Actin cytoskeletal regulation of ciliogenesis in development and disease.

Primary cilia are antenna-like sensory organelles that are evolutionarily conserved in nearly all modern eukaryotes, from the single-celled green alga, Chlamydomonas reinhardtii, to vertebrates and mammals. Cilia are microtubule-based cellular projections that have adapted to perform a broad range of species-specific functions, from cell motility to detection of light and the transduction of extracellular mechanical and chemical signals. These functions render cilia essential for organismal development and survival. The high conservation of cilia has allowed for discoveries in C. reinhardtii to inform our understanding of the basic biology of mammalian primary cilia, and to provide insight into the genetic etiology of ciliopathies. Over the last two decades, a growing number of studies has revealed that multiple aspects of ciliary homeostasis are regulated by the actin cytoskeleton, including centrosome migration and positioning, vesicle transport to the basal body, ectocytosis, and ciliary-mediated signaling. Here, we review actin regulation of ciliary homeostasis, and highlight conserved and divergent mechanisms in C. reinhardtii and mammalian cells. Further, we compare the disease manifestations of patients with ciliopathies to those with mutations in actin and actin-associated genes, and propose that primary cilia defects caused by genetic alteration of the actin cytoskeleton may underlie certain birth defects.

Bag-Valve-Mask Ventilation and Survival From Out-of-Hospital Cardiac Arrest: A Multicenter Study.

BACKGROUND: Few studies have measured ventilation during early cardiopulmonary resuscitation (CPR) before advanced airway placement. Resuscitation guidelines recommend pauses after every 30 chest compressions to deliver ventilations. The effectiveness of bag-valve-mask ventilation delivered during the pause in chest compressions is unknown. We sought to determine: (1) the incidence of lung inflation with bag-valve-mask ventilation during 30:2 CPR; and (2) the association of ventilation with outcomes after out-of-hospital cardiac arrest. METHODS: We studied patients with out-of-hospital cardiac arrest from 6 sites of the Resuscitation Outcomes Consortium CCC study (Trial of Continuous Compressions versus Standard CPR in Patients with Out-of-Hospital Cardiac Arrest). We analyzed patients assigned to the 30:2 CPR arm with ≥2 minutes of thoracic bioimpedance signal recorded with a cardiac defibrillator/monitor. Detectable ventilation waveforms were defined as having a bioimpedance amplitude ≥0.5 Ω (corresponding to ≥250 mL VT) and a duration ≥1 s. We defined a chest compression pause as a 3- to 15-s break in chest compressions. We compared the incidence of ventilation and outcomes in 2 groups: patients with ventilation waveforms in <50% of pauses (group 1) versus those with waveforms in ≥50% of pauses (group 2). RESULTS: Among 1976 patients, the mean age was 65 years; 66% were male. From the start of chest compressions until advanced airway placement, mean±SD duration of 30:2 CPR was 9.8±4.9 minutes. During this period, we identified 26 861 pauses in chest compressions; 60% of patients had ventilation waveforms in <50% of pauses (group 1, n=1177), and 40% had waveforms in ≥50% of pauses (group 2, n=799). Group 1 had a median of 12 pauses and 2 ventilations per patient versus group 2, which had 12 pauses and 12 ventilations per patient. Group 2 had higher rates of prehospital return of spontaneous circulation (40.7% versus 25.2%; P<0.0001), survival to hospital discharge (13.5% versus 4.1%; P<0.0001), and survival with favorable neurological outcome (10.6% versus 2.4%; P<0.0001). These associations persisted after adjustment for confounders. CONCLUSIONS: In this study, lung inflation occurred infrequently with bag-valve-mask ventilation during 30:2 CPR. Lung inflation in ≥50% of pauses was associated with improved return of spontaneous circulation, survival, and survival with favorable neurological outcome.

Association Between Emergency Medical Service Agency Intubation Rate and Intubation Success.

STUDY OBJECTIVE: Airway management is a crucial part of out-of-hospital care. It is not known if the rate of overall agency intubation attempts is associated with intubation success. We sought to evaluate the association between agency intubation attempt rate and intubation success using a national out-of-hospital database. METHODS: We conducted a retrospective secondary analysis of the ESO Data Collaborative from 2018 to 2019, and included all adult cases with an endotracheal intubation attempt. We calculated the number of intubations attempted per 100 responses, advanced life support responses, and transports for each agency. We excluded cases originating at health care facilities and outliers. We used multivariable logistic regression to evaluate the association between agency intubation attempt rate and 1) intubation success and 2) first-pass success. We adjusted for confounders. RESULTS: We included 1,005 agencies attempting 58,509 intubations. Overall, the intubation success rate was 78.8%, and the first-pass success rate was 68.5%. Per agency, the median rate of intubation attempts per 100 emergency medical service responses was 0.8 (interquartile range 0.6 to 1.1). Rates of intubation attempts per 100 responses (adjusted odds ratio [aOR] 1.7; 95% confidence interval [CI] 1.6 to 1.8), advanced life support responses (aOR 1.18; 95% CI 1.16 to 1.20), and transports (aOR 1.21; 95% CI 1.18 to 1.22) were all associated with intubation success. These relationships were similar for first-pass success but with smaller effect sizes. CONCLUSION: Higher agency rates of intubation attempts were associated with increased rates of intubation success and first-pass success.

A National Study on the Comparative Burden of Pedestrian Injuries from Falls Relative to Pedestrian Injuries from Motor Vehicle Collisions.

Pedestrian injuries from falls are an understudied cause of morbidity. Here, we compare the burden of pedestrian injuries from falls occurring on streets and sidewalks with that from motor vehicle collisions. Data on injurious falls on streets and sidewalks, and pedestrian-motor vehicle collisions, to which Emergency Medical Services responded, along with pedestrian and incident characteristics, were identified in the 2019 National Emergency Medical Services Information System database. In total, 118,520 injurious pedestrian falls and 33,915 pedestrians-motor vehicle collisions were identified, with 89% of the incidents occurring in urban areas. Thirty-two percent of pedestrians struck by motor vehicles were coded as Emergent or Critical by Emergency Medical Services, while 19% of pedestrians injured by falls were similarly coded. However, the number of pedestrians whose acuity was coded as Emergent or Critical was 2.1 times as high for injurious falls as compared with pedestrians-motor vehicle collisions. This ratio was 3.9 for individuals 50 years and older and 6.1 for those 65 years and older. In conclusion, there has been substantial and appropriate policy attention given to preventing pedestrian injuries from motor vehicles, but disproportionately little to pedestrian falls. However, the population burden of injurious pedestrian falls is significantly greater and justifies an increased focus on outdoor falls prevention, in addition to urban design, policy, and built environment interventions to reduce injurious falls on streets and sidewalks, than currently exists across the USA.

Bidirectional transport of amino acids regulates mTOR and autophagy.

Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase which regulates protein translation, cell growth, and autophagy. Cell surface transporters that allow amino acids to enter the cell and signal to mTOR are unknown. We show that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5 function inhibits cell growth and activates autophagy. The molecular basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a bidirectional transporter that regulates the simultaneous efflux of L-glutamine out of cells and transport of L-leucine/EAA into cells. Certain tumor cell lines with high basal cellular levels of L-glutamine bypass the need for L-glutamine uptake and are primed for mTOR activation. Thus, L-glutamine flux regulates mTOR, translation and autophagy to coordinate cell growth and proliferation.

Tubule dysfunction and injury and future risk of sepsis-associated acute kidney injury.

BACKGROUND: Novel biomarkers can quantify both kidney tubule function, including proximal tubule reabsorptive (urine α-1 microglobulin (uα1m)) and tubule protein synthesis capacities (urine uromodulin (uUMOD)), and tubular injury (urine neutrophil gelatinase-associated lipocalin (uNGAL)). In a blood pressure trial, we reported that lower reabsorptive and synthetic protein capacity at times of health predicted future risk of acute kidney injury (AKI), but most AKI was related to hemodynamic causes in this trial. Associations between tubular function and injury and future AKI related to other causes is unknown. MATERIALS AND METHODS: We performed a case-control study in REGARDS, a population-based cohort study, among participants who provided urine at the baseline visit. We matched each septic AKI case by age, sex, race, and time from baseline to hospital admission 1 : 1 to a participant with sepsis who did not develop AKI (controls). Using conditional logistic regression, we evaluated the associations of uα1m, uUMOD, urine ammonium, and uNGAL with septic AKI. RESULTS: Mean age was 69 ± 8 years, 44% were female, and 39% were Black participants. Median baseline eGFR among cases and controls was 73 (55, 90) and 82 (65, 92) mL/min/1.73m2, and median albuminuria was 19 (8, 87) vs. 9 (5, 22) mg/g, respectively. No independent associations were observed between the tubule function or injury markers and subsequent risk of septic AKI once models were adjusted for baseline albuminuria, estimated glomerular filtration rate, and other risk factors. CONCLUSION: Among community participants, tubule function and injury markers at times of health were not independently associated with future risk of septic AKI.

JEDI: A versatile code for strain analysis of molecular and periodic systems under deformation.

Stretching or compression can induce significant energetic, geometric, and spectroscopic changes in materials. To fully exploit these effects in the design of mechano- or piezo-chromic materials, self-healing polymers, and other mechanoresponsive devices, a detailed knowledge about the distribution of mechanical strain in the material is essential. Within the past decade, Judgement of Energy DIstribution (JEDI) analysis has emerged as a useful tool for this purpose. Based on the harmonic approximation, the strain energy in each bond length, bond angle, and dihedral angle of the deformed system is calculated using quantum chemical methods. This allows the identification of the force-bearing scaffold of the system, leading to an understanding of mechanochemical processes at the most fundamental level. Here, we present a publicly available code that generalizes the JEDI analysis, which has previously only been available for isolated molecules. Now, the code has been extended to two- and three-dimensional periodic systems, supramolecular clusters, and substructures of chemical systems under various types of deformation. Due to the implementation of JEDI into the Atomic Simulation Environment, the JEDI analysis can be interfaced with a plethora of program packages that allow the calculation of electronic energies for molecular systems and systems with periodic boundary conditions. The automated generation of a color-coded three-dimensional structure via the Visual Molecular Dynamics program allows insightful visual analyses of the force-bearing scaffold of the strained system.

Mobile Integrated Health Care Roles of US EMS Clinicians: A Descriptive Cross-Sectional Study.

OBJECTIVE: Mobile integrated health care (MIH) leverages emergency medical services (EMS) clinicians to perform local health care functions. Little is known about the individual EMS clinicians working in this role. We sought to describe the prevalence, demographics, and training of EMS clinicians providing MIH in the United States (US). METHODS: This is a cross-sectional study of US-based, nationally certified civilian EMS clinicians who completed the National Registry of Emergency Medical Technicians (NREMT) recertification application during the 2021-2022 cycle and completed the voluntary workforce survey. Workforce survey respondents self-identified their job roles within EMS, including MIH. If an MIH role was selected, additional questions clarified the primary role in EMS, type of MIH provided, and hours of MIH training received. We merged the workforce survey responses with the individual's NREMT recertification demographic profile. The prevalence of EMS clinicians with MIH roles and data on demographics, clinical care provided, and MIH training were calculated using descriptive statistics, including proportions with associated binomial 95% confidence intervals (CI). RESULTS: Of 38,960 survey responses, 33,335 met inclusion criteria and 490 (1.5%; 95%CI 1.3-1.6%) EMS clinicians indicated MIH roles. Of these, 62.0% (95%CI 57.7-66.3%) provided MIH as their primary EMS role. EMS clinicians with MIH roles were present in all 50 states and certification levels included emergency medical technician (EMT) (42.8%; 95%CI 38.5-47.2%), advanced emergency medical technician (AEMT) (3.5%; 95%CI 1.9-5.1%), and paramedic (53.7%; 95%CI 49.3-58.1%). Over one-third (38.6%; 95%CI 34.3-42.9%) of EMS clinicians with MIH roles received bachelor's degrees or above, and 48.4% (95%CI 43.9%-52.8%) had been in their MIH roles for less than 3 years. Nearly half (45.6%; 95%CI 39.8-51.6%) of all EMS clinicians with primary MIH roles received less than 50 hours (h) of MIH training; only one-third (30.0%; 95%CI 24.7-35.6%) received more than 100 h of training. CONCLUSION: Few nationally certified US EMS clinicians perform MIH roles. Only half of MIH roles were performed by paramedics; EMT and AEMT clinicians performed a substantial proportion of MIH roles. The observed variability in certification and training suggest heterogeneity in preparation and performance of MIH roles among US EMS clinicians.

Emergency department resource utilization among nursing home residents, a National Cross-Sectional Study.

OBJECTIVES: Persons 65 years and older (older persons), particularly residents of nursing homes (NHs), disproportionately access the emergency department (ED) and utilize more medical resources. The goal of this study is to provide a contemporary description of healthcare utilization patterns and disposition decisions for United States (US) NH residents presenting to EDs. METHODS: Older persons presenting to EDs in the US were identified in the National Hospital Ambulatory Medical Care Survey (NHAMCS) 2017, 2018 and 2019 datasets. We examined demographic, clinical, and resource use characteristics and outcomes. After survey weighting, we compared the frequency of different imaging, medications, clinical interventions, and outcomes in the ED between NH residents and those residing outside NHs. RESULTS: From 2017 to 2019, older persons made 24,441,285 annual visits to the ED, comprising 17.5% of all visits. Among these, 1,579,916 visits (6.5%) were by NH residents. Compared with non-NH residents, NH residents were older (mean age: 81.2 [95%CI 81.5-82.9] vs 76.1 [95%CI 75.8-76.4]), underwent more imaging (82.8% [95%CI 79.5-86.1] vs 71.6% [95%CI 69.9-73.3]), were administered fewer potentially inappropriate medications (PIMs) in the ED or upon discharge (9.5% [95%CI 6.2-2.7] vs 17.1% [95%CI 15.8-18.4]), and had a higher proportion of visits resulting in hospital admission (44.1% [95%CI 38.2-49.9] vs 26.0% [95%CI 23.3, 28.7]). CONCLUSIONS: Older NH residents presenting to the ED use more resources and are more likely to be hospitalized compared to older persons residing outside NHs. The resource-intensive nature of these visits highlights the importance of targeted, multi-disciplinary interventions that optimize ED care for this population.

CaspSites: A Database and Web Application for Experimentally Observed Human Caspase Substrates Using N-Terminomics.

CaspSites is a free-to-use database and web application for experimentally observed human caspase substrates using N-terminomics. It can be accessed and used by all users at the web URL www.caspsites.org. CaspSites stores cleavage site information identified for human caspases 1-9 in lysates and apoptotic cells, collected from their corresponding published studies. The database can be queried, viewed, and exported using the search page of the web application. The main parameters offered are protein substrate, cleavage site (P4-P4') residues, and individual caspase data sets, which can be connected using OR, AND, or NOT logical operators for custom user-built queries. CaspSites will be regularly updated with new experimental findings for understudied caspases, providing researchers insight into the distinctive roles human caspases play in cellular processes by identifying their target proteins in relation to each other.

A case of spontaneous basal ganglia hemorrhage with contralateral extension utilizing the canal of Gratiolet.

BACKGROUND: Intracranial hemorrhage accounts for 10-20% of stroke etiologies annually. Basal ganglia is the most common site for intracranial hemorrhage accounting for 50% of all cases. Bilateral spontaneous basal ganglia hemorrhages (BGH) are rare with few reported cases. CASE PRESENTATION: We report an unusual case of a 69-year-old female who presented with a spontaneous bilateral basal ganglia hemorrhage secondary to a right BGH with contralateral extension through the anterior commissure (AC) utilizing the Canal of Gratiolet. Clinical course and imaging findings are discussed. CONCLUSIONS: To our knowledge, this is the first case to specifically detail the extension of spontaneous hemorrhage across the AC via the Canal of Gratiolet, and imaging findings provide a novel depiction of AC anatomy and fiber distribution in a clinical context. These findings may explain the mechanism behind this rare clinical entity.

Racial, Ethnic, and Socioeconomic Disparities in Out-of-Hospital Pain Management for Patients With Long Bone Fractures.

STUDY OBJECTIVE: To evaluate racial and ethnic disparities in out-of-hospital analgesic administration, accounting for the influence of clinical characteristics and community socioeconomic vulnerability, among a national cohort of patients with long bone fractures. METHODS: Using the 2019-2020 ESO Data Collaborative, we retrospectively analyzed emergency medical services (EMS) records for 9-1-1 advanced life support transport of adult patients diagnosed with long bone fractures at the emergency department. We calculated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for out-of-hospital analgesic administration by race and ethnicity, accounting for age, sex, insurance, fracture location, transport time, pain severity, and scene Social Vulnerability Index. We reviewed a random sample of EMS narratives without analgesic administration to identify whether other clinical factors or patient preferences could explain differences in analgesic administration by race and ethnicity. RESULTS: Among 35,711 patients transported by 400 EMS agencies, 81% were White, non-Hispanic, 10% were Black, non-Hispanic, and 7% were Hispanic. In crude analyses, Black, non-Hispanic patients with severe pain were less likely to receive analgesics compared with White, non-Hispanic patients (59% versus 72%; Risk Difference: -12.5%, 95% CI: -15.8% to -9.9%). After adjustment, Black, non-Hispanic patients remained less likely to receive analgesics compared with White, non-Hispanic patients (aOR:0.65, 95% CI:0.53 to 0.79). Narrative review identified similar rates of patients declining analgesics offered by EMS and analgesic contraindications across racial and ethnic groups. CONCLUSIONS: Among EMS patients with long bone fractures, Black, non-Hispanic patients were substantially less likely to receive out-of-hospital analgesics compared with White, non-Hispanic patients. These disparities were not explained by differences in clinical presentations, patient preferences, or community socioeconomic conditions.

Improving childhood asthma outcomes in East Harlem: the East Harlem Asthma Center of Excellence's Asthma Counselor Program.

OBJECTIVES: To evaluate the effectiveness of the Asthma Counselor Program, a program of the New York City Department of Health and Mental Hygiene, designed to improve asthma outcomes among children. METHODS: We used a pre-post study design among children who enrolled in the program. We included self-reported outcome measures by comparing the previous 12 months (captured at intake) to the 12 months following program enrollment. To calculate the 12 months after enrollment, we added the number of outcome events reported at each follow-up session, which are conducted approximately three months apart, to compute 12-month (or "year-end") post-enrollment outcomes. RESULTS: We enrolled 136 children during the study period (2018); 85 children remained in the program for 12 months and 51 became lost-to-follow-up. Among those who remained in the program, at the "year-end" session, there were statistically significant reductions in the mean number of asthma-related unscheduled healthcare appointments or urgent-care visits (73%), uses of prednisone (65%), asthma-related school absences (60%), asthma-related ED visits (57%), and asthma-related hospitalizations (50%). CONCLUSIONS: Twelve months after children enrolled in the program, they had significantly improved asthma outcomes. Our findings, along with results from similar studies, support multicomponent interventions, especially those led by masters-level social workers.

Differences in Characteristics between EMS Clinicians with Patient Care and Non-Patient Care Roles.

OBJECTIVE: Emergency medical services (EMS) play a key role in access to prehospital emergency care. While EMS has defined levels of certification, the roles in the care paradigm fulfilled by these clinicians vary. The aim of this study is to describe the national differences between EMS clinicians with primary non-patient care vs. patient care roles. METHODS: We performed a cross sectional evaluation of nationally certified EMS clinicians in the United States who recertified in 2020. As part of the recertification process, applicants voluntarily complete profile questions regarding demographic, job, and service characteristics. We compared the characteristics between individuals self-reporting primary patient care roles vs. non-patient care roles. Using logistic regression, we determined independent predictors for having a non-patient care role. RESULTS: In 2020, 126,038 people completed recertification. Of the 96,661 completing the profile, 80,591 (83.4%) indicated that they provided patient care, and 16,070 (16.6%) did not provide patient care as a primary role. Non-patient care personnel were more likely to be older (median 43 years old vs 34 years old), and to have a higher level of education (bachelor's degree or more: OR 2.25, 95%CI [2.13-2.38]) compared with patient care practitioners. Non-patient care personnel were less likely to be female (0.67 [0.64-0.70]) and minorities (OR 0.80 [0.76-0.84]). Non-patient care personnel reported longer work experience (16 years or more: OR 6.30 [5.98-6.64]), were less likely to hold part time positions (OR 0.62 [0.59-0.65]), and were less often attached to more than one agency (OR 0.83 [0.79-0.86]). Non-patient care personnel were less likely to work in rural settings (OR 0.81 [0.78-0.85]). CONCLUSIONS: EMS clinicians in non-patient care roles account for 17% of the study population. The odds of performing as a non-patient care practitioner are associated with characteristics related to demographics and workforce experience. Future work will be necessary to identify mechanisms to encourage diversity within the patient care and non-patient care workforces.

Ttc21b deficiency attenuates autosomal dominant polycystic kidney disease in a kidney tubular- and maturation-dependent manner.

Primary cilia are sensory organelles built and maintained by intraflagellar transport (IFT) multiprotein complexes. Deletion of several IFT-B genes attenuates polycystic kidney disease (PKD) severity in juvenile and adult autosomal dominant polycystic kidney disease (ADPKD) mouse models. However, deletion of an IFT-A adaptor, Tulp3, attenuates PKD severity in adult mice only. These studies indicate that dysfunction of specific cilia components has potential therapeutic value. To broaden our understanding of cilia dysfunction and its therapeutic potential, we investigate the role of global deletion of an IFT-A gene, Ttc21b, in juvenile and adult mouse models of ADPKD. Both juvenile (postnatal day 21) and adult (six months of age) ADPKD mice exhibited kidney cysts, increased kidney weight/body weight ratios, lengthened kidney cilia, inflammation, and increased levels of the nutrient sensor, O-linked ß-N-acetylglucosamine (O-GlcNAc). Deletion of Ttc21b in juvenile ADPKD mice reduced cortical collecting duct cystogenesis and kidney weight/body weight ratios, increased proximal tubular and glomerular dilations, but did not reduce cilia length, inflammation, nor O-GlcNAc levels. In contrast, Ttc21b deletion in adult ADPKD mice markedly attenuated kidney cystogenesis and reduced cilia length, inflammation, and O-GlcNAc levels. Thus, unlike IFT-B, the effect of Ttc21b deletion in mouse models of ADPKD is development-specific. Unlike an IFT-A adaptor, deleting Ttc21b in juvenile ADPKD mice is partially ameliorative. Thus, our studies suggest that different microenvironmental factors, found in distinct nephron segments and in developing versus mature stages, modify ciliary homeostasis and ADPKD pathobiology. Further, elevated levels of O-GlcNAc, which regulates cellular metabolism and ciliogenesis, may be a pathological feature of ADPKD.

IFT-A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease.

Polycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with autosomal dominant polycystic kidney disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport-B (IFT-B) complex genes in adult mouse models of ADPKD attenuates the severity of PKD and PLD. Here we examine the role of deletion of an IFT-A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knockout mice. Perinatal deletion of Thm1 resulted in disorganized and expanded biliary regions, biliary fibrosis, increased serum bile acids, and a shortened primary cilium on cytokeratin 19+ (CK19+) epithelial cells. In contrast, perinatal deletion of Pkd2 caused PLD, with multiple CK19+ epithelial cell-lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knockout mice increased hepatomegaly, liver necrosis, as well as serum bilirubin and bile acid levels, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 alone in adult mice did not cause a biliary phenotype. Combined deletion of Pkd2 and Thm1 caused variable hepatic cystogenesis at 4 months of age, but differences in hepatic cystogenesis between Pkd2- and Pkd2;Thm1 knockout mice were not observed by 6 months of age. Similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2 conditional knockout cyst-lining epithelial cells. Taken together, Thm1 is required for biliary tract development, and proper biliary development restricts PLD severity. Unlike IFT-B genes, Thm1 does not markedly attenuate hepatic cystogenesis, suggesting differences in regulation of signaling and cystogenic processes in the liver by IFT-B and -A. Notably, increased Notch signaling in cyst-lining epithelial cells may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Association of Advanced Airway Insertion Timing and Outcomes After Out-of-Hospital Cardiac Arrest.

STUDY OBJECTIVE: While often prioritized in the resuscitation of patients with out-of-hospital cardiac arrest, the optimal timing of advanced airway insertion is unknown. We evaluated the association between the timing of advanced airway (laryngeal tube and endotracheal intubation) insertion attempt and survival to hospital discharge in adult out-of-hospital cardiac arrest. METHODS: We performed a secondary analysis of the Pragmatic Airway Resuscitation Trial (PART), a clinical trial comparing the effects of laryngeal tube and endotracheal intubation on outcomes after adult out-of-hospital cardiac arrest. We stratified the cohort by randomized airway strategy (laryngeal tube or endotracheal intubation). Within each subset, we defined a time-dependent propensity score using patients, arrest, and emergency medical services systems characteristics. Using the propensity score, we matched each patient receiving an initial attempt of laryngeal tube or endotracheal intubation with a patient at risk of receiving laryngeal tube or endotracheal intubation attempt within the same minute. RESULTS: Of 2,146 eligible patients, 1,091 (50.8%) and 1,055 (49.2%) were assigned to initial laryngeal tube and endotracheal intubation strategies, respectively. In the propensity score-matched cohort, timing of laryngeal tube insertion attempt was not associated with survival to hospital discharge: 0 to lesser than 5 minutes (risk ratio [RR]=1.35, 95% confidence interval [CI] 0.53 to 3.44); 5 to lesser than10 minutes (RR=1.07, 95% CI 0.66 to 1.73); 10 to lesser than 15 minutes (RR=1.17, 95% CI 0.60 to 2.31); or 15 to lesser than 20 minutes (RR=2.09, 95% CI 0.35 to 12.47) after advanced life support arrival. Timing of endotracheal intubation attempt was also not associated with survival: 0 to lesser than 5 minutes (RR=0.50, 95% CI 0.05 to 4.87); 5 to lesser than10 minutes (RR=1.20, 95% CI 0.51 to 2.81); 10 to lesser than15 minutes (RR=1.03, 95% CI 0.49 to 2.14); 15 to lesser than 20 minutes (RR=0.85, 95% CI 0.30 to 2.42); or more than/equal to 20 minutes (RR=0.71, 95% CI 0.07 to 7.14). CONCLUSION: In the PART, timing of advanced airway insertion attempt was not associated with survival to hospital discharge.

Design of a novel clinical trial of prehospital pediatric airway management.

Emergency Medical Services personnel are often the first to intervene in the care of critically ill children. Airway management is a fundamental step in prehospital resuscitation, yet there is significant variation in current prehospital airway management practices. Our objective is to present a methodologic approach to determine the optimal strategy for prehospital pediatric airway management. We describe the conceptual premise for the Pediatric Prehospital Airway Resuscitation Trial, a novel Bayesian adaptive sequential platform trial. We developed an innovative design to enable comparison of the three predominant prehospital pediatric airway techniques (bag-mask-ventilation, supraglottic airway insertion, and endotracheal intubation) in three distinct disease groups (cardiac arrest, major trauma, and other respiratory failure). We used a Bayesian statistical approach to provide flexible modeling that can adapt based on prespecified rules according to accumulating trial data with patient enrollment continuing until stopping rules are met. The approach also allows the comparison of multiple interventions in sequence across the different disease states. This Bayesian hierarchical model will be the primary analysis method for the Pediatric Prehospital Airway Resuscitation Trial. The model integrates information across subgroups, a technique known as "borrowing" to generate accurate global and subgroup-specific estimates of treatment effects and enables comparisons of airway intervention arms within the overarching trial. We will use this Bayesian hierarchical linear model that adjusts for subgroup to estimate treatment effects within each subgroup. The model will predict a patient-centered score of 30-day intensive care unit-free survival using arm, subgroup, and emergency medical services agency as predictors. The novel approach of Pediatric Prehospital Airway Resuscitation Trial will provide a feasible method to determine the optimal strategy for prehospital pediatric airway management and may transform the design of future prehospital resuscitation trials.

Thm2 interacts with paralog, Thm1, and sensitizes to Hedgehog signaling in postnatal skeletogenesis.

Mutations in the intraflagellar transport-A (IFT-A) gene, THM1, have been identified in skeletal ciliopathies. Here, we report a genetic interaction between Thm1, and its paralog, Thm2, in postnatal skeletogenesis. THM2 localizes to primary cilia, but Thm2 deficiency does not affect ciliogenesis and Thm2-null mice survive into adulthood. However, by postnatal day 14, Thm2-/-; Thm1aln/+ mice exhibit small stature and small mandible. Radiography and microcomputed tomography reveal Thm2-/-; Thm1aln/+ tibia are less opaque and have reduced cortical and trabecular bone mineral density. In the mutant tibial growth plate, the proliferation zone is expanded and the hypertrophic zone is diminished, indicating impaired chondrocyte differentiation. Additionally, mutant growth plate chondrocytes show increased Hedgehog signaling. Yet deletion of one allele of Gli2, a major transcriptional activator of the Hedgehog pathway, exacerbated the Thm2-/-; Thm1aln/+ small phenotype, and further revealed that Thm2-/-; Gli2+/- mice have small stature. In Thm2-/-; Thm1aln/+ primary osteoblasts, a Hedgehog signaling defect was not detected, but bone nodule formation was markedly impaired. This indicates a signaling pathway is altered, and we propose that this pathway may potentially interact with Gli2. Together, our data reveal that loss of Thm2 with one allele of Thm1, Gli2, or both, present new IFT mouse models of osteochondrodysplasia. Our data also suggest Thm2 as a modifier of Hedgehog signaling in postnatal skeletal development.

Critical Factors in Planning a Pediatric Prehospital Airway Trial.

Objective: The objective of this study was to assess factors influencing the design of a pediatric prehospital airway management trial, including minimum clinically significant differences for three clinical subgroups. Methods: We conducted a virtual consensus-conference among U.S. emergency medical services (EMS) agency medical directors and researchers in the Fall of 2020. This included (1) a preconference survey, (2) an interactive live videoconference, and (3) a postconference survey. Participants were identified through co-investigator relationships and by surveying "The Eagles," a consortium of medical directors from large urban EMS systems and, subsequently, through follow up email contact based on survey responses. Results: Twenty-seven of the 34 (80%) EMS agencies we invited responded to the prewebinar survey. Of the 27 agencies, 27 (100%) use BMV, 19 (70%) use endotracheal intubation (ETI), 21 (78%) use supraglottic airways (SGA). SGA use included 14 (52%) who use the iGel, 8 (30%) who use the King laryngeal tube (LT), and 2 (7%) who use a laryngeal mask airway (LMA). Three agencies use more than one of the available SGAs. Twenty (74%) of the EMS agencies indicated they had access to an SGA suitable for pediatric patients, and 9 (33%) agencies have access to pediatric video laryngoscopy. The majority of agencies indicated that the minimum clinically significant difference for survival to change practice was 1% for cardiac arrest patients with a baseline survival assumption of 7%, 4% for respiratory failure with a baseline survival assumption of 73%, and 3% for trauma with a baseline survival assumption of 42%. Overall, these agencies responded that BVM vs. SGA is the most important comparison that would change their practice. Conclusions: This virtual consensus conference provided a new perspective on current airway management practice and identified specific factors likely to drive change in pediatric prehospital airway management. This information will be leveraged in future trial design to ensure impactful clinical trials.