public health policy recommendations in England include specific oral health initiatives to tackle tooth decay. One of these initiatives is delivered as part of the Healthy Child Programme and includes providing workforce training in oral health, integrating oral health advice into home visits, and the timely provision of fluoride toothpaste. This protocol seeks to assess the delivery of the First Dental Steps intervention and uncertainties related to the acceptability, recruitment, and retention of participants. METHODS: This study seeks to explore the feasibility and acceptability of the First Dental Steps intervention and research methods. First Dental Steps intervention will be delivered in local authority areas in South West England and includes oral health training for health visitors (or community nursery nurses) working with 0-5-year-olds and their families. Further, for vulnerable families, integrating oral health advice and the provision of an oral health pack (including a free flow cup, an age appropriate toothbrush, and 1450 ppm fluoride toothpaste) during a mandated check by a health visitor. In this study five local authority areas will receive the intervention. Interviews with parents receiving the intervention and health visitors delivering the intervention will be undertaken, along with a range of additional interviews with stakeholders from both intervention and comparison sites (four additional local authority areas). DISCUSSION: This protocol was written after the start of the COVID-19 pandemic, as a result, some of the original methods were adjusted specifically to account for disruptions caused by the pandemic. Results of this study will primarily provide evidence on the acceptability and feasibility of both the First Dental Steps intervention and the research methods from the perspective of both families and stakeholders.