NEDD8 enhances Hippo signaling by mediating YAP1 neddylation.

The Hippo-YAP signaling pathway plays a central role in many biological processes such as regulating cell fate, organ size, and tissue growth, and its key components are spatiotemporally expressed and posttranslationally modified during these processes. Neddylation is a posttranslational modification that involves the covalent attachment of NEDD8 to target proteins by NEDD8-specific E1-E2-E3 enzymes. Whether neddylation is involved in Hippo-YAP signaling remains poorly understood. Here, we provide evidence supporting the critical role of NEDD8 in facilitating the Hippo-YAP signaling pathway by mediating neddylation of the transcriptional coactivator yes-associated protein 1 (YAP1). Overexpression of NEDD8 induces YAP1 neddylation and enhances YAP1 transactivity, but inhibition of neddylation suppresses YAP1 transactivity and attenuates YAP1 nuclear accumulation. Furthermore, inhibition of YAP1 signaling promotes MLN4924-induced ovarian granulosa cells apoptosis and disruption of nedd8 in zebrafish results in downregulation of yap1-activated genes and upregulation of yap1-repressed genes. Further assays show that the xiap ligase promotes nedd8 conjugates to yap1 and that yap1 neddylation. In addition, we identify lysine 159 as a major neddylation site on YAP1. These findings reveal a novel mechanism for neddylation in the regulation of Hippo-YAP signaling.

DNA methylation-mediated 11ßHSD2 downregulation drives the increases in angiotensin-converting enzyme and angiotensin II within preeclamptic placentas.

Preeclampsia (PE) is a complex human-specific complication frequently associated with placental pathology. The local renin-angiotensin system (RAS) in the human placenta, which plays a crucial role in regulating placental function, has been extensively documented. Glucocorticoids (GCs) are a class of steroid hormones. PE cases often have abnormalities in GCs levels and placental GCs barrier. Despite extensive speculation, there is currently no robust evidence indicating that GCs regulate placental RAS. This study aims to investigate these potential relationships. Plasma and placental samples were collected from both normal and PE pregnancies. The levels of angiotensin-converting enzyme (ACE), angiotensin II (Ang II), cortisol, and 11ß-hydroxysteroid dehydrogenases (11ßHSD) were analyzed. In PE placentas, cortisol, ACE, and Ang II levels were elevated, while 11ßHSD2 expression was reduced. Interestingly, a positive correlation was observed between ACE and cortisol levels in the placenta. A significant inverse correlation was found between the methylation statuses within the 11ßHSD2 gene promoter and its expression, meanwhile, 11ßHSD2 expression was negatively correlated with cortisol and ACE levels. In vitro experiments using placental trophoblast cells confirmed that active GCs can stimulate ACE transcription and expression through the GR pathway. Furthermore, 11ßHSD2 knockdown could enhance this activating effect. An in vivo study using a rat model of intrauterine GCs overexposure during mid-to-late gestation suggested that excess GCs in utero lead to increased ACE and Ang II levels in the placenta. Collectively, this study provides the first evidence of the relationships between 11ßHSD2 expression, GCs barrier, ACE, and Ang II levels in the placenta. It not only contributes to understanding the pathological features of the placental GCs barrier and RAS under PE conditions, also provides important information for revealing the pathological mechanism of PE.

Neuromedin S regulates goat ovarian granulosa cell proliferation and steroidogenesis via endoplasmic reticulum Ca2+-YAP1-ATF4-c-Jun pathway.

Neuromedin S (NMS) plays key roles in reproductive regulation, while its function and mechanism in follicular development remain unclear. The current study aims to investigate the specific role and mechanisms of NMS and its receptors in regulating the proliferation and steroidogenesis of ovarian granulosa cells (GCs). Phenotypically, a certain concentration of NMS addition promoted the proliferation and estrogen production of goat GCs, accompanied by an increase in the G1/S cell population and upregulation of the expression levels of cyclin D1, cyclin dependent kinase 6, steroidogenic acute regulatory protein, cytochrome P450, family 11, subfamily A, polypeptide 1, 3beta-hydroxysteroid dehydrogenase, and cytochrome P450, family 11, subfamily A, polypeptide 1, while the effects of NMS treatment were effectively hindered by knockdown of neuromedin U receptor type 2 (NMUR2). Mechanistically, activation of NMUR2 with NMS maintained endoplasmic reticulum (ER) calcium (Ca2+) homeostasis by triggering the PLCG1-IP3R pathway, which helped preserve ER morphology, sustained an appropriate level of endoplasmic reticulum unfolded protein response (UPRer), and suppressed the nuclear translocation of activating transcription factor 4. Moreover, NMS maintained intracellular Ca2+ homeostasis to activate the calmodulin 1-large tumor suppressor kinase 1 pathway, ultimately orchestrating the regulation of goat GC proliferation and estrogen production through the Yes1 associated transcriptional regulator-ATF4-c-Jun pathway. Crucially, the effects of NMS were mitigated by concurrent knockdown of the NMUR2 gene. Collectively, these data suggest that activation of NMUR2 by NMS enhances cell proliferation and estrogen production in goat GCs through modulating the ER and intracellular Ca2+ homeostasis, leading to activation of the YAP1-ATF4-c-Jun pathway. These findings offer valuable insights into the regulatory mechanisms involved in follicular growth and development, providing a novel perspective for future research.

Inhibition of insulin degrading enzyme suppresses osteoclast hyperactivity via enhancing Nrf2-dependent antioxidant response in glucocorticoid-induced osteonecrosis of the femoral head.

BACKGROUND: Osteoclast hyperactivation due to the pathological overproduction of reactive oxygen species (ROS) stimulated by glucocorticoids (GCs) is one of the key drivers behind glucocorticoid-induced osteonecrosis of the femoral head (GIONFH). The insulin degrading enzyme (IDE), a conserved Zn2+ metallo-endopeptidase, facilitates the DNA binding of glucocorticoid receptor and plays a substantial role in steroid hormone-related signaling pathways. However, the potential role of IDE in the pathogenesis of GIONFH is yet undefined. METHODS: In this study, we employed network pharmacology and bioinformatics analysis to explore the impact of IDE inhibition on GIONFH with 6bK as an inhibitory agent. Further evidence was collected through in vitro osteoclastogenesis experiments and in vivo evaluations involving methylprednisolone (MPS)-induced GIONFH mouse model. RESULTS: Enrichment analysis indicated a potential role of 6bK in redox regulation amid GIONFH development. In vitro findings revealed that 6bK could attenuate GCs-stimulated overactivation of osteoclast differentiation by interfering with the transcription and expression of key osteoclastic genes (Traf6, Nfatc1, and Ctsk). The use of an H2DCFDA probe and subsequent WB assays introduced the inhibitory effects of 6bK on osteoclastogenesis, linked with the activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2)-mediated antioxidant system. Furthermore, Micro-CT scans validated that 6bK could alleviate GIONFH in MPS-induced mouse models. CONCLUSIONS: Our findings suggest that 6bK suppresses osteoclast hyperactivity in GCs-rich environment. This is achieved by reducing the accumulation of intracellular ROS via promoting the Nrf2-mediated antioxidant system, thus implying that IDE could be a promising therapeutic target for GIONFH.

Agomelatine alleviates steroid-induced osteoporosis by targeting SIRT1/RANKL/FOXO1/OPG signalling in rats.

One of the major contributors to secondary osteoporosis is long-term glucocorticoid usage. Clinically used antidepressant agomelatine also has anti-inflammatory properties. Our research aimed to inspect the probable defensive effect of agomelatine against steroid-promoted osteoporosis. There were four groups of rats; group I had saline as a negative control; rats of group II had dexamethasone (0.6 mg/kg, s.c.), twice weekly for 12 weeks; rats of group III had agomelatine (40 mg/kg/day, orally), as a positive control, daily for 12 weeks; and rats of group IV had dexamethasone + agomelatine in the same previous doses combined for 12 weeks. Finally, biochemical as well as histopathological changes were evaluated and dexamethasone treatment caused osteoporosis, as evidenced by discontinuous thin cancellous bone trabeculae, minor fissures and fractures, irregular eroded endosteal surface with elevated alkaline phosphate, tartarate resistant acid phosphate (TRACP) and osteocalcin levels. Osteoprotegerin (OPG), calcium, and phosphorus levels decreased with disturbed receptor activator of nuclear factor κ B ligand (RANKL), forkhead box O1 (FOXO1), and silent information regulator 1 (SIRT1) protein expression. However, treatment with agomelatine restored the normal levels of biochemical parameters to a great extent, supported by SIRT activation with an improvement in histopathological changes. Here, we concluded that agomelatine ameliorates steroid-induced osteoporosis through a SIRT1/RANKL/FOXO1/OPG-dependent pathway.

Circulating soluble CD163 is associated with reduced Glasgow Coma Scale Score and 1-year all-cause mortality in traumatized patients.

Soluble CD163 (sCD163) is a biomarker of macrophage activation, not previously investigated in the circulation of traumatized patients. A biobank of 398 adult trauma patients was analyzed. Patients with an Injury Severity Score (ISS) >8 served as trauma patients (n = 195) and those with ISS ≤8 as trauma controls (n = 203). Serum samples obtained upon admission, 15h and 72h after were analyzed for sCD163 using an in-house ELISA. Multiple linear regression was used to analyze the association between admission levels of sCD163 with, 1: overall trauma severity (ISS), and 2: severity of injury to specified organs using Abbreviated Injury Score (AIS) and Glasgow Coma Scale (GCS). The association between the peak level of sCD163 with 1-year all-cause mortality was analyzed by logistic regression analysis. Median admission levels of sCD163 were higher in trauma patients than trauma controls [2.32 (IQR 1.73 to 2.86) vs. 1.92 (IQR 1.41 to 2.51) mg/L, p < 0.01]. Worsening GCS score was associated with a 10.3% (95% CI: 17.0 to 3.1, p < 0.01) increase in sCD163. Increasing Head-AIS score was associated with a 5.1% (95% CI: -0.5 to 11.0, p = 0.07) increase in sCD163. The remaining AIS scores and ISS were not consistently associated with sCD163 admission levels. Each mg/L increase in sCD163 peak level had an odds ratio 1.34 (95%CI: 0.98 to 1.83), p = 0.06) after adjustment for age, sex, and GCS. Circulating sCD163 is increased in traumatized patients and associated with worsening GCS. Our findings suggest an association between circulating sCD163 levels with 1-year all-cause mortality.

Mapping Glasgow Coma scale to AVPU scores among adults in the prehospital setting.

OBJECTIVE: To develop a translation between the Glasgow Come Scale and the Alert-Verbal-Pain-Unresponsive (AVPU) scale among adults with out-of-hospital emergencies. METHODS: We performed a retrospective analysis of adults (≥18 years) from the 2022 National Emergency Medical Services (EMS) Information System with a ground scene encounter with a concurrently documented GCS and AVPU assessment. Using a training partition of 2.5 million encounters, we performed a grid search to identify all combinations of mutually exclusive cutpoints which divided the GCS into four segments. We identified the combination with the highest Kappa statistic and reported metrics of performance in this sample in the test partition. RESULTS: We identified 16,321,299 encounters with a concurrent AVPU and GCS. Using the AVPU scale, 93.3 % were classified as Alert; 2.9 % as Verbal; 1.5 % as Pain; and 2.3 % as Unresponsive. Using a grid-based search, optimal cutpoints were identified when using a GCS of 14-15 for Alert, 10-13 for Verbal, 7-9 for Pain, and 3-6 for Unresponsive. Cohen's Kappa was 0.63 in the test partition, indicating substantial agreement. Intraclass F1 score varied across different alertness levels and were 0.97 for "Alert", 0.43 for "Verbal", 0.49 for "Pain", and 0.83 for "Unresponsive". Findings were similar in analyses performed by age group and by the presence or absence of trauma. CONCLUSION: We report an optimal crosswalk between the AVPU and GCS scales. Performance in the Verbal and Pain categories was lower than the Alert and Unresponsive categories. These findings may facilitate clinician handovers between EMS and non-EMS clinicians.

Incremental prognostic value of speckle tracking echocardiography and early follow-up echo assessment in predicting left ventricular recovery after reperfusion for ST-segment elevation myocardial infarction (STEMI).

PURPOSE: Up to 50% of patients do not achieve significant left ventricular ejection fraction (LVEF) recovery after primary percutaneous intervention (PPCI) for STEMI. We aimed to identify the echocardiographic predictors for LVEF recovery and assess the value of early follow-up echocardiography (Echo) in risk assessment of post-myocardial infarction (MI) patients. METHODS: One hundred one STEMI patients undergoing PPCI were enrolled provided EF below 50%. Baseline echocardiography assessed LVEF, volumes, wall motion score index (WMSI), global longitudinal strain (GLS), global circumferential strain (GCS), and E/e'. Follow-up echocardiography after 6 weeks reassessed left ventricular volumes, LVEF and GLS.GCS was not assessed at follow up. Patients were classified into recovery and non-recovery groups. Predictors of LVEF recovery and major adverse cardiovascular events (MACE) at 6 months were analysed. RESULTS: The mean change of EF was 8.04 ± 3.32% in group I versus -.39 ± 5.09 % in group II (p < .001). Recovered patients had better baseline GLS, baseline GCS, E/e', and follow-up GLS. Multivariate regression analysis revealed E/e', GCS, and follow-up GLS after 6 weeks to be strong independent predictors for LVEF recovery. Composite MACE was considerably higher in group II (32.7% vs. 4.1%, p < .001) mainly driven by higher heart failure hospitalisation Multivariate regression analysis revealed baseline GLS, E/e', and ejection fraction (EF) percentage recovery as strong independent predictors for MACE. CONCLUSIONS: Multiparametric echocardiographic approach incorporating LVEF, strain parameters, and diastolic function could allow early optimal risk stratification after STEMI treated with PPCI. Follow-up GLS and LVEF percentage change are the strongest predictors for early LV recovery and long term clinical outcome, respectively.

"Biomarkers in severe traumatic brain injury: enhancing prognostic accuracy and therapeutic strategies".

This study examines the emerging role of biomarkers in the prognosis and management of severe traumatic brain injury (sTBI). Key findings highlight the significance of serum RIP-3, STC1, Nrf2, and cerebrospinal fluid galectin-3 and cytokines in predicting disease severity, mortality, and functional outcomes in sTBI patients. Elevated levels of RIP-3 and STC1 were linked to poor prognosis and increased mortality, with RIP-3 associated with necroptosis and inflammation, and STC1 with neuroprotective properties. Nrf2 was found to correlate with oxidative stress and adverse outcomes, while elevated CSF galectin-3 and IL-6 indicated neuroinflammation and neurodegeneration. These biomarkers show promise not only as prognostic tools but also as potential therapeutic targets. The study suggests further validation through multicenter research to enhance clinical applications and improve treatment strategies for sTBI.

Comprehensive analysis of lncRNA-miRNA-mRNA ceRNA network and key genes in granulosa cells of patients with biochemical primary ovarian insufficiency.

Primary ovarian insufficiency (POI) is a common condition leading to the pathological decline of ovarian function in women of reproductive age, resulting in amenorrhea, hypogonadism, and infertility. Biochemical premature ovarian insufficiency (bPOI) is an intermediate stage in the pathogenesis of POI in which the fertility of patients has been reduced. Previous studies suggest that granulosa cells (GCs) play an essential role in the pathogenesis of POI, but their pathogenetic mechanisms remain unclear. To further explore the potential pathophysiological mechanisms of GCs in POI, we constructed a molecular long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network using GC expression data collected from biochemical premature ovarian failure (bPOI) patients in the GEO database. We discovered that the GCs of bPOI patients had differential expression of 131 mRNAs, 191 lncRNAs, and 28 miRNAs. By systematic network analysis, we identified six key genes, including SRSF1, PDIA5, NEURL1B, UNK, CELF2, and CFL2, and five hub miRNAs, namely hsa-miR-27a-3p, hsa-miR-24-3p, hsa-miR-22-3p, hsa-miR-129-5p, and hsa-miR-17-5p, and the results suggest that the expression of these key genes may be regulated by two hub miRNAs, hsa-miR-27a-3p and hsa-miR-17-5p. Additionally, a POI model in vitro was created to confirm the expression of a few important genes. In this study, we discovered a unique lncRNA-miRNA-mRNA network based on the ceRNA mechanism in bPOI for the first time, and we screened important associated molecules, providing a partial theoretical foundation to better understand the pathogenesis of POI.

Comparison of DNA damage in granulosa cells of women undergoing controlled ovarian stimulation in in vitro fertilization protocols with the recombinant human follicle-stimulating hormones Corneumon®, Gonal-F®, Pergoveris® and Puregon®: a randomized trial.

PURPOSE: To compare the DNA damage in granulosa cells (GCs) of women undergoing ovarian-stimulated cycles with four widely used recombinant human follicle-stimulating hormones (rhFSH) in in vitro fertilization (IVF) protocols (Corneumon®, Gonal-F®, Pergoveris® and Puregon®). METHODS: A randomized trial was carried out at a Mexican hospital. GCs were isolated from 18 women with infertility undergoing assisted reproductive techniques (ART). Four controlled ovarian stimulation (COS) protocols including Corneumon®, Gonal-F®, Pergoveris® or Puregon® were used. GCs DNA damage was assessed by the Comet assay. Two parameters were measured: comet tail length (CTL), and Olive tail moment (OTM, the percentage of DNA in the tail multiplied by the distance between the center of the tail and head). RESULTS: Use of the different hrFSH in COS caused variable and statistically significant levels of DNA damage in GCs of infertile women. CTL was similar in the Corneumon® and Pergoveris® groups (mean values of 48.73 and 55.18, respectively) and Corneumon® CTL was significantly lower compared to the Gonal-F® and Puregon® groups (mean values of 61.98 and 91.17, respectively). Mean OTM values were significantly lower in Corneumon® and Pergoveris® groups, compared to Gonal-F® and Puregon® groups (25.59, 27.35, 34.76, and 47.27, respectively). CONCLUSION: Use of Corneumon® and Pergoveris® in COS caused statistically significantly lower levels of DNA damage in GCs of infertile women undergoing ART, which could potentially correlate with better reproductive outcomes.

Evaluation of severe traumatic brain injury referrals to the National Tertiary Neurosurgical Centre in the Republic of Ireland.

BACKGROUND: Transfer of all severe TBI patients to a neurosurgical unit (NSU) has been advocated irrespective of levels of complexity and prognostic factors. Previous publications have suggested that only 50% of severe TBI patients in Ireland were managed in NSUs. AIMS: This study aims to audit severe TBI referrals to the National Neurosurgical Centre, to evaluate reasons for nonacceptance, assess for differences in the transferred and not transferred cohorts and to analyse observed and expected mortality rates. METHODS: Data on all patients with TBI referred in 2021 were prospectively collected using an electronic referral system. Patients with severe TBI (GCS ≤ 8 and AIS ≥ 3) were included and dichotomised into transferred and not transferred cohorts. RESULTS: Of 118 patients referred with severe TBI, 45 patients (38.1%) were transferred to the neurosurgical centre. Patients in the transferred cohort were significantly younger (p < 0.001), had a higher GCS score (p < 0.001) and a lower proportion of bilaterally unreactive pupils (p < 0.001) compared to the not transferred cohort. 93% (68/73) of those not transferred were either >65 years old, or had bilaterally unreactive pupils, or both. Based on the IMPACT model, the observed to expected mortality ratios in the transferred and not transferred cohorts were 0.65 (95% CI 0.25-1.05) and 0.88 (95% CI 0.65-1.11) respectively. CONCLUSION: The observed mortality rate for severe TBI in Ireland was similar to or better than expected mortality rates when adjusted for important prognostic factors. 93% of severe TBI patients not transferred to a neurosurgical centre were either elderly or had bilaterally unreactive pupils or both. These patients have an extremely poor prognosis and recommendation for transfer cannot be made based on current available evidence.

Reverse shock index multiplied by simplified motor score as a predictor of clinical outcomes for patients with COVID-19.

BACKGROUND: The reverse shock index (rSI) combined with the Simplified Motor Score (sMS), that is, the rSI-sMS, is a novel and efficient prehospital triage scoring system for patients with COVID-19. In this study, we evaluated the predictive accuracy of the rSI-sMS for general ward and intensive care unit (ICU) admission among patients with COVID-19 and compared it with that of other measures, including the shock index (SI), modified SI (mSI), rSI combined with the Glasgow Coma Scale (rSI-GCS), and rSI combined with the GCS motor subscale (rSI-GCSM). METHODS: All patients who visited the emergency department of Taipei Tzu Chi Hospital between January 2021 and June 2022 were included in this retrospective cohort. A diagnosis of COVID-19 was confirmed through a SARS-CoV-2 reverse-transcription polymerase chain reaction test or SARS-CoV-2 rapid test with oropharyngeal or nasopharyngeal swabs and was double confirmed by checking International Classification of Diseases, Tenth Revision, Clinical Modification codes in electronic medical records. In-hospital mortality was regarded as the primary outcome, and sepsis, general ward or ICU admission, endotracheal intubation, and total hospital length of stay (LOS) were regarded as secondary outcomes. Multivariate logistic regression was used to determine the relationship between the scoring systems and the three major outcomes of patients with COVID-19, including. The discriminant ability of the predictive scoring systems was investigated using the area under the receiver operating characteristic curve, and the most favorable cutoff value of the rSI-sMS for each major outcome was determined using Youden's index. RESULTS: After 74,183 patients younger than 20 years (n = 11,572) and without COVID-19 (n = 62,611) were excluded, 9,282 patients with COVID-19 (median age: 45 years, interquartile range: 33-60 years, 46.1% men) were identified as eligible for inclusion in the study. The rate of in-hospital mortality was determined to be 0.75%. The rSI-sMS scores were significantly lower in the patient groups with sepsis, hyperlactatemia, admission to a general ward, admission to the ICU, total length of stay ≥ 14 days, and mortality. Compared with the SI, mSI, and rSI-GCSM, the rSI-sMS exhibited a significantly higher accuracy for predicting general ward admission, ICU admission, and mortality but a similar accuracy to that of the rSI-GCS. The optimal cutoff values of the rSI-sMS for predicting general ward admission, ICU admission, and mortality were calculated to be 3.17, 3.45, and 3.15, respectively, with a predictive accuracy of 86.83%, 81.94%%, and 90.96%, respectively. CONCLUSIONS: Compared with the SI, mSI, and rSI-GCSM, the rSI-sMS has a higher predictive accuracy for general ward admission, ICU admission, and mortality among patients with COVID-19.

Gluteal compartment syndrome: who is most at risk?

PURPOSE: Gluteal compartment syndrome (GCS) is a rare but devastating condition with a paucity of literature to help guide diagnosis and management. This study aims to identify and describe the risk factors and patient characteristics associated with GCS to facilitate early diagnosis. METHODS: This is a retrospective case series of patients undergoing gluteal compartment release between 2015 and 2022 at an academic Level I trauma center. Chart reviews were performed to extract data on patient demographics, presenting symptoms, risk factors, operative findings, and postoperative outcomes. RESULTS: 14 cases of GCS were identified. 12 (85.7%) were male, with a mean age of 39.4 ± 13 years and a mean BMI of 25.1 ± 4.1 kg/m2. 12 (85.7%) patients did not present as traumas and only 3 had ≥ 1 fracture. 9 patients reported drug use. Hemoglobin (Hgb) (11.7 ± 4 g/dL) was generally low (5 had Hgb < 10 g/dL). Creatine kinase (49,617 ± 60,068 units/L) was consistently elevated in all cases, and lactate (2.8 ± 1.6 mmol/L) was elevated in 9. 13 had non-viable muscle requiring debridement. Postoperatively, the mean ICU length of stay was 12 ± 23 days. 2 patients died during admission and all remaining patients required discharge to rehabilitation facilities. CONCLUSION: GCS is more likely to present in a young to middle-aged, otherwise healthy, male using drugs who is either found down or experienced an iatrogenic injury. Recognizing that GCS is different from that of the leg, in terms of etiology, may help avoid delays in diagnosis and treatment.

Interictal respiratory variability predicts severity of hypoxemia after generalized convulsive seizures.

OBJECTIVE: Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In a mouse model of seizure-induced death, increased interictal respiratory variability was reported in mice that later died of respiratory arrest after GCS. We studied respiratory variability in epilepsy patients as a predictive tool for severity of postictal hypoxemia, a potential biomarker for SUDEP risk. We then explored the relationship between respiratory variability and central CO2 drive, measured by the hypercapnic ventilatory response (HCVR). METHODS: We reviewed clinical, video-electroencephalography, and respiratory (belts, airflow, pulse oximeter, and HCVR) data of epilepsy patients. Mean, SD, and coefficient of variation (CV) of interbreath interval (IBI) were calculated. Primary outcomes were: (1) nadir of capillary oxygen saturation (SpO2 ) and (2) duration of oxygen desaturation. Poincaré plots of IBI were created. Covariates were evaluated in univariate models, then, based on Akaike information criteria (AIC), multivariate regression models were created. RESULTS: Of 66 GCS recorded in 131 subjects, 30 had interpretable respiratory data. In the multivariate model with the lowest AIC value, duration of epilepsy was a significant predictor of duration of oxygen desaturation. Duration of tonic phase and CV of IBI during the third postictal minute correlated with SpO2 nadir, whereas CV of IBI during non-rapid eye movement sleep had a negative correlation. Poincaré plots showed that long-term variability was significantly greater in subjects with ≥200 s of postictal oxygen desaturation after GCS compared to those with <200 s desaturation. Finally, HCVR slope showed a negative correlation with measures of respiratory variability. SIGNIFICANCE: These results indicate that interictal respiratory variability predicts severity of postictal oxygen desaturation, suggesting its utility as a potential biomarker. They also suggest that interictal respiratory control may be abnormal in some patients with epilepsy.

A nomogram risk prediction model for poor outcome of primary brainstem hemorrhage based on clinical data and radiographic features.

OBJECTIVE: Primary brainstem hemorrhage (PBSH) is a devastating acute neurological disorder with a poor prognosis. This study aimed to identify risk factors associated with poor outcomes in PBSH patients and develop a novel nomogram for predicting prognosis, with external validation. METHODS: A total of 379 patients with PBSH were included in the training cohort. The primary outcome of interest was a modified Rankin Scale score (mRS) of 4-6 at 90 days post-onset. Multivariable logistic regression was used to construct a nomogram based on relevant variables. Model performance was tested in the training cohort and externally validated for discriminatory ability, calibration, and clinical utility at a separate institution. The nomogram was also compared to the ICH score in terms of predictive ability. RESULTS: The poor outcome rate at 90 days was 57.26% (217/379) in the training cohort and 61.27% (106/173) in the validation cohort. Multivariable logistic regression analysis identified age, Glasgow Coma Scale (GCS) score, and hematoma size as significant risk factors for poor outcomes. Nomograms based on these variables demonstrated good discrimination, with an area under the curve (AUC) of 0.855 and 0.836 in the training and validation cohorts, respectively. Furthermore, the nomogram showed superior predictive value to the ICH score for the 90-day outcome in both cohorts. CONCLUSION: This study developed and externally validated a nomogram risk prediction model for predicting poor outcomes at 90 days in patients with PBSH, using age, GCS score, and hematoma size as predictors. The nomogram demonstrated good discrimination, calibration, and clinical validity, serving as a valuable assessment and decision-making tool.

Role of two-dimensional strain echocardiographic parameters in suspected acute coronary syndrome patients with initial non-diagnostic electrocardiogram and troponins: An observational study.

INTRODUCTION: Diagnosis of acute coronary syndrome (ACS) is often challenging especially in presence of initial normal troponins and non-specific electrocardiogram. The index study aimed at determining the diagnostic value of strain echocardiography in patients with suspected ACS but with non-diagnostic electrocardiogram and echocardiography findings. METHODS: The study was conducted on 42 patients with suspected ACS and non-diagnostic electrocardiograms, normal quantitative troponin-T levels, and left ventricular function. All patients underwent conventional and 2D-strain echocardiography followed by coronary angiography, within 24 h of admission. Patients with regional wall motion abnormalities (RWMA), valvular heart disease, suspected myocarditis, and past coronary artery disease (CAD) were excluded. RESULTS: Amongst the global strains, the global circumferential strain (GCS) was significantly reduced (p = .014) amongst those with significant CAD on angiography as opposed to global longitudinal strain (GLS) which was similar in the two groups (p = .33). The GCS/GLS ratio was also significantly reduced in patients with significant CAD compared to those with normal/mild disease on coronary angiography (p = .025). Both the parameters had good accuracy in predicting significant CAD. GCS displayed a sensitivity of 80% and a specificity of 86% at an optimal cut-off 31.5% (AUROC: .93, 95% CI: .601-1.000; p = .03), and likewise GCS/GLS ratio had a sensitivity of 80% and a specificity and 86% at a cut-off of 1.89% (AUROC: .86, 95% CI: .592-1.000; p = .049). GLS and peak atrial longitudinal strain (PALS) did not differ significantly in patients with/without significant CAD (p = .32 and .58, respectively). CONCLUSION: GCS and GCS/GLS ratio provides incremental value in comparison to GLS, PALS, and tissue Doppler indices (E/e') in patients with suspected ACS and non-diagnostic electrocardiogram and troponins. GCS at cut-off of >31.5% and GCS/GLS ratio >1.89 can reliably exclude patients with significant CAD in this setting.

External validation of the GCS-Pupils Score as an outcome predictor after traumatic brain injury in adults: a single-center experience.

OBJECTIVE: The GCS-Pupils (GCS-P) score is a recently described scoring system to aid outcome prediction in patients with traumatic brain injury (TBI). The aim of this study was to provide the first external validation of the GCS-P score by identifying independent predictors of outcome in TBI patients. METHODS: Review of prospective adult (≥ 16 years) TBI database at a tertiary neurosurgical center with a catchment population of 1.5 million over a 12-month period commencing October 2016. Multivariate logistic regression was used to identify predictors of discharge destination and 30-day mortality. RESULTS: Three hundred and fifty-eight patients were included. The median age was 60 years with a male predominance of 64%. The median GCS-P was 14 (interquartile range 12-15) and the commonest GCS-P category was mild (13-15; 238/358, 66%). Discharge destination was home in 69% of patients and rehab services or equivalent in 31%. Multivariate analysis identified age (p = 0.01), CT findings of an acute subdural hematoma (p = 0.01) or diffuse axonal injury (p = 0.02), and a neurosurgical operation (p = 0.02) as independent predictors of discharge destination. The 30-day mortality rate was 11%. Within the category of severe TBI (GCS-P ≤ 8), GCS-P was able to identify patients with a very high likelihood of 30-day mortality (GCS-P ≤ 4; 16/31, 52%). Multivariate analysis revealed the Charlson comorbidity score (p = 0.01), GCS-P (p = 0.02), and traumatic subarachnoid hemorrhage (p = 0.05) as independent predictors of mortality. CONCLUSION: The GCS-P is a useful predictor of 30-day mortality, although its usefulness for other clinical outcomes remains to be proven.

Evaluation of the GCS-Pupils Score for PrOgnosis in trauMatic brAin injury- The COMA Study.

OBJECTIVES: Glasgow Coma Scale-Pupils (GCS-P) score has been found to be strongly related to in-hospital mortality in retrospective studies. We hypothesized that GCS-P would be better prognosticator than Glasgow Coma Scale (GCS) in patients with traumatic brain injury (TBI). METHODS: In this prospective, multicentric, observational study, GCS and GCS-P scores were noted in adult TBI patients at ICU admission. Demographic variables, relevant clinical history, clinical/radiological findings and ICU complications were also noted. Extended Glasgow Outcome scale was noted at hospital discharge and at 6 months post-injury. Logistic regression analysis was carried out to estimate the odds for poor outcome adjusted for covariates. Sensitivity, specificity, area under curve (AUC) and odds ratio are reported for poor outcome at estimated cutoff point. RESULTS: A total of 573 patients were included in this study. The predictive power for mortality, shown by the AUC, was 0.81 [95% CI: 0.77-0.85] for GCS and 0.81 [95% CI: 0.77-0.86] for GCS-P score, both being comparable. Similarly, the predictive ability for outcome at discharge and 6 months, the AUC-ROC for both GCS and GCS-P were comparable. CONCLUSIONS: GCS-P is a good predictor of mortality and poor outcome. However, the predictive performance of GCS and GCS-P for in-hospital mortality and functional outcome at discharge and at 6 months remains comparable.

Invasive beta-haemolytic streptococcal infections, Finland, 2006 to 2020: increase in Lancefield group C/G infections.

BackgroundInvasive infections with beta-haemolytic streptococci of Lancefield groups A (iGAS), B (iGBS) and C/G (iGCGS) are a major cause of morbidity and mortality worldwide.AimWe studied incidence trends of invasive beta-haemolytic streptococcal infections in Finland, focusing on iGCGS.MethodsWe conducted a retrospective register-based study. Cases were defined as isolations from blood and/or cerebrospinal fluid and retrieved from the National Infectious Disease Register where all invasive cases are mandatorily notified.ResultsBetween 2006 and 2020, the mean annual incidence was 4.1 per 100,000 for iGAS (range: 2.1-6.7), 5.2 for iGBS (4.0-6.3) and 10.1 for iGCGS (5.4-17.6). The incidence displayed an increasing trend for all groups, albeit for iGBS only for individuals 45 years and older. The increase was particularly sharp for iGCGS (8% annual relative increase). The incidence rate was higher in males for iGCGS (adjusted incidence rate ratio (IRR) = 1.6; 95% confidence interval (CI): 1.5-1.8) and iGAS (adjusted IRR = 1.3; 95% CI: 1.1-1.4); for iGBS, the association with sex was age-dependent. In adults, iGCGS incidence increased significantly with age. Recurrency was seen for iGCGS and secondarily iGBS, but not for iGAS. Infections with iGCGS and iGBS peaked in July and August.ConclusionsThe incidence of invasive beta-haemolytic streptococcal infections in Finland has been rising since 2006, especially for iGCGS and among the elderly population. However, national surveillance still focuses on iGAS and iGBS, and European Union-wide surveillance is lacking. We recommend that surveillance of iGCGS be enhanced, including systematic collection and typing of isolates, to guide infection prevention strategies.