Late surfactant administration after 48 hours of age in preterm neonates with respiratory insufficiency: a systematic review and meta-analysis.

OBJECTIVE: To systematically review and meta-analyse the effect of late surfactant administration versus placebo in reducing the incidence of death or bronchopulmonary dysplasia (BPD) in preterm infants. DESIGN: PubMed, EMBASE, CINAHL and Cochrane CENTRAL were searched until 30 May 2023, for randomised controlled trials (RCTs) comparing administration of surfactant after 48 hours of age versus placebo in preterm ventilator-dependent neonates. The primary outcome was incidence of death or BPD at 36 weeks' postmenstrual age (PMA). Secondary outcomes included incidence of BPD at 36 weeks PMA, pre-discharge mortality, use of postnatal steroids, post-discharge respiratory support, treatment with steroids or hospitalisation prior to 1-year corrected age. RESULTS: Pooled analyses of four RCTs (N=850) showed no statistically significant difference between groups in the incidence of death or BPD at 36 weeks' PMA (relative risk (RR) 0.99; 95% CI 0.90 to 1.10; Grades of Recommendation, Assessment, Development and Evaluation (GRADE): moderate). Late surfactant administration significantly decreased the need for post-discharge respiratory support prior to 1-year corrected age (two RCTs; N=522; RR 0.72; 95% CI 0.59 to 0.89; GRADE: low). Other secondary outcomes did not differ significantly between the groups. CONCLUSIONS: Administration of late surfactant does not improve the rates of death or BPD at 36 weeks when administered to preterm infants with prolonged respiratory insufficiency. Additional adequately powered trials are needed to establish the efficacy of late surfactant therapy in preterm infants. PROSPERO REGISTRATION NUMBER: CRD42023432463.

Omics-based analysis of honey bee (Apis mellifera) response to Varroa sp. parasitisation and associated factors reveals changes impairing winter bee generation.

The extensive annual loss of honey bees (Apis mellifera L.) represents a global problem affecting agriculture and biodiversity. The parasitic mite Varroa destructor, associated with viral co-infections, plays a key role in this loss. Despite years of intensive research, the complex mechanisms of Varroa - honey bee interaction are still not fully defined. Therefore, this study employed a unique combination of transcriptomic, proteomic, metabolomic, and functional analyses to reveal new details about the effect of Varroa mites and naturally associated factors, including viruses, on honey bees. We focused on the differences between Varroa parasitised and unparasitised ten-day-old worker bees collected before overwintering from the same set of colonies reared without anti-mite treatment. Supplementary comparison to honey bees collected from colonies with standard anti-Varroa treatment can provide further insights into the effect of a pyrethroid flumethrin. Analysis of the honey bees exposed to mite parasitisation revealed alterations in the transcriptome and proteome related to immunity, oxidative stress, olfactory recognition, metabolism of sphingolipids, and RNA regulatory mechanisms. The immune response and sphingolipid metabolism were strongly activated, whereas olfactory recognition and oxidative stress pathways were inhibited in Varroa parasitised honey bees compared to unparasitised ones. Moreover, metabolomic analysis confirmed the depletion of nutrients and energy stores, resulting in a generally disrupted metabolism in the parasitised workers. The combined omics-based analysis conducted on strictly parasitised bees revealed the key molecular components and mechanisms underlying the detrimental effects of Varroa sp. and its associated pathogens. This study provides the theoretical basis and interlinked datasets for further research on honey bee response to biological threats and the development of efficient control strategies against Varroa mites.

Bioactive Excreted/Secreted Products of Entomopathogenic Nematode Heterorhabditis bacteriophora Inhibit the Phenoloxidase Activity during the Infection.

Entomopathogenic nematodes (EPNs) are efficient insect parasites, that are known for their mutualistic relationship with entomopathogenic bacteria and their use in biocontrol. EPNs produce bioactive molecules referred to as excreted/secreted products (ESPs), which have come to the forefront in recent years because of their role in the process of host invasion and the modulation of its immune response. In the present study, we confirmed the production of ESPs in the EPN Heterorhabditis bacteriophora, and investigated their role in the modulation of the phenoloxidase cascade, one of the key components of the insect immune system. ESPs were isolated from 14- and 21-day-old infective juveniles of H. bacteriophora, which were found to be more virulent than newly emerged nematodes, as was confirmed by mortality assays using Galleria mellonella larvae. The isolated ESPs were further purified and screened for the phenoloxidase-inhibiting activity. In these products, a 38 kDa fraction of peptides was identified as the main candidate source of phenoloxidase-inhibiting compounds. This fraction was further analyzed by mass spectrometry and the de novo sequencing approach. Six peptide sequences were identified in this active ESP fraction, including proteins involved in ubiquitination and the regulation of a Toll pathway, for which a role in the regulation of insect immune response has been proposed in previous studies.

A Modified Definition for Obstructive Sleep Apnea in Home Sleep Apnea Testing after Stroke or Transient Ischemic Attack.

BACKGROUND: Home sleep apnea testing (HSAT) underestimates obstructive sleep apnea (OSA) severity. Overnight oxygen desaturation has been shown to be a strong predictor of incident stroke, and may be helpful in determining which patients with lower apnea-hypopnea indices (AHIs) should be offered treatment. OBJECTIVES: To examine whether a modified definition for OSA that uses oxygen desaturation (i.e., AHI 5-14.9 per hour and lowest O2 desaturation ≤88%), as compared to an AHI ≥ 15 per hour, would impact: (1) changes in Epworth Sleepiness Scale scores post-continuous positive airway pressure (CPAP) initiation; (2) CPAP compliance rates; and (3) the accuracy of automated versus manual scoring of HSAT. METHODS: One hundred and six patients with a prior stroke or transient ischemic attack (TIA) underwent HSAT. Epworth Sleepiness Scale and CPAP compliance were measured at baseline and 3-6 months. RESULTS: Median age was 67.5 years, 57.5% male, and 76.4% presented with stroke. Fifty-nine patients were diagnosed with OSA; of these 54.2% met criteria for the "modified definition" for OSA (AHI 5-14.9 per hour with oxygen desaturation) and 45.8% met criteria for the "classic definition" for OSA (AHI ≥15). The modified (versus classic) definition had: (1) a greater decrease in ESS (P = .05) post-CPAP initiation; (2) comparable CPAP compliance rates; and (3) comparable automatically versus manually scored AHIs (Spearman's rho = .96, Cohen's Kappa ≥ .75 for both definitions, P < .001). CONCLUSIONS: Using a modified definition of OSA that uses a lower AHI cutoff and includes an oxygen desaturation cutoff in the setting of HSAT for stroke or transient ischemic attack (TIA) patients may improve daytime sleepiness post-CPAP initiation, while not significantly affecting CPAP compliance rates nor the accuracy of automated scoring.

FoxD1 protein interacts with Wnt and BMP signaling to differentially pattern mesoderm and neural tissue.

The foxd1 gene (previously known as Brain Factor 2/BF2) is expressed during early Xenopus laevis development. At gastrula stages, foxd1 is expressed in dorsal mesoderm regions fated for muscle and notochord, while at neurula stages, foxd1 is expressed in the forebrain region. Previous studies in the neural plate showed that FoxD1 protein acts as transcriptional repressor downstream of BMP antagonism, neuralizing the embryo to control anterior neural cell fates. FoxD1 mesoderm function was not rigorously analyzed, but ectopic FoxD1 levels increased muscle marker expression in embryos. Using a FoxD1-specific antisense morpholino oligonucleotide, we knocked down endogenous FoxD1 protein activity in developing Xenopus embryos. In this present study, we show that FoxD1 is crucial for dorsal mesoderm formation. Analogous to neural tissue, FoxD1 acts downstream of BMP antagonism to induce dorsal mesoderm cell fates, such as muscle and notochord. FoxD1 is sensitive to its local signaling environment, having differential transcription factor activity in the presence or absence of Wnt or BMP signaling. FoxD1 induces posterior neural tissue in the presence of Wnt or BMP activities, but its activity is restricted to "normal" anterior neural tissue induction when BMP and Wnt activities are repressed. In dorsal mesoderm, FoxD1 interacts with Wnt signaling and BMP antagonism to induce muscle and notochord, while simultaneously repressing more anterior and ventral mesoderm cell fates. FoxD1 protein has multiple activities that are masked or released in the different germ layers as a function of the local signaling environment.

Unattended Hospital and Home Sleep Apnea Testing Following Cerebrovascular Events.

BACKGROUND: Home sleep apnea testing (HSAT) is an alternative to polysomnography for the detection of obstructive sleep apnea (OSA). We assessed the feasibility of HSAT as an unattended screening tool for patients with a stroke or transient ischemic attack (TIA). AIMS: The primary outcome was the feasibility of unattended HSAT, as defined by analyzability of the data. Secondary outcomes included determining (1) predictors of obtaining nonanalyzable sleep data and (2) time to OSA detection and continuous positive airway pressure (CPAP) initiation. METHODS: In this single-center prospective observational study, inpatients or outpatients who had sustained a stroke or TIA were screened for OSA using the ApneaLink Plus ambulatory sleep monitor in their home or hospital room. RESULTS: There were 102 patients who completed unattended sleep monitoring. Mean age was 68.7 ± 13.7 years, 55.9% were male, 57.8% were outpatients, and 77.5% had a stroke (22.5% with TIA). Eighty-two (80.4%) patients obtained four or more hours of analyzable sleep data. Functional dependence (defined as a modified Rankin Scale of >2) and elevated body mass index were independently associated with obtaining nonanalyzable data. OSA was detected in 63.4% (52 of 82) of patients and, of those, 34 of 52 (65.4%) initiated CPAP therapy. The mean time from study recruitment to HSAT was 1.7 days (median: 1, interquartile range [IQR]: 2) and CPAP was initiated on average within 62.7 days of recruitment (median: 53, IQR: 30). CONCLUSIONS: Unattended HSAT can be feasibly implemented after stroke or TIA. This method facilitates rapid diagnosis and management of OSA in both the outpatient and inpatient settings.

Identifying obstructive sleep apnea after stroke/TIA: evaluating four simple screening tools.

OBJECTIVE: Despite its high prevalence and unfavorable clinical consequences, obstructive sleep apnea (OSA) often remains underappreciated after cerebrovascular events. The purpose of our study was to evaluate the clinical utility of four simple paper-based screening tools for excluding OSA after stroke or transient ischemic attack (TIA). PATIENTS/METHODS: Sixty-nine inpatients and outpatients with stroke or TIA during the past 180 days completed the 4-Variable screening tool (4V), STOP-BAG questionnaire (ie, STOP-BANG questionnaire without the neck circumference measurement), Berlin questionnaire, and the Sleep Obstructive apnea score optimized for Stroke (SOS). They subsequently underwent objective testing using a portable sleep monitoring device. Cutoffs were selected to maximize sensitivity and exclude OSA (AHI ≥ 10) in ≥10% of the cohort. RESULTS: The mean age was 68.3 ± 14.2 years and 47.8% were male. Thirty-two patients (46.4%) were found to have OSA. Male sex, body mass index (BMI), and atrial fibrillation were independent predictors of OSA. Among the screening tools, the 4V had the greatest area under the curve (AUC) of 0.688 (p = 0.007); the sensitivity was 96.9% for a cutoff of <6. The STOP-BAG also significantly detected OSA with an AUC of 0.677 (p = 0.012); the sensitivity was 93.8% for a cutoff of <2. Scores on the 4V and STOP-BAG were significantly correlated with the AHI. CONCLUSIONS: The 4V and STOP-BAG questionnaire may aid clinicians with ruling out OSA within 180 days of stroke/TIA. Due to the atypical presentation of poststroke/TIA OSA, these tools are only moderately predictive; objective testing should still be used for OSA diagnosis in this population.

PTK7 modulates Wnt signaling activity via LRP6.

Protein tyrosine kinase 7 (PTK7) is a transmembrane protein expressed in the developing Xenopus neural plate. PTK7 regulates vertebrate planar cell polarity (PCP), controlling mesodermal and neural convergent-extension (CE) cell movements, neural crest migration and neural tube closure in vertebrate embryos. Besides CE phenotypes, we now show that PTK7 protein knockdown also inhibits Wnt/ß-catenin activity. Canonical Wnt signaling caudalizes the neural plate via direct transcriptional activation of the meis3 TALE-class homeobox gene, which subsequently induces neural CE. PTK7 controls meis3 gene expression to specify posterior tissue and downstream PCP activity. Furthermore, PTK7 morphants phenocopy embryos depleted for Wnt3a, LRP6 and Meis3 proteins. PTK7 protein depletion inhibits embryonic Wnt/ß-catenin signaling by strongly reducing LRP6 protein levels. LRP6 protein positively modulates Wnt/ß-catenin, but negatively modulates Wnt/PCP activities. The maintenance of high LRP6 protein levels by PTK7 triggers PCP inhibition. PTK7 and LRP6 proteins physically interact, suggesting that PTK7 stabilization of LRP6 protein reciprocally regulates both canonical and noncanonical Wnt activities in the embryo. We suggest a novel role for PTK7 protein as a modulator of LRP6 that negatively regulates Wnt/PCP activity.