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Purpose: The purpose of this investigation was to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) for pulmonary metastases from pediatric sarcomas. Methods and Materials: This study was a single institutional retrospective chart review including patients younger than 21 years of age at diagnosis who had received SBRT for pulmonary metastasis from metastatic sarcoma. Our current electronic record system was queried for all eligible patients. Primary endpoint was tumor response as defined by Respone Evaluation Criteria in Solid Tumors 1.1 criteria. Secondarily, we analyzed factors that affected tumor response as well as toxicity of treatment. Median dose was 50 Gy ranging from 30 to 60 Gy in 5 fractions to the planning tumor volume. Results: There were 7 patients, ranging in age from 6 to 21 years with a total of 14 pulmonary lesions treated with SBRT. Median and mean follow-up times for the 7 patients were 10.6 months and 15.9 months, respectively. The complete response rate was 50%, partial response 21%, stable disease 21%, and progressive disease 7%. Four of the 7 patients were treated with concurrent systemic therapy, 3 of which were targeted oral therapies. Additionally, we observed that patients who were on targeted therapy such as regorafenib or pazopanib seemed to have better local control compared with patients without targeted therapy. Conclusions: With an overall response rate of 92%, SBRT provided a noninvasive effective palliative treatment option with few side effects in this small retrospective study of 7 patients. A larger prospective clinical trial is warranted to evaluate the role of SBRT in the treatment of unresectable metastatic pediatric sarcomas.

Collagen VI-related dystrophies (COL6-RDs) are a group of severe, congenital-onset muscular dystrophies for which there is no effective causative treatment. Dominant-negative mutations are common in COL6A1, COL6A2, and COL6A3 genes, encoding the collagen α1, α2, and α3 (VI) chains. They act by incorporating into the hierarchical assembly of the three α (VI) chains and consequently produce a dysfunctional collagen VI extracellular matrix, while haploinsufficiency for any of the COL6 genes is not associated with disease. Hence, allele-specific transcript inactivation is a valid therapeutic strategy, although selectively targeting a pathogenic single nucleotide variant is challenging. Here, we develop a small interfering RNA (siRNA) that robustly, and in an allele-specific manner, silences a common glycine substitution (G293R) caused by a single nucleotide change in COL6A1 gene. By intentionally introducing an additional mismatch into the siRNA design, we achieved enhanced specificity toward the mutant allele. Treatment of patient-derived fibroblasts effectively reduced the levels of mutant transcripts while maintaining unaltered wild-type transcript levels, rescuing the secretion and assembly of collagen VI matrix by reducing the dominant-negative effect of mutant chains. Our findings establish a promising treatment approach for patients with the recurrent dominantly negative acting G293R glycine substitution.

Objective: The pedicled greater omentum, when applied onto stressed hearts using omentopexy, has been shown to be protective in humans and animals. The mechanisms underlying cardioprotection using omentopexy remain elusive. This study examined whether macrophage-mediated angiogenesis accounts for the cardioprotective effect of omentopexy in mice. Methods: C57BL/6 mice were subjected to minimally invasive transverse aortic constriction for 6 weeks and subsequent cardio-omentopexy for 8 weeks. Control mice underwent the same surgical procedures without aortic constriction or cardio-omentopexy. Results: Transverse aortic constriction led to left ventricular concentric hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice that underwent sham cardio-omentopexy surgery. The negative effects of transverse aortic constriction were prevented by cardio-omentopexy. Myocardial microvessel density was elevated in the mice that underwent aortic constriction and sham cardio-omentopexy surgery, and cardio-omentopexy further enhanced angiogenesis. Nanostring gene array analysis uncovered the activation of angiogenesis gene networks by cardio-omentopexy. Flow cytometric analysis revealed that cardio-omentopexy triggered the accumulation of cardiac MHCIIloLyve1+TimD4+ (Major histocompatibility complex class IIlow lymphatic vessel endothelial hyaluronan receptor 1+ T cell immunoglobulin and mucin domain conataining 4+) resident macrophages at the omental–cardiac interface. Intriguingly, the depletion of macrophages with clodronate-liposome resulted in the failure of cardio-omentopexy to protect the heart and promote angiogenesis. Conclusions: Cardio-omentopexy protects the heart from pressure overload-elicited left ventricular hypertrophy and dysfunction by promoting myocardial angiogenesis. Cardiac MHCIIloLyve1+TimD4+ resident macrophages play a critical role in the cardioprotective effect and angiogenesis of cardio-omentopexy. Video Abstract:

Objective: To synthesize qualitative literature exploring the lived experience of healthcare workers (HCWs) who cared for patients during the following infectious disease outbreaks (IDOs): the 2003 SARS epidemic, 2009 H1N1 pandemic, 2012 MERS outbreak, and 2014 EVD epidemic. We aim to reveal the collective experience of HCWs during these four IDOs and to create a reference for comparison of current and future IDOs. Methods: Three electronic databases were searched, yielding 823 results after duplicates were removed. Forty qualitative and mixed-methods studies met the criteria for full file review. Fourteen studies met the inclusion and exclusion criteria. The data from the Results or Findings sections were manually coded and themes were conceptualized using thematic analysis. Results: Of the 14 studies, 28.6% focused on SARS, 21.4% on H1N1, 21.4% on MERS, and 28.6% on EVD. Studies occurred in six different countries and included physicians, nurses, paramedics, and emergency medical technicians as participants. Five themes were conceptualized: Uncertainty, Adapting to Change, Commitment, Sacrifice, and Resilience. Conclusion: This review identified the collective experience of HCWs caring for patients during four 21st century IDOs. This qualitative systematic review offers a reference to compare similarities and differences of other IDOs, including the COVID-19 pandemic.

Molecular dynamics (MD) simulations were used to investigate the binding of four ligands to the Val122Ile mutant of the protein transthyretin. Dissociation, misfolding, and subsequent aggregation of mutated transthyretin proteins are associated with the disease Familial Amyloidal Cardiomyopathy. The ligands investigated were the drug candidate AG10 and its decarboxy and N-methyl derivatives along with the drug tafamidis. These ligands bound to the receptor in two halogen binding pockets (HBP) designated AB and A’B’. Inter-ligand distances, solvent accessible surface areas, root mean squared deviation measurements, and extracted structures showed very little change in the AG10 ligands' conformations or locations within the HBP during the MD simulation. In addition, the AG10 ligands experienced stable, two-point interactions with the protein by forming hydrogen bonds with Ser-117 residues in both the AB and A’B’ binding pockets and Lysine-15 residues found near the surface of the receptor. Distance measurements showed these H-bonds formed simultaneously during the MD simulation. Removal of the AG10 carboxylate functional group to form decarboxy-AG10 disrupted this two-point interaction causing the ligand in the AB pocket to undergo a conformational change during the MD simulation. Likewise, addition of a methyl group to the AG10 hydrazone functional group also disrupted the two-point interaction by decreasing hydrogen bonding interactions with the receptor. Finally, MD simulations showed that the tafamidis ligands experienced fewer hydrogen bonding interactions than AG10 with the protein receptor. The tafamidis ligand in pocket A’B’ was also found to move deeper into the HBP during the MD simulation. Keywords: Molecular dynamics simulation, Transthyretin, Tafamidis, AG10, Val122Ile mutant

Grinding is a finishing process typically done in most metallic manufacturing centers, primarily to achieve precision and surface improvement. Currently, the grinding process of titanium alloys generally requires flood coolant application. Electron Beam Powder Bed Fusion (EB-PBF) is an additive manufacturing process that uses an electron beam as the heat source to melt and fuse powder particles to build layer by layer to build a three-dimensional component. Grinding is a major secondary process applied to additively manufactured metals, but with the current methodologies, grinding may impart tensile residual stress on the surface, and thus the performance of the material under fatigue conditions is reduced. In this paper, a targeted cutting fluid application approach for grinding an additively manufactured titanium alloy is used to possibly impart a compressive residual stress upon the subsurface while also providing an improved surface roughness. This study uses samples ground with a traditional flood coolant and samples with targeted cutting fluid applications developed by the researchers. Metrics such as surface residual stress, surface roughness, microstructure, and microhardness were used to determine imparted qualities using the various grinding cooling methodologies. The results show that the subsurface maximum principal residual stresses decreased by 108%, the average surface roughness decreased by 33%, and the microhardness at 5 μm increased by 1% using targeted air as the cutting fluid compared to flood cooling while grinding additively manufactured Ti6Al4V. Overall, the targeted grinding cooling fluid application induced compressive subsurface residual stresses and reduced the average surface roughness.

Introduction: Articles published in the literature report neurological manifestations or “complications” of SARS-CoV-2 infection and conclude that the different neurological manifestations are relatively similar, but with different frequencies. This study aimed to determine the frequency of neurological manifestations of COVID-19 and to identify which are associated with mortality. Methods: We performed a retrospective study of all patients diagnosed with SARS-CoV-2 infection by RT-PCR at Hospital 1° de Octubre, in Mexico, from the beginning of the pandemic to 22 December 2020. A total of 561 patients were identified, 370 of whom presented neurological manifestations. Results: The global mortality rate was 37.8% (140/370), increasing to 92.4% among intubated patients (135/146). Of the 370 patients included, approximately 20% of neurological symptoms (headache, neurological impairment, anosmia, ageusia) accounted for 80% of cases of neurological manifestations. Conclusions: At our hospital, 80% of the patients with neurological manifestations of COVID-19 presented headache, neurological impairment, ageusia, and/or anosmia. Neurological impairment at admission or before arriving at hospital was identified as a risk factor for mortality. Resumen: Introducción: Los artículos se han referido a manifestaciones neurológicas o «complicaciones» producidas por el SARS-CoV-2, concluyendo que las diferentes manifestaciones neurológicas han sido relativamente similares, pero con diferentes proporciones. Por ello, el objetivo de este estudio es cuantificar las manifestaciones neurológicas en COVID-19, e identificar cuál está asociada a la muerte. Material y métodos: Se realizó un estudio retrospectivo con todos los pacientes del Hospital «1.° de Octubre» infectados por COVID-19, y detectados mediante RT-PCR, desde el inicio de la pandemia hasta el 22 de diciembre de 2020, donde se obtuvieron un total de 561 casos. Resultados: La tasa de mortalidad global fue del 37,8% (140/370), mientras que para los pacientes intubados fue del 92,4% (135/146). De los 370 pacientes obtenidos, aproximadamente el 20% de las manifestaciones (cefalea, deterioro neurológico, anosmia, ageusia) ocurrieron con una frecuencia del 80% de manifestaciones neurológicas. Conclusiones: Cefalea, afección neurológica, ageusia y anosmia representaron el 80% de las manifestaciones neurológicas en el Hospital «1.° de Octubre». El deterioro neurológico al ingreso al hospital o antes de llegar fue un factor de riesgo de muerte.

Privately-owned drinking water wells serving fewer than 25 people (private wells) are prevalent and understudied across most of the US. Private wells primarily serve rural households located outside of municipal drinking water and sewerage service coverage areas. These wells are not regulated by United States Environmental Protection Agency (EPA) under the Safe Drinking Water Act, are not regularly monitored by any public agency or utility, and generally do not undergo disinfection treatment. Coliphages are a group of viruses that infect coliform bacteria and are useful viral surrogates for fecal contamination in water systems in much the same way that fecal indicator bacteria (FIB), such as E. coli and to a lesser extent total coliforms, are used to quantify fecal contamination. Coliphages are approved by the EPA for regulatory monitoring in groundwater wells in the USA, but are not routinely used for this purpose. The present study characterizes the occurrence of male-specific and somatic coliphages, along with FIB, in private wells (n = 122) across two different counties in North Carolina. While occurrences of E. coli were rare and frequency of total coliform was generally low (~20%), male-specific and somatic coliphages were detectable in 66% and 54% of samples, respectively. Concentrations of male-specific coliphages were higher than somatics at each county and on a monthly basis. Rainfall appears to be partly influencing higher coliphage concentrations in December, January and February. This research underscores the need for increased surveillance in private wells and consideration of using coliphages in order to better characterize occurrence of fecal contamination at the time of sampling, especially during rainier months.

Psychosomatic plasticity, defined as an extreme capacity to turn suggestions into bodily realities, is as phenomenon well worth investigating, as it challenges mainstream conceptions about the relationship between mind and body in health as well as illness. The field of psychoneuroimmunology (PNI) offers a framework within which to understand this phenomenon, as PNI makes a compelling case for the biological unity of self. Hartmann’s Boundaries concept is particularly applicable, as it suggests that the minds of ‘thin-boundary’ persons are relatively fluid and able to make numerous connections. Wilson and Barber’s identification of the fantasy prone person, and Thalbourne’s transliminality concept, are similarly relevant. Taking these explorations a step further, the author proposes that the flow of feeling within individuals represents the key to psychosomatic plasticity. Blushing, psoriasis, and immune reactions are offered as examples, as are more anomalous reports such as those provided by heart transplant recipients and cases said to be indicative of reincarnation. In each instance, persons who are highly sensitive (i.e., have a speedier and more direct flow of feeling) are more likely to evidence physical reactions. Psychosomatic plasticity represents an emerging area of interest in personality research, one that clearly merits further investigation.

Background: Cardiac implantable electronic device (CIED) procedures can cause significant postoperative pain. Opioid use for postoperative pain is associated with risk of persistent use. The benefits of pectoral nerve (PECs) blocks have been established for other chest wall surgeries, but adoption in electrophysiology has been limited., Objectives: The purpose of this study was to evaluate the efficacy of intraoperative ultrasound-guided PECs blocks performed at the time of CIED procedures by the implanting physician from within the device pocket., Methods: Patients undergoing a pectoral CIED procedure at 7 centers from 2022-2023 were included. Patients underwent intraoperative PECs blocks and subcutaneous local anesthetic vs subcutaneous local anesthetic only at the discretion of the operator. Patients were prospectively evaluated for postoperative pain., Results: Six hundred ten patients (age 67 ± 15 years old; 63% male) were enrolled. and half (n = 305) underwent PECs block. Patients who underwent PECs block were more likely to have a history of chronic pain (32% vs 11%, P <.001). PECs block was associated with lower pain scores in the 4 hours after the procedure (1.5 ± 2.1 vs 4.5 ± 2.5, P <.001). Pain scores were not different after 24 hours (2.8 ± 1.7 vs 3.1 ± 2.2) and 2 weeks (0.9 ± 1.4 vs 0.9 ± 1.2). PECs block patients were less likely to receive inpatient opioids (10% vs 48%, P <.001) and to be discharged with an opioid prescription (15% vs 59%, P <.001). In multivariable linear regression, PECs block (P <.001), age (P = .002), and absence of chronic pain (P = .009) were associated with lower acute postoperative pain., Conclusion: Intraoperative PECs block can reduce postoperative pain and opioid use. This procedure can be readily performed by the implanting physician from within the device pocket., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Fibrillar collagens and glycosaminoglycans (GAGs) are structural biomolecules that are natively abundant to the extracellular matrix (ECM). Prior studies have quantified the effects of GAGs on the bulk mechanical properties of the ECM. However, there remains a lack of experimental studies on how GAGs alter other biophysical properties of the ECM, including ones that operate at the length scales of individual cells such as mass transport efficiency and matrix microstructure. This study focuses on the GAG molecules chondroitin sulfate (CS), dermatan sulfate (DS), and hyaluronic acid (HA). CS and DS are stereoisomers while HA is the only non-sulfated GAG. We characterized and decoupled the effects of these GAG molecules on the stiffness, transport, and matrix microarchitecture properties of type I collagen hydrogels using mechanical indentation testing, microfluidics, and confocal reflectance imaging, respectively. We complement these biophysical measurements with turbidity assays to profile collagen aggregate formation. Surprisingly, only HA enhanced the ECM indentation modulus, while all three GAGs had no effect on hydraulic permeability. Strikingly, we show that CS, DS, and HA differentially regulate the matrix microarchitecture of hydrogels due to their alterations to the kinetics of collagen self-assembly. In addition to providing information on how GAGs define key physical properties of the ECM, this work shows new ways in which stiffness measurements, microfluidics, microscopy, and turbidity kinetics can be used complementarily to reveal details of collagen self-assembly and structure. STATEMENT OF SIGNIFICANCE: Collagen and glycosaminoglycans (GAGs) are integral to the structure, function, and bioactivity of the extracellular matrix (ECM). Despite widespread interest in collagen-GAG composite hydrogels, there is a lack of quantitative understanding of how different GAGs alter the biophysical properties of the ECM across tissue, cellular, and subcellular length scales. Here we show using mechanical, microfluidic, microscopy, and analytical methods and measurements that the GAG molecules chondroitin sulfate, dermatan sulfate, and hyaluronic acid differentially regulate the mechanical, transport, and microstructural properties of hydrogels due to their alterations to the kinetics of collagen self-assembly. As such, these results will inform improved design and utilization of collagen-based scaffolds of tailored composition, mechanical properties, molecular availability due to mass transport, and microarchitecture., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Cardiac stereotactic body radiotherapy (SBRT) has emerged as a promising noninvasive treatment for refractory ventricular tachycardia (VT)., Objective: The purpose of this study was to describe the safety and effectiveness of SBRT for VT in refractory to extensive ablation., Methods: After maximal medical and ablation therapy, patients were enrolled in a prospective registry. Available electrophysiological and imaging data were integrated to generate a plan target volume. All SBRTs were planned with a single 25 Gy fraction using respiratory motion mitigation strategies. Clinical outcomes at 6 weeks, 6 months, and 12 months were analyzed and compared with the 6 months prior to treatment. VT burden (implantable cardioverter-defibrillator [ICD] shocks and antitachycardia pacing sequences) as well as clinical and safety outcomes were the main outcomes., Results: Fifteen patients were enrolled and underwent planning. Fourteen (93%) underwent treatment, with 12 (80%) surviving to the end of the 6-week period and 10 (67%) surviving to 12 months. From 6 week to 12 months, there was recurrence of VT, which resulted in either appropriate antitachycardia pacing or ICD shocks in 33% (4 of 12). There were significant reductions in treated VT at 6 weeks to 6 months (98%) and at 12 months (99%) compared to the 6 months before treatment. There was a nonsignificant trend toward lower amiodarone dose at 12 months. Four deaths occurred after treatment, with no changes in ventricular function., Conclusion: For a select group of high-risk patients with VT refractory to standard therapy, SBRT is associated with a reduction in VT and appropriate ICD therapies over 1 year., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Streptococcus pneumoniae is the most common etiology of bacterial pneumonia, one of the leading causes of death in children and the elderly worldwide. During non-lethal infections with S. pneumoniae, lymphocytes accumulate in the lungs and protect against reinfection with serotype-mismatched strains. Cluster of differentiation CD4 + resident memory T (T RM ) cells are known to be crucial for this protection, but the diversity of lung CD4 + T RM cells has yet to be fully delineated. We aimed to identify unique subsets and their contributions to lung immunity. After recovery from pneumococcal infections, we identified a distinct subset of CD4 + T cells defined by the phenotype CD11a hi CD69 + GL7 + in mouse lungs. Phenotypic analyses for markers of lymphocyte memory and residence demonstrated that GL7 + T cells are a subset of CD4 + T RM cells. Functional studies revealed that unlike GL7 - T RM subsets that were mostly (RAR-related Orphan Receptor gamma T) RORγT + , GL7 + T RM cells exhibited higher levels of (T-box expressed in T cells) T-bet and Gata-3, corresponding with increased synthesis of interferon-γ, interleukin-13, and interleukin-5, inherent to both T helper 1 (T H 1) and T H 2 functions. Thus, we propose that these cells provide novel contributions during pneumococcal pneumonia, serving as important determinants of lung immunity., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Many college women make self-disparaging comments about their appearance to others. This "fat talk" (negative body talk) is a causal risk factor for body image disturbance, which in turn predicts eating disorders and depression. Research is needed to identify effective responses to negative body talk; namely, those that reduce negative body talk without shaming its initiator or damaging the relationship. The current study examined the impact of different responses to negative body talk on the likelihood of future negative body talk and on individual and relationship factors. College women (N = 160) recalled a situation using negative body talk with a female friend. Participants listened to audio recordings of four responses (Deny/Reassure, Challenge, Empathize/Reciprocate, Ignore) and rated appearance satisfaction, shame, friendship support, and likelihood of future negative body talk after each. Linear mixed models indicated that the Deny/Reassure response followed closely by the Challenge response were most beneficial for individual and relationship factors; however, participants reported being least likely to use future negative body talk after the Ignore response. Recommendations for developing promising responses to negative body talk include combining responses to balance validation (Deny/Reassure) and change (Challenge), and studying the contribution of other relationships and varying body dissatisfaction levels., Competing Interests: Declarations of Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Genome-wide copy number profiling by single-nucleotide polymorphism (SNP) array is increasingly employed in the clinical diagnostic workup of melanocytic tumors. We present our SNP array results on 675 melanocytic tumors, including 615 histologically ambiguous tumors evaluated by our institution's dermatopathology consultation service and a separate validation cohort of 26 known benign nevi and 34 known malignant melanomas. The total number of somatic copy number abnormalities, sub-chromosomal copy number abnormalities, regions of homozygosity, and abnormalities at disease-associated regions was significantly associated with a diagnosis of malignancy across disease categories. In our study, the number of copy number abnormalities was the factor that best discriminated between benign versus malignant diagnoses, confirming recent published research. Histologically ambiguous tumors had a range and spectrum of abnormalities, including recurrent 11p gains, copy state transitions over kinase genes, and 3p deletions overlapping BAP1 in neoplasms with Spitzoid morphology. Our data suggest that histologically ambiguous melanocytic neoplasms and early primary melanomas have a range of abnormalities that is intermediate between unambiguous benign or malignant melanocytic neoplasms. Careful technical review and an integrated diagnostic approach are essential for the accurate interpretation of SNP array results on histologically ambiguous melanocytic tumors., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: To characterize and compare the stability of cortical potentials evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) across the naïve, parkinsonian, and pharmacologically treated parkinsonian states. To advance cortical potentials as possible biomarkers for DBS programming., Materials and Methods: Serial electrocorticographic (ECoG) recordings were made more than nine months from a single non-human primate instrumented with bilateral ECoG grids spanning anterior parietal to prefrontal cortex. Cortical evoked potentials (CEPs) were generated through time-lock averaging of the ECoG recordings to DBS pulses delivered unilaterally in the STN region using a chronically implanted, six-contact, scaled DBS lead. Recordings were made across the naïve followed by mild and moderate parkinsonian conditions achieved by staged injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin. In addition to characterizing the spatial distribution and stability of the response within each state, changes in the amplitude and latency of CEP components as well as in the frequency content were examined in relation to parkinsonian severity and dopamine replacement., Results: In the naïve state, the STN DBS CEP presented as a multiphase response maximal over M1 cortex, with components attributable to physiological activity distinguishable from stimulus artifact as early as 0.45-0.75 msec poststimulation. When delivered using therapeutically effective parameters in the parkinsonian state, the CEP was highly stable across multiple recording sessions within each behavioral state. Across states, significant differences were present with respect to both the latency and amplitude of individual response components, with greater differences present for longer-latency components (all p < 0.05). Power spectral density analysis revealed a high-beta peak within the evoked response, with significant changes in power between disease states across multiple frequency bands., Conclusions: Our findings underscore the spatiotemporal specificity and relative stability of the DBS-CEP associated with different disease states and with therapeutic benefit. DBS-CEP may be a viable biomarker for therapeutic programming., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

The world's population is shifting to the cities, and consequently, cities worldwide are growing in number and in size. Cities are complex systems, making it extremely difficult to build and run cities in a way that all the elements of the system operate in harmony. Recently a concept of urbanome, the genome of the city was proposed to address this complexity. Here we first explore this concept and analogy, taking advantage of the potential of other 'omics, modern data collection techniques, Big Data analysis methods and a transdisciplinary approach. Then, we propose a theoretical approach to build the urbanome as a means of quantifying and qualifying population outcomes, being a function of the form of an urban area including the built environment, the physical and social services it provides, and the population density., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to compare the immediate and midterm echocardiographic performance of the Melody (Medtronic Inc) and Sapien (Edwards Lifesciences Inc) valves after transcatheter pulmonary valve replacement (TPVR) in native and conduit right ventricular outflow tracts (RVOTs)., Background: TPVR is now a common procedure, but limited data exist comparing postimplantation echocardiographic findings between Melody and Sapien valves., Methods: This was a single-institution retrospective cohort study of all patients who underwent successful TPVR from 2011 to 2020. Patient demographics, procedural details, and immediate and midterm echocardiographic findings were collected and compared between valve types using the Wilcoxon rank sum, chi-square, or Fisher exact test as appropriate. Subgroups were analyzed individually and were adjusted for multiple comparisons using the Bonferroni method., Results: A total of 328 patients underwent successful TPVR (Melody: n = 202, Sapien: n = 126). The groups had a similar baseline age, weight, and diagnosis. The most common indications for TPVR were pulmonary stenosis (32.2%) or mixed disease (46%) in the Melody group and pulmonary insufficiency in the Sapien group (52.4%) (P < 0.001). Sapien valves were more often placed in native RVOTs (43.7% vs 18.8%; P < 0.001). The discharge and follow-up mean and peak Doppler gradients were similar between the Melody and Sapien groups. Valves implanted in native RVOTs had significantly lower postimplantation gradients at each follow-up period., Conclusions: Echocardiographic performance after TPVR was generally acceptable and similar when comparing Melody and Sapien valves despite differences in the indication and anatomy in each group. The peak and mean gradients were lower in transcatheter valves implanted in native RVOTs compared with those implanted in conduits or bioprosthetic valves., Competing Interests: Funding Support and Author Disclosures This investigation was supported by the University of Utah Population Health Research (PHR) Foundation, with funding in part from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR002538 (formerly 5UL1TR001067-05, 8UL1TR000105 and UL1RR025764). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Episodic memory is supported by hippocampal interactions with a distributed network. Aging is associated with memory decline and network de-differentiation. However, the role of de-differentiation in memory decline has not been directly tested. We reasoned that hippocampal network-targeted stimulation could test these theories, as age-related changes in the network response to stimulation would indicate network reorganization, and corresponding changes in memory would suggest that this reorganization is functional. We compared effects of stimulation on fMRI connectivity and memory in younger versus older adults. Theta-burst network-targeted stimulation of left lateral parietal cortex selectively increased hippocampal network connectivity and modulated memory in younger adults. In contrast, stimulation in older adults increased connectivity throughout the brain, without network selectivity, and did not influence memory. These findings provide evidence that network responses to stimulation are de-differentiated in aging and suggest that age-related de-differentiation is relevant for memory. This manuscript is part of the Special Issue entitled "Cognitive Neuroscience of Healthy and Pathological Aging" edited by Drs. M. N. Rajah, S. Belleville, and R. Cabeza. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP., Competing Interests: Disclosure statement All authors report no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Methadone has been associated with prolongation of the QTc interval (QTc) on electrocardiogram (ECG). In infants, the effects of methadone on the QTc are not well described. Our study's objective is to evaluate the QTc in infants being treated with methadone., Methods: We conducted a retrospective study in infants receiving methadone. We collected demographic data, methadone dose, and QTc. A blinded-to-disease-state pediatric electrophysiologist determined the QTc. Baseline ECG was defined as an ECG obtained while not on methadone therapy, and QTc on baseline ECG was compared with treatment QTc. A significant change was defined as any absolute QTc greater than 500 or a QTc greater than 460 with an increase from baseline of greater than 40 ms., Results: A total of 44 infants comprised the study population. The mean gestational age was 32.3 ± 5.51 weeks. The median age of initiation was 66 days. The median dose was 0.52 mg/kg/day in oral methadone equivalents. Nine patients were on high dose methadone (>1 mg/kg/day in oral methadone equivalents). The mean baseline QTc was 421 ± 27 and the mean change on methadone was -2 ms. No patient had a QTc greater than 500 on methadone. One patient had a QTc of 467 and 46 ms change from baseline, with no clinically significant impact., Conclusion: In our study population, methadone did not significantly prolong the QTc. Further prospective study is warranted to determine the utility and frequency of ECGs in infants receiving methadone., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Severe congenital neutropenia (SCN) is a collection of diverse disorders characterized by chronically low absolute neutrophil count in the peripheral blood, increased susceptibility to infection, and a significant predisposition to the development of myeloid malignancies. SCN can be acquired or inherited. Inherited forms have been linked to variants in a group of diverse genes involved in the neutrophil-differentiation process. Variants that promote resistance to treatment have also been identified. Thus, genetic testing is important for the diagnosis, prognosis, and management of SCN. Herein we describe clinically validated assay developed for assessing patients with suspected SCN. The assay is performed from a whole-exome backbone. Variants are called across all coding exons, and results are filtered to focus on 48 genes that are clinically relevant to SCN. Validation results indicated 100% analytical sensitivity and specificity for the detection of constitutional variants among the 48 reportable genes. To date, 34 individuals have been referred for testing (age range: birth to 67 years). Several pathogenic and likely pathogenic variants have been identified, including one in a patient with late-onset disease. The pattern of cases referred for testing suggests that this assay has clinical utility in a broader spectrum of patients beyond those in the pediatric population who have classic early-onset symptoms characteristic of SCN., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: There is a significant interest in improving adolescent access to primary care, yet limited attempts to incorporate youth feedback within these efforts. The purpose of this study was to describe the experiences related to primary care among a large national sample of adolescents to improve patient-centered care., Methods: Youth were sent open-ended text message prompts via an ongoing study of 14- to 24-year-olds in the U.S. Text responses were analyzed using qualitative thematic analysis, including descriptive coding, consensus building, and theme development. Secondary quantitative analyses were conducted to determine differences by demographics., Results: Of 1,123 eligible participants, 789 (70.2%) responded to at least one prompt. Four themes were developed: (1) youth recognized the importance of primary care, but barriers exist that limited their utilization; (2) youth felt that improving convenience would increase the use of primary care; (3) youth were unsure how to transition between primary care settings; and (4) feeling respected was essential to youth having positive experiences in a primary care health care setting. Older youth and those identifying as female, nonbinary, or transgender were more likely to report previous bad experiences with primary care., Conclusions: Our findings describe barriers and possible solutions to primary care among youth. Because attitudes toward health and health care are established during adolescence, a transformation is needed to create more patient-centered care that aligns with young people's values and experiences. Thus, primary care providers have the opportunity to positively impact the health of young people today and the adults of the future., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)