Factors that influence parents’ experiences with results disclosure after newborn screening identifies genetic carrier status for cystic fibrosis or sickle cell hemoglobinopathy

Objective

Newborn screening (NBS) identifies genetic carriers for sickle cell hemoglobinopathy and cystic fibrosis. We aimed to identify factors during initial NBS carrier results disclosure by primary care providers (PCPs) that influenced parents’ experiences and reactions.

Methods

Open-ended responses from telephone interviews with 270 parents of carriers were analyzed using mixed-methods. Conventional content analysis identified influential factors; chi-square tests analyzed relationships between factors and parent-reported reactions.

Results

Parents reported positive (35%) or negative (31%) reactions to results disclosure. Parents’ experiences were influenced by specific factors: content messages (72%), PCP traits (47%), and aspects of the setting (30%). Including at least one of five specific content messages was associated (p < 0.05) with positive parental reactions; omitting at least one of four specific content messages was associated (p < 0.05) with negative parental reactions. Parents reported positive reactions when PCPs avoided jargon or were perceived as calm. Parents reported negative reactions to jargon usage and results disclosure by voicemail.

Conclusion

Parents identified aspects of PCP communication which influenced their reactions and results disclosure experiences.

Practice implications

Our findings suggest ways PCPs may improve communication of carrier results. PCPs should provide specific content messages and consider how their actions, characteristics, and setting can influence parental reactions.     

Plasma membrane Ca2+ ATPase 1 (PMCA1) but not PMCA4 is critical for B-cell development and Ca2+ homeostasis in mice

The amplitude and duration of Ca²⁺ signaling is crucial for B-cell development and self-tolerance; however, the mechanisms for terminating Ca²⁺ signals in B cells have not been determined. In lymphocytes, plasma membrane Ca²⁺ ATPase (PMCA) isoforms 1 and 4 (PMCA1 and PMCA4, aka ATP2B1 and ATP2B4) are the main candidates for expelling Ca²⁺ from the cell through the plasma membrane. We report here that Pmca4 (Atp2b4) KO mice had normal B-cell development, while mice with a conditional KO of Pmca1 (Atp2b1) had greatly reduced numbers of B cells, particularly splenic follicular B cells, marginal zone B cells, and peritoneal B-1a cells. Mouse and naïve human B cells showed only PMCA1 expression and no PMCA4 by western blot, in contrast to T cells, which did express PMCA4. Calcium handling was normal in Pmca4^−/− B cells, but Pmca1 KO B cells had elevated basal levels of Ca²⁺, elevated levels in ER stores, and reduced Ca²⁺ clearance. These findings show that the PMCA1 isoform alone is required to ensure normal B-cell Ca²⁺ signaling and development, which may have implications for therapeutic targeting of PMCAs and Ca²⁺ in B cells.     

Multidetector row computed tomography for identification of left atrial appendage filling defects in patients undergoing pulmonary vein isolation for treatment of atrial fibrillation: Comparison with transesophageal echocardiography

BACKGROUND: Advances in multidetector computed tomography (MDCT) technology now permit three-dimensional cardiac imaging with high spatial and temporal resolution. Historically, transesophageal echocardiography (TEE) has been the gold standard for assessment of the left atrial appendage (LAA) in patients with atrial fibrillation and other atrial arrhythmias. Findings on TEE, including demonstration of LAA thrombus and dense nonclearing spontaneous echocardiographic contrast (SEC), predict future fatal and nonfatal thromboembolic events. OBJECTIVE: The purpose of this study was to compare the diagnostic performance of 64-detector row MDCT in detecting LAA thrombus and dense nonclearing SEC as identified by TEE in patients undergoing pulmonary vein isolation for treatment of atrial fibrillation. METHODS: A total of 72 consecutive patients (69.4% male; mean age 56.1 +/- 10.3 years) underwent both MDCT and TEE for evaluation of the LAA (median intertest interval 0 days, interquartile range 0-5 days). MDCT assessment of the LAA was performed by two methods: (1) comparison of Hounsfield unit (HU) densities in the LAA apex to the ascending aorta (AscAo) in the same axial plane and (2) nonquantitative visual identification of a filling defect in the LAA. TEE evaluation of the LAA included identification of echodense intracavitary masses in the LAA as well as pulsed-wave Doppler interrogation of the LAA ostium. RESULTS: Patients with LAA thrombus or dense nonclearing SEC by TEE exhibited significantly lower LAA/AscAo HU ratios than patients who did not (0.82 +/- 0.22 vs 0.39 +/- 0.19, P <.001). LAA/AscAo HU cutoff ratios < or = 0.75 correlated to LAA thrombus or dense nonclearing SEC by TEE, with 100% sensitivity, 72.2% specificity, 28.6% positive predictive value, and 100% negative predictive value. HU ratios < or = 0.75 were associated with pulsed-wave Doppler velocities <50 cm/s of the LAA ostium (P <.001). In multivariable analysis, LAA/AscAo HU ratio < or = 0.75 remained a robust predictor of LAA thrombus or dense nonclearing SEC by TEE (P <.001). In contrast, MDCT identification of TEE-identified LAA thrombus or dense nonclearing SEC by visual detection of LAA filling defects resulted in lower sensitivity (50%) and negative predictive value (95.1%). CONCLUSION: Current-generation MDCT successfully identifies LAA thrombus and dense nonclearing SEC with high sensitivity and moderate specificity. Importantly, LAA/AscAo HU ratios >0.75 demonstrate 100% negative predictive value for exclusion of LAA thrombus or dense nonclearing SEC. These results suggest that in patients undergoing pulmonary vein isolation procedures, MDCT examinations that demonstrate LAA/AscAo HU ratios >0.75 may preclude the need for preprocedural TEE.     

Fertility desires and preferences for safer conception strategies among people receiving care for HIV at a publicly-funded clinic in Seattle,WA

Understanding fertility desires and preferences for HIV prevention among individuals living with HIV, including the potential use of pre-exposure prophylaxis (PrEP) by HIV uninfected partners, can inform the delivery of safer conception counseling to reduce the risk of HIV transmission during pregnancy attempts. Men and women, predominantly heterosexual, engaged in HIV care in Seattle, WA, self-administered a questionnaire and we abstracted antiretroviral therapy (ART) status and HIV viral levels from medical records. We summarized participants’ sexual behavior, fertility desires, and preferences for safer conception strategies and used log-binomial regression to identify demographic, sexual, and behavioral factors associated with perceived acceptability of PrEP for HIV uninfected partners during pregnancy attempts. 52% of the 150 participants were female and the mean age was 48 years (range 23–74). 94.7% of participants were using ART and 79.3% had HIV viral load < 40 copies/mL. 22.2% of men and 34.6% of women reported that a healthcare provider had initiated discussion about fertility desires. 28.7% of participants were reproductive-age and desired children. Among sexually active reproductive-age participants with fertility desires, 56.3% reported inconsistent condom use and 62.5% did not report using effective birth control. 74.4% of reproductive age participants with fertility desires perceived that PrEP would be acceptable to an HIV uninfected partner and there were no significant predictors of PrEP acceptability. Nearly one third of reproductive-aged individuals living with HIV expressed fertility desires, highlighting a need for safer conception counseling in this setting. PrEP and ART were favored safer conception strategies.     

Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy

The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R² = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.