Flexible and Rigid Bronchoscopy for Critically Ill Children on Extracorporeal Membrane Oxygenation.

BACKGROUND: We aim to describe our experience with bronchoscopy to diagnose and relieve tracheobronchial obstruction in anticipation of decannulation in children on extracorporeal membrane oxygenation (ECMO) support. METHODS: A retrospective cohort study of children on ECMO between 1/2018 and 12/2022. RESULTS: A total of 107 children required ECMO support during the study period for cardiac (n = 48, 45%), pulmonary (n = 38, 36%), or cardiopulmonary dysfunction (n = 21, 20%). Thirty-seven (35%) patients underwent 99 bronchoscopies while on ECMO. Most (76%, n = 75) experienced no improvement or worsening of chest radiography 24 hours following bronchoscopy. Clinical improvement in tidal volumes 48 hours after the first bronchoscopy was noted in 13/25 patients with available data (p = 0.05). Adverse events were seen in 18 (49%) patients who underwent bronchoscopy, including pneumothorax (n = 8, 22%), pneumonia (n = 7, 19%), pulmonary hemorrhage (n = 6, 16%), and sepsis (n = 5, 14%). ECMO courses were longer (25.4 ± 37.2 vs 6.1 ± 8.8 days, p < 0.0001) and more likely to be complicated by pneumonia (p = 0.0004) and sepsis (p = 0.047) in patients who underwent bronchoscopy compared with those who did not. Adverse events following bronchoscopy were associated with the number of bronchoscopies (p = 0.0003) and the presence of obstructive materials but not with the type of bronchoscopy or indication for ECMO. Mortality rates were similar between patients who underwent bronchoscopy and those who did not. CONCLUSION: Children requiring bronchoscopy represent a subset of the sickest children on ECMO. Bronchoscopy may provide benefit in children with persistent cardiopulmonary failure who could not otherwise be decannulated. Adverse events are associated with the number of bronchoscopies and the presence of obstructive material. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Transtracheal Pressure for Evaluation of Decannulation Readiness.

BACKGROUND: Pediatric tracheostomy decannulation protocols vary among institutions and may include toleration of Passy Muir Valve (PMV), microlaryngoscopy and bronchoscopy (MLB) findings, and polysomnography evaluation. Transtracheal pressure (TTP) is an objective measurement utilized to evaluate PMV toleration. We aimed to investigate the role of TTP in decannulation candidates and compare TTP measurements with polysomnography and MLB findings. METHODS: A retrospective cohort study of children who underwent TTP measurement during PMV trial between December 2012 and November 2022. RESULTS: A total of 79 patients underwent TTP measurement and MLB evaluation; of these, 16 (20.3%) patients had a capped polysomnography. Twenty-eight (35.4%) patients had TTPs ≤10 cm H2O, and 51 (64.6%) patients had TTPs >10 cm H2O. The most common indication for tracheostomy was upper airway obstruction (n = 41, 51.9%), followed by a need for mechanical ventilation (n = 24, 30.4%). Twenty-five (31.6%) patients were decannulated. Patients with TTPs ≤10 cm H2O had a mean Apnea-Hypopnea Index of 0.17 ± 0.26/h compared with 6.93 ± 7.67/h in those with TTPs >10 cm H2O, p = 0.0365. Patients with TTPs >10 cm H2O were found to have a significantly higher occurrence of airway obstruction (96.1% vs. 46.4%, p < 0.0001) and multilevel airway obstruction (70.6% vs. 21.4%, p < 0.0001) on MLB. Neither TTP measured at time of PMV assessment nor capped polysomnography was associated with successful decannulation. CONCLUSIONS: TTP measurements at time of PMV evaluation are associated with polysomnography and MLB findings. One-time PMV measurements were not indicative of decannulation success. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3377-3383, 2024.

Swallowing Function After Epiglottopexy in Children.

OBJECTIVE: Epiglottopexy has been an increasingly utilized intervention in children with epiglottic prolapse and airway obstruction. Given the role of the epiglottis in protecting the airway during swallowing and the potential effect of repositioning the epiglottis on the passage of the bolus, we aimed to compare swallowing outcomes before and after epiglottopexy in children. STUDY DESIGN: A retrospective cohort study. SETTING: Tertiary care children's hospital. METHODS: Data were extracted from charts of children who underwent epiglottopexy and had a subsequent instrumental swallowing evaluation between January 2018 and September 2022. RESULTS: A total of 93 patients underwent epiglottopexy. Of these, 38 patients met inclusion requirements. The mean age at surgery was 41 ± 47 months. Most patients (n = 37, 97.4%) had significant comorbidities such as secondary airway lesions (n = 33, 91.7%), a genetic or syndromic disorder (n = 25, 69.4%), and dysphagia (n = 29, 76.3%). All patients had a concurrent procedure at the time of epiglottopexy with supraglottoplasty (n = 24, 63.2%) and lingual tonsillectomy (n = 16, 42.1%) being the most common. No changes in initiation or patterns of swallowing were noted postoperatively. A total of 7 (18.4%) patients had worsening swallow function: 2 had new-onset dysphagia, and 5 had worsening pre-existing dysphagia. Liquid or food textures penetrated remained unchanged or improved in most cases. No risk factors for worsening dysphagia were identified in our cohort. CONCLUSION: Children with medical comorbidities undergoing epiglottopexy with additional airway interventions may experience new or worsening dysphagia. However, the procedure is generally safe without notable patterned changes in the swallowing mechanism.

Persistence of aerodigestive symptoms after vascular ring repair.

OBJECTIVE: Vascular rings are often associated with respiratory and swallowing difficulties due to tracheal or esophageal compression. While the results of a vascular ring repair are considered excellent, the long-term effect of tracheal and esophageal remodeling and the persistence of symptoms have scarcely been reported. Our study aims to evaluate the respiratory and swallowing outcomes of vascular ring repair. STUDY DESIGN AND METHODS: A retrospective cohort study of children who underwent vascular ring repair between 2010 and 2022 in a tertiary-care children's hospital. RESULTS: There were 108 patients enrolled: sixty-three patients (57.41 %) with a right aortic arch, 42 patients (38.89 %) with a double aortic arch, and 3 patients (2.78 %) with other vascular rings. Forty-three (39.81 %) patients were diagnosed prenatally. Of the 65 patients (60.19 %) diagnosed postnatally, 35/65 (53.85 %) had either respiratory or swallowing symptoms as the indication for diagnostic workup. Persistent respiratory and swallowing symptoms were noted in 34/108 (31.48 %) and 30/108 (27.78 %) patients, respectively, within a year of surgical repair. Fourteen patients underwent repeated laryngoscopy and bronchoscopy that demonstrated residual tracheomalacia; however, only 2/14 (1.9 %) patients required tracheostomy tube placement, and 6-out-of-7 patients were weaned off positive pressure airway support. Persistent respiratory symptoms were significantly more common in patients with a double aortic arch compared to a right aortic arch. No differences were noted in demographics, comorbidities, and preoperative aerodigestive symptoms between patients with residual symptoms and patients with no residual symptoms. CONCLUSIONS: Persistent respiratory and swallowing symptoms after vascular ring repair are not uncommon. Postoperative evaluation should be pursued by a dedicated team, and treatment considered as appropriate.

Fibrous food and particle size influence electromyography and the kinematics of oral processing.

Structure-sensory relationships are essential for understanding food perception. Food microstructure impacts how a food is comminuted and processed by the human masticatory system. This study investigated the impact of anisotropic structures, explicitly the structure of meat fibers, on the dynamic process of mastication. For a general understanding of texture-structure relationships, the three typically used deformation-tests: Kramer shear cell-, Guillotine cutting- and texture-profile-analyses were conducted. 3D jaw movements and muscle activities of the masseter muscle were additionally tracked and visualized using a mathematical model. Particle size had a significant effect on jaw movements and muscle activities for both the homogeneous (isotropic) and fibrous (anisotropic) meat-based samples with the same composition. Mastication was described using jaw movement and muscle activity parameters determined for each individual chew. The adjusted effect of fiber length was extracted from the data, suggesting that longer fibers induce a more strenuous chewing in which the jaw undergoes faster and wider movements requiring more muscle activity. To the authors' knowledge, this paper presents a novel data analysis approach for identifying oral processing behavior differences. This is an advancement on previous studies because a holistic overview of the entire mastication process can be visualized.

Evaluation of a Type 2 diabetes risk reduction online program for women with recent gestational diabetes: a randomised trial.

BACKGROUND: To evaluate the preliminary efficacy, feasibility and acceptability of the 3-month Body Balance Beyond (BBB) online program among Australian women with overweight/obesity and recent gestational diabetes mellitus. METHODS: Women were randomised into either: 1) High Personalisation (HP) (access to 'BBB' website, video coaching sessions, text message support); 2) Medium Personalisation (MP) (website and text message support); or 3) Low Personalisation (LP) (website only). Generalised linear mixed models were used to evaluate preliminary efficacy, weight, diet quality, physical activity levels, self-efficacy and quality of life (QoL) at baseline and 3-months. Feasibility was assessed by recruitment and retention metrics and acceptability determined via online process evaluation survey at 3-months. RESULTS: Eighty three women were randomised, with 76 completing the study. Self-efficacy scores showed significant improvements in confidence to resist eating in a variety of situations from baseline to 3-months in HP compared to MP and LP groups (P=.03). The difference in mean QoL scores favoured the HP compared to MP and LP groups (P=.03). Half of the women (HP n=17[81%], MP n=12[75%], LP n=9[56%]) lost weight at 3-months. No significant group-by-time effect were reported for other outcomes. Two-thirds of women in the HP group were satisfied with the program overall and 86% would recommend it to others, compared with 25% and 44% in the MP group, and 14% and 36% in the LP group, respectively. CONCLUSIONS: Video coaching sessions were associated with improvements in QoL scores and self-efficacy, however further refinement of the BBB website and text messages support could improve program acceptability. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12619000162112 , registered 5 February 2019.

Food Oral Processing-An Industry Perspective.

We illustrate how scientific understanding of Food Oral Processing enables food product development with specific benefits for several target populations. in vivo, in vitro, and in silico approaches are discussed in the context of their ability to quantify oral processing from the molecular to the macroscopic scale. Based on this understanding, food structures with enhanced performance in terms of hedonic and nutritional properties as well as appropriateness for age and certain medical conditions can be developed. We also discuss current gaps and highlight development opportunities from an industry perspective.

The Feasibility and Preliminary Efficacy of an eHealth Lifestyle Program in Women with Recent Gestational Diabetes Mellitus: A Pilot Study.

Self-administered eHealth interventions provide a potential low-cost solution for reducing diabetes risk. The aim of this pilot randomised controlled trial (RCT) was to evaluate the feasibility, including recruitment, retention, preliminary efficacy (primary outcome) and acceptability (secondary outcome) of the "Body Balance Beyond" eHealth intervention in women with previous gestational diabetes mellitus (GDM). Women with overweight/obesity who had recent GDM (previous 24 months) were randomised into one of three groups: 1) high personalisation (access to "Body Balance Beyond" website, individual telehealth coaching via video call by a dietitian and exercise physiologist, and text message support); 2) low personalisation (website only); or 3) waitlist control. To evaluate preliminary efficacy, weight (kg), glycosylated hemoglobin, type A1C (HbA1c), cholesterol (total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)), diet quality and moderate-vigorous physical activity were analysed at baseline and at 3 and 6 months using generalised linear mixed models. To investigate acceptability, process evaluation was conducted at 3 and 6 months. Of the 327 potential participants screened, 42 women (mean age 33.5 ± 4.0 years and BMI 32.4 ± 4.3 kg/m2) were randomised, with 30 (71%) completing the study. Retention at 6 months was 80%, 54% and 79% for high personalisation, low personalisation and waitlist control, respectively (reasons: personal/work commitments, n = 4; started weight-loss diet, n = 1; pregnant, n = 1; resources not useful, n = 1; and not contactable, n = 5). No significant group-by-time interactions were observed for preliminary efficacy outcomes, with the exception of HDL cholesterol, where a difference favoured the low personalisation group relative to the control (p = 0.028). The majority (91%) of women accessed the website in the first 3 months and 57% from 4-6 months. The website provided useful information for 95% and 92% of women at 3 and 6 months, respectively, although only a third of women found it motivating (30% and 25% at 3 and 6 months, respectively). Most women agreed that the telehealth coaching increased their confidence for improving diet (85%) and physical activity (92%) behaviours, although fewer women regarded the text messages as positive (22% and 31% for improving diet and physical activity, respectively). The majority of women (82% at 3 months and 87% at 6 months) in the high personalisation group would recommend the program to other women with GDM. Recruiting and retaining women with a recent diagnosis of GDM is challenging. The "Body Balance Beyond" website combined with telehealth coaching via video call is largely acceptable and useful for women with recent GDM. Further analysis of the effect on diabetes risk reduction in a larger study is needed.

Impact of Early Tranexamic Acid Administration on Overall Blood Product Utilization at 24 Hours.

Antifibrinolytics have demonstrated a mortality benefit in trauma patients when utilized early after injury. In line with recent literature, the authors hypothesize that early tranexamic acid (TXA) administration will decrease overall blood product administration at 24 hr. This is a retrospective cohort evaluation of 65 trauma patients admitted and discharged between May 1, 2015, and December 31, 2017, who received packed red blood cells (PRBCs) and TXA within 3 hr following injury. The primary outcome was overall PRBC utilization at 24 hr when TXA was administered less than 1 hr of injury compared with 1-3 hr of injury. A subgroup analysis compared PRBC usage at 24 hr when PRBC to TXA administration time was less than 30 min compared with 30 min or more. During the study time, 15 patients received TXA early, less than 1 hr from injury, and 50 patients received TXA within 1-3 hr of injury. Patients received a median of 7 units of PRBCs in the early group and 8 units in the standard group (p = .64) at 24 hr. Patients who received TXA less than 30 min after first PRBC received a median of 6 units at 24 hr compared with 9 units when PRBC to TXA time was 30 min or more (p = .014). There was no difference in PRBCs at 24 hr in patients who received TXA early compared with 1-3 hr from injury. There was a significant increase in PRBC requirement at 24 hr when patients received TXA 30 min or more from first PRBC. Further inquiry into the optimal timing of TXA administrated is needed.

Community Health Worker Intervention in Subsidized Housing: New York City, 2016-2017.

From April 2016 to June 2017, the Health + Housing Project employed four community health workers who engaged residents of two subsidized housing buildings in New York City to address individuals' broadly defined health needs, including social and economic risk factors. Following the intervention, we observed significant improvements in residents' food security, ability to pay rent, and connection to primary care. No immediate change was seen in acute health care use or more narrowly defined health outcomes.

Executive functions and health behaviors associated with the leading causes of death in the United States: A systematic review.

Research indicates that executive functioning may predict health behavior. This systematic review provides an overview of the relationship between domains of executive functioning and health behaviors associated with the leading causes of death in the United States. A total of 114 articles met the inclusion criteria (adult sample, published in English between 1990 and November 2016) and were reviewed and synthesized. Results indicated that although many studies had mixed findings, at least one executive function component was associated with every health behavior. Based on these results, health professionals should consider the role of executive functions in behavior change interventions.

Point Prevalence of Children Hospitalized With Chronic Critical Illness in the General Inpatient Units.

OBJECTIVES: Children with medical complexity (CMC) have high rates of mortality and morbidity, prolonged lengths of stay, and use a disproportionately high amount of health care expenditures. A subset of children with CMC have chronic critical illness requiring even higher levels of clinical support and resource use. We aimed to describe the point prevalence of children hospitalized in general inpatient care units with pediatric chronic critical illness (PCCI). METHODS: Point prevalence analysis across 6 pediatric tertiary medical centers in the United States on a "snapshot day" (May 17, 2017). On the day of sampling, a number of demographic, historical, and clinical descriptors were collected. A previously published definition of PCCI was used to establish inclusion criteria. RESULTS: The point prevalence of patients with PCCI in general inpatient care units was 41% (232 out of 571). Of these, 91% (212 out of 232) had been admitted more than once in the previous 12 months, 50% (117 out of 232) had a readmission within 30 days of a previous admission, and 20% (46 out of 232) were oncology patients. Only 1 had a designated complex care team, and there were no attending physicians designated primarily for medically complex children. CONCLUSIONS: Children with chronic critical illness, a subset of CMC, may make up a substantial proportion of pediatric patients hospitalized in general inpatient care units. There is a critical need to understand how to better care for this medically fragile population. In our data, it is suggested that resources should be allocated for PCCI in nonintensive care clinical areas.

Theory-Based Predictors of Mindfulness Meditation Mobile App Usage: A Survey and Cohort Study.

BACKGROUND: Mindfulness meditation has become increasingly popular over the last few years, due in part to the increase in mobile apps incorporating the practice. Although studies have demonstrated the potential of mindfulness meditation to positively impact health, little has been uncovered about what predicts engagement in mindfulness meditation. Understanding the predictors of mindfulness meditation may help practitioners and phone app developers improve intervention strategies and app experience. OBJECTIVE: The purpose of this study was to use the Theory of Planned Behavior and Temporal Self-Regulation Theory to determine factors predicting mindfulness meditation mobile app use. METHODS: The sample consisted of 85 undergraduate students with no prior mindfulness meditation experience. During their first laboratory visit, participants completed tasks to measure their executive functioning and a survey to measure Theory of Planned Behavior constructs about mindfulness meditation. Over the following 2 weeks, participants logged the days and minutes that they practiced mindfulness meditation using a phone app. Hierarchical regression modeling was used to analyze the data. RESULTS: After controlling for demographic factors, participant subjective norms (beta=14.51, P=.001) and intentions (beta=36.12, P=.001) were predictive of the number of minutes practicing mindfulness. Participant executive functioning did not predict mindfulness meditation practice, nor did it moderate the link between intentions and mindfulness meditation practice. Participant attitudes (beta=0.44, P<.001) and perceived control (beta=0.42, P=.002) were positively associated with intentions to practice mindfulness. CONCLUSIONS: These results suggest that among college student populations, the Theory of Planned Behavior may be useful in predicting the use of mindfulness meditation phone apps. However, participant executive functioning was not a predictor or moderator of mindfulness practice, and Temporal Self-Regulation Theory may be less useful for explaining mindfulness meditation behaviors using phone apps over a short period of time among college students. The results have implications for public health professionals, suggesting that a focus on subjective norms and intentions may promote mindfulness meditation practice using phone apps.

Cooked color of precooked ground beef patties manufactured with mature bull trimmings.

Lean (80%) ground beef was formulated with 0, 25, 50, 75, or 100% mature bull trimmings, formed into patties, cooked to 71 °C in an air-impingement oven, and stored at -20 °C until reheating to 71 °C either in a microwave oven or on a gas-fired chargrill. Instrumental color of raw patties was not (P ≥ .080) affected by levels of bull trim. After initial cooking, internal cooked redness values were not affected (P ≥ .202) by the proportion of bull trim; however, the internal reheated patty redness increased (greater a* values and lesser HA; P ≤ .001) with increasing proportions of bull trimmings. Formulating ground beef with high levels (>50%) of mature, bull trimmings had minimal effects on raw ground beef color, but patties formulated with the highest proportions of bull trimmings appeared undercooked even after cooking twice to 71 °C.

A Synthetic Cross-Species CD200R1 Agonist Suppresses Inflammatory Immune Responses In Vivo.

Functional aptamers displaying agonistic or antagonistic properties are showing great promise as modulators of immune responses. Here, we report the development of a polyethylene glycol-modified (PEGylated) DNA aptamer as a cross-species (murine and human) CD200R1 agonist that modulates inflammatory responses in vivo. Specifically, DNA aptamers were discovered by performing independent SELEX searches on recombinant murine and human CD200R1. Aptamer motifs identified by next generation sequencing (NGS) were subsequently compared, leading to the discovery of motifs common to both targets. The CD200R1 DNA aptamer CCS13 displayed the highest agonistic activity toward CD200R1 in terms of suppressing the induction of cytotoxic T-lymphocytes (CTLs) in both human and murine allogeneic-mixed lymphocyte cultures (allo-MLCs). A 20-kDa polyethylene glycol (PEG) chain was covalently attached to the 5' end of this aptamer, and the resulting conjugate was shown to block inflammatory responses in murine models of skin graft rejection and house-dust-mite-induced allergic airway inflammation. Importantly, this agonistic aptamer does not suppress CTL induction in 5-day allo-MLCs with responder cells derived from CD200R1-/- mice, indicating that its mode of action is directly linked to CD200R1 activation. This study suggests that one can derive agonistic DNA aptamers that can be verified as immuno-modulators in murine models with outcomes potentially translatable to the treatment of human conditions.

Effects of Fat Polymorphic Transformation and Nonfat Particle Size Distribution on the Surface Changes of Untempered Model Chocolate, Based on Solid Cocoa Mass.

This study aims to understand the bloom process in untempered chocolate by investigating the polymorphic transformation of cocoa butter and changes in chocolate surface. Cocoa mass with varying particle size distributions (PSD) were used to produce untempered model chocolate. Optical microscopy showed that during 25 d of storage, the chocolate surface gradually became honeycombed in appearance with dark spots surrounded by white sandy bloom areas. In conjunction with X-ray diffraction this indicates that the polymorphic transformation of form IV cocoa butter to more stable form V crystals caused the observed surface changes with the most significant changes occurring within 6 d. As bloom developed the surface whiteness increased, but the PSD of nonfat particles showed limited impact on the changes in whiteness. Moreover, scanning electron microscopy showed separated fat crystals on fat-rich dark spots and empty spaces between particles in bloom areas suggesting redistribution of fat in the chocolate matrix. PRACTICAL APPLICATION: The results reported in this work can facilitate the understanding of fat bloom formation in untempered chocolate with respect to the changes in microstructure and surface appearances. It also contributes to show the details of IV-to-V polymorphic transformation in the fat phase as time went by.

Between-Session Reliability of Isometric Midthigh Pull Kinetics and Maximal Power Clean Performance in Male Youth Soccer Players.

Dos'Santos, T, Thomas, C, Comfort, P, McMahon, JJ, Jones, PA, Oakley, NP, and Young, AL. Between-session reliability of isometric midthigh pull kinetics and maximal power clean performance in male youth soccer players. J Strength Cond Res 32(12): 3373-3381, 2018-The aim of the study was to determine the between-session reliability of isometric midthigh pull (IMTP) kinetics and maximal weight lifted during the power clean (PC) in male youth soccer players, and to identify the smallest detectable differences between sessions. Thirteen male youth soccer players (age: 16.7 ± 0.5 years, height: 1.80 ± 0.08 m, and mass: 70.5 ± 9.4 kg) performed 3 IMTP trials, whereas only 10 soccer players performed maximal PCs. These were performed twice, separated by 48 hours to examine the between-session reliability. Intraclass correlation coefficients (ICCs) and coefficient of variation (CV) demonstrated high levels of within-session (ICC = 0.84-0.98, CV = 4.05-10.00%) and between-session reliability (ICC = 0.86-0.96, CV = 3.76-7.87%) for IMTP kinetics (peak force [PF] and time-specific force values 30-250 ms) and maximal PC (ICC = 0.96, CV = 3.23%), all meeting minimum acceptable reliability criteria. No significant differences (p > 0.05, effect size ≤0.22) were revealed between sessions for IMTP kinetics and maximal PC performance. Strength and conditioning coaches and practitioners should consider changes of >6.04% in maximal PC and changes in IMTP kinetics of >14.31% in force at 30 ms, >14.73% in force at 50 ms, >12.36% in force at 90 ms, >12.37% in force at 100 ms, >14.51% in force at 150 ms, >11.71% in force at 200 ms, >7.23% in force at 250 ms, and >8.50% in absolute PF as meaningful improvements in male youth soccer players. Decrements in the IMTP kinetics greater than the aforementioned values could possibly be used as an indicator of neuromuscular fatigue and preparedness for training or competition.

Penile Erosion in a Paraplegic Man With Indwelling Urinary Catheter and Scrotal Edema.

The chronic use of urinary indwelling catheters is a common practice in the setting of long-term patient care and is associated with numerous complications. More awareness about urogenital trauma from urinary catheterization is needed, as it is as common as symptomatic urinary tract infections. There are a number of preventable measures that can be taken to decrease the risk of mechanical trauma to the urethra and glans penis caused by chronic catheterization. We present a case of a 27-year old paraplegic male needing a chronic indwelling catheter that acquired ventral penile erosion while being cared for in the ICU setting.

Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations.

Germline coding mutations in different telomere-related genes have been linked to autosomal-dominant familial pulmonary fibrosis. Individuals with these inherited mutations demonstrate incomplete penetrance of clinical phenotypes affecting the lung, blood, liver, skin, and other organs. Here, we describe the somatic acquisition of promoter mutations in telomerase reverse transcriptase (TERT) in blood leukocytes of approximately 5% of individuals with inherited loss-of-function coding mutations in TERT or poly(A)-specific ribonuclease (PARN), another gene linked to telomerase function. While these promoter mutations were initially identified as oncogenic drivers of cancer, individuals expressing the mutations have no history of cancer. Neither promoter mutation was found in population-based cohorts of similar or advanced age. The TERT promoter mutations were found more frequently in cis with the WT allele than the TERT coding sequence mutation. EBV-transformed lymphoblastoid B cell lines (LCLs) derived from subjects with TERT promoter mutations showed increased telomerase expression and activity compared with cell lines from family members with identical coding mutations. TERT promoter mutations resulted in an increased proliferation of LCLs and demonstrated positive selection over time. The persistence and recurrence of noncoding gain-of-function mutations in these cases suggests that telomerase activation is not only safely tolerated but also advantageous for clonal expansion.

P73 tumor suppressor and its targets, p21 and PUMA, are required for madin-darby canine kidney cell morphogenesis by maintaining an appropriate level of epithelial to mesenchymal transition.

P73, a member of p53 tumor suppressor family, plays a crucial role in tumor suppression and neural development. Due to the usage of two promoters, p73 is expressed as two isoforms, TAp73 and ∆Np73, with opposing functions. Here, we investigated the potential role of p73 in epithelial polarity and morphogenesis by using Madin-Darby canine kidney (MDCK) cells as a model system. We found that knockdown of TAp73 enhances, whereas knockdown of ∆Np73 inhibits, MDCK cell proliferation and migration in two-dimensional (2-D) culture. We also found that knockdown of TAp73, but not ∆Np73, disrupts cyst formation of MDCK cells in three-dimensional (3-D) culture. Interestingly, we found that p21 and PUMA, both of which are induced by TAp73 but repressed by ∆Np73, are required for suppressing cell proliferation and migration in 2-D culture and for MDCK ce ll morphogenesis in 3-D culture. Finally, we showed knockdown of TAp73, p21 or PUMA induces epithelial to mesenchymal transition (EMT) with a decrease in E-cadherin and an increase in EMT transcription factors. Together, our data suggest that TAp73, p21 and PUMA play a critical role in modulating MDCK cell morphogenesis by maintaining an appropriate level of the EMT.