Coagulopathy in Penetrating Ballistic Cranial Trauma: A 7-Year Experience.

BACKGROUND AND OBJECTIVES: Penetrating ballistic cranial trauma (PBCT) carries significant mortality when compared with blunt trauma. The development of coagulopathy in PBCT is a strong predictor of mortality. The goal of the study was to describe the incidence and risk factors of coagulopathy in PBCT and to report the value of tranexamic acid administration in PBCT. METHODS: We retrospectively analyzed 270 patients who presented with PBCT to a single, Level 1 trauma center between 2016 and 2023. RESULTS: A total of 47% (127/270) of patients with PBCT developed coagulopathy at presentation. Fifty-seven patients received tranexamic acid at presentation, which did not affect the development of coagulopathy. Coagulopathic patients were more likely to have more serious injury patterns (bihemispheric [adjusted odds ratio, aOR: 2.6 CI: 1.4-4.9, P = .004] or transventricular trajectories [aOR: 4.9 CI: 1.9-19.6, P = .03]). In addition, they presented with a larger base deficit (aOR: 0.9 CI: 1.002-1.2 per mEq/L, P = .006) which negatively correlated with the international normalized ratio (ρ: -0.46, P < .0001, Spearman correlation). Using thromboelastography helped to identify an additional 20% of patients who presented with normal coagulation on conventional testing. CONCLUSION: Coagulopathy is prevalent in approximately 50% of patients with PBCT and is persistent despite treatment in a substantial subset of patients. The addition of thromboelastography with its increased coagulopathy sensitivity can potentially guide treatment more efficiently than traditional coagulopathy laboratory tests and fibrinogen alone. Patients with a significant base deficit on arterial blood gas are at higher risk for coagulopathy.

The Neurosurgeon's Dilemma-Do Antiplatelet/Anticoagulant Medications Increase the Risk of Catheter-Associated Hemorrhage in External Ventricular Drain Placement?

OBJECTIVE: External ventricular drain (EVD) placement is a common neurosurgical procedure that can be performed at bedside. A frequent complication following EVD placement is catheter-associated hemorrhage (CAH). The hemorrhage itself is rarely clinically significant but may be complicated in patients taking anticoagulant or antiplatelet (AC/AP) medications. METHODS: A total of 757 patients were who underwent EVD placement at bedside were included as part of a retrospective study at a large academic medical center. Demographic factors, use of AC/AP therapies, and several other clinical variables were recorded and assessed in univariate and multivariate regression analysis for association with CAH and mortality. RESULTS: One hundred (13.2%) patients experienced CAH within 24 hours of the procedure. After univariate analysis, in 2 tandem-run multivariate regression analyses after stepwise variable selection, use of 2 or more AC/AP agents (odds ratio [OR] = 2.362, P = 0.020) and dual antiplatelet therapy with aspirin and clopidogrel (OR = 3.72, P = 0.009) were significantly associated with CAH. Use of noncoated catheters was a protective factor against CAH compared to use of antibiotic-coated catheters (OR = 0.55, P = 0.019). Multivariate analysis showed age, multiagent therapy, and thrombocytopenia were significantly associated with increased mortality. CONCLUSIONS: There was increased risk of CAH after EVD placement in patients taking more than one AC/AP agent regardless of presenting pathology. In particular, use of aspirin and clopidogrel combined was associated with significantly higher odds of CAH, although it was not associated with higher mortality. In addition, there appears to be an association between use of antibiotic-coated catheters and CAH across univariate and multivariate analysis.

Differences in microorganisms causing infection after cranial and spinal surgeries.

OBJECTIVE: The primary aim of this retrospective study was to assess differences in the pathogens causing surgical site infections (SSIs) following craniectomies/craniotomies and open spinal surgery. The secondary aim was to assess differences in rates of SSI among these operative procedures. METHODS: ANOVA tests with Bonferroni correction and incidence risk ratios (RRs) were used to identify differences in pathogens by surgical site and procedure using retrospective, de-identified records of 19,993 postneurosurgical patients treated between 2007 and 2020. RESULTS: The overall infection rates for craniotomy/craniectomy, laminectomy, and fusion were 2.1%, 1.1%, and 1.5%, respectively, and overall infection rates for cervical, thoracic, and lumbar spine surgery were 0.3%, 1.6%, and 1.9%, respectively. Craniotomy/craniectomy was more likely to result in an SSI than spine surgery (RR 1.8, 95% CI 1.4-2.2, p < 0.0001). Cutibacterium acnes (RR 24.2, 95% CI 7.3-80.0, p < 0.0001); coagulase-negative staphylococci (CoNS) (methicillin-susceptible CoNS: RR 2.9, 95% CI 1.6-5.4, p = 0.0006; methicillin-resistant CoNS: RR 5.6, 95% CI 1.4-22.3, p = 0.02); Klebsiella aerogenes (RR 6.5, 95% CI 1.7-25.1, p = 0.0003); Serratia marcescens (RR 2.4, 95% CI 1.1-7.1, p = 0.01); Enterobacter cloacae (RR 3.1, 95% CI 1.2-8.1, p = 0.02); and Candida albicans (RR 3.9, 95% CI 1.2-12.3, p = 0.02) were more commonly associated with craniotomy/craniectomy cases than fusion or laminectomy SSIs. Pseudomonas aeruginosa was more commonly associated with fusion SSIs than craniotomy SSIs (RR 4.4, 95% CI 1.3-14.8, p = 0.02), whereas Escherichia coli was nonsignificantly associated with fusion SSIs compared to craniotomy SSIs (RR 4.1, 95% CI 0.9-18.1, p = 0.06). Infections with E. coli and P. aeruginosa occurred primarily in the lumbar spine (p = 0.0003 and p = 0.0001, respectively). CONCLUSIONS: SSIs due to typical gastrointestinal or genitourinary gram-negative bacteria occur most commonly following lumbar surgery, particularly fusion, and are likely to be due to contamination of the surgical bed with microbial flora in the perianal area and genitourinary tract. Cutibacterium acnes in the skin flora of the head and neck increases risk of infection due to this microbe following surgical interventions in these body sites. The types of gram-negative bacteria associated with craniotomy/craniectomy SSIs suggest potential environmental sources of these pathogens. Based on the authors' findings, neurosurgeons should consider using a two-step skin preparation with benzoyl peroxide, in addition to a standard antiseptic such as alcoholic chlorhexidine for cranial, cervical, and upper thoracic surgeries. Additionally, broader gram-negative bacterial coverage, such as use of a third-generation cephalosporin, should be considered for lumbar/lumbosacral fusion surgical antibiotic prophylaxis.

Structure-Activity Relationships of Flupirtine Analogues for Liver Esterase-Mediated Cleavage of the 4-Fluorobenzylamine Moiety and Its Possible Relevance to Liver Toxicity.

Flupirtine and retigabine were essential drugs to combat pain and epilepsy. However, the Kv 7 potassium channel openers are fraught with hepatotoxicity and tissue discoloration, respectively, limiting their therapeutic value. Both adverse events are likely due to reactive metabolites arising from oxidative metabolism. Designing safer analogues lacking the structural elements leading to described side effects is an active area of current research. One of the main metabolites of flupirtine is the biologically inactive 4-fluorohippuric acid. Hitherto unexplained, the proposed metabolic pathway leading to the formation of 4-fluorohippuric acid from flupirtine is verified here. Through the use of eighteen flupirtine analogues, mechanistic details of this pathway could be elucidated. A possible connection with the in vitro hepatotoxicity of the flupirtine analogues and the levels of 4-fluorobenzoic acid formed in enzyme incubations was examined by correlation analysis. These findings provide important information for the design of new flupirtine analogues as potential drug candidates.

Near-lifespan longitudinal tracking of brain microvascular morphology, topology, and flow in male mice.

In age-related neurodegenerative diseases, pathology often develops slowly across the lifespan. As one example, in diseases such as Alzheimer's, vascular decline is believed to onset decades ahead of symptomology. However, challenges inherent in current microscopic methods make longitudinal tracking of such vascular decline difficult. Here, we describe a suite of methods for measuring brain vascular dynamics and anatomy in mice for over seven months in the same field of view. This approach is enabled by advances in optical coherence tomography (OCT) and image processing algorithms including deep learning. These integrated methods enabled us to simultaneously monitor distinct vascular properties spanning morphology, topology, and function of the microvasculature across all scales: large pial vessels, penetrating cortical vessels, and capillaries. We have demonstrated this technical capability in wild-type and 3xTg male mice. The capability will allow comprehensive and longitudinal study of a broad range of progressive vascular diseases, and normal aging, in key model systems.

Drying stresses in cellulose nanocrystal coatings: Impact of molecular and macromolecular additives.

The industrial implementation of cellulose nanocrystals (CNCs) in films and coatings requires thorough evaluation of the internal stresses post-consolidation, as they cause fracturing and peeling. Characterizing the impact of plasticizing additives on stress is therefore critical. Herein, we use the deflection of thin glass substrates to measure drying stresses in consolidating CNC films, and benchmark the impact of five additives (glucose, glycerol, poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA) and bovine serum albumin). Glycerol and PEG reduced drying stresses effectively, while PEG of increased molecular weight (from 0.2 to 10 kDa), PVA, and BSA were less effective. We analyzed the temporal aspects of the process, where stress relaxation of up to 30 % was observed 2 years after coating formation. Finally, we provide a framework to evaluate the impact of CNC morphology on residual stresses. The introduced approach is expected to fast-track the optimization and implementation of coatings based on biocolloids.

Replacing the oxidation-sensitive triaminoaryl chemotype of problematic KV 7 channel openers: Exploration of a nicotinamide scaffold.

KV 7 channel openers have proven their therapeutic value in the treatment of pain as well as epilepsy and, moreover, they hold the potential to expand into additional indications with unmet medical needs. However, the clinically validated but meanwhile discontinued KV 7 channel openers flupirtine and retigabine bear an oxidation-sensitive triaminoraryl scaffold, which is suspected of causing adverse drug reactions via the formation of quinoid oxidation products. Here, we report the design and synthesis of nicotinamide analogs and related compounds that remediate the liability in the chemical structure of flupirtine and retigabine. Optimization of a nicotinamide lead structure yielded analogs with excellent KV 7.2/3 opening activity, as evidenced by EC50 values approaching the single-digit nanomolar range. On the other hand, weighted KV 7.2/3 opening activity data including inactive compounds allowed for the establishment of structure-activity relationships and a plausible binding mode hypothesis verified by docking and molecular dynamics simulations.

Reducing ventriculoperitoneal shunt infection with intraoperative glove removal.

BACKGROUND: Contamination of ventriculoperitoneal shunts (VPS) by cutaneous flora, particularly coagulase-negative staphylococci, is a common cause of shunt infection and failure, leading to prolonged hospital stay, higher costs of care, and poor outcomes. Glove contamination may occur during VPS insertion, increasing risk of such infections. METHODS: We performed a systematic search of the PubMed database for studies published January 1, 1970, through August 31, 2021 that documented VPS infection rates before and after implementing a practice of double gloving with change or removal of the outer glove immediately prior to shunt insertion. RESULTS: Among 272 reports screened, 4 were eligible for review based on our inclusion criteria. The incidence of VPS infection was reduced in all 4 quasi-experimental studies with an aggregate incidence of VPS infection of 11.8% before the change in intraoperative protocol and 4.9% after protocol change. One study documented reduced hospital stay with this change in protocol. CONCLUSION: The risk of VPS infection is reduced by removal or replacement of the outer surgical gloves immediately prior to intraoperative insertion of a VPS as part of an infection control bundle.

A Novel Deep Learning Model as a Donor-Recipient Matching Tool to Predict Survival after Liver Transplantation.

BACKGROUND: The "digital era" in the field of medicine is the new "here and now". Artificial intelligence has entered many fields of medicine and is recently emerging in the field of organ transplantation. Solid organs remain a scarce resource. Being able to predict the outcome after liver transplantation promises to solve one of the long-standing problems within organ transplantation. What is the perfect donor recipient match? Within this work we developed and validated a novel deep-learning-based donor-recipient allocation system for liver transplantation. METHOD: In this study we used data collected from all liver transplant patients between 2004 and 2019 at the university transplantation centre in Munich. We aimed to design a transparent and interpretable deep learning framework to predict the outcome after liver transplantation. An individually designed neural network was developed to meet the unique requirements of transplantation data. The metrics used to determine the model quality and its level of performance are accuracy, cross-entropy loss, and F1 score as well as AUC score. RESULTS: A total of 529 transplantations with a total of 1058 matching donor and recipient observations were added into the database. The combined prediction of all outcome parameters was 95.8% accurate (cross-entropy loss of 0.042). The prediction of death within the hospital was 94.3% accurate (cross-entropy loss of 0.057). The overall F1 score was 0.899 on average, whereas the overall AUC score was 0.940. CONCLUSION: With the achieved results, the network serves as a reliable tool to predict survival. It adds new insight into the potential of deep learning to assist medical decisions. Especially in the field of transplantation, an AUC Score of 94% is very valuable. This neuronal network is unique as it utilizes transparent and easily interpretable data to predict the outcome after liver transplantation. Further validation must be performed prior to utilization in a clinical context.

Carba Analogues of Flupirtine and Retigabine with Improved Oxidation Resistance and Reduced Risk of Quinoid Metabolite Formation.

The KV 7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain and epilepsy. However, as a result of adverse reactions, both drugs are currently no longer in therapeutic use. The flupirtine-induced liver injury and the retigabine linked tissue discolouration do not appear related at first glance; nevertheless, both events can be attributed to the triaminoaryl scaffold, which is affected by oxidation leading to elusive reactive quinone diimine or azaquinone diimine metabolites. Since the mechanism of action, i. e. KV 7 channel opening, seems not to be involved in toxicity, this study aimed to further develop safer replacements for flupirtine and retigabine. In a ligand-based design strategy, replacing amino substituents of the triaminoaryl core with alkyl substituents led to carba analogues with improved oxidation resistance and negligible risk of quinoid metabolite formation. In addition to these improved safety features, some of the novel analogues exhibited significantly improved KV 7.2/3 channel opening activity, indicated by an up to 13-fold increase in potency and an efficacy of up to 176 % compared to flupirtine, thus being attractive candidates for further development.

Risk factors and outcomes associated with external ventricular drain infections.

BACKGROUND: Insertion of an external ventricular drain (EVD) is a common neurosurgical procedure which may lead to serious complications including infection. Some risk factors associated with EVD infection are well established. Others remain less certain, including specific indications for placement, prior neurosurgery, and prior EVD placement. OBJECTIVE: To identify risk factors for EVD infections. METHODS: We reviewed all EVD insertions at our institution from March 2015 through May 2019 following implementation of a standardized infection control protocol for EVD insertion and maintenance. Cox regression was used to identify risk factors for EVD infections. RESULTS: 479 EVDs placed in 409 patients met inclusion criteria, and 9 culture-positive infections were observed during the study period. The risk of infection within 30 days of EVD placement was 2.2% (2.3 infections/1,000 EVD days). Coagulase-negative staphylococci were identified in 6 of the 9 EVD infections). EVD infection led to prolonged length of stay post-EVD-placement (23 days vs 16 days; P = .045). Cox regression demonstrated increased infection risk in patients with prior brain surgery associated with cerebrospinal fluid (CSF) diversion (HR, 8.08; 95% CI, 1.7-39.4; P = .010), CSF leak around the catheter (HR, 21.0; 95% CI, 7.0-145.1; P = .0007), and insertion site dehiscence (HR, 7.53; 95% CI, 1.04-37.1; P = .0407). Duration of EVD use >7 days was not associated with infection risk (HR, 0.62; 95% CI, 0.07-5.45; P = .669). CONCLUSION: Risk factors associated with EVD infection include prior brain surgery, CSF leak, and insertion site dehiscence. We found no significant association between infection risk and duration of EVD placement.

Modifications of the Triaminoaryl Metabophore of Flupirtine and Retigabine Aimed at Avoiding Quinone Diimine Formation.

The potassium channel opening drugs flupirtine and retigabine have been withdrawn from the market due to occasional drug-induced liver injury (DILI) and tissue discoloration, respectively. While the mechanism underlying DILI after prolonged flupirtine use is not entirely understood, evidence indicates that both drugs are metabolized in an initial step to reactive ortho- and/or para-azaquinone diimines or ortho- and/or para-quinone diimines, respectively. Aiming to develop safer alternatives for the treatment of pain and epilepsy, we have attempted to separate activity from toxicity by employing a drug design strategy of avoiding the detrimental oxidation of the central aromatic ring by shifting oxidation toward the formation of benign metabolites. In the present investigation, an alternative retrometabolic design strategy was followed. The nitrogen atom, which could be involved in the formation of both ortho- or para-quinone diimines of the lead structures, was shifted away from the central ring, yielding a substitution pattern with nitrogen substituents in the meta position only. Evaluation of KV7.2/3 opening activity of the 11 new specially designed derivatives revealed surprisingly steep structure-activity relationship data with inactive compounds and an activity cliff that led to the identification of an apparent "magic methyl" effect in the case of N-(4-fluorobenzyl)-6-[(4-fluorobenzyl)amino]-2-methoxy-4-methylnicotinamide. This flupirtine analogue showed potent KV7.2/3 opening activity, being six times as active as flupirtine itself, and by design is devoid of the potential for azaquinone diimine formation.

Entanglement Thresholds of Doubly Parametric Quantum Transducers.

Doubly parametric quantum transducers, such as electro-optomechanical devices, show promise for providing the critical link between quantum information encoded in highly disparate frequencies such as in the optical and microwave domains. This technology would enable long-distance networking of superconducting quantum computers. Rapid experimental progress has resulted in impressive reductions in decoherence from mechanisms such as thermal noise, loss, and limited cooperativities. However, the fundamental requirements on transducer parameters necessary to achieve quantum operation have yet to be characterized. In this work we find simple, protocol-independent expressions for the necessary and sufficient conditions under which doubly parametric transducers in the resolved-sideband, steady-state limit are capable of entangling optical and microwave modes. Our analysis treats the transducer as a two-mode bosonic Gaussian channel capable of both beamsplitter-type and two-mode squeezing-type interactions between optical and microwave modes. For the beamsplitter-type interaction, we find parameter thresholds that distinguish regions of the channel's separability, capacity for bound entanglement, and capacity for distillable entanglement. By contrast, the two-mode squeezing-type interaction always produces distillable entanglement with no restrictions on temperature, cooperativities, or losses. Counterintuitively, for both interactions, we find that achieving quantum operation does not require either a quantum cooperativity exceeding one, or ground-state cooling of the mediating mode. Finally, we discuss where two state-of-the-art implementations are relative to these thresholds and show that current devices operating in either mode of operation are in principle capable of entangling optical and microwave modes.

Survival Outcomes and Clinicopathological Features in Inflammatory Bowel Disease-associated Colorectal Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of our study was to conduct a systematic review and meta-analysis comparing the survival outcomes of IBD-associated and non-IBD-associated CRC. SUMMARY OF BACKGROUND DATA: Investigations comparing the prognosis in CRC patients with and without IBD have yielded conflicting results. METHODS: PubMed/MEDLINE, Embase, Web of Science, Cochrane Library were searched for studies evaluating the prognostic outcomes between CRC patients with IBD and those without IBD. Estimates of survival-related outcomes and clinicopathological features in IBD-CRC and non-IBD CRC were pooled through random-effects or fix-effects models. The study is registered with PROSPERO, CRD42021261513. RESULTS: Of 12,768 records identified, twenty-five studies with 8034 IBD-CRC and 810,526 non-IBD CRC patients were included in the analysis. IBD-CRC patients have a significant worse overall survival (OS) with the hazard ratio (HR) of 1.33 [95% confidence interval (CI): 1.20-1.47] than those without IBD. Pooled estimates of cancer-specific survival demonstrated that IBD-CRC patients had a poorer cancer-specific survival than those without IBD with fixed-effect model (HR, 2.17; 95% CI: 1.68-2.78; P < 0.0001). Moreover, ulcerative colitis-associated CRC patients have favorable OS than Crohn's disease-associated CRC (HR 0.79,95% CI: 0.72-0.87). Compared to non-IBD-CRC, patients with IBD-associated CRC are characterized by an increased rate of poor differentiation (OR 2.02, 95% CI: 1.57-2.61), mucinous or signet ring cell carcinoma (OR 2.43, 95% CI: 1.34-4.42), synchronous tumors (OR 3.18, 95% CI: 2.26-4.47), right-sided CRC (OR 1.62, 95%CI: 1.05-2.05), male patients (OR 1.10, 95% CI: 1.05-1.16), and a reduced rate of R0 resections (OR 0.60, 95% CI: 0.44-0.82). CONCLUSIONS: IBD-CRC patients have a significant worse OS than patients with non-IBD CRC, which may be attributed to more aggressive histological characteristics and a lower rate of R0 resections at the primary tumor site. Optimized therapeutic standards and tailored follow-up strategies might improve the prognosis of IBD-CRC patients.

Experimental Constraint on Axionlike Particles over Seven Orders of Magnitude in Mass.

We use our recent electric dipole moment (EDM) measurement data to constrain the possibility that the HfF^{+} EDM oscillates in time due to interactions with candidate dark matter axionlike particles (ALPs). We employ a Bayesian analysis method which accounts for both the look-elsewhere effect and the uncertainties associated with stochastic density fluctuations in the ALP field. We find no evidence of an oscillating EDM over a range spanning from 27 nHz to 400 mHz, and we use this result to constrain the ALP-gluon coupling over the mass range 10^{-22}-10^{-15} eV. This is the first laboratory constraint on the ALP-gluon coupling in the 10^{-17}-10^{-15} eV range, and the first laboratory constraint to properly account for the stochastic nature of the ALP field.

Infiltration of Proteins in Cholesteric Cellulose Structures.

Cellulose nanocrystals (CNCs) can spontaneously self-assemble into chiral nematic (cn) structures, similar to natural cholesteric organizations. The latter display highly dissipative fracture propagation mechanisms given their "brick" (particles) and "mortar" (soft matrix) architecture. Unfortunately, CNCs in liquid media have strong supramolecular interactions with most macromolecules, leading to aggregated suspensions. Herein, we describe a method to prepare nanocomposite materials from chiral nematic CNCs (cn-CNCs) with strongly interacting secondary components. Films of cn-CNCs were infiltrated at various loadings with strongly interacting silk proteins and bovine serum albumin. For comparison and to determine the molecular weight range of macromolecules that can infiltrate cn-CNC films, they were also infiltrated with a range of poly(ethylene glycol) polymers that do not interact strongly with CNCs. The extent and impact of infiltration were evaluated by studying the optical reflection properties of the resulting hybrid materials (UV-vis spectroscopy), while fracture dissipation mechanisms were observed via electron microscopy. We propose that infiltration of cn-CNCs enables the introduction of virtually any secondary phase for nanocomposite formation that is otherwise not possible using simple mixing or other conventional approaches.

Decreasing External Ventricular Drain Infection Rates in the Neurocritical Care Unit: 12-Year Longitudinal Experience at a Single Institution.

OBJECTIVE: External ventricular drain (EVD) placement is a common neurosurgical procedure, and EVD-related infection is a significant complication. We examined the effect of infection control protocol changes on EVD-related infection incidence. METHODS: Changes in EVD placement protocol and incidence density of infections after implementation of protocol changes in the neurocritical care unit were tracked from 2007 to 2019. EVD infections were defined using a modified U.S. Centers for Disease Control and Prevention National Healthcare Safety Network surveillance definition of meningitis/ventriculitis for patients with EVDs in situ for at least 2 days confirmed by positive culture. Contribution of protocol changes to EVD infection risk was assessed via multivariate regression. RESULTS: Fifteen major changes in EVD protocol were associated with a reduction in infections from 6.7 to 2.0 per 1000 EVD days (95% confidence interval [CI], 4.1-5.3; P < 0.001). Gram-positive bacterial infection incidence decreased from 4.8 to 1.7 per 1000 EVD days (95% CI, 2.3-3.9; P = 0.00882) and gram-negative infection incidence decreased from 1.9 to 0.5 per 1000 EVD days (95% CI, 0.6-2.3; P = 0.0303). Of all protocol changes since 2007, the largest reduction in incidence was 3.9 infections per 1000 days (95% CI, 0.50-7.30; P = 0.011), associated with combined standardization of reduced EVD sampling frequency, cutaneous antisepsis with alcoholic chlorhexidine before EVD placement, and use of a subcutaneous tunneling technique during EVD insertion. CONCLUSIONS: The most significant reduction in EVD infections may be achieved through the combination of reducing EVD sampling frequency and standardizing alcoholic chlorhexidine cutaneous antisepsis and subcutaneous tunneling of the EVD catheter.