Identifying Gender and Racial Bias in Pediatric Fellowship Letters of Recommendation: Do Word Choices Influence Interview Decisions?

OBJECTIVES: To describe linguistic differences in letters of recommendation (LORs) for pediatric fellowship candidates based on applicant and letter writer demographics and to examine if these differences influenced the decision to interview a candidate for a fellowship position. STUDY DESIGN: LORs for applicants to 8 pediatric subspecialty fellowships at a single academic center from the 2020 Match were analyzed in this cross-sectional study. Frequency of validated agentic and communal terms in each letter were determined by a language processing web application. Bias was determined as having a >5% surplus of agentic or communal terms. RESULTS: We analyzed 1521 LORs from 409 applicants: 69% were women, 28% were under-represented minorities in medicine (URM), and 50% were invited to interview. Overall, 66% of LORs were agentic biased, 16% communal biased, and 19% neutral. There was no difference in bias in LORs by an applicant's gender (woman 67% agentic vs man 62% agentic; P = .058), race, or ethnicity (non-URM 65% agentic vs URM 67% agentic; P = .660). Despite a lower frequency of agentic terms in LORs for applicants invited for interviews, when accounting for other components of an application and applicant demographics, no significant association was made between language bias in LORs and fellowship interview status. CONCLUSIONS: The frequency of agentic and communal terms in LORs for pediatric subspecialty fellowship candidates were not found to influence the decision to invite a candidate to interview. However, raising awareness of potential areas of bias within the pediatric fellowship selection process might lead to a more equitable and holistic approach to application review.

Unique clinical challenges for the teenager with congenital heart disease.

PURPOSE OF REVIEW: On top of existing rites of passage, adolescents with congenital heart disease (CHD) face additional challenges as related to their underlying medical condition. These include compliance with medications and appointments, establishing heart-healthy behaviors, navigating potential at-risk situations, and transition to adult-oriented care. RECENT FINDINGS: Teenagers with CHD should focus on the importance of exercise as this seems to have important long-term benefits and may help improve weight management. Mental health concerns are a major issue for teens with CHD and awareness and appropriate screening are critical. Discussion regarding sexual health, contraception, pregnancy, and CHD risk in offspring occur rarely in clinical practice, and their absence sets up the CHD adolescent for potential complications. Establishing patterns of trust and communication between physicians and teenage CHD patients are critical to enable the appropriate transition of care to adult congenital care, yet gaps in transition remain common. SUMMARY: The outpatient cardiologist has a critical role to help the teenager with CHD navigate difficult terrain. Returning to the roots of careful history taking, motivational interviewing, and open-ended questions may be of great benefit in warding off complications and helping steer the adolescent with CHD towards a life as a successful adult living with CHD.

Relative effects of polymer composition and sample preparation on glass dynamics.

Modern design of common adhesives, composites and polymeric parts makes use of polymer glasses that are stiff enough to maintain their shape under a high stress while still having a ductile behavior after the yield point. Typically, material compositions are tuned with co-monomers, polymer blends, plasticizers, or other additives to arrive at a tradeoff between the elastic modulus and toughness. In contrast, strong changes to the mechanics of a glass are possible by changing only the molecular packing during vitrification or even deep in the glassy state. For example, physical aging or processing techniques such as physical vapor deposition increase the density, embrittle the material, and increase elastic modulus. Here, we use molecular simulations, validated by positron annihilation lifetime spectroscopy (PALS) and quasi-elastic neutron scattering, to understand the free volume distribution and the resulting dynamics of glassy co-polymers where the composition is systemically varied between polar 5-norbornene-2-methanol (NBOH) and non-polar ethylidene norbornene (ENB) monomers. In these polymer glasses, we analyze the structural features of the unoccupied volume using clustering analysis, where the clustering is parameterized to reproduce experimental measurements of the same features from PALS. Further, we analyze the dynamics, quantified by the Debye-Waller factor, and compare the results with softer, lower density states. Our findings indicate that faster structural relaxations and potentially improved ductility are possible through changes to the geometric structure and fraction of the free volume, and that the resulting changes to the glass dynamics are comparable to large changes in the monomer composition.

Frequency of QTc Interval Prolongation in Children and Adults with Williams Syndrome.

QTc prolongation (≥ 460 ms), according to Bazett formula (QTcB), has been identified to be increased in Williams syndrome (WS) and suggested as a potential cause of increased risk of sudden cardiac death. The Bazett formula tends to overestimate QTc in higher heart rates. We performed a retrospective chart review of WS patients with ≥ 1 electrocardiogram (EKG) with sinus rhythm, no evidence of bundle branch blocks, and measurable intervals. A total of 280 EKGs from 147 patients with WS were analyzed and 123 EKGs from 123 controls. The QTc was calculated using Bazett formula. The average QTcB for individuals with WS and controls was 444 ± 24 ms and 417 ± 26 ms, respectively (p < 0.001). In our WS cohort 34.4% had at least 1 EKG with a QTcB ≥ 460 ms. The mean heart rate (HR) from patients with WS was significantly higher than controls (96 bpm vs 76 bpm, p < 0.001). Linear regression showed that HR contributed 27% to QTcB prolongation in the patients with WS. Patients with WS have a mean QTcB in the normal range but higher than controls, and a higher than expected frequency of QTc ≥ 460 ms compared to the general population. HR is also higher in WS and contributes modestly to the WS QTcB prolongation. Future studies are needed to assess if these findings contribute risk to sudden cardiac death but in the interim we recommend routine EKG testing, especially when starting QTc prolonging medications.

Noonan syndrome and pregnancy outcomes.

BACKGROUND: Noonan syndrome is a genetic disorder with high prevalence of congenital heart defects, such as pulmonary stenosis, atrial septal defect and hypertrophic cardiomyopathy. Scarce data exists regarding the safety of pregnancy in patients with Noonan syndrome, particularly in the context of maternal cardiac disease. STUDY DESIGN: We performed a retrospective chart review of patients at Yale-New Haven Hospital from 2012 to 2020 with diagnoses of Noonan syndrome and pregnancy. We analysed medical records for pregnancy details and cardiac health, including echocardiograms to quantify maternal cardiac dysfunction through measurements of pulmonary valve peak gradient, structural heart defects and interventricular septal thickness. RESULTS: We identified five women with Noonan syndrome (10 pregnancies). Three of five patients had pulmonary valve stenosis at the time of pregnancy, two of which had undergone cardiac procedures. 50% of pregnancies (5/10) resulted in pre-term birth. 80% (8/10) of all deliveries were converted to caesarean section after a trial of labour. One pregnancy resulted in intra-uterine fetal demise while nine pregnancies resulted in the birth of a living infant. 60% (6/10) of livebirths required care in the neonatal intensive care unit. One infant passed away at 5 weeks of age. CONCLUSIONS: The majority of mothers had pre-existing, though mild, heart disease. We found high rates of prematurity, conversion to caesarean section, and elevated level of care. No maternal complications resulted in long-term morbidity. Our study suggests that women with Noonan syndrome and low-risk cardiac lesions can become pregnant and deliver a healthy infant with counselling and risk evaluation.

Hair and skin predict cardiomyopathies: Carvajal and erythrokeratodermia cardiomyopathy syndromes.

Carvajal and erythrokeratodermia cardiomyopathy syndromes (EKC) are rare, inherited cardiocutaneous disorders with potentially fatal consequences in young children. Some patients display features of congestive heart failure and rapidly deteriorate; others exhibit no evident warning signs until sudden death reveals underlying heart disease. We present two patients to illustrate the characteristic hair, skin, teeth, and nail abnormalities, which-especially when distinct from that of other family members-should prompt cardiac evaluation and genetic analysis. In this article, we discuss established treatments as well as a promising, novel therapeutic that has led to nearly complete resolution of the cutaneous and cardiac pathology in EKC syndrome.

T-Cell Receptor Excision Circles in Newborns with Congenital Heart Disease.

OBJECTIVES: To determine if children with congenital heart disease (CHD) have lower newborn T-cell receptor excision circles (TREC) levels than the general population and to evaluate if low TREC levels in newborns with CHD are associated with clinical complications such as hospitalization for infection. STUDY DESIGN: The Connecticut Newborn Screening Program reported TREC levels for newborns with CHD delivered between October 2011 and September 2016 at 2 major Connecticut children's hospitals. TREC levels for children with CHD were compared with the general population. TREC levels and outcome measures, including hospitalization for infection, were compared. RESULTS: We enrolled 575 participants with CHD in the study. The median TREC level for newborns with CHD was lower than the general population (180.1 copies/µL vs 312.5 copies/µL; P < .01). patients with CHD requiring hospitalization for infection had lower median TREC levels than their counterparts (143.0 copies/µL vs 186.7 copies/µL; P < .01). The combination of prematurity and low TREC level had a strong relationship to hospitalization for infection (area under the receiver operative characteristic curve of 0.89). There was no association between TREC level and CHD severity. CONCLUSIONS: Newborns with CHD demonstrated lower TREC levels than the general population. Low TREC levels were associated with hospitalization for infection in preterm children with CHD. Study limitations include that this was a retrospective chart review. These findings may help to identify newborns with CHD at highest risk for infection, allowing for potential opportunities for intervention.

Ventricular arrhythmias immediately following transcatheter pulmonary valve implantation: A cause for concern?

BACKGROUND: Transcatheter pulmonary valve implantation (TPVI) has revolutionized the care of patients with congenital disorders of the right ventricular outflow tract (RVOT) and is increasingly being used in patients with native outflow tracts. This is the first study to specifically report the occurrence of ventricular arrhythmias in the immediate post-TPVI period. METHODS AND RESULTS: Medical records of all adult and pediatric patients who underwent TPVI at our institution between May 1, 2011 and March 1, 2016, were reviewed for the presence of clinically significant ventricular arrhythmias occurring within 30 days of TPVI. We defined a clinically significant arrhythmia as any ventricular arrhythmia that led to hemodynamic instability, resulted in a change of dose or addition of a new anti-arrhythmic medication, caused a delay in discharge, or was the primary reason for readmission. Seventy-five patients, with a median age of 19 years (range 4-65 years), underwent TPVI. In total, 12 (16%) patients had a clinically significant ventricular arrhythmia within 30 days following TPVI. Patients with native outflow tracts were at higher risk of post-TPVI arrhythmias than non-native outflow tract (29% vs. 9%, P = 0.02, adjusted OR 4.8, 95%CI 1.2-20.2). There were no cases of hemodynamic compromise or sudden cardiac death. The arrhythmias were well controlled with beta-blocker therapy. CONCLUSION: In this single center study, ventricular arrhythmias were common following TPVI, particularly in native outflow tract patients. However, the arrhythmias were generally benign and responded well to medical therapy when indicated. Long term therapy was often not needed.

Mechanics and nanovoid nucleation dynamics: effects of polar functionality in glassy polymer networks.

We use molecular simulations and experiments to rationalize the properties of a class of networks based on dicyclopentadiene (DCPD), a polymer with excellent fracture toughness and a high glass transition temperature (Tg), copolymerized with 5-norbornene-2-methanol (NBOH). DCPD is a highly non-polar hydrocarbon, while NBOH contains a hydroxy group, introducing polar functionality and hydrogen bonds (H-bonds). NBOH thus represents a possible route to improve the chemical compatibility of DCPD-based networks with less-hydrophobic materials. We systematically vary the NBOH content (polar chemistry) in DCPD networks, while keeping other network parameters nearly constant, including the molecular weight between cross-links, chain rigidity, and Tg. Using molecular dynamics (MD) simulations, we quantify the thermovolumetric and mechanical properties, including Tg, cohesive energy density, stiffness, and yield strength. We compare these results with experiments on networks of similar composition, finding good agreement. The relation between these properties and polar chemistry are studied by examining a secondary network of physical cross-links, formed by hydrogen bonds between NBOH units. Further, we examine nanovoid formation, an energy dissipation mechanism hypothesized to contribute to the toughness of pDCPD. Using metadynamics to accelerate sampling, we quantify the nanovoid nucleation rate under hydrostatic tension, similar to the stress state in the plastic zone preceding a crack tip. Small additions of NBOH have minimal effect, but the rate drops steeply with larger amounts. Several properties are mapped at nanometer scales, including stiffness and mobility, and associated with void nucleation. Estimates of the length- and time-scale of the plastic zone near a crack tip are used in discussing nanovoid formation as a plausible toughening mechanism in these materials. Overall, the results suggest that pDCPD tolerates the addition of some polar chemistry without degrading its excellent mechanical properties.

Parameter-free predictions of the viscoelastic response of glassy polymers from non-affine lattice dynamics.

We study the viscoelastic response of amorphous polymers using theory and simulations. By accounting for internal stresses and considering instantaneous normal modes (INMs) within athermal non-affine theory, we make parameter-free predictions of the dynamic viscoelastic moduli obtained in coarse-grained simulations of polymer glasses at non-zero temperatures. The theoretical results show very good correspondence with rheology data collected from molecular dynamics simulations over five orders of magnitude in frequency, with some instabilities that accumulate in the low-frequency part on approach to the glass transition. These results provide evidence that the mechanical glass transition itself is continuous and thus represents a crossover rather than a true phase transition. The relatively sharp drop of the low-frequency storage modulus across the glass transition temperature can be explained mechanistically within the proposed theory: the proliferation of low-eigenfrequency vibrational excitations (boson peak and nearly-zero energy excitations) is directly responsible for the rapid growth of a negative non-affine contribution to the storage modulus.

Influence of molecular weight between crosslinks on the mechanical properties of polymers formed via ring-opening metathesis.

The apparent molecular weight between crosslinks (Mc,a) in a polymer network plays a fundamental role in the network mechanical response. We systematically varied Mc,a independent of strong noncovalent bonding by using ring-opening metathesis polymerization (ROMP) to co-polymerize dicyclopentadiene (DCPD) with a chain extender that increases Mc,a or a di-functional crosslinker that decreases Mc,a. We compared the ROMP series quasi-static modulus (E), tensile yield stress (σy), and fracture toughness (KIC and GIC) in the glassy regime with literature data for more polar thermosets. ROMP resins showed high KIC (>1.5 MPa m0.5), high GIC (>1000 J m-2), and 4-5 times higher high rate impact resistance than typical polar thermosets with similar Tg values (100 °C to 178 °C). The overall E values were lower for ROMP systems. The σy dependence on Mc,a and T-Tg for ROMP resins was qualitatively similar to more polar thermosets, but the overall σy values were lower. In contrast to more polar thermosets, the KIC and GIC values of the ROMP resins showed strong Mc,a and T-Tg dependence. High rate impact (∼104-105 s-1) trends were similar to the KIC and GIC behavior, but were also correlated to σy. Overall, a ductile failure mode was observed for quasi-static and high rate results for a linear ROMP polymer (Mc,a = 1506 g mol-1 due to chain entanglement), and this gradually transitioned to a fully brittle failure mode for highly crosslinked ROMP polymers (Mc,a ≤ 270 g mol-1). Molecular dynamics (MD) simulations showed that low Mc,a ROMP resins were more likely to form molecular scale nanovoids. The higher chain stiffness in low Mc,a ROMP resins inhibited stress relaxation in the vicinity of these nanovoids, which correlated with brittle mechanical responses. Overall, these differences in mechanical properties were attributed to the weak non-covalent interactions in ROMP resins.

Topological structure and mechanics of glassy polymer networks.

The influence of chain-level network architecture (i.e., topology) on mechanics was explored for unentangled polymer networks using a blend of coarse-grained molecular simulations and graph-theoretic concepts. A simple extension of the Watts-Strogatz model is proposed to control the graph properties of the network such that the corresponding physical properties can be studied with simulations. The architecture of polymer networks assembled with a dynamic curing approach were compared with the extended Watts-Strogatz model, and found to agree surprisingly well. The final cured structures of the dynamically-assembled networks were nearly an intermediate between lattice and random connections due to restrictions imposed by the finite length of the chains. Further, the uni-axial stress response, character of the bond breaking, and non-affine displacements of fully-cured glassy networks were analyzed as a function of the degree of disorder in the network architecture. It is shown that the architecture strongly affects the network stability, flow stress, onset of bond breaking, and ultimate stress while leaving the modulus and yield point nearly unchanged. The results show that internal restrictions imposed by the network architecture alter the chain-level response through changes to the crosslink dynamics in the flow regime and through the degree of coordinated chain failure at the ultimate stress. The properties considered here are shown to be sensitive to even incremental changes to the architecture and, therefore, the overall network architecture, beyond simple defects, is predicted to be a meaningful physical parameter in the mechanics of glassy polymer networks.

Hypercalcemia in Patients with Williams-Beuren Syndrome.

OBJECTIVE: To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study. STUDY DESIGN: Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities. RESULTS: On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported. CONCLUSIONS: Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis.

Nanovoid formation and mechanics: a comparison of poly(dicyclopentadiene) and epoxy networks from molecular dynamics simulations.

Protective equipment in civilian and military applications requires the use of polymer materials that are both stiff and tough over a wide range of strain rates. However, typical structural materials, like tightly cross-linked epoxies, are very brittle. Recent experiments demonstrated that cross-linked poly(dicyclopentadiene) (pDCPD) networks can circumvent this trade-off by providing structural properties such as a high glass transition temperature and glassy modulus, while simultaneously exhibiting excellent toughness and high-rate impact resistance. The greater performance of pDCPD was attributed to more facile plastic deformation and nano-scale void formation, but the chemical and structural mechanisms underlying this response were not clear. Here, we use atomistic molecular dynamics to compare the molecular- and chain-level properties of pDCPD and epoxy networks undergoing high strain rate deformation. We quantify the tensile modulus and yield strength of the networks as well as the prevalence and characteristics of nanovoids that form during deformation. Networks of similar molecular weight between cross-links are compared. Two key molecular-level properties are identified - monomer flexibility and polar chemistry - that influence the behavior of the networks. Increasing monomer flexibility reduces the modulus and yield strength, while strong non-covalent interactions (e.g., hydrogen bonds) that accompany polar moieties provide higher modulus and yield strength. The lack of strong non-covalent interactions in pDCPD was found to account for its lower modulus and yield strength compared to the epoxies. We examine the molecular-level properties of nanovoids, such as shape, alignment, and local stress distribution, as well as the local chemical environment, finding that nanovoid formation and growth are increased by the monomer rigidity but decreased by polar chemistry. As a result, the pDCPD network, which has a stiff chain backbone with nonpolar alkane chemistry, exhibits more and larger nanovoids that grow more readily during deformation, which could account for the higher toughness and more ductile behavior observed in pDCPD.

Clinical Approaches to the Patient with a Failing Fontan Procedure.

The Fontan operation has been nothing short of revolutionary in its influence on the modern management of patients born with functionally univentricular hearts. The vast majority of these individuals are now surviving well into adulthood. In the 45 years since its introduction, however, there has been increasing recognition of Fontan survivors as a vulnerable population with an altered physiology that has remarkably broad, adverse impact on their long-term health. In this review, the authors discuss the varied manifestations, both cardiac and extracardiac, of the failing Fontan circulation and potential therapeutic options. In addition, a general clinical approach to the patient presenting with Fontan failure is proposed. Ultimately, the key to improving our care and understanding of the Fontan population lies in multi-institutional collaboration and partnership between subspecialty cardiologists and specialists in other organ systems.

Superior Mesenteric Arterial Flow Pattern is Associated with Major Adverse Events in Adults with Fontan Circulation.

Factors contributing to the failure of Fontan circulation in adults are poorly understood. Reduced superior mesenteric arterial (SMA) flow has been identified in pediatric Fontan patients with protein-losing enteropathy. SMA flow has not been profiled in an adult Fontan population and its association with adverse events is unknown. We aimed to examine associations between SMA flow patterns and adverse events in adult Fontan patients. We performed a retrospective review of adult Fontan patients who underwent echocardiograms between 2008 and 2014. SMA Doppler data included peak systolic and end-diastolic velocity and velocity time integral (VTI). Systolic/diastolic (S/D) ratio and resistive index were calculated. The relationship between SMA flow parameters and major adverse events (death or transplantation) was examined using proportional hazard Cox regression analyses. Kaplan-Meyer analysis was conducted to construct survival curve of patients with and without adverse events. 91 post-Fontan adult patients (76 % systemic left ventricle, 20 % atriopulmonary Fontan, mean age 27.9 years) were analyzed. Adverse events occurred in nine patients (death = 4, transplant = 5). When compared with the non-event group, the event group had increased end-diastolic velocity [hazard ratio (HR) 1.5, 95 % confidence interval (CI) 1.1-1.8; p = 0.002], increased systolic VTI (HR 1.5, 95 % CI 1.1-2.2, p = 0.02), increased diastolic VTI (HR 1.7, 95 % CI 1.2-2.4, p = 0.004), decreased S/D velocity ratio (HR 0.32, 95 % CI 0.14-0.71, p = 0.006), decreased S/D VTI ratio (HR 0.76, 95 % CI 0.61-0.97, p = 0.02), and decreased resistive index (HR 0.29, 95 % CI 0.14-0.60, p = 0.0007). Increased end-diastolic velocity and VTI in mesenteric arterial flow, with lower systolic/diastolic ratio and resistive index, were associated with death and need for heart transplant in adult Fontan patients. The mesenteric hyperemic flow was also associated with clinical signs of portal venous outflow obstruction, suggesting the presence of vasodilatory state in end-stage adult Fontan circulation.

Effect of Hydrophobic and Hydrophilic Surfaces on the Stability of Double-Stranded DNA.

DNA hybridization is the foundation for numerous technologies like DNA origami and DNA sensing/microarrays. Using molecular simulations, enhanced-sampling methods, and free-energy calculations, we show the effects of hydrophilic and hydrophobic surfaces on DNA hybridization. Hydrophilic surfaces compete with terminal bases' H-bonds but stabilize central base stacking. Hydrophobic surfaces strengthen terminal H-bonds but destabilize central base stacking. Regardless of surface chemistry, for terminal bases, melting proceeds through breaking H-bonds, followed by unstacking from the neighboring base. For central bases in bulk or near hydrophobic surfaces, melting proceeds by disruption of H-bonds, followed by unstacking, whereas on hydrophilic surfaces, unstacking from one neighboring base precedes complete disruption of the H-bonds, followed by unstacking from the second neighboring base. Kinetic barriers to melting and hybridization show that the central bases melt rapidly near hydrophobic surfaces, which can accelerate conformational searching and thereby accelerate folding into the desired conformation.

Immunologic Aging in Adults with Congenital Heart Disease: Does Infant Sternotomy Matter?

Thymectomy is performed routinely in infants undergoing cardiothoracic surgery. Children post-sternotomy have decreased numbers of T lymphocytes, although the mechanisms involved and long-term consequences of this have not been defined. We hypothesized that lymphopenia in patients with adult congenital heart disease (ACHD) would be reflective of premature T cell maturation and exhaustion. Adults with ACHD who had sternotomy to repair congenital heart disease as infants (<1 year) and age-matched ACHD patients without prior sternotomy were studied using polychromatic flow cytometry interrogating markers of lymphocyte maturation, exhaustion and senescence. Group differences were analyzed using Mann-Whitney U and Fisher's exact tests. Eighteen ACHD patients aged 21-40 years participated: 10 cases and 8 controls. Median age at sternotomy for cases was 52 days. Cases and controls were matched for age (28.9 vs. 29.1 years; p = 0.83), gender (p = 0.15) and race (p = 0.62) and had similar case complexity. Cases had a lower mean percentage of cytotoxic CD8 lymphocytes compared to controls (26.8 vs. 33.9 %; p = 0.016), with fewer naive, undifferentiated CD8 T cells (31.0 vs. 53.6 %; p = 0.027). CD8 cells expressing PD1, a marker of immune exhaustion, trended higher in cases versus controls (25.6 vs. 19.0 %; p = 0.083). Mean percentage of CD4 cells was higher in cases versus controls (65.6 vs. 59.6 %; p = 0.027), without differences in CD4 T cell maturation subtype. In summary, ACHD patients who undergo sternotomy as infants exhibit differences in T lymphocyte composition compared to ACHD controls, suggesting accelerated immunologic exhaustion. Investigation is warranted to assess the progressive nature and clinical impact of this immune phenotypic change.

Regulation of unbalanced redox homeostasis induced by the expression of wild-type HIV-1 viral protein R (NL4-3Vpr) in fission yeast.

The wild-type viral protein R (Vpr) of human immunodeficiency virus type 1 exerts multiple effects on cellular activities during infection, including the induction of cell cycle G2 arrest and the death of human cells and cells of the fission yeast Schizosaccharomyces pombe. In this study, wild-type Vpr (NL4-3Vpr) integrated as a single copy gene in S. pombe chromosome was used to investigate the molecular impact of Vpr on cellular oxidative stress. NL4-3Vpr triggered an atypical response in early (14-h), and a wellregulated oxidative stress response in late (35-h) log-phase cultures. Specifically, NL4-3Vpr expression induced oxidative stress in the 14-h cultures leading, to decreased levels of superoxide anion (O(2)(·-)), hydroxyl radical (·OH) and glutathione (GSH), and significantly decreased activities of catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione S-transferase. In the 35-h cultures, elevated levels of O(2)(·-) and peroxides were accompanied by increased activities of most antioxidant enzymes, suggesting that the Vpr-induced unbalanced redox state of the cells might contribute to the adverse effects in HIV-infected patients.

Interaction of hyaluronan binding peptides with glycosaminoglycans in poly(ethylene glycol) hydrogels.

This study investigates the incorporation of hyaluronan (HA) binding peptides into poly(ethylene glycol) (PEG) hydrogels as a mechanism to bind and retain hyaluronan for applications in tissue engineering. The specificity of the peptide sequence (native RYPISRPRKRC vs non-native RPSRPRIRYKC), the role of basic amino acids, and specificity to hyaluronan over other GAGs in contributing to the peptide-hyaluronan interaction were probed through experiments and simulations. Hydrogels containing the native or non-native peptide retained hyaluronan in a dose-dependent manner. Ionic interactions were the dominating mechanism. In diH2O the peptides interacted strongly with HA and chondroitin sulfate, but in phosphate buffered saline the peptides interacted more strongly with HA. For cartilage tissue engineering, chondrocyte-laden PEG hydrogels containing increasing amounts of HA binding peptide and exogenous HA had increased retention and decreased loss of cell-secreted proteoglycans in and from the hydrogel at 28 days. This new matrix-interactive hydrogel platform holds promise for tissue regeneration.