Differential Delay Research Articles

Dihydropyrimidine dehydrogenase polymorphisms in patients with gastrointestinal malignancies and their impact on fluoropyrimidine tolerability: Experience from a single Italian institution.

Fluoropyrimidines are metabolized in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. About 7% of the European population is a carrier of DPYD gene polymorphisms associated with reduced DPD enzyme activity. To assess the prevalence of DPYD polymorphisms and their impact on fluoropyrimidine tolerability in Italian patients with gastrointestinal malignancies. A total of 300 consecutive patients with a diagnosis of gastrointestinal malignancy and treated with a fluoropyrimidine-based regimen were included in the analysis and divided into two cohorts: (1) 149 patients who started fluoropyrimidines after DPYD testing; and (2) 151 patients treated without DPYD testing. Among the patients in cohort A, 15% tested only the DPYD2A polymorphism, 19% tested four polymorphisms (DPYD2A, HapB3, c.2846A>T, and DPYD13), and 66% tested five polymorphisms including DPYD6. Overall, 14.8% of patients were found to be carriers of a DPYD variant, the most common being DPYD6 (12.1%). Patients in cohort A reported ≥ G3 toxicities (P = 0.00098), particularly fewer nonhematological toxicities (P = 0.0028) compared with cohort B, whereas there was no statistically significant difference between the two cohorts in hematological toxicities (P = 0.6944). Significantly fewer chemotherapy dose reductions (P = 0.00002) were observed in cohort A compared to cohort B, whereas there was no statistically significant differences in chemotherapy delay. Although this study had a limited sample size, it provides additional information on the prevalence of DPYD polymorphisms in the Italian population and highlights the role of pharmacogenetic testing to prevent severe toxicity.

Low-polarization-sensitive 1 × 2 carrier-injection-type silicon photonic switch consisting of input-/ output-side polarization splitter/rotators and a single Mach-Zehnder interferometer.

We propose a low-polarization-sensitive 1 × 2 carrier-injection-type silicon photonic switch consisting of a single Mach-Zehnder interferometer, an input-/output-side polarization splitter and rotators, bidirectional light injection, and an external optical circulator. A polarization-dependent loss (PDL) of 1.3 dB was achieved using the proposed structure, whereas a PDL exceeding 17 dB was observed without the structure. In addition, owing to the large birefringence of the silicon waveguide, a differential group delay (DGD) of 10 ps for a 10 Gbps OOK signal was observed. However, a reduced polarization dependence was confirmed through bit error rate measurements, with the power penalty difference lower than 1 dB.

Applying Stiff Integrators for Ordinary Differential Equations and Delay Differential Equations to Problems with Distributed Delays

Applying Stiff Integrators for Ordinary Differential Equations and Delay Differential Equations to Problems with Distributed Delays

Leishmania mexicana N-Acetyltransferease 10 Is Important for Polysome Formation and Cell Cycle Progression.

Leishmania presents a complex life cycle that involves both invertebrate and vertebrate hosts. By regulating gene expression, protein synthesis, and metabolism, the parasite can adapt to various environmental conditions. This regulation occurs mainly at the post-transcriptional level and may involve epitranscriptomic modifications of RNAs. Recent studies have shown that mRNAs in humans undergo a modification known as N4-acetylcytidine (ac4C) catalyzed by the enzyme N-acetyltransferase (NAT10), impacting mRNAs stability and translation. Here, we characterized the NAT10 homologue of L. mexicana, finding that the enzyme exhibits all the conserved acetyltransferase domains although failed to functionally complement the Kre33 mutant in Saccharomyces cerevisiae. We also discovered that LmexNAT10 is nuclear, and seems essential, as evidenced by unsuccessful attempts to obtain null mutant parasites. Phenotypic characterization of single-knockout parasites revealed that LmexNAT10 affects the multiplication of procyclic forms and the promastigote-amastigote differentiation. Additionally, invivo infection studies using the invertebrate vector Lutzomyia longipalpis showed a delay in the parasite differentiation into metacyclics. Finally, we observed changes in the cell cycle progression and protein synthesis in the mutant parasites. Together, these results suggest that LmexNAT10 might be important for parasite differentiation, potentially by regulating ac4C levels.

Foxm1 promotes differentiation of neural progenitors in the zebrafish inner ear.

During development of the vertebrate inner ear, sensory epithelia and neurons of the statoacoustic ganglion (SAG) arise from lineage-restricted progenitors that proliferate extensively before differentiating into mature post-mitotic cell types. Development of progenitors is regulated by Fgf, Wnt and Notch signaling, but how these pathways are coordinated to achieve an optimal balance of proliferation and differentiation is not well understood. Here we investigate the role in zebrafish of Foxm1, a transcription factor commonly associated with proliferation in developing tissues and tumors. Targeted knockout of foxm1 causes no overt defects in development. Homozygous mutants are viable and exhibit no obvious defects except male sterility. However, the mutant allele acts dominantly to reduce accumulation of SAG neurons, and maternal loss-of-function slightly enhances this deficiency. Neural progenitors are specified normally but, unexpectedly, persist in an early state of rapid proliferation and are delayed in differentiation. Progenitors eventually shift to a slower rate of proliferation similar to wild-type and differentiate to produce a normal number of SAG neurons, although the arrangement of neurons remains variably disordered. Mutant progenitors remain responsive to Fgf and Notch, as blocking these pathways partially alleviates the delay in differentiation. However, the ability of elevated Wnt/beta-catenin to block neural specification is impaired in foxm1 mutants. Modulating Wnt at later stages has no effect on progenitors in mutant or wild-type embryos. Our findings document an unusual role for foxm1 in promoting differentiation of SAG progenitors from an early, rapidly dividing phase to a more mature slower phase prior to differentiation.

RENEWED: A follow-up study of the opicinumab phase 2 RENEW study in participants with acute optic neuritis

BackgroundThe randomized, phase 2 RENEW trial (NCT01721161) evaluated efficacy/safety of opicinumab (anti-LINGO-1) versus placebo in patients with first-episode unilateral acute optic neuritis (AON). Although no significant differences in the latency recovery of visual evoked potential (VEP) were observed between opicinumab and placebo groups in the intention to treat (ITT) population, the prespecified per-protocol (PP) population showed better recovery with opicinumab than with placebo. RENEWED (NCT02657915) was a one-visit, follow-up study 2 years after the last RENEW study visit (Week 32) designed to assess the long-term electrophysiological and clinical outcomes for participants previously enrolled and having received study treatment in RENEW. MethodsIn the original study (RENEW), participants (aged 18–55 years) with a first unilateral AON episode were enrolled ≤28 days from first symptom onset and after treatment with methylprednisolone 1 g/day intravenously for 3–5 days; these participants were randomized to receive opicinumab 100 mg/kg or placebo intravenously once every 4 weeks from baseline to Week 20, assessed up to Week 32. Participants who received ≥1 dose of opicinumab 100 mg/kg or placebo in RENEW were eligible for the RENEWED follow-up study. Participants enrolled in RENEWED at 2 years (with an additional up to 12-month window) after the last RENEW study visit (Week 32) in both ITT and PP populations. The primary endpoint was change in full-field VEP (FF-VEP) latency of the affected eye at RENEWED study visit versus baseline of the fellow eye in RENEW, comparing between participants who received opicinumab and placebo in RENEW. Clinical progression and severity of multiple sclerosis (MS) were assessed. A substudy evaluated latency recovery using multifocal VEP (mfVEP) as an exploratory endpoint. ResultsOf 82 RENEW participants, 52 (63.4%; opicinumab n=28, placebo n=24) enrolled in and completed RENEWED. The adjusted mean (95% CI) difference in FF-VEP latency delay between opicinumab and placebo groups was −6.0 (−14.6, 2.6) msec (p=0.165) for the PP population and −4.5 (−12.6, 3.7) msec (p=0.274) for the ITT population at the RENEWED study visit. Nominally significant improvement on mfVEP latency in the opicinumab group versus placebo was observed in participants of the mfVEP substudy (p=0.009). In participants from the PP population without clinically definite MS (CDMS) at RENEW baseline,12 (55%) in the opicinumab group and 12 (67%) in the placebo group developed CDMS from enrollment in the RENEW study up to RENEWED Day 1; the estimated proportion of participants with CDMS at 2 years after the last study visit assessment in RENEW was lower when treated with opicinumab (0.50) than when treated with placebo (0.61) (hazard ratio p-value=0.23). No benefit on visual acuity or other neurological functions was observed in the opicinumab group vs placebo in RENEWED. ConclusionThe numerically increased VEP latency recovery with opicinumab treatment in RENEWED was consistent with those observed in the parent study RENEW. However, the VEP latency and clinical data in RENEWED should be interpreted with caution, given the nature of the follow-up study, the small sample size and the limitation in study design.

LEO Satellite-Enabled Random Access with Large Differential Delay and Doppler Shift

LEO Satellite-Enabled Random Access with Large Differential Delay and Doppler Shift

Assessment of Oral Anticoagulant Reversal Strategies in Emergency Surgery: Insights from a Prospective Study

Introduction: The management of thrombotic risk in clinical medicine has been a longstanding challenge. Oral anticoagulants, specifically vitamin K antagonists (VKAs) like warfarin, have been used for over fifty years. However, VKAs present significant challenges such as frequent monitoring and dietary interactions. Direct oral anticoagulants (DOACs) were developed to address these limitations, offering simplified dosing and fewer interactions. Both VKAs and DOACs, however, pose challenges in managing major bleeding and urgent surgical interventions. Methods: This prospective study, conducted at Mohammed V Military Hospital in Rabat from January 2022 to January 2023, examined the clinical practice, efficacy, and safety of different treatment strategies in patients on oral anticoagulants (VKAs and DOACs) requiring emergency surgery within 24 hours of hospital admission. Inclusion criteria included being over 18 years of age, on anticoagulant therapy, and requiring emergency surgery. Patients were evaluated for bleeding before and after surgery, use of hemostatic agents, blood loss, transfusions, and adverse events. Results: A total of 69 patients were included, with 48 treated with VKAs and 21 with DOACs. The mean age was 63.8 years (range 36-78), with a mean age of 62.5 years (±10.2) for the VKA group and 66.7 years (±9.1) for the DOAC group (p = 0.44). There was no significant difference in delays to surgery between the VKA (68%) and DOAC (66.6%) groups for surgeries performed within 24 hours. Hemostatic treatment varied significantly, with more VKA patients receiving resh frozen plasma (77% vs. 52%) and more DOAC patients receiving prothrombin complex concentrates (48% vs. 23%). Bleeding complications were observed in 12.5% of VKA patients and 9.5% of DOAC patients. Thromboembolic events were observed in one patient within 30 days, specifically, a pulmonary embolism occurring on day 3 in a patient who underwent surgery for a hip fracture. The mortality rate ...

KMT2d regulates tooth enamel development.

Amelogenesis, the process of enamel formation, is tightly regulated and essential for producing the tooth enamel that protects teeth from decay and wear. Disruptions in amelogenesis can result in amelogenesis imperfecta, a group of genetic conditions characterized by defective enamel, including enamel hypoplasia, marked by thin or underdeveloped enamel. Mutations in the KMT2D (MLL4) gene, which encodes a histone H3-lysine 4-methyltransferase, are associated with Kabuki syndrome, a developmental disorder that can involve dental anomalies such as enamel hypoplasia. However, the specific role of KMT2D in amelogenesis remains poorly understood. To address this gap, we generated a conditional knockout mouse model with ectoderm-specific deletion of Kmt2d (Krt14-Cre;Kmt2dfl/fl, or Kmt2d-cKO) and characterized the resulting enamel defects using gross, radiographic, histological, cellular, and molecular analyses. Micro-computed tomography and scanning electron microscopy revealed that adult Kmt2d-cKO mice exhibited 100% penetrant amelogenesis imperfecta, characterized by hypoplastic and hypomineralized enamel, partially phenocopying human Kabuki syndrome. Additionally, Kmt2d-cKO neonates developed molar tooth germs with subtle cusp shape alterations and mild delays in ameloblast differentiation at birth. RNA-seq analysis of the first molar tooth germ at birth revealed that 33.7% of known amelogenesis-related genes were significantly downregulated in the Kmt2d-cKO teeth. Integration with KMT2D CUT&RUN-seq results identified 8 overlapping genes directly targeted by KMT2D. Re-analysis of a single-cell RNA-seq dataset in the developing mouse incisors revealed distinct roles for these genes in KMT2D-regulated differentiation across various cell subtypes within the dental epithelium. Among these genes, Satb1 and Sp6 are likely direct targets involved in the differentiation of pre-ameloblasts into ameloblasts. Taken together, we propose that KMT2D plays a crucial role in amelogenesis by directly activating key genes involved in ameloblast differentiation, offering insights into the molecular basis of enamel development and related dental pathologies.

Low-loss weakly coupled four-mode hollow-core antiresonant fiber based on centrosymmetric nested structure

Abstract This paper designs a novel centrosymmetric double-layer nested antiresonant fiber (CDNAF) with few-mode transmission characteristics. The cladding structure of the CDNAF incorporates glass plates and multilayer capillaries, effectively mitigating the coupling between various core modes and cladding modes. Simulation results show that the CDNAF can support four modes of low-loss transmission from LP01 to LP02 at 1550 nm. The confinement loss (CL) of the four modes is less than 0.008 dB/km, 0.07 dB/km, 0.42 dB/km, and 4.8 dB/km, respectively, and the CDNAF has a sizeable differential group delay (DGD) and weak bending sensitivity. The loss of high-order modes is much greater than that of the other four transmission modes, ensuring high-purity transmission of the four modes. In the wavelength range of 1200–1700 nm, the CDNAF ensures few-mode characteristics with at least two low-loss transmission modes. Furthermore, the effective refractive index difference (Δneff) between adjacent modes is much greater than 10^(-4), eliminating or significantly reducing the need for multiple-input multiple-output digital signal processing (MIMO-DSP) techniques in optical communication systems. Additionally, the results demonstrate that CDNAF can transmit three modes at an ultimate bending radius of 5 cm and can transmit four modes like a straight fiber at a bending radius of 18 cm, which demonstrates that CDNAF has excellent bending performance. These excellent characteristics give the CDNAF great potential for application in large-capacity optical communication systems.

Spectrally encoded flow cytometry using few-mode fiber collection.

In fiber-based confocal microscopy, using two separate fibers for illumination and collection enables the use of a few-mode fiber to achieve an effect similar to opening the pinhole in a conventional confocal microscope. In some Fourier-domain applications, however, or when a spectral measurement is involved, the coherent light detection would lead to noticeable spectral modulation artifacts that result from differential mode delay, an effect caused by the multimode propagation in the collection fiber. After eliminating these artifacts by using mode-dependent polarization control, we demonstrate effective spectrally encoded imaging with improved signal efficiency and lower speckle noise, and only a minor, negligible reduction in lateral and axial resolutions.

Sex Differences in Stroke in a Sri Lankan Cohort

Introduction: Stroke characteristics, subtypes, and risk factors in women may differ from men. Data on sex differences in stroke are scarce in developing countries, especially the South Asian region. We aimed to describe the sex differences in patients with stroke admitted to a tertiary care hospital in Sri Lanka. Methods: Consecutive patients with stroke enrolled in the Ragama Stroke Registry over 3 years (2020–2023) were studied. Sex differences in demographics, presentation delays, clinical characteristics, stroke subtypes, risk factors, stroke severity, and early functional outcomes were compared using χ2 test, independent sample t test and Wilcoxon rank-sum test. Associations of early functional dependence were studied using multiple logistic regression. Results: Of 949 patients with stroke, 387 (40.8%) were women, with a median age of 66 (interquartile range [IQR] 57–73) years compared to 63 (IQR 54–70) years in men (p < 0.001). Women had more ischaemic strokes (85.8% vs. 78.6% in men, p = 0.005). Swallowing difficulty (p = 0.039) and bladder involvement (p = 0.001) were more common in women, whereas dysarthria (p = 0.002) and cerebellar signs (p = 0.005) were more common in men. More women had hypertension (74.4% vs. 59.4%, p < 0.001) and diabetes (52.2% vs. 41.6%, p = 0.001), whereas smoking (0.3% vs. 35.1%, p < 0.001), alcohol use (0.3% vs. 55.0%, p < 0.001), and other substance abuse (0.8% vs. 5.2%, p < 0.001) were almost exclusively seen in men. No differences were noted in delays to hospital admission (delay ≥4.5 h: women 45.4% vs. men 41.3%, p = 0.222). There were no sex differences in the rates of CT scanning (women 100% vs. men 99.6%, p = 0.516) or thrombolysis for ischaemic stroke (women 7.8% vs. men 10.2%, p = 0.458), but more men received stroke unit care (women 37.2% vs. men 45.4%, p = 0.012). No differences were noted between sexes in the clinical (Oxfordshire classification, p = 0.671) or aetiological (TOAST criteria, p = 0.364) subtypes of stroke. Stroke severity on admission was similar between sexes (median NIHSS score; women 8.0 vs. men 8.0, p = 0.897). More women had a discharge Barthel index (BI) <60 than men (62.6% vs. 53.5%, p = 0.007), but female sex was not associated with BI <60 on multivariate logistic regression (p = 0.134). There was no difference in in-hospital mortality (women 5.9% vs. men 5.9%, p = 0.963). Conclusions: Women with stroke in this Sri Lankan cohort were older, had different risk factor profiles and clinical stroke characteristics, and had more ischaemic strokes. Female sex was not independently associated with functional disability on discharge or in-hospital mortality.

Synchronization of Neural Networks With Unbounded and Non‐Differentiable Delays via Decentralized Adaptive Control

ABSTRACTSynchronization of delayed neural networks has been investigated in recent years via decentralized adaptive control methods. However, the effectiveness of the reported results heavily depends on the assumptions that network delays are bounded or differentiable. For more general cases involving unbounded and non‐differentiable delays, it remains unclear whether the existing analytical methods and controller designs are still effective. To this end, in this article, a novel method is established to analyze the asymptotical convergence of the controlled error system with adaptive parameters by employing the differential inequality techniques for unbounded delay and Barbalat's lemma, which can effectively overcome the limitations of traditional methods in handling general delay scenarios. The theoretical results demonstrate that traditional decentralized adaptive controller for network synchronization remains effective even if the boundedness and differentiability of delay are removed. A numerical simulation further validates the effectiveness of the proposed theories.

Shadowing and hyperbolicity for linear delay difference equations

It is known that hyperbolic linear delay difference equations are shadowable on the half-line. In this article, we prove the converse and hence the equivalence between hyperbolicity and the positive shadowing property for the following two classes of linear delay difference equations: (a) for non-autonomous equations with finite delays and uniformly bounded compact coefficient operators in Banach spaces and (b) for Volterra difference equations with infinite delay in finite dimensional spaces.

No associations between neuroborreliosis in children and psychiatric neurodevelopmental disorders: a nationwide, population‐based, matched cohort study

BackgroundIt has been suggested that neuroborreliosis in children can manifest as psychiatric neurodevelopmental disorders or cause long‐term neurodevelopmental sequelae. However, previous studies were limited by size and design.MethodsWe performed a nationwide, population‐based, matched cohort study in Denmark between 1995 and 2021. We included all Danish residents &lt;16 years old with a positive Borrelia burgdorferi sensu lato intrathecal antibody index test (children with neuroborreliosis). To form a comparison cohort, we randomly extracted individuals from the general population matched on date of birth and sex 10:1 to children with neuroborreliosis. We calculated hazard ratios (HRs) with 95% CIs of contact to departments of psychiatry, diagnosis of attention deficit disorder, diagnosis of learning or intellectual developmental disorders, or receipt of psychostimulants for attention deficit disorder among children with neuroborreliosis compared with comparison cohort members. We did a sensitivity analysis in the form of a case‐control study, where we examined whether these outcomes were more frequent among children with neuroborreliosis than in the comparison cohort before study inclusion to account for differential delay in diagnosis.ResultsWe included 1,132 children with neuroborreliosis and 11,320 comparison cohort members with an observation time of 168,858 person‐years. We found no associations between neuroborreliosis and contact with departments of psychiatry (HR: 1.0, 95% CI 0.9–1.2), diagnosis of attention deficit disorder (HR: 0.9, 95% CI 0.6–1.3), diagnosis of learning or intellectual developmental disorders (HR 0.8, 95% CI 0.5–1.4), or receipt of psychostimulants for attention deficit disorder (HR: 0.8, 95% CI 0.6–1.1). Also, in the sensitivity analyses, these outcomes were not more present among children with neuroborreliosis than in the comparison cohort before study inclusion.ConclusionsOur results do not support that neuroborreliosis in children manifests as psychiatric neurodevelopmental disorders or causes long‐term neurodevelopmental sequelae.

Equatorial plasma bubble model and integrity risk evaluation for ground based augmentation system in Hong Kong

The spatial gradient induced by the Equatorial Plasma Bubble (EPB) in low latitude regions is a major challenge for the Ground Based Augmentation System (GBAS). To facilitate the implementation and operation of GBAS Approach Service Type (GAST)-D at Hong Kong International Airport, the impact of EPB induced spatial gradients needs to be analyzed. Previous simulations using a two-dimensional trapezoid model neglected the three-dimensional structure of the EPB, assuming ionospheric delay on a thin shell at a specific altitude. To address this limitation, this paper adopts a cube above the magnetic equator to characterize the EPB threat model. The ionospheric delay difference between satellite signals passing through the EPB model is limited by the upper bound spatial gradient derived with the data collected from Hong Kong Satellite Positioning Reference Station Network. The simulation results reveal that ionospheric monitors in GAST D can satisfy the Category II/III approach requirement, i.e., the probability of missed detection PMD\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${P}_{\ ext{MD}}$$\\end{document} for the differential range error Er larger than 2.75 m is lower than 1×10-9\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${1\ imes 10}^{-9}$$\\end{document}. The potentially hazardous event with the largest Er of 2.47 m and PMD\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${P}_{\ ext{MD}}$$\\end{document} of 1.86×10-9\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${1.86\ imes 10}^{-9}$$\\end{document} occurs when the satellite signal moves parallel to the equator near the Equatorial Ionization Anomaly (EIA) region, and its significant portion traverses in the EPB depletion region.

Self-tuning architecture enabling bidirectional transceiver normalization and low differential latency

Due to having only one working wavelength, single wavelength bidirectional transmission combines the advantages of fiber saving and transceiver normalization. This is beneficial for reducing the CAPEX and OPEX of networks, and can also improve the time synchronization accuracy of mobile CRAN networks. However, the performance of single wavelength bidirectional transmission is invariably sensitive to backward reflected emission light. Frequency shifting and digital signal processing are typical approaches to eliminate this penalty, but it leads to higher cost and power consumption. In this paper, we first apply a self-tuning architecture and physical layer negotiation in bidirectional transceiver, to allow the transceiver to support two modes. Then a single-fiber bidirectional transmission can be setup by this normalized transceiver as single working wavelength but without performance penalty. Except wavelength, other performances of manufactured 25 G Baud PAM4 self-tuning bidirectional transceiver are compliant with IEEE 802.3cp 40 km ER specification. When the two working mode wavelength interval is 0.4 nm, the latency difference over 40 km is 250 ps, which is on the same order of magnitude as the delay difference in single wavelength bidirectional transmission.

Transcriptional Regulation of Mammary Alveolar Proliferation and Differentiation during Early Pregnancy.

Proliferation and differentiation of the mammary gland during pregnancy is regulated by a wide variety of factors. Using gene expression data, we have predicted that the E2F5 transcription factor has a role in the mammary gland during pregnancy. Using CUT&RUN for E2F5 in combination with gene expression data revealed that there were a number of E2F5 target genes associated with gene expression in early pregnancy, suggesting a critical role. This prediction was then functionally tested through analysis of mice with an ablation of E2F5 in the mouse mammary epithelium using a Floxed E2F5 in combination with MMTV-Cre. This revealed a striking delay in alveolar proliferation and differentiation at the early stages of pregnancy. The significance of this effect was lost in both a second pregnancy and by the mid-point of pregnancy in single parous females. Analysis of E2F5 targets revealed overlap but a slight divergence from the consensus E2F sequence and that E2F5 was bound to the promoter of many genes involved in cellular proliferation, including known regulators of pregnancy associated alveolar expansion such as Stat6. However, progesterone stimulation of cells in a reporter assay revealed that it counteracts the repression of Stat6 by E2F5, leading to expression of Stat6. Together these data reveal the complexity of the transcriptional regulation of alveolar proliferation in early pregnancy.

Language Preference, Surgical Wait Time, and Outcomes Among Older Adults With Hip Fracture

Patients with a non-English language preference served within English-dominant health care settings are at increased risk of adverse events that may be associated with communication barriers and inequitable access to care. To investigate the association of non-English language preference with surgical wait time and postoperative outcomes in older patients undergoing hip fracture repair. This population-based, retrospective cohort study was conducted using linked databases to measure surgical wait time and postoperative outcomes among older adults (aged ≥66 years) in Ontario, Canada, who underwent hip fracture surgery between January 1, 2017, and December 31, 2022. Propensity-based overlap weighting accounting for baseline patient characteristics was used to compare primary and secondary outcomes. Non-English language preference. The primary outcome was surgical delay beyond 24 hours. Secondary outcomes included time to surgery, surgical delay beyond 48 hours, postoperative medical complications, length of stay, discharge destination, 30-day mortality, and 30-day hospital readmission. Among 35 238 patients who underwent hip fracture surgery, 28 815 individuals (81.8%) were English speakers (mean [SD] age, 84.4 [8.0] years; 19 965 female [69.3%]) and 6423 individuals (18.2%) were non-English speakers (mean [SD] age, 85.5 [7.0] years; 4556 female [70.9%]). The median (IQR) wait time for surgery was similar for English (24 [16-41] hours) and non-English (25 [16-42] hours) speakers. There was no significant difference in surgical delay beyond 24 hours between English-speaking and non-English-speaking patients (3321 patients [51.7%] vs 14 499 patients [50.3%]; adjusted relative risk [aRR], 1.00; 95% CI, 0.98-1.03). Compared with English speakers, patients with a non-English language preference had increased risk of delirium (4207 patients [14.6%] vs 1209 patients [18.8%]; aRR, 1.10; 95% CI, 1.03-1.17), myocardial infarction (150 patients [0.5%] vs 43 patients [0.7%]; aRR, 1.52; 95% CI, 1.04-2.22), longer length of stay (median [IQR], 10 [6-17] vs 11 [7-20] days; aRR per 1-day increase, 1.11; 95% CI, 1.06-1.15), and more frequent discharge to a nursing home (1814 of 26 673 patients surviving to discharge [6.8%] vs 413 of 5903 patients surviving to discharge [7.0%]; aRR, 1.13; 95% CI, 1.01-1.27). In this study of older adults with hip fracture, non-English language preference was associated with increased risk of delirium, myocardial infarction, longer length of stay, and discharge to a nursing home. These findings suggest inequities in hip fracture care for patients with a non-English language preference.

Stability of Stochastic Differential Delay Systems With Integral/Fragment‐Integral Term and Applications

Stability of Stochastic Differential Delay Systems With Integral/Fragment‐Integral Term and Applications