PIWI-interacting RNAs (piRNAs) protect germline genomes and maintain fertility by repressing transposons. Daedalus and Gasz act together as a mitochondrial scaffold for Armitage, a necessary factor for Zucchini-dependent piRNA processing. However, the mechanism underlying this function remains unclear. Here, we find that the roles of Daedalus and Gasz in this process are distinct, although both are necessary: Daedalus physically interacts with Armitage, whereas Gasz supports Daedalus to maintain its function. Daedalus binds to Armitage through two distinct regions, an extended coiled coil identified in this study and a sterile α motif (SAM). The former tethers Armitage to mitochondria, while the latter controls Zucchini endonucleolysis to define the length of piRNAs in an exonuclease-independent manner. piRNAs produced in the absence of the Daedalus SAM do not exhibit full transposon silencing functionality. Daedalus is Dipteran specific. Unlike Drosophila and mosquitoes, other species, such as mice, rely on exonucleases after Zucchini processing to specify the length of piRNAs.
The Daedalus ultrafast x-ray imager is the latest generation in Sandia's hybrid CMOS detector family. With three frames along an identical line of sight, 1 ns minimum integration time, a higher full well than Icarus, and added features, Daedalus brings exciting new capabilities to diagnostic applications in inertial confinement fusion and high energy density science. In this work, we present measurements of time response, dynamic range, spatial uniformity, pixel cross-talk, and absolute x-ray sensitivity using pulsed optical and x-ray sources. We report a measured 1.5 Me- full well, pixel sensitivity at 9.58 × 10-7 V/e-, and an estimate of spatial uniformity at ∼5% across the sensor array.
Haematopoiesis relies on tightly controlled gene expression patterns as development proceeds through a series of progenitors. While the regulation of hematopoietic development has been well studied, the role of noncoding elements in this critical process is a developing field. In particular, the discovery of new regulators of lymphopoiesis could have important implications for our understanding of the adaptive immune system and disease. Here we elucidate how a noncoding element is capable of regulating a broadly expressed transcription factor, Ikaros, in a lymphoid lineage-specific manner, such that it imbues Ikaros with the ability to specify the lymphoid lineage over alternate fates. Deletion of the Daedalus locus, which is proximal to Ikaros, led to a severe reduction in early lymphoid progenitors, exerting control over the earliest fate decisions during lymphoid lineage commitment. Daedalus locus deletion led to alterations in Ikaros isoform expression and a significant reduction in Ikaros protein. The Daedalus locus may function through direct DNA interaction as Hi-C analysis demonstrated an interaction between the two loci. Finally, we identify an Ikaros-regulated erythroid-lymphoid checkpoint that is governed by Daedalus in a lymphoid-lineage-specific manner. Daedalus appears to act as a gatekeeper of Ikaros's broad lineage-specifying functions, selectively stabilizing Ikaros activity in the lymphoid lineage and permitting diversion to the erythroid fate in its absence. These findings represent a key illustration of how a transcription factor with broad lineage expression must work in concert with noncoding elements to orchestrate hematopoietic lineage commitment.
To study the trade-off between economic, social and health outcomes in the management of a pandemic, DAEDALUS integrates a dynamic epidemiological model of SARS-CoV-2 transmission with a multi-sector economic model, reflecting sectoral heterogeneity in transmission and complex supply chains. The model identifies mitigation strategies that optimize economic production while constraining infections so that hospital capacity is not exceeded but allowing essential services, including much of the education sector, to remain active. The model differentiates closures by economic sector, keeping those sectors open that contribute little to transmission but much to economic output and those that produce essential services as intermediate or final consumption products. In an illustrative application to 63 sectors in the United Kingdom, the model achieves an economic gain of between £161 billion (24%) and £193 billion (29%) compared to a blanket lockdown of non-essential activities over six months. Although it has been designed for SARS-CoV-2, DAEDALUS is sufficiently flexible to be applicable to pandemics with different epidemiological characteristics.
Mechanical ventilation goals include restoration of gas exchange, lung protection, and patient comfort. Improving patient comfort through synchronous patient-ventilator interaction represents a common clinical challenge in the management of these patients. Patient-ventilator discordance describes a mismatch between the patient's intrinsic respiratory timing and effort with the ventilatory support provided by the ventilator. Achieving concordance requires an understanding of physiologic principles related to the control of breathing, expertise in recognition of discordance using the pressure and flow waveforms, and an in-depth knowledge of ventilator operation. Discordance is a common occurrence in ventilated patients, and over the past two decades, the recognition of patient-ventilator discordance has improved with education, simulation, and advances in instrumentation. Despite these advances, the impact of patient-ventilator discordance remains controversial. Growing evidence suggests patient-ventilator discordance is associated with adverse outcomes including mortality, increased sedation requirements, and duration of mechanical ventilation, although a cause-and-effect relationship has not been clearly demonstrated. Discordance may simply be a marker of the severity of illness. However, the impact of discordance varies based on the type and timing of discordance, lung mechanics, and the magnitude of patient effort. Some types of discordance may have positive effects. This article aims to explore the pathophysiology and identification of patient-ventilator discordance related to timing.
To evaluate the effectiveness of a novel suspension bending cast (SBC) technique for early-onset scoliosis (EOS) that enables coronal correction through suspension-assisted bending and facilitates derotational molding, and to identify factors associated with curve improvement. A retrospective review was conducted on 49 patients with EOS who underwent SBC between 2011 and 2023. For inclusion, patients had to be < 10 years at casting initiation and have ≥ 2 years of follow-up. Curves were measured before the first cast, after the first cast, at the end of casting, and at final follow-up. We analyzed curve improvement, scoliosis type, rib phase, and rib-vertebral angle difference (RVAD). Median age at initial casting was 44 months (interquartile range [IQR] 25-78). The median number of casts was 3 (IQR 2-6); the median follow-up was 58 months (IQR 35.0-81.6). The median curve was 63° before casting, corrected to 21° in the first cast, and 67° at final follow-up. Of the 49 patients, 30.6% went from casting to definitive fusion, and an additional 30.6% underwent additional surgery before definitive fusion, while the remaining 38.8% were "cured" or remain under non-operative management. Time from first cast application to any surgery was 38.6 months (IQR 21.9-58.5). Curve improvement (from initial to final) was associated with higher initial correction rates. Idiopathic scoliosis demonstrated greater initial correction than non-idiopathic scoliosis. No differences were observed in final curve or correction rate based on rib phase or RVAD. Suspension bending casts showed high initial correction in patients with moderate to severe EOS and contributed to delayed surgical intervention. A higher correction rate after the first cast was associated with long-term curve improvement, indicating that initial correction of casting may be an important prognostic factor.
Identifying patients at the highest risk of developmental dysplasia of the hip (DDH) is critical to the success of an efficient selective screening program. Defining and evaluating risk factors is, therefore, vital. This study was designed to analyze the relationship between classic risk factors and rates of DDH in a contemporary United States-based population. All patients presenting before 12 months of age to a single tertiary care pediatric hospital's orthopaedic department for DDH screening, with explicit medical record documentation of DDH risk factors from 2018 to 2022 were included. Classic risk factors were defined as breech presentation, female sex, firstborn status, and family history of hip dysplasia. Ultrasounds and radiographs obtained at initial presentation were reviewed to determine Graf and IHDI classifications. Reasons for referral for DDH screening were obtained from the chart review. One thousand two hundred twenty-six patients were eligible for the study. The probability of having DDH increased as the number of risk factors present for DDH increased ( P <0.001). Female sex and firstborn status were found to be independent risk factors for DDH. Females were 2.5 times more likely to have DDH than males ( P <0.001). Firstborn children were 1.3 times more likely to have DDH than subsequent birth-order children ( P =0.048). There was no difference in the proportion of DDH in breech presenting patients compared with non-breech ( P =0.511) or in subjects with a family history of DDH ( P =0.16). The primary risk factor for DDH in this contemporary cohort was female sex. Female patients without any other risk factors for DDH had a 25.2% rate of DDH, significantly higher than the estimated population incidence. Fifteen percent of these patients had no notable physical exam findings consistent with DDH. Given the high rate of DDH in female patients in the absence of notable physical exam findings, universal ultrasound screening for females at the age of 6 weeks should be considered. Level IV.
We report light-triggered charge separation in two discrete supramolecular architectures that self-assemble in a single step from donor (D) and acceptor (A) functionalized bridging ligands and Pd(II) cations. The "shape complementary assembly" (SCA) strategy allows for exclusive formation of the cis-[Pd2D2A2]4+ cage isomer. Compared to previously reported statistical DA assemblies, lacking stoichiometry and stereo control, the number of possible electron transfer routes was reduced. This enables a better understanding and tunability of the excited state dynamics. Cage assembly was investigated by NMR, MS, and single crystal X-ray diffraction analysis. Steady-state absorption and electrochemical properties indicate that donor and acceptor moieties remain largely independent in the electronic ground state. Femtosecond pump-probe spectroscopy in the visible and infrared was applied to compare the fate of photoexcited states for pure ligands, donor- and acceptor-only assemblies, and the donor-acceptor heteroleptic cages. For the latter, ultrafast intracage ligand-to-ligand charge separation is followed by two back electron transfer pathways, occurring on timescales of hundreds of picoseconds and around one nanosecond, assignable to D/A ligands facing each other in cis- or trans-position. Our work shows that non-statistical modular self-assembly can be used for the precise positioning of photoredox-active components in defined distances on the nanoscale.
Patient-ventilator discordance commonly occurs in patients receiving noninvasive ventilation (NIV). Unintentional leaks contribute to trigger and cycle asynchrony. Historically, ventilators designed for NIV with an intentional leak circuit compensated for unintentional leaks better than critical care ventilators. However, many critical care ventilators now have NIV settings for leak compensation. Per bench studies and some clinical studies, NIV settings for leak compensation variably improve synchrony related to leak. Some interfaces, such as the helmet, can contribute to asynchrony. Ventilator modes such a neurally adjusted ventilatory assist might improve synchrony but might not lead to better patient outcomes. Adaptive pressure control modes have the potential to remove support with increased patient effort, resulting in work shifting from the ventilator to the patient. Moreover, these modes are complicated if the ventilator does not correctly estimate tidal volume during NIV. Adding flow to the circuit, such as adding oxygen to increase FIO2, can also contribute to asynchrony. This article addresses issues related to discordance with NIV and strategies to improve patient-ventilator interactions during NIV.
Craniofacial distraction osteogenesis (DO) has proven clinical effectiveness in the management of syndromic craniosynostosis and other complex craniofacial abnormalities. However, current craniofacial distraction systems rely on external activation ports which, in turn, increase the risk of infection, mechanical failure, premature removal of the distraction system and significant sociopsychological burden. To address these problems, we developed the Magnet-Actuated Craniofacial (MAC) distraction system, a fully-internalized distraction system to eliminate the need for external activation ports. We conducted a comprehensive three-dimensional magnetostatic finite element modeling (FEM) framework to optimize the magnetic coupling efficiency of the MAC distraction system. Magnetic coupling configurations included a traditional coaxial dipole coupling and a redesigned U-shaped, flux-guided magnetic circuit incorporating high-energy neodymium magnets and a ferromagnetic shunt plate. Parametric analyses quantified torque-angle behavior, torsional stiffness, and axial forces over variable air domains (separation distances) up to 11.5 mm. The coaxial dipole configuration exhibited steep torque and force decay with increasing air domain, limiting reliable actuation and torque transmission across variable, clinically relevant soft-tissue thicknesses. In contrast, the U-shaped, flux-guided architecture enforced a dominant magnetic return path, yielding up to a six-fold increase in peak torque and over a five-fold improvement in torsional stiffness at small air domains, while maintaining clinically relevant transmissible torque and attractive forces even at larger air domains. Magnetic actuation limitations are not intrinsic but design-dependent. Flux-guided magnetic circuit engineering enabled robust, precise, predictable, and anatomy-tolerant transdermal torque transmission, supporting the feasibility of a fully-internalized, magnetically-actuated craniofacial distraction.
Growth modulation is an established technique for limb deformity correction and is increasingly applied to spinal deformities. While distraction-based posterior and anterior compressive methods have been explored, spinal growth modulation through fixation across vertebral growth centers remains unstudied. We hypothesized that unilateral trans-endplate screws-spinal epiphysiodesis trajectory (SET) screws-could induce partial anterior growth arrest and promote scoliotic deformity in a porcine model. Four male piglets (two experimental, two control) underwent unilateral posterior spinal instrumentation at four lower thoracic levels at eight weeks of age. Experimental animals received trans-endplate SET screws; controls received pedicle screws. Radiographs obtained three months postoperatively assessed vertebral height and Cobb angles. MRI and CT were also used to evaluate vertebral wedging, disc and facet health, physeal bars, and endplate changes. After three months, no significant differences in coronal or sagittal Cobb angles were observed between SET and pedicle screw groups (p > 0.05). No vertebral wedging or restriction of vertical growth was seen in either group. Disc and facet health remained unchanged by Pfirrmann and Fujiwara grading. No physeal bars were identified; one SET specimen showed endplate irregularities. In this pilot porcine model, SET screws did not produce scoliotic or kyphotic deformity. Further research is necessary to clarify the mechanisms and timing required for effective anterior spinal growth modulation. IV.
This paper describes two new species of the genus Xizicus Gorochov, 1993 (Tettigoniidae: Meconematini) from China (Guangxi and Sichuan), i.e. Xizicus (Xizicus) rectangulatus sp. nov., Xizicus (Haploxizicus) carinicaudatus sp. nov., reports Xizicus (Xizicus) daedalus Gorochov, 2011 from China for the first time. In addition, the first description of the female of Acosmetides dilobosa Chang, Wang & Shi, 2021 is presented.
An atlas of wing photographs and a key to 91 species of biting midges in the genus Culicoides from Mexico. Culicoides (Diphaomyia) evansi Wirth & Blanton from Morelos and C. (Drymodesmyia) pilosus Wirth & Blanton from Hidalgo are recorded from Mexico. Two new species from Chiapas are described and illustrated, Culicoides ostotlae sp. nov. in the Daedalus group and Culicoides tzotzil sp. nov. in the subgenus Diphaomyia. We proposed a new status for Culicoides neghmei Vargas in the Limai group, which is closely related to C. luglani Jones & Wirth, and C. propinquus Macfie to be included in the subgenus Drymodesmyia. Culicoides wirthomyia Vargas is now a junior synonym of C. jamaicensis Edwards.
Exacerbations in COPD can be life-threatening and can lead to irreversible declines in lung function and quality of life. Medications that reduce exacerbation burden are an unmet need, because exacerbations put patients at risk of more exacerbations and decrease quality of life. Ensifentrine is a first-in-class selective dual inhibitor of phosphodiesterase 3 and 4 with demonstrated nonsteroidal antiinflammatory activity and bronchodilatory effects. Does ensifentrine reduce the rate or risk of COPD exacerbations? A prespecified, pooled analysis of the phase 3 clinical trials Ensifentrine as a Novel Inhaled Nebulized COPD Therapy (ENHANCE)-1 (ClinicalTrials.gov Identifier: NCT04535986) and ENHANCE-2 (ClinicalTrials.gov Identifier: NCT04542057) was conducted to assess the effect of ensifentrine on exacerbation rate and risk (time to first exacerbation). The trials included symptomatic patients aged 40 to 80 years with moderate to severe COPD who received 3 mg twice-daily ensifentrine over 24 weeks or placebo. Subgroup analyses and frequent exacerbator transition risk assessment were conducted post hoc. In total, 975 patients treated with ensifentrine and 574 patients who received placebo were included in the pooled analysis, including 62% of patients receiving concomitant long-acting muscarinic antagonist or long-acting β2-agonist therapy and 18% receiving concomitant inhaled corticosteroid therapy. Ensifentrine was associated with significant reductions in the rate (rate ratio, 0.59; 95% CI, 0.43-0.80; P < .001) and risk (hazard ratio, 0.59; 95% CI, 0.44-0.81; P < .001) of moderate to severe exacerbations compared with placebo. Reductions in the rate and risk of exacerbations generally were consistent across patient subgroups, including age, sex, race, background maintenance medication use, chronic bronchitis, eosinophil count, COPD severity, and exacerbation history. Ensifentrine was associated with a numerical delay in transitioning from an infrequent exacerbator (Global Initiative for Chronic Obstructive Lung Disease group B) to a frequent exacerbator (Global Initiative for Chronic Obstructive Lung Disease group E) compared with placebo. Ensifentrine reduced the rate of exacerbations and increased the time to first exacerbation among patients with COPD across a broad range of clinically relevant subgroups.
Many patients who are extubated after receiving mechanical ventilation for acute respiratory failure experience extubation failure (ie, require reintubation hours to days after extubation). High-quality evidence shows that extubating patients directly to non-invasive ventilation (NIV) or high-flow nasal cannula oxygen (HFNC), rather than conventional low-flow oxygen, can prevent extubation failure. These guideline-recommended interventions, however, require care coordination involving multiple intensive care unit (ICU) team members and are infrequently used. Interprofessional education (IPE), which teaches members of multiple professions together, could effectively address this implementation gap in complex, team-based, critical care settings, particularly when paired with a customisable protocol. This batched, stepped-wedge, cluster-randomised, type 2 hybrid effectiveness-implementation trial will test three hypotheses: (1) when compared with traditional online education (OE), IPE increases implementation of preventive postextubation respiratory support, (2) the benefits of IPE are increased when paired with a clinical protocol and (3) preventive postextubation NIV for high-risk patients and preventive postextubation HFNC for low-risk patients reduce in-hospital mortality when compared with conventional postextubation oxygen therapy. The trial will recruit 24 clusters made up of one or more ICUs that care for at least 100 mechanically ventilated patients per year in a large multihospital health system in the USA. All clusters will receive OE, IPE and a clinical protocol, with timing determined by randomisation. We will also randomise half of the clusters to education promoting postextubation NIV for patients at high risk of extubation failure and preventive, postextubation HFNC for patients at lower risk, whereas the other half will be randomised to education promoting postextubation HFNC for all eligible patients. We will include all patients who are invasively mechanically ventilated for at least 24 hours. The primary implementation endpoint is the rate of use of postextubation NIV or HFNC among eligible participants. The primary clinical endpoint is in-hospital mortality truncated at 60 days from intubation. This study was approved by the institutional review board of the University of Pittsburgh and an independent data safety monitoring board. We describe the methods herein using the Standard Protocol Items for Randomised Trials framework and discuss key design decisions. We will disseminate results to participating healthcare providers, through publication in a peer-reviewed medical journal and via presentations at international conferences. NCT05523479.
Gross-slip fretting corrosion occurs frequently inside taper joints of endoprosthetic implants and is expected to be accompanied by the formation of a metal-organic tribomaterial, which may influence the friction and wear behavior of implants. While it is hypothesized that it contains compounds of the surrounding human body fluid and worn particles of the implant materials, its structure, composition, formation mechanism, and distribution inside the wear area remain elusive. In a multiscale structural-chemical study using Raman scattering spectroscopy and transmission electron microscopy, we reveal the tribological formation of nanocrystalline cobalt sulfide for a CoCrMo/TiAlV couple that was subjected to in vitro gross-slip fretting in bovine calf serum. We demonstrate that sulfur atoms released from the mechanochemical decomposition of cysteine/cystine disulfide bonds in serum proteins ─ as evidenced by the complete absence of characteristic S-S Raman modes and concurrent protein unfolding from α-helix to β-sheet structures ─ react with cobalt ions released tribocorrosively from the alloy to form the CoSx tribomaterial. The resulting tribofilm is substoichiometric (x < 2) with a primary cubic structure partially mixed by a hexagonal phase. It perfectly adheres to the Co alloy through mechanical mixing, thus exhibiting the structural features of extreme-pressure antiwear additives. The CoSx tribofilm covers 12.2% of the fretting track in the CoCrMo alloy, while maintaining a consistent thickness of approximately 15 nm. Multiple mechanisms driving this transformation are discussed: mechanical protein unfolding exposes disulfide bonds to forces that reduce their cleavage activation energy, local temperatures allow for thermal decomposition, and the acidic crevice environment facilitates chemical cleavage. The observations on the fretting-generated CoSx tribomaterial provide the first comprehensive structural-chemical insight into tribologically beneficial features of transition metal sulfides formed in medical alloys through protein-derived sulfur. Understanding this mechanism may enable strategies to deliberately promote such protective film formation to improve the longevity of taper junctions in medical applications.
Cohort study. Validate the Surgical Apgar Score (SAS) as a means of predicting perioperative major complications occurring within 30 days after scoliosis surgery in pediatric patients with cerebral palsy (CP). A patient's SAS, which is composed of three commonly recorded intraoperative variables, predicts postoperative complications after various types of spine surgery. This has not; however, been studied in pediatric patients with scoliosis and CP, a population that experiences a high incidence of complications after corrective spinal surgery. Pediatric CP patients who underwent spinal correction surgery were included in this study. Patient background, surgical variables, and perioperative complications occurring within 30 days after surgery were collected. Patients were divided into 4 groups based on their SAS: SAS 0 to 4, SAS 5 to 6, SAS 7 to 8, and SAS 9 to 10. The incidences of perioperative complications for each group were compared using a receiver operating characteristic analysis. The area under the curve (AUC) is reported. A total of 111 patients met the inclusion criteria. There were no death cases. There were 44 (39.6%) perioperative major complications in 37 (33.3%) patients that occurred within 30 days after spine surgery. The most frequent perioperative complications were pulmonary issues (13.5%). The incidence of perioperative major complication in each SAS group was as follows: SAS 0 to 4; 51.6%, SAS 5 to 6; 30.2%, SAS 7 to 8; 18.5%, SAS 9 to 10; 0/0. When the SAS 7 to 8 group was set as the reference, there was no significant difference compared to SAS 5 to 6 ( P =0.34), while the incidence rate was significantly increased in SAS 0 to 4 ( P =0.02). The AUC was 0.65 (95% CI: 0.54-0.75). Overall, there were 37 (33.3%) patients with CP who had a major complication within 30 days after spinal surgery. Lower SAS, with the 0 to 4 group being the cutoff, were associated with significantly higher complication rates than higher SAS groups.
Physiologic closed-loop control (PCLC) of inspired oxygen during mechanical ventilation involves frequent adjustment of inspired oxygen fraction (FiO2) based on feedback from monitoring peripheral oxygen saturation (SpO2). Safety assessments of PCLC algorithms are important prerequisites for patient care, but clinical trials often fail to represent worst-case scenarios that identify limits of safe usage and often do not quantify performance sensitivity to physiologic deviations. The objective of this study was to develop and validate a virtual patient model of pulmonary and systemic gas exchange to assess the safety and efficacy of a PCLC algorithm for FiO2 control. A large-scale (3,780,000 simulated patients) virtual observational study was conducted with three clinically relevant scenarios: (1) a step change in patient cardiorespiratory condition; (2) a step change in target SpO2; and (3) a step change in PCLC activation. Virtual patients were simulated using a uniform sampling approach to evaluate controller performance in challenging and extreme conditions representing worst-case scenarios. Results in the virtual cohort are not intended to convey predictions of controller performance in typical real-world cohorts. The results demonstrate that PCLC of FiO2 is effective for reducing the duration and severity of desaturation during a sudden change in patient condition, and in many cases prevents desaturation altogether (e.g., reducing the occurrence of prolonged desaturation from 69.8 % to 1.5 %). Performance was most sensitive to the physiologic delay between changes in arterial and peripheral oxygenation saturations. Longer physiologic delays (120-300 s) coupled with positive SpO2 sensor bias (1.5-3.0 %) were also associated with increased likelihood of system response oscillations. The impact of initial FiO2 setting on performance metrics was nonuniform (although 0.4 initial FiO2 was optimal in most cases), and was most affected by variations in pulmonary shunt fraction and SpO2 sensor bias. This study demonstrates the utility of large-scale virtual patient modeling for sampling wide ranges of physiologic parameters using a multifactorial approach. Sampled conditions may be rarely observed in clinical practice or underrepresented in clinical trials yet warrant careful consideration when evaluating safety and efficacy of autonomous medical device control. The potential impact of the virtual patient model and proposed study design is improved rigor in the evaluation of medical device safety and efficacy, achieved by using computational modeling to complement the shortcomings of clinical trials.