Early Intraventricular Antibiotic Therapy Improved In-Hospital-Mortality in Neurocritical Patients with Multidrug-Resistant Bacterial Nosocomial Meningitis and Ventriculitis.

BACKGROUND: Hospital-acquired multidrug-resistant (MDR) bacterial meningitis and/or ventriculitis (MEN) is a severe condition associated with high mortality. The risk factors related to in-hospital mortality of patients with MDR bacterial MEN are unknown. We aimed to examine factors related to in-hospital mortality and evaluate their prognostic value in patients with MDR bacterial MEN treated in the neurointensive care unit. METHODS: This was a single-center retrospective cohort study of critically ill neurosurgical patients with MDR bacterial MEN admitted to our hospital between January 2003 and March 2021. Data on demographics, admission variables, treatment, time to start of intraventricular (IVT) therapy, and in-hospital mortality were analyzed. Both univariate and multivariable analyses were performed to identify determinants of in-hospital mortality. RESULTS: All 142 included patients received systemic antibiotic therapy, and 102 of them received concomitant IVT treatment. The median time to start of IVT treatment was 2 days (interquartile range 1-5 days). The time to start of IVT treatment had an effect on in-hospital mortality (hazard ratio 1.17; 95% confidence interval 1.02-1.34; adjusted p = 0.030). The cutoff time to initiate IVT treatment was identified at 3 days: patients treated within 3 days had a higher cerebrospinal fluid (CSF) sterilization rate (81.5%) and a shorter median time to CSF sterilization (7 days) compared with patients who received delayed IVT treatment (> 3 days) (48.6% and 11.5 days, respectively) and those who received intravenous antibiotics alone (42.5% and 10 days, respectively). CONCLUSIONS: Early IVT antibiotics were associated with superior outcomes in terms of the in-hospital mortality rate, time to CSF sterilization, and CSF sterilization rate compared with delayed IVT antibiotics and intravenous antibiotics alone.

Baicalein Ameliorates Epilepsy Symptoms in a Pilocarpine-Induced Rat Model by Regulation of IGF1R.

Treatment for epilepsy, particularly temporal lobe epilepsy, is challenging. Baicalein has multiple effects, including anti-inflammatory action. However, little is known about its efficacy in treatment of epilepsy. In this study, we established a pilocarpine-induced rat model and used it for assessment of baicalein efficacy in vivo. We predicted the pharmacological mechanism of baicalein by network pharmacology and RNA sequencing analyses. Pilocarpine epileptic rats treated with baicalein exhibited improved average seizure severity, seizure frequency, seizure duration, and survival time. Network pharmacology and RNA sequencing identified the differentially expressed genes between the baicalein treatment and epileptic groups. Insulin-like growth factor 1 receptor (IGF1R) was chosen as the top candidate target because of its overlapping findings in RNA sequencing and network pharmacology data. Western blotting, immunofluorescence, and polymerase chain reaction analyses showed that baicalein inhibited microglial proliferation, IGF1R, and inflammatory cytokine expression. Moreover, baicalein improved epilepsy symptoms. Inhibition of IGF1R function by blocking with AXL1717 enhanced baicalein treatment efficacy both in vivo and in vitro. In conclusion, baicalein exerted antiepileptic effects by regulation of IGF1R in a pilocarpine-induced rat model.

Reconfigurable Soft Actuators with Multiple-Stimuli Responses.

Multiple-stimuli responsive soft actuators with tunable initial shapes would have substantial potential in broad technological applications, ranging from advanced sensors, smart robots to biomedical devices. However, existing soft actuators are often limited to single initial shape and are unable to reversibly reconfigure into desirable shapes, which severely restricts the multifunctions that can be integrated into one actuator. Here, a novel reconfigurable supramolecular polymer/polyethylene terephthalate (PET) bilayer actuator exhibiting multiple-stimuli responses is presented. In this bilayer actuator, the supramolecular polymer layer constructed of poly(5-Norbornene-2-carboxylic acid-1,3-cyclooctadiene) (PNCCO) and azopyridine derivative (PyAzoPy) via H-bonds provides multiple-stimuli responses: PyAzoPy offers light response and carboxylic groups in PNCCO endow the actuator with humidity response. Meanwhile thermoplastic PET layer enables the bilayer actuators to be reconfigured into various shapes by thermal stimuli. The rationally designed actuators exhibit versatile capabilities to reversibly reconfigure into a set of initial shapes and carry out multiple functions, such as photo-driven "foldback-clip" and Ω-shaped crawling robots. In addition, bio-inspired plants constructed by reconfiguration of such actuators demonstrate reversible multiple-stimuli responses. It is anticipated that these novel actuators with highly tunable geometries and actuation modes would be useful to develop multifunctional devices capable of performing diverse tasks.

Circulating neutrophil-to-lymphocyte ratio at admission predicts the long-term outcome in acute traumatic cervical spinal cord injury patients.

BACKGROUND: The prognostic value of Neutrophil-to-Lymphocyte Ratio (NLR) for the outcome of acute cervical traumatic spinal cord injury (tSCI) patients has rarely been studied by now throughout the world. METHODS: We performed a single-center retrospective cohort study to evaluate the prognostic value of NLR from peripheral whole blood count in patients with acute cervical tSCI. Patients within 6 h of acute cervical tSCI treated between Dec 2008 and May 2018 in Huashan Hospital of Fudan University were enrolled. Outcomes of patients with tSCI were assessed using American spinal injury association Impairment Scale (AIS). 6-month outcomes were dichotomized into poor outcome group (AIS A to C) and good outcome group (AIS D and E). Uni- and multivariate analyses were performed to assess the independent predictors of 6-month outcome. Two prediction models based on admission characteristics were built to evaluate the prognostic value of NLR. The discriminative ability of predictive models was evaluated using the area under the curve (AUC). RESULTS: A total of 377 patients were identified from our single center in China PR. Multivariate analysis showed that age, AIS grade at admission, NLR (p < 0.001) and coagulopathy (p = 0.003) were independent predictors of the 6-months outcome for acute cervical tSCI patients. The model combing NLR and standard variables (AUC = 0.944; 95% CI, 0.923-0.964) showed a more favorable prognostic value than that without NLR (AUC = 0.841; 95% CI, 0.798-0.885) in terms of 6-month outcome. CONCLUSIONS: NLR is firstly identified as an independent predictor of the 6-month outcome in acute cervical tSCI patients worldwide. The prognostic value of NLR is favorable, and a high NLR is associated with poor outcome in patients with acute cervical tSCI.

Job satisfaction, engagement, and burnout in the population of orthopedic surgeon and neurosurgeon trainees in mainland China.

OBJECTIVE: In China, orthopedics and neurosurgery are among the most desired majors for medical students. However, little is known about the working and living status of specialists in these two fields. This study was aimed at evaluating job satisfaction, engagement, and burnout in the population of Chinese orthopedist and neurosurgeon trainees. METHODS: A nationwide online survey was administered in mainland China. Questionnaires were answered anonymously. Job satisfaction, engagement, and burnout were assessed using the Job Descriptive Index, the Utrecht Work Engagement Scale, and the Maslach Burnout Inventory, respectively. RESULTS: Data were collected from 643 orthopedist trainees and 690 neurosurgeon trainees. Orthopedists and neurosurgeons showed no statistical difference in terms of age, sex, job titles, and preference for working in tertiary hospitals. Orthopedists had a higher marriage rate (p < 0.01), a lower divorce rate (p = 0.017), relatively shorter working hours (p < 0.01), and a higher annual income (p = 0.023) than neurosurgeons. Approximately 40% of respondents experienced workplace violence in the last 5 years. Less than 10% of respondents were satisfied with their pay, and over 70% would not encourage their offspring to become a doctor. Orthopedists were more satisfied with their careers than neurosurgeons (p < 0.01) and had a higher level of work engagement (p < 0.01). In addition, a higher proportion of orthopedists were burnt out (p < 0.01) than neurosurgeons, though the difference between the two groups was not significant (p = 0.088). Multivariate regressions suggested that younger age (≤ 25 years old), being a senior trainee, getting divorced, working in a regional hospital, long working hours (≥ 71 hrs/wk), a low annual income (<¥100,000), sleeping < 6 hrs/day, and experience with workplace violence were significantly related to burnout for both groups. CONCLUSIONS: Chinese orthopedic surgical and neurosurgical trainees are under significant stress. Orthopedic surgeons showed relatively optimistic data in their assessments of job satisfaction, engagement, and burnout. This study may provide valuable information for orthopedic and neurosurgical candidates considering either specialty as a career.

The 135 Gene of Goatpox Virus Encodes an Inhibitor of NF-κB and Apoptosis and May Serve as an Improved Insertion Site To Generate Vectored Live Vaccine.

Goatpox virus (GTPV) is an important member of the Capripoxvirus genus of the Poxviridae Capripoxviruses have large and complex DNA genomes encoding many unknown proteins that may contribute to virulence. We identified that the 135 open reading frame of GTPV is an early gene that encodes an ∼18-kDa protein that is nonessential for viral replication in cells. This protein functioned as an inhibitor of NF-κB activation and apoptosis and is similar to the N1L protein of vaccinia virus. In the natural host, sheep, deletion of the 135 gene from the GTPV live vaccine strain AV41 resulted in less attenuation than that induced by deletion of the tk gene, a well-defined nonessential gene in the poxvirus genome. Using the 135 gene as the insertion site, a recombinant AV41 strain expressing hemagglutinin of peste des petits ruminants virus (PPRV) was generated and elicited stronger neutralization antibody responses than those obtained using the traditional tk gene as the insertion site. These results suggest that the 135 gene of GTPV encodes an immunomodulatory protein to suppress host innate immunity and may serve as an optimized insertion site to generate capripoxvirus-vectored live dual vaccines.IMPORTANCE Capripoxviruses are etiological agents of important diseases in sheep, goats, and cattle. There are rare reports about viral protein function related to capripoxviruses. In the present study, we found that the 135 protein of GTPV plays an important role in inhibition of innate immunity and apoptosis in host cells. Use of the 135 gene as the insertion site to generate a vectored vaccine resulted in stronger adaptive immune responses than those obtained using the tk locus as the insertion site. As capripoxviruses are promising virus-vectored vaccines against many important diseases in small ruminants and cattle, the 135 gene may serve as an improved insertion site to generate recombinant capripoxvirus-vectored live dual vaccines.

Effects and Clinical Characteristics of Intracranial Pressure Monitoring-Targeted Management for Subsets of Traumatic Brain Injury: An Observational Multicenter Study.

OBJECTIVES: To evaluate the efficacy of traumatic brain injury management guided by intracranial pressure monitoring and to explore the specific subgroups for which intracranial pressure monitoring might be significantly associated with improved outcomes based on a classification of the various traumatic brain injury pathophysiologies using the clinical features and CT scans. DESIGN: Retrospective observational multicenter study. SETTING: Twenty-two hospitals (16 level I trauma centers and six level II trauma centers) in nine provinces in China. PATIENTS: Moderate or severe traumatic brain injury patients who were more than 14 years old. INTERVENTIONS: Intracranial pressure monitoring. MEASUREMENTS AND MAIN RESULTS: All data were collected by physicians from medical records. The 6-month mortality and favorable outcome were assessed with the Glasgow Outcome Scale Extended score. An intracranial pressure monitor was inserted into 838 patients (58.1%). The mean duration of intracranial pressure monitoring was 4.44 ± 3.65 days. The significant predictors of intracranial pressure monitoring included the mechanism of injury, a Glasgow Coma Scale score of 9-12 at admission that dropped to a score of 3-8 within 24 hours after injury, a Marshall CT classification of III-IV, the presence of a major extracranial injury, subdural hematoma, intraparenchymal lesions, trauma center level, and intracranial pressure monitoring utilization of hospital. The intracranial pressure monitoring and no intracranial pressure monitoring groups did not significantly differ in terms of complications. For the total sample, the placement of intracranial pressure monitoring was not associated with either 6-month mortality (16.9% vs 20.5%; p = 0.086) or 6-month unfavorable outcome (49.4% vs 45.8%; p = 0.175). For patients with a Glasgow Coma Scale score of 3-8 at admission, intracranial pressure monitoring was also not significantly associated with 6-month mortality (20.9% vs 26.0%; p = 0.053) or an unfavorable outcome (56.9% vs 55.5%; p = 0.646). Multivariate logistic regression analyses showed that intracranial pressure monitoring resulted in a significantly lower 6-month mortality for patients who had a Glasgow Coma Scale score of 3-5 at admission (adjusted odds ratio, 0.57; 95% CI, 0.36-0.90; adjusted p = 0.016), those who had a Glasgow Coma Scale score of 9-12 at admission that dropped to 3-8 within 24 hours after injury (adjusted odds ratio, 0.28; 95% CI, 0.08-0.96; adjusted p = 0.043), and those who had a probability of death at 6 months greater than 0.6 (adjusted odds ratio, 0.55; 95% CI, 0.32-0.94; adjusted p = 0.029). CONCLUSIONS: There were multiple differences between the intracranial pressure monitoring and no intracranial pressure monitoring groups regarding patient characteristics, injury severity, characteristics of CT scan, and hospital type. Intracranial pressure monitoring in conjunction with intracranial pressure-targeted therapies is significantly associated with lower mortality in some special traumatic brain injury subgroups. The prospective randomized controlled trials specifically investigating these subgroups will be required to further characterize the effects of intracranial pressure monitoring on behavioral outcomes in patients with traumatic brain injury.

Subdural hygroma following decompressive craniectomy or non-decompressive craniectomy in patients with traumatic brain injury: Clinical features and risk factors.

OBJECTIVE: Subdural hygroma (SDG) is a common complication that can occur after head trauma or secondary to decompressive craniectomy (DC). SDGs can be located not only ipsilateral or contralateral to the side of the DC, but also bilateral or unilateral in patients without DC. This study investigated the incidence and risk factors for different types of SDG in a large cohort of patients with traumatic brain injury (TBI). METHODS: A retrospective study was conducted involving 379 adult patients with TBI who were admitted to Huashan Hospital, Fudan University between January 2009 and December 2013. As the outcome was dichotomous (SDG vs no SDG or hydrocephalus vs no hydrocephalus), multivariate logistic regression analyses were used to identify independent risk factors for the development of SDGs in patients without DC, ipsilateral SDG after unilateral DC, contralateral SDG after unilateral DC or SDG after bilateral DC. Risk factors for the development of hydrocephalus were also evaluated in patients with and without DC. RESULTS: Among the 207 (54.6%) patients without DC, 30 (14.5%) had unilateral SDGs and 34 (16.4%) had bilateral SDGs. Of the 172 patients (45.4%) with DC, 134 (77.9%) underwent unilateral DC and 38 (22.1%) underwent bilateral DC. Of the 134 patients who underwent unilateral DC, 49 developed SDG, including 22 (16.4%) ipsilateral SDG, 19 (14.2%) contralateral SDG and eight (6.0%) both ipsilateral and contralateral SDGs. For patients undergoing bilateral DC, 13 (34.2%) developed a SDG. No significant difference in the incidence of SDG was observed between the patients with and without DC (36.0% vs 30.9%, p = 0.291), but the characteristics of SDGs were different between the two groups. Logistic regression analysis showed that factors independently associated with the development of SDG were male sex (odds ratio [OR] = 3.861; 95% CI = 1.642-9.091; p = 0.002), older age (OR = 1.046; 95% CI = 1.021-1.070; p < 0.001), basal cistern haemorrhage (OR = 4.608; 95% CI = 1.510-14.064; p = 0.007), diffuse injury and swelling (OR = 3.158; 95% CI = 1.341-7.435; p = 0.008) or diffuse injury and shift (OR = 3.826; 95% CI = 1.141-12.830; p = 0.030) in patients without DC. Temporal haematoma or contusion in the non-DC side (OR = 2.623; 95% CI = 1.070-6.428; p = 0.035) and traumatic SAH (OR = 3.751; 95% CI = 1.047-13.438; p = 0.042) were independently associated with the development of ipsilateral SDG in patients who underwent unilateral DC. However, factors independently associated with the development of contralateral SDG were frontal haematoma or contusion on the non-DC side (OR = 3.145; 95% CI = 1.272-7.774; p = 0.013) and SDH on the non-DC side (OR = 7.024; 95% CI = 1.477-33.390; p = 0.014). Only craniectomy area (OR = 1.030; 95% CI = 1.008-1.052; p = 0.008) was independently associated with the development of SDG in patients with bilateral DC. In the multivariate analysis, SDG in patients without DC was not associated with the development of hydrocephalus. However, SDG was significantly associated with the development of hydrocephalus for patients who underwent DC (OR = 2.173; 95% CI = 1.362-3.467; p = 0.001). CONCLUSIONS: This study suggested that the incidence of SDG in patients who have and have not undergone DC was identical; however, the patients' characteristics and risk factors differed. Therefore, the management and prediction of SDG should be performed according to SDG type.

Tetranectin knockout mice develop features of Parkinson disease.

BACKGROUND/AIMS: Aggregation of insoluble α-synuclein to form Lewy bodies (LBs) may contribute to the selective loss of midbrain dopaminergic neurons in Parkinson disease (PD). Lack of robust animal models has impeded elucidation of the molecular mechanisms of LB formation and other critical aspects of PD pathogenesis. METHODS: We established a mouse model with targeted deletion of the plasminogen-binding protein tetranectin (TN) gene (TN(-/-)) and measured the behavioral and histopathological features of PD. RESULTS: Aged (15-to 20-month-old) TN(-/-) mice displayed motor deficits resembling PD symptoms, including limb rigidity and both slower ambulation (bradykinesia) and reduced rearing activity in the open field. In addition, these mice exhibited more numerous α-synuclein-positive LB-like inclusions within the substantia nigra pars compacta (SNc) and reduced numbers of SNc dopaminergic neurons than age-matched wild type (WT) mice. These pathological changes were also accompanied by loss of dopamine terminals in the dorsal striatum. CONCLUSION: The TN(-/-) mouse exhibits several key features of PD and so may be a valuable model for studying LB formation and testing candidate neuroprotective therapies for PD and other synucleinopathies.

Continuous measurement of the cumulative amplitude and duration of hyperglycemia best predicts outcome after traumatic brain injury.

BACKGROUND: This study aimed to assess the accuracy and utility of high-resolution continuous glucose recording in patients with traumatic brain injury (TBI) and to establish whether a relationship exists between the cumulative amplitude and duration of hyperglycemia and outcome after TBI. METHODS: Glucose data for 56 TBI patients were collected continuously at 5-min intervals. The degree and duration of hyperglycemia above treatment thresholds were calculated as "glucose times time dose" (GTD; mg/dL d) using continuous recordings (GTD) for early stage (first 3 days). Long-term neurological functional outcome was assessed using the extended Glasgow Outcome Scale (GOSE). Receiver operating characteristic (ROC) curves were constructed to determine the predictive values of GTD, percentage readings, mean, and range of glucose for in-hospital mortality and GOSE. RESULTS: All measurements of GTD were statistically significantly higher in the group that died. GTD of glucose >150 and glucose >180 had a high-predictive power for in-hospital mortality (areas under the ROC curve [AUC] = 0.917; 95 % CI, 0.837-0.998 and 0.876; 95 % CI, 0.784-0.967, respectively) and demonstrated significantly higher predictive power for mortality when compared with %reading >150 and %reading >180, respectively (p < 0.05). GTD of glucose >150 also had a significantly higher predictive power for mortality than mean glucose and range of glucose. GTD of glucose >150 and glucose >180 also had a high-predictive power for poor outcome (areas under the ROC curve [AUC] = 0.913; 95 % CI, 0.843-0.983 and 0.858; 95 % CI, 0.760-0.956, respectively). CONCLUSIONS: Continuous collection of glucose recordings is more reliable and accurate than routine discontinuous recordings. Assessing both the duration and the amplitude of the episodes using continuous collection of glucose data helps in better predicting outcomes than the total duration of episodes.

Interplay between FGF2 and BMP controls the self-renewal, dormancy and differentiation of rat neural stem cells.

Mouse and human central nervous system progenitor cells can be propagated extensively ex vivo as stem cell lines. For the rat, however, in vitro expansion has proven to be problematic owing to proliferation arrest and differentiation. Here, we analyse the establishment, in adherent culture, of undifferentiated tripotent neural stem (NS) cell lines derived from rat foetal brain and spinal cord. Rat NS cells invariably undergo growth arrest and apparent differentiation after several passages; however, conditioned medium from proliferating cultures can overcome this block, enabling continuous propagation of undifferentiated rat NS cells. We found that dormancy is induced by autocrine production of bone morphogenetic proteins (BMPs). Accordingly, the BMP antagonist noggin can replace conditioned medium to sustain continuous self-renewal. Noggin can also induce dormant cells to re-enter the cell cycle, upon which they reacquire neurogenic potential. We further show that fibroblast growth factor 2 (FGF2) is required to suppress terminal astrocytic differentiation and maintain stem cell potency during dormancy. These findings highlight an extrinsic regulatory network, comprising BMPs, BMP antagonists and FGF2 signals, that governs the proliferation, dormancy and differentiation of rat NS cells and which can be manipulated to enable long-term clonogenic self-renewal.

Proteomic analysis of the cerebrospinal fluid of Parkinson's disease patients pre- and post-deep brain stimulation.

AIMS: To investigate alterations in protein expression associated with deep brain stimulation (DBS) in an attempt to elucidate possible mechanisms of action . METHODS: Cerebrospinal fluid (CSF), obtained from six Parkinson's disease (PD) patients (pre- and post-DBS) and from six normal healthy controls, was studied for differentially expressed proteins. 2-D DIGE, in combination with MALDI-TOF and TOF-TOF Mass Spectrometry (MS) or ESI-MS, was used to identify the changed proteins (3 PD patients and 3 controls). Selected proteins were further studied using western blotting (6 PD patients and 6 controls). RESULTS: Twenty-one proteins were identified after MS and protein database interrogation. Apart from apolipoprotein A-I (apoA-I), the expression levels of complement C4 (C4), IgA, tetranectin, and extracellular superoxide dismutase (EC-SOD), detected by western blotting, correlated well with the 2-D DIGE results. In the follow-up period, the expression levels of C4, apoA-I and IgA were stable whereas EC-SOD and tetranectin were significantly elevated. In addition, when DBS was ceased in one patient due to a suicide attempt, the levels of EC-SOD and tetranectin significantly decreased. CONCLUSION: Our preliminary results suggest that variations in the expression levels of EC-SOD and tetranectin in CSF is related to DBS.

Predictive value of initial intracranial pressure for refractory intracranial hypertension in persons with traumatic brain injury: a prospective observational study.

UNLABELLED: Abstract Objective: To prospectively investigate the predictive value of initial intracranial pressure (ICP) for refractory intracranial hypertension and outcomes in persons with diffuse traumatic brain injury (TBI). METHODS: A prospective observational study was conducted in 107 adult persons with diffuse TBI (Marshall CT Class II-IV). Initial ICP was defined as the first ICP recorded in the operating room. Refractory intracranial hypertension was defined as ICP increases to more than 30 mmHg and/or reduces in cerebral perfusion pressure to less than 60 mmHg for a period longer than 15 minutes and failure to respond to the maximum medical treatment. Baseline demographics and injury-specific data were recorded. Multiple logistic regression models were used to determine independent risk factors for refractory intracranial hypertension and unfavourable outcomes. A receiver-operating characteristic (ROC) curve was then drawn. RESULTS: The initial ICP allowed for a better refractory intracranial hypertension prediction (ROC area = 0.868; 95% CI = 0.799-0.937) than the Marshall Classification (ROC area = 0.670; 95% CI = 0.569-0.772) or Rotterdam Classification scores (ROC area = 0.679; 95% CI = 0.577-0.780). An initial ICP value higher than 20 mmHg had 83% sensitivity and 83% specificity, whereas an initial ICP value higher than 25 mmHg had 64% sensitivity and 92% specificity for refractory intracranial hypertension. A multivariable logistic regression model showed that any 5 mmHg pressure increase in a patient with initial ICP led to 2.884-times higher odds of refractory intracranial hypertension (95% CI = 1.893-4.395; p < 0.001). Head Abbreviated Injury Scale score, initial Glasgow Coma Scale (GCS) and initial GCS motor scores were not predictive of refractory intracranial hypertension (p > 0.05). CONCLUSION: For persons with diffuse TBI, the initial ICP provides great prognostic discrimination and is an independent predictor of refractory intracranial hypertension.

[Role of small-dose recombinant human coagulation factor VIIa for coagulopathy in patients with isolated traumatic brain injury].

OBJECTIVE: To explore the role of small-dose recombinant human coagulation factor VIIa (rFVIIa) for coagulopathy in patients with isolated traumatic brain injury. METHODS: A total of 86 isolated traumatic brain patients with coagulopathy were treated at our neurosurgery intensive care unit (NICU) from January 2010 to December 2012. Their trauma registry data included mortality, pre-and post-rFVIIa coagulation parameters. Two-tailed paired t-test was used to determine significant changes in coagulation parameters and other major clinical parameters. RESULTS: Twenty-seven patients made up the low-dose rFVIIa (20 µg/kg) group. And the control group had 59 well-matched subjects. At admission, age, blood pressure, Glasgow coma scale score, hemoglobin, platelets and international normalize ratio were similar in both groups. After treatment, the INR of patients on rFVIIa was lower than that of the conventional treatment group (1.1 ± 0.2 vs 1.2 ± 0.2, P < 0.01) and it declined more in the rFVIIa group (0.3 ± 0.2 vs 0.1 ± 0.4, P = 0.05). No significant difference existed in mortality or length of stay between two groups.There was no occurrence of subsequent thromboembolic events. CONCLUSION: The application of small-dose rFVIIa can effectively reduce the value of INR and improve the coagulation status of patients. During the course of treatment, no major adverse events occur.

Prediction of in-hospital hypokalemia using machine learning and first hospitalization day records in patients with traumatic brain injury.

AIMS: Hypokalemia is a common complication following traumatic brain injury, which may complicate treatment and lead to unfavorable outcomes. Identifying patients at risk of hypokalemia on the first day of admission helps to implement prophylactic treatment, reduce complications, and improve prognosis. METHODS: This multicenter retrospective study was performed between January 2017 and December 2020 using the electronic medical records of patients admitted due to traumatic brain injury. A propensity score matching approach was adopted with a ratio of 1:1 to overcome overfitting and data imbalance during subgroup analyses. Five machine learning algorithms were applied to generate a best-performed prediction model for in-hospital hypokalemia. The internal fivefold cross-validation and external validation were performed to demonstrate the interpretability and generalizability. RESULTS: A total of 4445 TBI patients were recruited for analysis and model generation. Hypokalemia occurred in 46.55% of recruited patients and the incidences of mild, moderate, and severe hypokalemia were 32.06%, 12.69%, and 1.80%, respectively. Hypokalemia was associated with increased mortality, while severe hypokalemia cast greater impacts. The logistic regression algorithm had the best performance in predicting decreased serum potassium and moderate-to-severe hypokalemia, with an AUC of 0.73 ± 0.011 and 0.74 ± 0.019, respectively. The prediction model was further verified using two external datasets, including our previous published data and the open-assessed Medical Information Mart for Intensive Care database. Linearized calibration curves showed no statistical difference (p > 0.05) with perfect predictions. CONCLUSIONS: The occurrence of hypokalemia following traumatic brain injury can be predicted by first hospitalization day records and machine learning algorithms. The logistic regression algorithm showed an optimal predicting performance verified by both internal and external validation.

Breast Cancer Mutations HER2V777L and PIK3CAH1047R Activate the p21-CDK4/6-Cyclin D1 Axis to Drive Tumorigenesis and Drug Resistance.

In metastatic breast cancer, HER2-activating mutations frequently co-occur with mutations in PIK3CA, TP53, or CDH1. Of these co-occurring mutations, HER2 and PIK3CA are the most commonly comutated gene pair, with approximately 40% of HER2-mutated breast cancers also having activating mutations in PIK3CA. To study the effects of co-occurring HER2 and PIK3CA mutations, we generated genetically engineered mice with the HER2V777L; PIK3CAH1047R transgenes (HP mice) and studied the resulting breast cancers both in vivo as well as ex vivo using cancer organoids. HP breast cancers showed accelerated tumor formation in vivo and increased invasion and migration in in vitro assays. HP breast cancer cells were resistant to the pan-HER tyrosine kinase inhibitor, neratinib, but were effectively treated with neratinib plus the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan. Proteomic and RNA-seq analysis of HP breast cancers identified increased gene expression of cyclin D1 and p21WAF1/Cip1 and changes in cell-cycle markers. Combining neratinib with CDK4/6 inhibitors was another effective strategy for treating HP breast cancers, with neratinib plus palbociclib showing a statistically significant reduction in development of mouse HP tumors as compared to either drug alone. The efficacy of both the neratinib plus trastuzumab deruxtecan and neratinib plus palbociclib combinations was validated using a human breast cancer patient-derived xenograft with very similar HER2 and PIK3CA mutations to the HP mice. Further, these two drug combinations effectively treated spontaneous lung metastasis in syngeneic mice transplanted with HP breast cancer organoids. This study provides valuable preclinical data to support the ongoing phase 1 clinical trials of these drug combinations in breast cancer. SIGNIFICANCE: In HER2-mutated breast cancer, PIK3CA mutation activates p21-CDK4/6-cyclin D1 signaling to drive resistance to HER2-targeted therapies, which can be overcome using CDK4/6 inhibitors.

Prediction of Intracranial Infection in Patients under External Ventricular Drainage and Neurological Intensive Care: A Multicenter Retrospective Cohort Study.

Objective: To generate an optimal prediction model along with identifying major contributors to intracranial infection among patients under external ventricular drainage and neurological intensive care. Methods: A retrospective cohort study was conducted among patients admitted into neurointensive care units between 1 January 2015 and 31 December 2020 who underwent external ventricular drainage due to traumatic brain injury, hydrocephalus, and nonaneurysmal spontaneous intracranial hemorrhage. Multivariate logistic regression in combination with the least absolute shrinkage and selection operator regression was applied to derive prediction models and optimize variable selections. Other machine-learning algorithms, including the support vector machine and K-nearest neighbor, were also applied to derive alternative prediction models. Five-fold cross-validation was used to train and validate each model. Model performance was assessed by calibration plots, receiver operating characteristic curves, and decision curves. A nomogram analysis was developed to explicate the weights of selected features for the optimal model. Results: Multivariate logistic regression showed the best performance among the three tested models with an area under curve of 0.846 ± 0.006. Six variables, including hemoglobin, albumin, length of operation time, American Society of Anesthesiologists grades, presence of traumatic subarachnoid hemorrhage, and a history of diabetes, were selected from 37 variable candidates as the top-weighted prediction features. The decision curve analysis showed that the nomogram could be applied clinically when the risk threshold is between 20% and 100%. Conclusions: The occurrence of external ventricular-drainage-associated intracranial infections could be predicted using optimal models and feature-selection approaches, which would be helpful for the prevention and treatment of this complication in neurointensive care units.

Characteristics and therapeutic profile of TBI patients who underwent bilateral decompressive craniectomy: experience with 151 cases.

BACKGROUND: Decompressive craniectomy (DC) and intracranial pressure (ICP) monitoring are common approaches to reduce the death rate of Traumatic brain injury (TBI) patients, but the outcomes of these patients are unfavorable, particularly those who receive bilateral DC. The authors discuss their experience using ICP and other potential methods to improve the outcomes of TBI patients who receive bilateral DC. METHODS: Data from TBI patients receiving bilateral DC from Jan. 2008 to Jan. 2022 were collected via a retrospective chart review. Included patients who received unplanned contralateral DC after initial surgery were identified as unplanned secondary surgery (USS) patients. Patients' demographics and baseline medical status; pre-, intra-, and postoperative events; and follow-up visit outcome data were analyzed. RESULTS: A total of 151 TBI patients were included. Patients who underwent USS experienced more severe outcomes as assessed using the 3-month modified Rankin Scale score (P = 0.024). In bilateral DC TBI patients, USS were associated with worsen outcomes, moreover, ICP monitoring was able to lower their death rate and was associated with a lower USS incidence. In USS patients, ICP monitoring was not associated with improved outcomes but was able to lower their mortality rate (2/19, 10.5%, vs. 10/25, 40.0%; P = 0.042). CONCLUSION: The avoidance of USS may be associated with improved outcomes of TBI patients who underwent bilateral DC. ICP monitoring was a potential approach to lower USS rate in TBI patients, but its specific benefits were uncertain.

N-terminal pro-B-type natriuretic peptide in patients with isolated traumatic brain injury: a prospective cohort study.

BACKGROUND: The role of brain natriuretic peptide (BNP) after traumatic brain injury (TBI) remains unclear, and its relationship with hyponatremia is still controversial. The aim of this study is to investigate the secretion pattern of N-terminal (NT)-proBNP in patients with TBI and to assess the relationship between NT-proBNP, sodium balance, and intracranial pressure (ICP). METHODS: We measured serum NT-proBNP levels of 84 patients with isolated TBI on a daily basis from day 1 to day 14 after injury. RESULTS: In average, the peak of BNP level was measured at 703.9 pg/mL±179.1 pg/mL on day 3 after injury, which was correlated to the severity of TBI. Among patients with severe TBI, plasma NT-proBNP concentrations in patients with hyponatremia were statistically higher than those without hyponatremia (p<0.05). In the hyponatremic group, the plasma NT-proBNP increased to a peak of 1001.16 pg/mL±131.52 pg/mL within 48 hours after injury and maintained at a high level for 3 days. In the normonatremic group, the plasma NT-proBNP reached a peak of 826.43 pg/mL±337.43 pg/mL on day 5 and quickly decreased thereafter. In addition, we found plasma NT-proBNP concentrations in patients with ICP>15 mm Hg were significantly higher than those in patients with ICP≤15 mm Hg (p<0.01). CONCLUSIONS: This study provides evidence that BNP plasma concentrations increase rapidly after TBI. Plasma BNP concentrations are correlated with hyponatremia in severe TBI patients but not in mild and moderate TBI patients. Furthermore, patients with elevated ICP have a higher serum BNP level in first 4 days after injury.

Validating the incidence of coagulopathy and disseminated intravascular coagulation in patients with traumatic brain injury--analysis of 242 cases.

OBJECTIVES: To estimate the incidence of coagulopathy and disseminated intravascular coagulation (DIC) in patients with traumatic brain injury (TBI) and to investigate its relationship to patient outcome. DESIGN: A prospective observational study. MEASUREMENTS AND MAIN RESULTS: From January 2007 to June 2009, 242 consecutive adult patients with TBI seen in three independent hospitals were recruited. Glasgow Coma Score (GCS) on admission, platelet counts (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D-dimer (D-DT) and DIC scores were recorded for each case on admission. Clinical outcome was measured according to the Glasgow Outcome Scale (GOS) at 3 months after injury. Statistical analysis was carried using Student's t-test, one-way analysis of variance (ANOVA), and Tudey test. Coagulation abnormalities were present in approximately 50% of patients with TBI. Prolonged PT and increased D-DT and FIB levels occurred in patients with more severe brain injury and poorer outcome, and these findings were statistically significant. CONCLUSIONS: Coagulation changes, particularly the incidence of DIC, may occur within 6 h after TBI and are more pronounced in patients with severe injuries and poor outcome. PT, D-DT levels and more comprehensively a DIC scores may be useful prognostic indicators in patients with TBI.