TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia.

Hypoglycemia triggers autonomic and endocrine counter-regulatory responses to restore glucose homeostasis, a response that is impaired in patients with diabetes and its long-term complication hypoglycemia-associated autonomic failure (HAAF). We show that insulin-evoked hypoglycemia is severely aggravated in mice lacking the cation channel proteins TRPC1, TRPC4, TRPC5, and TRPC6, which cannot be explained by alterations in glucagon or glucocorticoid action. By using various TRPC compound knockout mouse lines, we pinpointed the failure in sympathetic counter-regulation to the lack of the TRPC5 channel subtype in adrenal chromaffin cells, which prevents proper adrenaline rise in blood plasma. Using electrophysiological analyses, we delineate a previously unknown signaling pathway in which stimulation of PAC1 or muscarinic receptors activates TRPC5 channels in a phospholipase-C-dependent manner to induce sustained adrenaline secretion as a crucial step in the sympathetic counter response to insulin-induced hypoglycemia. By comparing metabolites in the plasma, we identified reduced taurine levels after hypoglycemia induction as a commonality in TRPC5-deficient mice and HAAF patients.

Neuropathic pain caused by miswiring and abnormal end organ targeting.

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1-3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents-which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4-7-did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.

Time of day does not impact spinal serotonin levels in humans.

Spinal serotonin enables neuro-motor recovery (i.e., plasticity) in patients with debilitating paralysis. While there exists time of day fluctuations in serotonin-dependent spinal plasticity, it is unknown, in humans, whether this is due to dynamic changes in spinal serotonin levels or downstream signaling processes. The primary objective of this study was to determine if time of day variations in spinal serotonin levels exists in humans. To assess this, intrathecal drains were placed in seven adults with cerebrospinal fluid (CSF) collected at diurnal (05:00 to 07:00) and nocturnal (17:00 to 19:00) intervals. High performance liquid chromatography with mass spectrometry was used to quantify CSF serotonin levels with comparisons being made using univariate analysis. From the 7 adult patients, 21 distinct CSF samples were collected: 9 during the diurnal interval and 12 during nocturnal. Diurnal CSF samples demonstrated an average serotonin level of 216.6 ± $ \pm $ 67.7 nM. Nocturnal CSF samples demonstrated an average serotonin level of 206.7 ± $ \pm $ 75.8 nM. There was no significant difference between diurnal and nocturnal CSF serotonin levels (p = .762). Within this small cohort of spine healthy adults, there were no differences in diurnal versus nocturnal spinal serotonin levels. These observations exclude spinal serotonin levels as the etiology for time of day fluctuations in serotonin-dependent spinal plasticity expression.

Topical tranexamic acid (TXA) is non-inferior to intravenous TXA in adult spine surgery: a meta-analysis.

Tranexamic acid (TXA) has long been utilized in spine surgery and can be administered through intravenous (IV) and topical routes. Although, topical and IV administration of TXA are both effective in decreasing blood loss during spine surgery, complications like deep vein thrombosis (DVT) and pulmonary embolism have been reported with the use of intravenous TXA (ivTXA). These potential complications may be mitigated through the use of topical TXA (tTXA). To assess optimal dosing protocols and efficacy of topical TXA in spine surgery, Embase, Ovid-MEDLINE, Scopus, Cochrane, and clinicaltrials.gov were queried for original research on the use of tTXA in adult patients undergoing spine surgery. Data parameters analyzed included blood loss, transfusion rate, thromboembolic, and other complications. Data was synthesized and confidence evaluated according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. Nineteen studies were included in the final analysis with 2197 patients. Of the 18 published studies, 9 (50%) displayed high levels of evidence. Topical TXA showed a trend towards a lower risk of transfusion and complications. Protocols that used 1g tTXA showed a significantly reduced risk for transfusion when compared to controls (risk ratio -1.05, 95% CI (-1.62, -0.48); P = 0.94, I2 = 0%). Complications associated with tTXA included DVTs and wound infections. Topical TXA was non-inferior to intravenous TXA with similar efficacy and complication profiles for bleeding control in spine surgery; however, more studies are needed to discern benefits and risks.

A guide to selecting upper thoracic versus lower thoracic uppermost instrumented vertebra in adult spinal deformity correction.

PURPOSE: Operative treatment of adult spinal deformity (ASD) has been shown to improve patient health-related quality of life (HRQOL). Selection of the uppermost instrumented vertebra (UIV) in either the upper thoracic (UT) or lower thoracic (LT) spine is a pivotal decision with effects on operative and postoperative outcomes. This review overviews the multifaceted decision-making process for UIV selection in ASD correction. METHODS: PubMed was queried for articles using the keywords "uppermost instrumented vertebra", "upper thoracic", "lower thoracic", and "adult spinal deformity". RESULTS: Optimization of UIV selection may lead to superior deformity correction, better patient-reported outcomes, and lower risk of proximal junctional kyphosis (PJK) and failure (PJF). Patient alignment characteristics, including preoperative thoracic kyphosis, coronal deformity, and the magnitude of sagittal correction influence surgical decision-making when selecting a UIV, while comorbidities such as poor body mass index, osteoporosis, and neuromuscular pathology should also be taken in to account. Additionally, surgeon experience and resources available to the hospital may also play a role in this decision. Currently, it is incompletely understood whether postoperative HRQOLs, functional and radiographic outcomes, and complications after surgery differ between selection of the UIV in either the UT or LT spine. CONCLUSION: The correct selection of the UIV in surgical planning is a challenging task, which requires attention to preoperative alignment, patient comorbidities, clinical characteristics, available resources, and surgeon-specific factors such as experience.

Neuroimaging with Rotterdam Scoring System and long-term outcomes in severe traumatic brain injury patients.

PURPOSE: The Rotterdam Scoring System (RSS) attempts to prognosticate early mortality and early functional outcome in patients with traumatic brain injury (TBI) based on non-contrast head computed tomography (CT) imaging findings. The purpose of this study was to identify the relationship between RSS scores and long-term outcomes in patients with severe TBI. METHODS: Consecutively treated patients with severe TBI enrolled between 2008 and 2011, in the prospective, observational, Brain Trauma Research Center database were included. The Glasgow Outcome Scale (GOS) was used to measure long-term functional outcomes at three, six, 12, and 24 months. GOS scores were categorized into favorable (GOS = 4-5) and unfavorable (GOS = 1-3) outcomes. RSS scores were calculated at the time of image acquisition. RESULTS: Of the 89 patients included, 74 (83.4%) were male, 81 (91.0%) were Caucasian, and the mean age of the cohort was 41.9 ± 18.5 years old. Patients with an RSS score of 3 and lower were more likely to have a favorable outcome with increased survival rates than patients with RSS scores greater than 3. CONCLUSIONS: The RSS score determined on the head CT scan acquired at admission in a cohort of patients with severe TBI correlated with long-term survival and functional outcomes up to two years following injury.

Laparoscopy-guided transverse abdominis plane block versus port site infiltration for post-operative pain relief after laparoscopic cholecystectomy.

INTRODUCTION: Post-operative analgesia is an important component of patient satisfaction and early discharge from the hospital. A variety of modalities have been tested and are still evolving. The present study is one such evaluation of a novel technique of laparoscopy-guided transverse abdominis plane (LTAP) block for post-operative analgesia in laparoscopic cholecystectomy. PATIENTS AND METHODS: A prospective randomised control trial was conducted to verify the effectiveness of LTAP block over port site local anaesthesia infiltration (PSLAI) for post-operative analgesia in patients undergoing laparoscopic cholecystectomy. This study was done over a period of 18 months in a tertiary hospital. A total of 84 patients were recruited and were divided equally into two groups (LTAP and PSLAI). RESULTS: There was no statistical difference between the two groups with respect to gender distribution, comorbidities, number of gallstones, duration of symptoms and surgery time. The rescue dose of diclofenac requirement was less for the LTAP group in comparison to the PSLAI group. No difference was observed in the pain score at 1st h. However, LTAP proved efficient later in the post-operative course (6 h, 24 h and at discharge). There was significant a difference in the pain scores between the two groups, favouring the LTAP group. Hospital stay in the LTAP group was less in comparison to the PSLAI group. CONCLUSION: LTAP block is an effective method of post-operative analgesia. It impacts analgesia to the whole anterior abdominal wall for a prolonged period when compared to the PSLAI without adding any extra procedural time.

Efficacy, safety, and tolerability of soticlestat as adjunctive therapy for the treatment of seizures in patients with Dup15q syndrome or CDKL5 deficiency disorder in an open-label signal-finding phase II study (ARCADE).

OBJECTIVE: Chromosome 15q duplication (Dup15q) syndrome and cyclin­dependent kinase-like 5 deficiency disorder (CDD) are rare neurodevelopmental disorders associated with epileptic encephalopathies, with a lack of specifically approved treatment options. ARCADE assessed the efficacy and safety of adjunctive soticlestat (TAK-935) for the treatment of seizures in patients with Dup15q syndrome or CDD (NCT03694275). METHODS: ARCADE was a phase II, open-label, pilot study of soticlestat (≤300 mg/day twice daily, weight-adjusted) in pediatric and adult patients 2-55 years of age with Dup15q syndrome or CDD who experienced ≥3 motor seizures per month in the 3 months before screening and at baseline. The 20-week treatment period consisted of a dose-optimization period and a 12-week maintenance period. Efficacy endpoints included the change from baseline in motor seizure frequency during the maintenance period and the proportion of treatment responders. Safety endpoints included the incidence of treatment-emergent adverse effects (TEAEs). RESULTS: The modified-intent-to-treat population included 20 participants who received ≥1 dose of soticlestat and had ≥1 efficacy assessment (Dup15q syndrome, n = 8; CDD, n = 12). Soticlestat administration during the maintenance period was associated with a median change from baseline in motor seizure frequency of +11.7% in the Dup15q syndrome group and -23.6% in the CDD group. Reductions in all seizure frequency of -23.4% and -30.5% were also observed during the maintenance period in the Dup15q syndrome group and the CDD group, respectively. Most TEAEs were of mild or moderate severity. Serious TEAEs were reported by three patients (15.0%); none were considered drug related. The most common TEAEs were constipation, rash, and seizure. No deaths were reported. CONCLUSIONS: Adjunctive soticlestat treatment was associated with a decrease in motor seizure frequency from baseline in patients with CDD and a decrease in all seizure frequency in both patient groups. Soticlestat treatment was associated with an increase in motor seizure frequency in patients with Dup15q syndrome.

Evaluating the state of non-invasive imaging biomarkers for traumatic brain injury.

Non-invasive imaging biomarkers are useful for prognostication in patients with traumatic brain injury (TBI) at high risk for morbidity with invasive procedures. The authors present findings from a scoping review discussing the pertinent biomarkers. Embase, Ovid-MEDLINE, and Scopus were queried for original research on imaging biomarkers for prognostication of TBI in adult patients. Two reviewers independently screened articles, extracted data, and evaluated risk of bias. Data was synthesized and confidence evaluated with the linked evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. Our search yielded 3104 unique citations, 44 of which were included in this review. Study populations varied in TBI severity, as defined by Glasgow Coma Scale (GCS), including: mild (n=9), mild and moderate (n=3), moderate and severe (n=7), severe (n=6), and all GCS scores (n=17). Diverse imaging modalities were used for prognostication, predominantly computed tomography (CT) only (n=11), magnetic resonance imaging (MRI) only (n=9), and diffusion tensor imaging (DTI) (N=9). The biomarkers included diffusion coefficient mapping, metabolic characteristics, optic nerve sheath diameter, T1-weighted signal changes, cortical cerebral blood flow, axial versus extra-axial lesions, T2-weighted gradient versus spin echo, translocator protein levels, and trauma imaging of brainstem areas. The majority (93%) of studies identified that the imaging biomarker of interest had a statistically significant prognostic value; however, these are based on a very low to low level of quality of evidence. No study directly compared the effects on specific TBI treatments on the temporal course of imaging biomarkers. The current literature is insufficient to make a strong recommendation about a preferred imaging biomarker for TBI, especially considering GRADE criteria revealing low quality of evidence. Rigorous prospective research of imaging biomarkers of TBI is warranted to improve the understanding of TBI severity.

Minimally invasive versus open transforaminal lumbar interbody fusion for grade I lumbar spondylolisthesis: 5-year follow-up from the prospective multicenter Quality Outcomes Database registry.

OBJECTIVE: Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) has been used to treat degenerative lumbar spondylolisthesis and is associated with expedited recovery, reduced operative blood loss, and shorter hospitalizations compared to those with traditional open TLIF. However, the impact of MI-TLIF on long-term patient-reported outcomes (PROs) is less clear. Here, the authors compare the outcomes of MI-TLIF to those of traditional open TLIF for grade I degenerative lumbar spondylolisthesis at 60 months postoperatively. METHODS: The authors utilized the prospective Quality Outcomes Database registry and queried for patients with grade I degenerative lumbar spondylolisthesis who had undergone single-segment surgery via an MI or open TLIF method. PROs were compared 60 months postoperatively. The primary outcome was the Oswestry Disability Index (ODI). The secondary outcomes included the numeric rating scale (NRS) for back pain (NRS-BP), NRS for leg pain (NRS-LP), EQ-5D, North American Spine Society (NASS) satisfaction, and cumulative reoperation rate. Multivariable models were constructed to assess the impact of MI-TLIF on PROs, adjusting for variables reaching p < 0.20 on univariable analyses and respective baseline PRO values. RESULTS: The study included 297 patients, 72 (24.2%) of whom had undergone MI-TLIF and 225 (75.8%) of whom had undergone open TLIF. The 60-month follow-up rates were similar for the two cohorts (86.1% vs 75.6%, respectively; p = 0.06). Patients did not differ significantly at baseline for ODI, NRS-BP, NRS-LP, or EQ-5D (p > 0.05 for all). Perioperatively, MI-TLIF was associated with less blood loss (108.8 ± 85.6 vs 299.6 ± 242.2 ml, p < 0.001) and longer operations (228.2 ± 111.5 vs 189.6 ± 66.5 minutes, p < 0.001) but had similar lengths of hospitalizations (MI-TLIF 2.9 ± 1.8 vs open TLIF 3.3 ± 1.6 days, p = 0.08). Discharge disposition to home or home health was similar (MI-TLIF 93.1% vs open TLIF 91.1%, p = 0.60). Both cohorts improved significantly from baseline for the 60-month ODI, NRS-BP, NRS-LP, and EQ-5D (p < 0.001 for all comparisons). In adjusted analyses, MI-TLIF, compared to open TLIF, was associated with similar 60-month ODI, ODI change, odds of reaching ODI minimum clinically important difference, NRS-BP, NRS-BP change, NRS-LP, NRS-LP change, EQ-5D, EQ-5D change, and NASS satisfaction (adjusted p > 0.05 for all). The 60-month reoperation rates did not differ significantly (MI-TLIF 5.6% vs open TLIF 11.6%, p = 0.14). CONCLUSIONS: For symptomatic, single-level grade I degenerative lumbar spondylolisthesis, MI-TLIF was associated with decreased blood loss perioperatively, but there was no difference in 60-month outcomes for disability, back pain, leg pain, quality of life, or satisfaction between MI and open TLIF. There was no difference in cumulative reoperation rates between the two procedures. These results suggest that in appropriately selected patients, either procedure may be employed depending on patient and surgeon preferences.

Developing nonlinear k-nearest neighbors classification algorithms to identify patients at high risk of increased length of hospital stay following spine surgery.

OBJECTIVE: Spondylolisthesis is a common operative disease in the United States, but robust predictive models for patient outcomes remain limited. The development of models that accurately predict postoperative outcomes would be useful to help identify patients at risk of complicated postoperative courses and determine appropriate healthcare and resource utilization for patients. As such, the purpose of this study was to develop k-nearest neighbors (KNN) classification algorithms to identify patients at increased risk for extended hospital length of stay (LOS) following neurosurgical intervention for spondylolisthesis. METHODS: The Quality Outcomes Database (QOD) spondylolisthesis data set was queried for patients receiving either decompression alone or decompression plus fusion for degenerative spondylolisthesis. Preoperative and perioperative variables were queried, and Mann-Whitney U-tests were performed to identify which variables would be included in the machine learning models. Two KNN models were implemented (k = 25) with a standard training set of 60%, validation set of 20%, and testing set of 20%, one with arthrodesis status (model 1) and the other without (model 2). Feature scaling was implemented during the preprocessing stage to standardize the independent features. RESULTS: Of 608 enrolled patients, 544 met prespecified inclusion criteria. The mean age of all patients was 61.9 ± 12.1 years (± SD), and 309 (56.8%) patients were female. The model 1 KNN had an overall accuracy of 98.1%, sensitivity of 100%, specificity of 84.6%, positive predictive value (PPV) of 97.9%, and negative predictive value (NPV) of 100%. Additionally, a receiver operating characteristic (ROC) curve was plotted for model 1, showing an overall area under the curve (AUC) of 0.998. Model 2 had an overall accuracy of 99.1%, sensitivity of 100%, specificity of 92.3%, PPV of 99.0%, and NPV of 100%, with the same ROC AUC of 0.998. CONCLUSIONS: Overall, these findings demonstrate that nonlinear KNN machine learning models have incredibly high predictive value for LOS. Important predictor variables include diabetes, osteoporosis, socioeconomic quartile, duration of surgery, estimated blood loss during surgery, patient educational status, American Society of Anesthesiologists grade, BMI, insurance status, smoking status, sex, and age. These models may be considered for external validation by spine surgeons to aid in patient selection and management, resource utilization, and preoperative surgical planning.

Which supervised machine learning algorithm can best predict achievement of minimum clinically important difference in neck pain after surgery in patients with cervical myelopathy? A QOD study.

OBJECTIVE: The purpose of this study was to evaluate the performance of different supervised machine learning algorithms to predict achievement of minimum clinically important difference (MCID) in neck pain after surgery in patients with cervical spondylotic myelopathy (CSM). METHODS: This was a retrospective analysis of the prospective Quality Outcomes Database CSM cohort. The data set was divided into an 80% training and a 20% test set. Various supervised learning algorithms (including logistic regression, support vector machine, decision tree, random forest, extra trees, gaussian naïve Bayes, k-nearest neighbors, multilayer perceptron, and extreme gradient boosted trees) were evaluated on their performance to predict achievement of MCID in neck pain at 3 and 24 months after surgery, given a set of predicting baseline features. Model performance was assessed with accuracy, F1 score, area under the receiver operating characteristic curve, precision, recall/sensitivity, and specificity. RESULTS: In total, 535 patients (46.9%) achieved MCID for neck pain at 3 months and 569 patients (49.9%) achieved it at 24 months. In each follow-up cohort, 501 patients (93.6%) were satisfied at 3 months after surgery and 569 patients (100%) were satisfied at 24 months after surgery. Of the supervised machine learning algorithms tested, logistic regression demonstrated the best accuracy (3 months: 0.76 ± 0.031, 24 months: 0.773 ± 0.044), followed by F1 score (3 months: 0.759 ± 0.019, 24 months: 0.777 ± 0.039) and area under the receiver operating characteristic curve (3 months: 0.762 ± 0.027, 24 months: 0.773 ± 0.043) at predicting achievement of MCID for neck pain at both follow-up time points, with fair performance. The best precision was also demonstrated by logistic regression at 3 (0.724 ± 0.058) and 24 (0.780 ± 0.097) months. The best recall/sensitivity was demonstrated by multilayer perceptron at 3 months (0.841 ± 0.094) and by extra trees at 24 months (0.817 ± 0.115). Highest specificity was shown by support vector machine at 3 months (0.952 ± 0.013) and by logistic regression at 24 months (0.747 ± 0.18). CONCLUSIONS: Appropriate selection of models for studies should be based on the strengths of each model and the aims of the studies. For maximally predicting true achievement of MCID in neck pain, of all the predictions in this balanced data set the appropriate metric for the authors' study was precision. For both short- and long-term follow-ups, logistic regression demonstrated the highest precision of all models tested. Logistic regression performed consistently the best of all models tested and remains a powerful model for clinical classification tasks.

A prospective study on skin and soft tissue infections: a fact-finding mission from a tertiary centre in north India.

OBJECTIVE: Despite the high prevalence and poor outcome of skin and soft tissue infections (SSTIs), very few studies from India have dealt with the subject. We planned a prospective study of inpatients with SSTIs to study the aetiology, clinical presentation (severity) and outcome of patients with SSTIs in our facility. METHOD: Patients with SSTIs involving >5% body surface area (BSA) and/or systemic signs were admitted to the surgery department of a teaching tertiary level hospital in Delhi, India, and were clinically classified into cellulitis, necrotising soft tissue infections (NSTIs), pyomyositis, and abscess. Demographic and clinical variables such as: age; sex; occupation; history of trauma/insect or animal bites; duration of illness; presenting symptoms and signs; comorbid conditions; predisposing factors such as lymphoedema or venous disease; hospital course; treatment instituted; complications; hospital outcome; presence of crepitus, bullae, gangrene, muscle necrosis and compartment syndrome were recorded. The chief outcome parameters were death and length of hospital stay; others, such as abscess drainage, the need for plastic surgical procedures and amputations were also noted. RESULTS: Out of 250 patients enrolled in the study, 145 (58%) had NSTIs, 64 (26%) had abscesses, 15 (6%) had cellulitis and 26 (10%) had pyomyositis. Mortality was observed with NSTIs (27/145, 19%) and with pyomyositis (3/26, 11.5%). Factors affecting mortality by univariate analysis in the NSTI group were: abnormal pulse; hypotension; tachypnea; bullae; increased blood urea and serum creatinine; inotrope or ventilator support (all with p<0.001); local tenderness, gangrene, dialysis support and BSA (9.33±6.44 versus 5.12±3.62; p<0.05 for the last four). No factor was found to be significant on multivariate analysis. Variables associated with hospital stay >12 days were immunocompromise, pus discharge, ulceration or gangrene, and after interventions such as blood transfusion, drainage or skin grafting. CONCLUSION: High prevalence of NSTI and pyomyositis with high mortality was observed in our SSTI patients, often in immunocompetent young individuals. Epidemiological studies focused on virulent strains of Staphylococcus aureus may be required to identify the cause, since Staphylococcal toxins have been implicated in other infections.

Developing an agent-based model to minimize spreading of malicious information in dynamic social networks.

This research introduces a systematic and multidisciplinary agent-based model to interpret and simplify the dynamic actions of the users and communities in an evolutionary online (offline) social network. The organizational cybernetics approach is used to control/monitor the malicious information spread between communities. The stochastic one-median problem minimizes the agent response time and eliminates the information spread across the online (offline) environment. The performance of these methods was measured against a Twitter network related to an armed protest demonstration against the COVID-19 lockdown in Michigan state in May 2020. The proposed model demonstrated the dynamicity of the network, enhanced the agent level performance, minimized the malicious information spread, and measured the response to the second stochastic information spread in the network.

Smoothened (SMO) regulates insulin-like growth factor 1 receptor (IGF1R) levels and protein kinase B (AKT) localization and signaling.

The oncoprotein Smoothened (SMO), a Frizzled-class-G-protein-coupled receptor, is the central transducer of hedgehog (Hh) signaling. While canonical SMO signaling is best understood in the context of cilia, evidence suggests that SMO has other functions in cancer biology that are unrelated to canonical Hh signaling. Herein, we provided evidence that elevated levels of human SMO show a strong correlation with elevated levels of insulin-like growth factor 1 receptor (IGF1R) and reduced survival in diffuse large B-cell lymphoma (DLBCL). As an integral component of raft microdomains, SMO plays a fundamental role in maintaining the levels of IGF1R in lymphoma and breast cancer cells as well IGF1R-associated activation of protein kinase B (AKT). Silencing of SMO increases lysosomal degradation and favors a localization of IGF1R to late endosomal compartments instead of early endosomal compartments from which much of the receptor would normally recycle. In addition, loss of SMO interferes with the lipid raft localization and retention of the remaining IGF1R and AKT, thereby disrupting the primary signaling context for IGF1R/AKT. This activity of SMO is independent of its canonical signaling and represents a novel and clinically relevant contribution to signaling by the highly oncogenic IGF1R/AKT signaling axis.

Evolution of polyetheretherketone (PEEK) and titanium interbody devices for spinal procedures: a comprehensive review of the literature.

INTRODUCTION: Interbody fusion is commonly utilized for arthrodesis and stability among patients undergoing spine surgery. Over the last few decades, interbody device materials, such as titanium and polyetheretherketone (PEEK), have been replacing traditional autografts and allografts for interbody fusion. As such, with the exponential growth of bioengineering, a large variety cage surface technologies exist. Different combinations of cage component materials and surface modifications have been created to optimize interbody constructs for surgical use. This review aims to provide a comprehensive overview of common surface technologies, their performance in the clinical setting, and recent modifications and material combinations. MATERIALS AND METHODS: We performed a comprehensive review of the literature on titanium and PEEK as medical devices between 1964 and 2021. We searched five major databases, resulting in 4974 records. Articles were screened for inclusion manually by two independent reviewers, resulting in 237 articles included for review. CONCLUSION: Interbody devices have rapidly evolved over the last few decades. Biomaterial and biomechanical modifications have allowed for continued design optimization. While titanium has a high osseointegrative capacity, it also has a high elastic modulus and is radio-opaque. PEEK, on the other hand, has a lower elastic modulus and is radiolucent, though PEEK has poor osseointegrative capacity. Surface modifications, material development advancements, and hybrid material devices have been utilized in search of an optimal spinal implant which maximizes the advantages and minimizes the disadvantages of each interbody material.

3D printing applications in spine surgery: an evidence-based assessment toward personalized patient care.

PURPOSE: Spine surgery entails a wide spectrum of complicated pathologies. Over the years, numerous assistive tools have been introduced to the modern neurosurgeon's armamentarium including neuronavigation and visualization technologies. In this review, we aimed to summarize the available data on 3D printing applications in spine surgery as well as an assessment of the future implications of 3D printing. METHODS: We performed a comprehensive review of the literature on 3D printing applications in spine surgery. RESULTS: Over the past decade, 3D printing and additive manufacturing applications, which allow for increased precision and customizability, have gained significant traction, particularly spine surgery. 3D printing applications in spine surgery were initially limited to preoperative visualization, as 3D printing had been primarily used to produce preoperative models of patient-specific deformities or spinal tumors. More recently, 3D printing has been used intraoperatively in the form of 3D customizable implants and personalized screw guides. CONCLUSIONS: Despite promising preliminary results, the applications of 3D printing are so recent that the available data regarding these new technologies in spine surgery remains scarce, especially data related to long-term outcomes.

Decision tree-based machine learning analysis of intraoperative vasopressor use to optimize neurological improvement in acute spinal cord injury.

OBJECTIVE: Previous work has shown that maintaining mean arterial pressures (MAPs) between 76 and 104 mm Hg intraoperatively is associated with improved neurological function at discharge in patients with acute spinal cord injury (SCI). However, whether temporary fluctuations in MAPs outside of this range can be tolerated without impairment of recovery is unknown. This retrospective study builds on previous work by implementing machine learning to derive clinically actionable thresholds for intraoperative MAP management guided by neurological outcomes. METHODS: Seventy-four surgically treated patients were retrospectively analyzed as part of a longitudinal study assessing outcomes following SCI. Each patient underwent intraoperative hemodynamic monitoring with recordings at 5-minute intervals for a cumulative 28,594 minutes, resulting in 5718 unique data points for each parameter. The type of vasopressor used, dose, drug-related complications, average intraoperative MAP, and time spent in an extreme MAP range (< 76 mm Hg or > 104 mm Hg) were collected. Outcomes were evaluated by measuring the change in American Spinal Injury Association Impairment Scale (AIS) grade over the course of acute hospitalization. Features most predictive of an improvement in AIS grade were determined statistically by generating random forests with 10,000 iterations. Recursive partitioning was used to establish clinically intuitive thresholds for the top features. RESULTS: At discharge, a significant improvement in AIS grade was noted by an average of 0.71 levels (p = 0.002). The hemodynamic parameters most important in predicting improvement were the amount of time intraoperative MAPs were in extreme ranges and the average intraoperative MAP. Patients with average intraoperative MAPs between 80 and 96 mm Hg throughout surgery had improved AIS grades at discharge. All patients with average intraoperative MAP > 96.3 mm Hg had no improvement. A threshold of 93 minutes spent in an extreme MAP range was identified after which the chance of neurological improvement significantly declined. Finally, the use of dopamine as compared to norepinephrine was associated with higher rates of significant cardiovascular complications (50% vs 25%, p < 0.001). CONCLUSIONS: An average intraoperative MAP value between 80 and 96 mm Hg was associated with improved outcome, corroborating previous results and supporting the clinical verifiability of the model. Additionally, an accumulated time of 93 minutes or longer outside of the MAP range of 76-104 mm Hg is associated with worse neurological function at discharge among patients undergoing emergency surgical intervention for acute SCI.

CXCL10 and CCL21 Promote Migration of Pancreatic Cancer Cells Toward Sensory Neurons and Neural Remodeling in Tumors in Mice, Associated With Pain in Patients.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by excruciating pain, which has been associated with attraction of cancer cells and their invasion of intrapancreatic sensory nerves. Neutralization of the chemokine CCL2 reduced cancer-associated pain in a clinical trial, but there have been no systematic analyses of the highly diverse chemokine families and their receptors in PDAC. METHODS: We performed an open, unbiased RNA-interference screen of mammalian chemokines in co-cultures of mouse PDAC cells (K8484) and mouse peripheral sensory neurons, and confirmed findings in studies of DT8082 PDAC cells. We studied the effects of chemokines on migration of PDAC cell lines. Orthotopic tumors were grown from K8484 cells in mice, and mice were given injections of neutralizing antibodies against chemokines, antagonists, or control antibodies. We analyzed abdominal mechanical hypersensitivity and collected tumors and analyzed them by histology and immunohistochemistry to assess neural remodeling. We collected PDAC samples and information on pain levels from 74 patients undergoing resection and measured levels of CXCR3 and CCR7 by immunohistochemistry and immunoblotting. RESULTS: Knockdown of 9 chemokines in DRG neurons significantly reduced migration of PDAC cells towards sensory neurons. Sensory neuron-derived CCL21 and CXCL10 promoted migration of PDAC cells via their receptors CCR7 and CXCR3, respectively, which were expressed by cells in orthotopic tumors and PDAC specimens from patients. Neutralization of CCL21 or CXCL10, or their receptors, in mice with orthotopic tumors significantly reduced nociceptive hypersensitivity and nerve fiber hypertrophy and improved behavioral parameters without affecting tumor infiltration by T cells or neutrophils. Increased levels of CXCR3 and CCR7 in human PDAC specimens were associated with increased frequency of cancer-associated pain, determined from patient questionnaires. CONCLUSIONS: In an unbiased screen of chemokines, we identified CCL21 and CXCL10 as proteins that promote migration of pancreatic cancer cells toward sensory neurons. Inhibition of these chemokines or their receptors reduce hypersensitivity in mice with orthotopic tumors, and patients with PDACs with high levels of the chemokine receptors of CXCR3 and CCR7 had increased frequency of cancer-associated pain.

Patient perception of scoliosis correction surgery on Instagram.

OBJECTIVE: Patient feedback surveys provide important insight into patient outcomes, satisfaction, and perioperative needs. Recent critiques have questioned provider-initiated surveys and their capacity to accurately gauge patient perspectives due to intrinsic biases created by question framing. In this study, the authors sought to evaluate provider-independent, patient-controlled social media Instagram posts in order to better understand the patient experience following scoliosis correction surgery. METHODS: Twitter and Instagram were queried for posts with two tagged indicators, #scoliosissurgery or @scoliosissurgery, resulting in no relevant Twitter posts and 25,000 Instagram posts. Of the initial search, 24,500 Instagram posts that did not directly involve the patient's own experience were eliminated. Posts were analyzed and coded for the following criteria: the gender of the patient, preoperative or postoperative timing discussed in the post, and classified themes related to the patient's experiences with scoliosis correction surgery. RESULTS: Females made 87.6% of the Instagram posts about their experience following scoliosis correction surgery. The initial postoperative stage of surgery was mentioned in 7.6% of Instagram posts. The most common theme on Instagram involved offering or seeking online support from other patients, which constituted 85.2% of all posts. Other common themes included concern about the surgical scar (31.8%), discussing the results of treatment (28.8%), and relief regarding results (21.2%). CONCLUSIONS: Social media provided a platform to analyze unprompted feedback from patients. Patients were most concerned with their scoliosis correction surgery in the period of time 2 weeks or more after surgery. Themes that were most commonly found on Instagram posts were offering or seeking online support from other patients and concern about the surgical scar. Patient-controlled social media platforms, like Instagram, may provide a useful mechanism for healthcare providers to understand the patient experience following scoliosis correction surgery. Such platforms may help in evaluating postoperative satisfaction and improving postoperative quality of care.