The FAM13A Long Isoform Regulates Cilia Movement and Coordination in Airway Mucociliary Transport.

Single nucelotide polymorphisms (SNPs) at the FAM13A locus are among the most commonly reported risk alleles associated with chronic obstructive pulmonary disease (COPD) and other respiratory diseases; however, the physiological role of FAM13A is unclear. In humans, two major protein isoforms are expressed at the FAM13A locus: "long" and "short," but their functions remain unknown, partly because of a lack of isoform conservation in mice. We performed in-depth characterization of organotypic primary human airway epithelial cell subsets and show that multiciliated cells predominantly express the FAM13A long isoform containing a putative N-terminal Rho GTPase-activating protein (RhoGAP) domain. Using purified proteins, we directly demonstrate the RhoGAP activity of this domain. In Xenopus laevis, which conserve the long-isoform, Fam13a deficiency impaired cilia-dependent embryo motility. In human primary epithelial cells, long-isoform deficiency did not affect multiciliogenesis but reduced cilia coordination in mucociliary transport assays. This is the first demonstration that FAM13A isoforms are differentially expressed within the airway epithelium, with implications for the assessment and interpretation of SNP effects on FAM13A expression levels. We also show that the long FAM13A isoform coordinates cilia-driven movement, suggesting that FAM13A risk alleles may affect susceptibility to respiratory diseases through deficiencies in mucociliary clearance.

Mitral valve orifice area predicts outcome after biventricular repair in patients with hypoplastic left ventricles.

BACKGROUND: Identification of risk factors for biventricular (BiV) repair in children with hypoplastic left ventricles (HLV) has been challenging. We sought to identify preoperative cardiovascular magnetic resonance (CMR) predictors of outcome in patients with HLVs who underwent BiV repair, with a focus on the mitral valve (MV). METHODS: Single-center retrospective analysis of preoperative CMRs on patients with HLV (≤50 mL/m2) and no endocardial fibroelastosis who underwent BiV repair from 2005-2022. CMR measurements included MV orifice area in diastole. The primary composite outcome included time to death, transplant, BiV takedown, heart failure admission, left atrial decompression, or unexpected reoperation; and the secondary outcome included more than or equal to moderate mitral stenosis and/or regurgitation. RESULTS: Median follow-up was 0.7 (interquartile range 0.1, 2.2) years. Of 122 patients [59 atrioventricular canal (AVC) and 63 non-AVC] age 3 ± 2.8 years at the time of BiV repair, freedom from the primary outcome at 2 years was 53% for AVC and 69% for non-AVC (log rank p = 0.12), and freedom from the secondary outcome at 2 years was 49% for AVC and 79% for non-AVC (log rank p < 0.01). Independent predictors of primary outcome for AVC patients included MV orifice area z-score <-2 and transitional AVC; for non-AVC patients, predictors included MV orifice area z-score <-2, abnormal MV anatomy, and conal-septal ventricular septal defect. Independent predictors of secondary outcome for AVC patients included older age at surgery, transitional AVC, and transposition of the great arteries. CONCLUSION: In children with HLV, low MV orifice area and pre-existing MV pathology are risk factors for adverse outcome after BiV repair.

Design and implementation of multicenter pediatric and congenital studies with cardiovascular magnetic resonance: Big data in smaller bodies.

Cardiovascular magnetic resonance (CMR) has become the reference standard for quantitative and qualitative assessment of ventricular function, blood flow, and myocardial tissue characterization. There is a preponderance of large CMR studies and registries in adults; However, similarly powered studies are lacking for the pediatric and congenital heart disease (PCHD) population. To date, most CMR studies in children are limited to small single or multicenter studies, thereby limiting the conclusions that can be drawn. Within the PCHD CMR community, a collaborative effort has been successfully employed to recognize knowledge gaps with the aim to embolden the development and initiation of high-quality, large-scale multicenter research. In this publication, we highlight the underlying challenges and provide a practical guide toward the development of larger, multicenter initiatives focusing on PCHD populations, which can serve as a model for future multicenter efforts.

Coronary Events Following Dobutamine Stress Cardiac Magnetic Resonance Imaging in Pediatric Patients.

Dobutamine stress cardiac magnetic resonance (dsCMR) has demonstrated value in identifying patients at risk for adverse cardiovascular events in adults with coronary artery disease, but its prognostic value in younger patients is unknown. This study sought to evaluate the relationship between dsCMR results and the risk of subsequent cardiovascular events in children. Patients age < 23 years who underwent dsCMR at Boston Children's Hospital were eligible for inclusion. Patients were excluded if no follow-up data were available after dsCMR or the dsCMR protocol was not completed. Data regarding the presence of inducible regional wall motion abnormalities and subsequent cardiovascular events during follow-up were analyzed. Cardiovascular events included myocardial infarction, surgical or catheter-based coronary artery intervention, and ischemic symptoms. Among 80 dsCMR studies in 64 patients with median age 5.3 years (range 0.5-22.4 years), 3 patients had a positive dsCMR with inducible regional wall motion abnormalities. Over a median follow-up of 7.4 years (IQR 4.0-11.2), 2 of these patients underwent surgical intervention (coronary artery bypass grafting and unroofing of a myocardial bridge) and the third remained asymptomatic with no interventions. Among 61 patients with a negative dsCMR, none experienced myocardial infarction, death, or aborted sudden death. Four underwent cardiac interventions (cardiac transplantation, coronary artery bypass grafting, and unroofing) due to symptoms or catheterization findings. In pediatric patients undergoing dsCMR, wall motion abnormalities indicating inducible ischemia were uncommon. Those with a negative dsCMR were unlikely to experience an adverse cardiac event or undergo a cardiac intervention on medium-term follow-up.

Perinatal Factors Associated with Successful Pharmacologic Closure of the Patent Ductus Arteriosus in Premature Infants.

The patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. While pharmacologic closure of the PDA is common and effective, it can be difficult to identify which patients will respond. As such, the objective of this study was to identify factors associated with successful pharmacologic closure of the PDA. We hypothesized that clinical factors such as gestational age, birth weight, and hypertensive disorders of pregnancy would be associated with successful closure. We performed a retrospective cohort study of preterm infants who received pharmacologic treatment for a PDA at two large neonatal intensive care units in Boston, MA between January 2016 and December 2021. Infants were excluded if they received prophylactic indomethacin, had early termination of therapy, did not have an echocardiogram prior to therapy, or had congenital heart disease. The primary outcome was closure after initial course. Relevant perinatal data were collected on enrolled infants. Of the 215 enrolled infants, 131 (61%) had successful closure. Older gestational age (OR, 1.23; 95% CI,1.03-1.47), male sex (OR, 2.17; 95% CI,1.18-3.99), and maternal preeclampsia (OR, 2.75; 95% CI,1.07-7.02) were associated with successful closure. Infants who received postnatal steroids (OR, 0.49; 95% CI,0.25-0.96) were less likely to have had successful closure. In this study, we identified previously established associations of gestational age and male sex with successful pharmacologic closure. However, the associations with maternal preeclampsia and postnatal steroids are novel. While further investigation is warranted, these associations can help inform decision-making around management of the PDA.

mRNA Display in Cell Lysates Enables Identification of Cyclic Peptides Targeting the BRD3 Extraterminal Domain.

mRNA display is a powerful technology to screen libraries of >1012 cyclic peptides against a protein target, enabling the rapid discovery of high affinity ligands. These cyclic peptides are particularly well suited to challenging protein targets that have been difficult to drug with small molecules. However, target choice can still be limited as screens are typically performed against purified proteins which often demands the use of isolated domains and precludes the use of aggregation-prone targets. Herein, we report a method to perform mRNA display selections in mammalian cell lysates without the need for prior target purification, vastly expanding the potential target scope of mRNA display. We have applied the methodology to identify low to sub-nanomolar peptide binders for two targets: a NanoLuc subunit (LgBiT) and full-length bromodomain-containing protein 3 (BRD3). Our cyclic peptides for BRD3 were found to bind to the extraterminal (ET) domain of BRD3 and the closely related BRD proteins, BRD2 and BRD4. While many chemical probes exist for the bromodomains of BRD proteins, the ET domain is relatively underexplored, making these peptides valuable additions to the BRD toolbox.

Cardiac magnetic resonance parameters associated with successful conversion from a single ventricular to a one-and-a-half or biventricular circulation in patients with a hypoplastic right ventricle.

BACKGROUND: Some patients with pulmonary atresia with an intact ventricular septum (PA/IVS) or a left ventricle dominant atrioventricular canal defect (LDAVC) with a hypoplastic right ventricle (RV) and univentricular (1 V) circulation may be candidates for conversion to either a complete biventricular (2 V) repair or a one-and-a-half ventricle repair (1.5 V). We sought to identify pre-operative cardiovascular magnetic resonance (CMR) findings associated with successful conversion from 1V to 1.5V or 2V circulation. METHODS: In this single center retrospective study, subjects with PA/IVS or LDAVC and no conotruncal abnormalities were included if they had a 1 V circulation at the time of CMR followed by a surgical intervention intended to convert them to a 1.5 V or 2 V circulation. Conversion failure was defined as any of the following: (1) oxygen saturation < 90% at the most recent follow-up, (2) conversion back to a 1.5 V or 1 V circulation, or (3) death. RESULTS: In the PA/IVS cohort (n = 15, median age 1.32 years), 10 patients underwent surgical conversion to a 1.5 V circulation and 5 to a 2 V circulation. In the attempted 1.5 V group, there were 2 failures, and these cases had a lower RV mass (p = 0.04). In the attempted 2 V group, there was 1 failure, and no CMR parameters were significantly different compared to the successes. Among the successful 2 V group patients, the minimum RV end-diastolic volume (EDV) was 27 ml/m2. In the LDAVC cohort (n = 15, median age 1.0 years), 1 patient underwent surgical conversion to a 1.5 V circulation and 14 patients to a 2 V circulation. In the attempted 1.5 V group, the 1 conversion was a failure and had an RV EDV of 15 ml/m2. In the attempted 2 V group, there were 2 failures, and these cases had a smaller RV:LV stroke volume ratio (p = 0.05) and a lower RV ejection fraction (p = 0.05) compared to the successes. Among the successful 2 V group patients, the minimum RV EDV was 22 ml/m2. CONCLUSIONS: We identified multiple CMR parameters associated with successful conversion from 1 V circulation to 1.5 V or 2 V circulation in patients with PA/IVS and LDAVC. This information may improve patient selection for conversion procedures and encourage larger studies to better define the role of CMR.

Magnetic resonance three-dimensional steady-state free precession imaging of the thoracic duct in patients with Fontan circulation and its relationship to outcomes.

BACKGROUND: Lymphatic complications are common in patients with Fontan circulation. Three-dimensional balanced steady-state free precession (3D bSSFP) angiography by cardiovascular magnetic resonance (CMR) is widely used for cardiovascular anatomical assessment. We sought to determine the frequency of thoracic duct (TD) visualization using 3D bSSFP images and assess whether TD characteristics are associated with clinical outcomes. METHODS: This was a retrospective, single-center study of patients with Fontan circulation who underwent CMR. Frequency matching of age at CMR was used to construct a comparison group of patients with repaired tetralogy of Fallot (rTOF). TD characteristics included maximum diameter and a qualitative assessment of tortuosity. Clinical outcomes included protein-losing enteropathy (PLE), plastic bronchitis, listing for heart transplantation, and death. A composite outcome was defined as presence of any of these events. RESULTS: The study included 189 Fontan patients (median age 16.1 years, IQR 11.0-23.2 years) and 36 rTOF patients (median age 15.7 years, IQR 11.1-23.7 years). The TD diameter was larger (median 2.50 vs. 1.95 mm, p = 0.002) and more often well visualized (65% vs. 22%, p < 0.001) in Fontan patients vs. rTOF patients. TD dimension increased mildly with age in Fontan patients, R = 0.19, p = 0.01. In Fontan patients, the TD diameter was larger in those with PLE vs. without PLE (age-adjusted mean 4.11 vs. 2.72, p = 0.005), and was more tortuous in those with NYHA class ≥ II vs. class I (moderate or greater tortuosity 75% vs. 28.5%, p = 0.02). Larger TD diameter was associated with a lower ventricular ejection fraction that was independent of age (partial correlation = - 0.22, p = 0.02). More tortuous TDs had a higher end-systolic volume (mean 70.0 mL/m2 vs. 57.3 mL/m2, p = 0.03), lower creatinine (mean 0.61 mg/dL vs. 0.70 mg/dL, p = 0.04), and a higher absolute lymphocyte count (mean 1.80 K cells/µL vs. 0.76 K cells/µL, p = 0.003). The composite outcome was present in 6% of Fontan patients and was not associated with TD diameter (p = 0.50) or tortuosity (p = 0.09). CONCLUSIONS: The TD is well visualized in two-thirds of patients with Fontan circulation on 3D-bSSFP images. Larger TD diameter is associated with PLE and increased TD tortuosity is associated with an NYHA class ≥ II.

Reverse Coding of a Common-Sense Physical Activity Intervention for Older Adults Using Elements of the Behaviour Change Wheel Framework.

"Common-sense" physical activity (PA) interventions for older adults may be more effective if developed in accordance with behavior change theory. One way to achieve this is through retrospectively applying a theoretical behavior change framework to "reverse code" an existing intervention and guide its ongoing development. This study aimed to detail a clear and systematic procedure that applied elements of the Behaviour Change Wheel (BCW) framework to reverse code the Active Ageing Pathway (AAP) intervention. The objectives of the procedure were to characterize the content of the AAP and its links to behavior change theory. The content of the AAP was first deconstructed through the examination of "standard operating procedures" documents, in-person observation, and a series of face-to-face discussions with AAP management. Then, the behavior change techniques (BCT) and BCW intervention functions associated with the AAP's content were identified and coded using the BCT Taxonomy version 1. Forty-one active components were identified within the AAP, which involved numerous professionals, and pertained to a diverse and interlinked range of factors, across various modes of delivery. The components were classified under 20 separate BCT labels, which related to eight of the nine BCW intervention functions. These outcomes were demonstrated to have practical applications for identifying gaps in intervention content as well as for guiding future intervention evaluation. This study supports previous work detailing the usefulness of reverse coding procedures as a tool for developing common-sense interventions, and is the first to do so in the context of a PA intervention for older adults.

The NHLBI Study on Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC): Design and Objectives.

BACKGROUND: The Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC) study aims to characterize the frequency and time course of acute and long-term cardiac and non-cardiac sequelae in multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C), which are currently poorly understood. METHODS: This multicenter observational cohort study will enroll at least 600 patients <21 years old who meet the Centers for Disease Control and Prevention case definition of MIS-C across multiple North American centers over 2 years. The study will collect detailed hospital and follow-up data for up to 5 years, and optional genetic testing. Cardiac imaging at specific time points includes standardized echocardiographic assessment (all participants) and cardiac magnetic resonance imaging (CMR) in those with left ventricular ejection fraction (LVEF) <45% during the acute illness. The primary outcomes are the worst LVEF and the highest coronary artery z-score of the left anterior descending or right coronary artery. Other outcomes include occurrence and course of non-cardiac organ dysfunction, inflammation, and major medical events. Independent adjudication of cases will classify participants as definite, possible, or not MIS-C. Analysis of the outcomes will include descriptive statistics and regression analysis with stratification by definite or possible MIS-C. The MUSIC study will provide phenotypic data to support basic and translational research studies. CONCLUSION: The MUSIC study, with the largest cohort of MIS-C patients and the longest follow-up period to date, will make an important contribution to our understanding of the acute cardiac and non-cardiac manifestations of MIS-C and the long-term effects of this public health emergency.

Survey of centers performing cardiovascular magnetic resonance in pediatric and congenital heart disease: a report of the Society for Cardiovascular Magnetic Resonance.

BACKGROUND: There are few data on practice patterns and trends for cardiovascular magnetic resonance (CMR) in pediatric and congenital heart disease. The Society for Cardiovascular Magnetic Resonance (SCMR) sought to address this deficiency by performing an international survey of CMR centers. METHODS: Surveys consisting of 31 (2014) and 33 (2018) items were designed to collect data on the use of CMR for the evaluation of pediatric and congenital heart disease patients. They were sent to all SCMR members in 2014 and 2018. One response per center was collected. RESULTS: There were 93 centers that responded in 2014 and 83 in 2018. The results that follow show data from 2014 and 2018 separated by a dash. The median annual number of pediatric/congenital CMR cases per center was 183-209. The median number of scanners for CMR was 2-2 (range, 1-8) with 58-63% using only 1.5T scanners and 4-4% using only 3T scanners. The mean number of attending/staff reading CMRs was 3.7-2.6; among them, 52-61% were pediatric or adult cardiologists and 47-38% were pediatric or adult radiologists. The median annual case volume per attending was 54-86. The median number of technologists per center doing CMRs was 4-5. The median scanner time allocated for a non-sedated examination was 75-75 min (range, 45-120). Among the 21 centers responding to both surveys, the mean annual case volume increased from 320 in 2014 to 445 in 2018; 17 (81%) of the centers had an increase in annual case volume. For this subgroup, the median attending/staff per center was 4 in both 2014 and 2018. The median scanner time allotted per study was unchanged at 90 min. The mean time for an attending/staff physician to perform a typical CMR examination including reporting was 143-141 min. CONCLUSION: These survey data provide a novel comprehensive view of CMR practice in pediatric and congenital heart disease. This information is useful for internal benchmarking, resource allocation, addressing practice variation, quality improvement initiatives, and identifying unmet needs.

Longitudinal changes in ventricular size and function are associated with death and transplantation late after the Fontan operation.

BACKGROUND: Cross-sectional studies have reported that ventricular dilation and dysfunction are associated with adverse clinical outcome in Fontan patients; however, longitudinal changes and their relationship with outcome are not known. METHODS: This was a single-center retrospective analysis of Fontan patients with at least 2 cardiovascular magnetic resonance (CMR) scans without intervening interventions. Serial measures of end-diastolic volume index (EDVI), end-systolic volume index (ESVI), ejection fraction (EF), indexed mass (massi), mass-to-volume ratio, and end-systolic wall stress (ESWS) were used to estimate within-patient change over time. Changes were compared for those with and without a composite outcome (death, heart transplant, or transplant listing) as well as between patients with left (LV) and right ventricular (RV) dominance. RESULTS: Data from 156 patients were analyzed with a mean age at 1st CMR of 17.8 ± 9.6 years. 490 CMRs were included with median of 3 CMRs/patient (range 2-9). On regression analysis with mixed effects models, volumes and ESWS increased, while mass, mass-to-volume ratio, and EF decreased over time. With a median follow-up of 10.2 years, 14% met the composite outcome. Those with the composite outcome had a greater increase in EDVI compared to those without (4.7 vs. 0.8 ml/BSA1.3/year). Compared with LV dominance, RV dominance was associated with a greater increase in ESVI (1.4 vs. 0.5 ml/BSA1.3/year), a greater decrease in EF (- 0.61%/year vs. - 0.24%/year), and a higher rate of the composite outcome (21% vs. 8%). CONCLUSIONS: Ventricles in the Fontan circulation exhibit a steady decline in performance with an increase in EDVI, ESVI, and ESWS, and decrease in EF, mass index, and mass-to-volume ratio. Those with death or need for heart transplantation have a faster increase in EDVI. Patients with rapid increase in EDVI (> 5 ml/BSA1.3/year) may be at a higher risk of adverse outcomes and may benefit from closer surveillance. RV dominance is associated with worse clinical outcomes and remodeling compared to LV dominance.

Prognostic factors for outcome following lumbar spine fusion surgery: a systematic review and narrative synthesis.

PURPOSE: The objective of this study was to identify and evaluate the value of prognostic factors related to disability, pain and quality of life (QoL) for adult patients undergoing lumbar spine fusion surgery (LSFS). METHODS: Two reviewers independently searched the literature, assessed eligibility, extracted data and assessed risk of bias and certainty of evidence. Key electronic databases were searched [PubMed, CINAHL, EMBASE, MEDLINE, PEDro and ZETOC] using pre-defined terms [e.g. LSFS] to 20/9/2020; with additional searching of journals, reference lists and unpublished literature. Prospective cohort studies with ≥ 12-month follow-up after LSFS were included. Narrative synthesis was based on recommendations by Cochrane Consumers and Communication Review Group. The GRADE tool enabled assessment of certainty of evidence. Prognostic factors and outcome were analysed and summarised when examined in ≥ 2 studies and when results pointed in the same direction in ≥ 75% of studies. RESULTS: Sixteen studies (n = 8388, 2 low and 14 high risk of bias) were included with 39 prognostic factors identified. There is low certainty evidence that higher pre-operative severity of leg pain predicts greater improvement of leg pain and that pre-operative working predicts less post-operative disability both at 1-2-year follow-up. Other found associations were of very low certainty evidence. CONCLUSION: No moderate to high certainty evidence exists. Use of leg pain and pre-operative working may be valuable predictors of outcome to inform clinical decision-making and advice regarding LSFS surgery. There is need for adequately powered low-risk-of-bias prospective observational studies to further investigate candidate prognostic factors.

Therapeutic Alliance and Its Potential Application to Physical Activity Interventions for Older Adults: A Narrative Review.

Increasing the physical activity (PA) levels of inactive older adults to promote healthy aging and to reduce preventable health conditions is a public health priority. However, there remains uncertainty on what constitutes the most important components and characteristics of effective PA interventions for older adults, and previous research has largely focused on the cognitive and behavioral strategies they adopt to increase uptake and adherence to PA. This narrative review puts forward the novel idea, with supporting evidence, that the strength, quality, and collaborative nature of the professional-client relationship, a concept drawn from the field of psychotherapy and known as therapeutic alliance, may be a vital and foundational element of effective PA interventions. This article will offer a new understanding, and a new direction of research to aid the future conceptualization, design, and development of interventions that aim to increase the PA levels of older adults.

Novel Anti-Neuroinflammatory Properties of a Thiosemicarbazone-Pyridylhydrazone Copper(II) Complex.

Neuroinflammation has a major role in several brain disorders including Alzheimer's disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with CuII(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecular-weight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone-pyridylhydrazone copper(II) complex (CuL5), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer's disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.

Improving CPMG liver iron estimates with a T 1 -corrected proton density estimator.

PURPOSE: CPMG spin echo acquisitions are attractive for diagnosing and monitoring liver iron concentration in iron overload disorders due to their time efficiency and potential to reveal unique information about tissue iron distribution. Clinical adoption remains low due to the insensitivity of CPMG-based R 2 estimates to liver iron concentration (LIC) when common fitting techniques are applied. In this work, we demonstrate that the inclusion of a proton density estimator (PDE) derived from the CPMG acquisition increase the sensitivity of CPMG R 2 estimates to LIC in both simulated and in-vivo human data. THEORY AND METHODS: CPMG R 2 acquisitions from 50 clinically indicated MRI studies in patients with iron overload were analyzed with and without PDE constraints. Liver regions of interest were fit to monoexpontial and nonexponential signal decay equations. LIC by R 2 ∗ served as the reference standard. The observed calibration between CPMG R 2 values and LIC were compared to results predicted from a previously validated Monte Carlo model. RESULTS: The sensitivity of CPMG-derived R 2 triples when a proton density constraint is applied. When compared with R 2 ∗ -LIC estimates, both monoexponential and nonexponential models were unbiased but demonstrated broad 95% confidence intervals particularly for LIC values below 12 mg/g. Absolute error did not increase with LIC. CONCLUSION: A proton density constraint can increase the sensitivity of CPMG-based models to iron. CPMG acquisitions are time-efficient and could potentially improve the dynamic range of single spin echo techniques as well as providing insight into tissue iron distribution.

Impact of pulmonary valve replacement on left ventricular rotational mechanics in repaired tetralogy of Fallot.

BACKGROUND: In repaired tetralogy of Fallot (rTOF), abnormal left ventricular (LV) rotational mechanics are associated with adverse clinical outcomes. We performed a comprehensive analysis of LV rotational mechanics in rTOF patients using cardiac magnetic resonance (CMR) prior to and following surgical pulmonary valve replacement (PVR). METHODS: In this single center retrospective study, we identified rTOF patients who (1) had both a CMR ≤ 1 year before PVR and ≤ 5 years after PVR, (2) had no other intervening procedure between CMRs, (3) had a body surface area > 1.0 m2 at CMR, and (4) had images suitable for feature tracking analysis. These subjects were matched to healthy age- and sex-matched control subjects. CMR feature tracking analysis was performed on a ventricular short-axis stack of balanced steady-state free precession images. Measurements included LV basal and apical rotation, twist, torsion, peak systolic rates of rotation and torsion, and timing of events. Associations with LV torsion were assessed. RESULTS: A total of 60 rTOF patients (23.6 ± 7.9 years, 52% male) and 30 healthy control subjects (20.8 ± 3.1 years, 50% male) were included. Compared with healthy controls, rTOF patients had lower apical and basal rotation, twist, torsion, and systolic rotation rates, and these parameters peaked earlier in systole. The only parameters that were correlated with LV torsion were right ventricular (RV) end-systolic volume (r = - 0.28, p = 0.029) and RV ejection fraction (r = 0.26, p = 0.044). At a median of 1.0 year (IQR 0.5-1.7) following PVR, there was no significant change in LV rotational parameters versus pre-PVR despite reductions in RV volumes, RV mass, pulmonary regurgitation, and RV outflow tract obstruction. CONCLUSION: In this comprehensive study of CMR-derived LV rotational mechanics in rTOF patients, rotation, twist, and torsion were diminished compared to controls and did not improve at a median of 1 year after PVR despite favorable RV remodeling.

Systematic evaluation of structure-property relationships and pharmacokinetics in 6-(hetero)aryl-substituted matched pair analogs of amiloride and 5-(N,N-hexamethylene)amiloride.

The K+-sparing diuretic amiloride elicits anticancer activities in multiple animal models. During our recent medicinal chemistry campaign aiming to identify amiloride analogs with improved properties for potential use in cancer, we discovered novel 6-(hetero)aryl-substituted amiloride and 5-(N,N-hexamethylene)amiloride (HMA) analogs with up to 100-fold higher potencies than the parent compounds against urokinase plasminogen activator (uPA), one of amiloride's putative anticancer targets, and no diuretic or antikaliuretic effects. Here, we report the systematic evaluation of structure-property relationships (lipophilicity, aqueous solubility and in vitro metabolic stability in human and mouse liver microsomes) in twelve matched pair analogs selected from our 6-substituted amiloride and HMA libraries. Mouse plasma stability, plasma protein binding, Caco-2 cell permeability, cardiac ion channel activity and pharmacokinetics in mice (PO and IV) and rats (IV) are described alongside amiloride and HMA comparators for a subset of the four most promising matched-pair analogs. The findings combined with earlier uPA activity/selectivity and other data ultimately drove selection of two analogs (AA1-39 and AA1-41) that showed efficacy in separate mouse cancer metastasis studies.

A Step Too Far? Whittington Hospital NHS Trust v XX [2020] UKSC 14.

This comment piece explores the decision in Whittington Hospital NHS Trust v XX [2020] UKSC 14. It argues that despite notable shifts in public policy in respect of the acceptability of surrogacy as a means of family formation in the past twenty years, the Supreme Court has taken a step too far in deciding that foreign commercial surrogacy is as widely socially accepted. This impacts on the reasonableness of any claim for damages in negligence for the costs of commercial surrogacy. It is posited that the issue of whether damages for foreign commercial surrogacy are reasonable or not will be the key battleground in future negligence cases of this type.

microRNA-184 is induced by store-operated calcium entry and regulates early keratinocyte differentiation.

Extracellular calcium (Ca2+ ) and store-operated Ca2+ entry (SOCE) govern homoeostasis in the mammalian epidermis. Multiple microRNAs (miRNA) also regulate epidermal differentiation, and raised external Ca2+ modulates the expression of several such miRNAs in keratinocytes. However, little is known about the regulation of miR-184 in keratinocytes or the roles of miR-184 in keratinocyte differentiation. Here we report that exogenous Ca2+ stimulates miR-184 expression in primary epidermal keratinocytes and that this occurs in a SOCE-dependent manner. Levels of miR-184 were raised by about 30-fold after exposure to 1.5 mM Ca2+ for 5 days. In contrast, neither phorbol ester nor 1,25-dihydroxyvitamin D3 had any effect on miR-184 levels. Pharmacologic and genetic inhibitors of SOCE abrogated Ca2+ -dependent miR-184 induction by 70% or more. Ectopic miR-184 inhibited keratinocyte proliferation and led to a fourfold increase in the expression of involucrin, a marker of early keratinocyte differentiation. Exogenous miR-184 also triggered a threefold rise in levels of cyclin E and doubled the levels of γH2AX, a marker of DNA double-strand breaks. The p21 cyclin-dependent kinase inhibitor, which supports keratinocyte growth arrest, was also induced by miR-184. Together our findings point to an SOCE:miR-184 pathway that targets a cyclin E/DNA damage regulatory node to facilitate keratinocyte differentiation.