A pilot initiative to enhance quality improvement teaching with simulation.

BACKGROUND: Quality Improvement and Patient Safety (QIPS) is a recognised competency across residency programmes. Although a variety of teaching modalities exist, many do not represent the multifaceted clinical environment that trainees work in. Residents have reported challenges in linking QIPS classroom-based learning with their clinical duties. High-fidelity simulation has been used to bridge this gap within clinical skills teaching and therefore has potential to address this issue in QIPS learning. APPROACH: We developed and piloted four high-fidelity simulation scenarios with 15 surgical residents (Orthopaedics, General Surgery, Gynaecology and Neurosurgery). Each scenario contained elements of both latent and active safety errors. Residents were provided with a short pre-reading from an open-access resource on basic QIPS methodology and underwent a debriefing by a trained QIPS faculty. Residents were then tasked to apply their learning to their scenario to develop a QIPS-focused solution. EVALUATION: Objective knowledge acquisition was assessed with the Quality Improvement Knowledge Assessment Tool-Revised (QIKAT-R) in conjunction with a survey based upon the Kirkpatrick Model of Learning. Overall, residents agreed that the simulation was helpful in learning QIPS methodology and agreed that they could perform fundamental QIPS tasks. The average QIKAT-R score demonstrated a trend towards improvement. IMPLICATIONS: High-fidelity simulation is a potential means to provide residents with hands-on experience in QIPS knowledge acquisition and application. Future directions should aim to compare the efficacy of simulation with other teaching modalities and evaluate the long-term impact of QIPS teaching on resident behaviours and motivation to take part in QIPS initiatives.

Audit of surgeon billing in workers compensation-insured elective spinal surgery in New South Wales, Australia from 2010 to 2018.

BACKGROUND: Medical billing practices have received increasing scrutiny in Australia and worldwide. In 2015, the Australian Government initiated a comprehensive review of the Medicare Benefits Schedule (MBS), including spinal surgery. This study provides a snapshot of five spinal surgeon billing patterns and associated costs in the workers compensation system in New South Wales prior to these changes. METHODS: This retrospective cohort study used workers compensation billing data from the State Insurance Regulatory Authority to capture elective spinal surgeries in New South Wales from 2010 to 2018. The main outcome measures were: proportion of items billed within recommended limits (up to 150% of the listed Australian Medical Association (AMA) fee); surgical billing patterns including repeat billing of items during a single episode of surgery; use of paediatric or scoliosis items; use of surgical items from outside the spinal surgery schedule; co-billing of items not permitted as per the AMA Fees List item descriptions and associated costs. RESULTS: There were 12 622 spinal surgeries in 9520 patients. While only 2.2% of items were billed above the recommended limits, 38% of surgeries included at least one of the five billing patterns. The average cost increase was AU$4700 per surgery, 47% greater than surgeries which did not include the specified billing patterns, for a total additional cost of AU$22.9 M over the 9-year study period. CONCLUSION: Five spinal surgery billing patterns accounted for an additional AU$22.9 million in direct surgical costs from 2010 to 2018.

Balloon assisted Woven endobridge deployment (BAWD): A safety and efficacy study.

BACKGROUND: Balloon-assisted deployment/remodelling is a proven adjunctive technique for coil embolization of intracranial aneurysms, and it may be a helpful adjunct in delivering the Woven EndoBridge (WEB) device. OBJECTIVE: To evaluate the safety, efficacy and feasibility of balloon-assisted WEB deployment in both ruptured and unruptured intracranial aneurysms in both typical and atypical locations. METHODS: Patients who underwent treatment of ruptured and unruptured intracranial aneurysms with the BAWD technique were retrospectively identified from a prospectively maintained database at two neurointerventional centres. Patient demographics, aneurysm characteristics, technical procedure details, clinical and imaging outcomes were reviewed. RESULTS: Thirty-three aneurysms (23 women) were identified with a median age of 58 years. There were 15 (45.5%) ruptured aneurysms, 25 (64.3%) in the anterior circulation and 12 (36.4%) aneurysms having an atypical location for WEB treatment. The average aneurysm size was 6.8 mm (greatest dimension), 4.6 mm (height) and 4.5 mm (width), and 25 (75.8%) aneurysms had a wide neck morphology. One patient died (3.0%) secondary to a procedure-related complication, and there was no procedure-related permanent morbidity. Complete and adequate aneurysm occlusion on mid-term follow-up DSA was 85.2% and 92%, respectively. CONCLUSION: Balloon-assisted WEB deployment appears to be a safe and effective technique that may increase the utility of the WEB device. Further prospective studies on BAWD should be considered.

The GH/IGF axis in the sea lamprey during metamorphosis and seawater acclimation.

How the growth hormone (GH)/insulin-like growth factor (IGF) system affects osmoregulation in basal vertebrates remains unknown. We examined changes in the expression of components of the GH/IGF axis and gill ion transporters during metamorphosis and following seawater (SW) exposure of sea lamprey. During metamorphosis, increases in gill nka and nkcc1 and salinity tolerance were accompanied by increases in pituitary gh, liver igf1, gill ghr and igf1, but not liver ghr. SW exposure of fully metamorphosed sea lamprey resulted in slight increases in plasma chloride concentrations after SW exposure, indicating a high level of SW tolerance, but no major changes in mRNA levels of gill ion transporters or components of the GH/IGF axis. Our results indicate that metamorphosis is a critical point in the lifecycle of sea lamprey for stimulation of the GH/IGF axis and is temporally associated with and likely promotes metamorphosis and SW tolerance.

Environmental estrogens inhibit insulin-like growth factor (IGF) receptor mRNA expression, IGF binding, and IGF signaling ex vivo in rainbow trout (Oncorhynchus mykiss).

In this study, we used juvenile rainbow trout to examine the direct effects of selected environmental estrogens (EE), specifically, 17 ß-estradiol (E2), ß-sitosterol (ßS), and 4-n-nonylphenol (NP), on target tissue sensitivity to insulin-like growth factor (IGF) as assessed by expression of IGF receptor type 1 (IGFR1) mRNAs and IGF-1 binding capacity, as well as on the cell signaling pathways through which EE exert their effects. E2 and NP inhibited IGFR1A and IGFR1B mRNA expression in a time- and concentration-related manner in gill and muscle; however, ßS had no effect on expression of IGFR1 mRNAs in either tissue. NP reduced 125I-IGF binding in gill and E2 and NP reduced 125I-IGF in white muscle; ßS had no effect on 125I-IGF binding in either gill or white muscle. Treatment of gill filaments with either E2 or NP rapidly deactivated (via reduced proportion of phosphorylation) JAK2, STAT5, Akt, and ERK; ßS had no effect on the activation state of any cell signaling elements tested. The effects of EE on IGFR mRNA expression in gill were estrogen receptor (ER) dependent as the inhibitory effects were rescued by the ER antagonist, ICI 182,780. All EE tested blocked growth hormone (GH)-stimulated IGFR mRNA expression in gill filaments. GH-stimulated activation of JAK2, STAT5, Akt, and ERK were blocked by E2, ßS, and NP. Lastly, E2 and NP stimulated suppressor of cytokine signaling 2 (SOCS-2) mRNA expression, an effect that also was ER dependent. These results indicate that EE directly reduce the sensitivity of peripheral tissues to IGF by reducing mRNA and functional expression of IGFRs. Such inhibitory actions of EE are mediated, at least in part, by ER-dependent mechanisms that deactivate JAK, STAT, Akt, and ERK and enhance expression of SOCS-2. These findings together with our previous results show that EE retard growth of post-embryonic rainbow trout through widespread direct effects on the GH-IGF system, specifically, by reducing tissue sensitivity to GH, inhibiting IGF production, reducing tissue sensitivity to IGF, and by deactivating post-receptor IGF cell signaling pathways.

Surgical decompression for malignant cerebral oedema after ischaemic stroke.

BACKGROUND: Large territory middle cerebral artery (MCA) ischaemic strokes account for around 10% of all ischaemic strokes and have a particularly devastating prognosis when associated with malignant oedema. Progressive cerebral oedema starts developing in the first 24 to 48 hours of stroke ictus with an associated rise in intracranial pressure. The rise in intracranial pressure may eventually overwhelm compensatory mechanisms leading to a cascading secondary damage to surrounding unaffected parenchyma. This downward spiral can rapidly progress to death or severe neurological disability. Early decompressive craniectomy to relieve intracranial pressure and associated tissue shift can help ameliorate this secondary damage and improve outcomes. Evidence has been accumulating of the benefit of early surgical decompression in stroke patients. Earlier studies have excluded people above the age of 60 due to associated poor outcomes; however, newer trials have included this patient subgroup. This review follows a Cochrane Review published in 2012. OBJECTIVES: To assess the effectiveness of surgical decompression in people with malignant oedema after ischaemic stroke with regard to reduction in mortality and improved functional outcome. We also aimed to examine the adverse effects of surgical decompression in this patient cohort. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2022, Issue 7 of 12), MEDLINE Ovid, Embase Ovid, Web of Science Core Collection, Scopus databases, ClinicalTrials.gov, and the WHO ICTRP to July 2022. We also reviewed the reference lists of relevant articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing decompressive craniectomy with medical management to best medical management alone for people with malignant cerebral oedema after MCA ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed study eligibility, performed risk of bias assessment, and extracted the data. The primary outcomes were death and death or severe disability (modified Rankin Scale (mRS) > 4) at 6 to 12 months follow-up. Other outcomes included death or moderate disability (mRS > 3), severe disability (mRS = 5), and adverse events. We assessed the certainty of the evidence using the GRADE approach, categorising it as high, moderate, low, or very low. MAIN RESULTS: We included nine RCTs with a total of 513 participants included in the final analysis. Three studies included patients younger than 60 years of age; two trials accepted patients up to 80 years of age; and one trial only included patients 60 years or older. The majority of included trials (six) mandated a time from stroke ictus to treatment of < 48 hours, whilst in two of them this was < 96 hours. Surgical decompression was associated with a reduction in death (odds ratio (OR) 0.18, 95% confidence interval (CI) 0.12 to 0.27, 9 trials, 513 participants, P < 0.001; high-certainty evidence); death or severe disability (mRS > 4, OR 0.22, 95% CI 0.15 to 0.32, 9 trials, 513 participants, P < 0.001; high-certainty evidence); and death or moderate disability (mRS > 3, OR 0.34, 95% CI 0.22 to 0.52, 9 trials, 513 participants, P < 0.001; moderate-certainty evidence). Subgroup analysis did not reveal any significant effect on treatment outcomes when analysing age (< 60 years versus ≥ 60 years); time from stroke ictus to intervention (< 48 hours versus ≥ 48 hours); or dysphasia. There was a significant subgroup effect of time at follow-up (6 versus 12 months, P = 0.02) on death as well as death or severe disability (mRS > 4); however, the validity of this finding was affected by fewer participant numbers in the six-month follow-up subgroup. There was no consistent reporting of per-participant adverse event rates in any of the included studies, which prevented further analysis. AUTHORS' CONCLUSIONS: Surgical decompression improves outcomes in the management of malignant oedema after acute ischaemic stroke, including a considerable reduction in death or severe disability (mRS > 4) and a reduction in death or moderate disability (mRS > 3). Whilst there is evidence that this positive treatment effect is present in patients > 60 years old, it is important to take into account that these patients have a poorer prospect of functional survival independent of this treatment effect. In interpreting these results it must also be considered that the data demonstrating benefit are drawn from a unique patient subset with profound neurological deficit, reduced level of consciousness, and no pre-morbid disability or severe comorbidity.

Discovery of prolactin-like in lamprey: Role in osmoregulation and new insight into the evolution of the growth hormone/prolactin family.

We used a representative of one of the oldest extant vertebrate lineages (jawless fish or agnathans) to investigate the early evolution and function of the growth hormone (GH)/prolactin (PRL) family. We identified a second member of the GH/PRL family in an agnathan, the sea lamprey (Petromyzon marinus). Structural, phylogenetic, and synteny analyses supported the identification of this hormone as prolactin-like (PRL-L), which has led to added insight into the evolution of the GH/PRL family. At least two ancestral genes were present in early vertebrates, which gave rise to distinct GH and PRL-L genes in lamprey. A series of gene duplications, gene losses, and chromosomal rearrangements account for the diversity of GH/PRL-family members in jawed vertebrates. Lamprey PRL-L is produced in the proximal pars distalis of the pituitary and is preferentially bound by the lamprey PRL receptor, whereas lamprey GH is preferentially bound by the lamprey GH receptor. Pituitary PRL-L messenger RNA (mRNA) levels were low in larvae, then increased significantly in mid-metamorphic transformers (stage 3); thereafter, levels subsided in final-stage transformers and metamorphosed juveniles. The abundance of PRL-L mRNA and immunoreactive protein increased in the pituitary of juveniles under hypoosmotic conditions, and treatment with PRL-L blocked seawater-associated inhibition of freshwater ion transporters. These findings clarify the origin and divergence of GH/PRL family genes in early vertebrates and reveal a function of PRL-L in osmoregulation of sea lamprey, comparable to a role of PRLs that is conserved in jawed vertebrates.

Repeated intraperitoneal injection of ovine growth hormone accelerates growth in sub-yearling Siberian sturgeon Acipenser baerii.

The role of growth hormone (GH) in chondrosteans is poorly understood, particularly with regard to its effects on growth. In this study, we examined the influence of exogenous GH on growth performance and body composition in juvenile Siberian sturgeon (Acipenser baerii). Fish with initial weight of 80.2 ± 0.1 g (mean ± S.E) were injected once every 10 days with either purified ovine GH (oGH) at 1, 2, 4, and 8 µg oGH/g body weight (BW) or with saline over a 50-day period. Treatment with the highest dose of oGH significantly enhanced growth performance (final body weight and length, body weight increase and specific growth rate, SGR). Notably, 8 µg oGH/g BW increased body weight by 33% and SGRw by 141% compared to control fish. GH-stimulated (8 µg oGH/g BW) growth was accompanied by increased crude protein content; however, oGH treatment did not affect levels of total protein, total lipid, cholesterol, triglyceride, or glucose in plasma. oGH decreased plasma levels of thyroxine (at 4 µg oGH/g BW), but had no significant effect on plasma levels of triiodothyronine or cortisol compared to controls. These findings indicate that 8 µg oGH/g BW enhances somatic growth and synthesis of body protein in juvenile Siberian sturgeon and demonstrate the feasibility of exogenous oGH treatment in conservation and aquaculture programs for this ancient species.

Cerebrospinal fluid white cell count to red cell count ratio as a predictor of ventriculitis in patients with external ventricular drains.

INTRODUCTION: External ventricular drain (EVD) associated ventriculitis is a complication of EVD placement associated with significant morbidity and mortality. Gold-standard for EVD associated bacterial ventriculitis diagnosis involves cerebrospinal fluid (CSF) sampling from the EVD with microscopy, culture and sensitivity testing. The ratio of white blood cells to red blood cells has anecdotally been considered a predictive factor in diagnosing EVD associated ventriculitis, however no study has been done demonstrating this. METHODS: A retrospective cross-sectional study was designed to assess whether the ratio of CSF white blood cells to red blood cells could be used to diagnose EVD associated ventriculitis. Data was collected for all patients undergoing EVD insertion at a major neurosurgical unit in Sydney, Australia. A receiver operator characteristics (ROC) curve was used to determine if this ratio was useful, and Youden's index was calculated to determine the appropriate cut-off point. RESULTS: This sample of n = 157 consecutive patients a total of 29 patients were diagnosed with ventriculitis. The area under the ROC curve was significant (0.706, P <0.001), and Youden's index demonstrated an appropriate cut-off point was a ratio of 1:106. DISCUSSION: CSF parameters have long been considered predictive of EVD associated ventriculitis. We demonstrated that using a component of routine testing it is possible to accurately predict a ventriculitis diagnosis. As the ratio is used, it enables discrimination in a raised white blood cell count due to local trauma with interventricular bleeding. CONCLUSION: CSF white blood cell to red blood cell ratio is an appropriate diagnostic test for ventriculitis.

Roles of leptin in initiation of acquired growth hormone resistance and control of metabolism in rainbow trout.

Catabolic conditions often induce concomitant changes in plasma leptin (Lep), growth hormone (GH), and insulin growth factor I (IGF-I) levels in teleost fish, but it is unclear whether these parts of the endocrine system are responding independently or functionally linked. In this study, fasted rainbow trout was used to study the effects of Lep on the GH-IGF-I system and metabolism. Fish were implanted intraperitoneally with recombinant rainbow trout Lep pellets and remained unfed. After 4 days, plasma GH levels were elevated in the Lep-treated fish in a dose-dependent manner; the expression of hepatic igf1 and plasma IGF-I levels were suppressed accordingly. In vitro Lep treatment reversed ovine GH (oGH)-stimulated expression of igf1 and igf2 in hepatocytes isolated from fasted fish, similar to the inhibitory effects of the MEK1/2 inhibitor U0126 treatment. However, Lep treatment alone had no effect on the expression of igfs or oGH-stimulated ghr2a expression in the hepatocytes. These results demonstrate an additive effect of Lep on suppression of IGF-I under catabolic conditions, indicating that Lep is likely involved in initiation of acquired GH resistance. Although the Lep-implant treatment had no effect on standard metabolic rate, it significantly suppressed gene expression of hepatic hydroxyacyl-CoA dehydrogenase, phosphoenolpyruvate carboxykinase, and glucose 6-phosphatase, which are key enzymes in lipid utilization and gluconeogenesis, in different patterns. Overall, this study indicates that the Lep increase in fasting salmonids is an important regulatory component for physiological adaptation during periods of food deprivation, involved in suppressing growth and hepatic metabolism to spare energy expenditure.

Is neurotrauma training in rural New South Wales still required following the implementation of the New South Wales State Trauma Plan?

BACKGROUND: In New South Wales (NSW), Australia, trauma accounts for 6% of deaths. Trauma patients receiving definitive care in regional trauma centres are 34% more likely to have a fatal outcome compared to level 1 centres. Following the implementation of the NSW State Trauma Plan where patients with major trauma are fast tracked to regional trauma services, should NSW rural surgeons and retrieval doctors continue to receive surgical training in neurotrauma? METHODS: The study's primary objective was to ascertain which NSW regional and rural hospitals have the equipment to perform neurotrauma and when it was last used. The study also examined the outcome of those patients who had undergone an emergency neurosurgical procedure. RESULTS: Of the 149 regional and rural hospitals in NSW, 16 stored a Hudson brace, perforator, burr and Gigli saw sterile and ready to use in the operating theatre. Only one hospital utilised the equipment in the last year and 11 in the last 10 years. Of those patients who had undergone an emergency neurosurgical procedure, two patients died prior to transfer and three were confirmed deceased after transfer to a tertiary centre. CONCLUSION: The implementation of the NSW State Trauma Plan has streamlined the trauma triage process and transport of neurotrauma patients to regional and major trauma services. However, it is likely that knowledge of how to perform burr hole and craniectomy for the evacuation of extradural haematoma remains a useful skill for the rural surgeon and retrieval doctor if transport is delayed.

Coordinate regulation of feeding, metabolism, and growth: Perspectives from studies in fish.

This paper develops a model for coordinate regulation of feeding, metabolism, and growth based on studies in fish. Many factors involved with the control of feeding [e.g., cholecystokinin (CCK) and ghrelin (GRLN)], energy metabolism [e.g., insulin (INS), glucagon (GLU), glucagon-like peptide (GLP), and somatostatins (SS), produced in the endocrine pancreas; and leptin (LEP) produced broadly], and growth [e.g., GRLN, growth hormone (GH), insulin-like growth factors (IGFs), GH receptors (GHR), IGF receptors (IGFR)] interact at various levels. Many such interactions serve to coordinate these systems to favor anabolic processes (i.e., lipid and protein synthesis, glycogenesis) and growth, including GH promotion of feeding and stimulation of INS production/secretion and the upregulation of GHR and IGFR by GRLN. As nutrient and stored energy status change, various feedbacks serve to curtail feeding and transition the animal from an anabolic/growth state to a catabolic state. Many factors, including LEP and IGF, promote satiety, whereas SS downregulates INS signaling as well as IGF production and GHR and IGFR abundance. As INS and IGF levels fall, GH becomes disconnected from growth as a result of altered linkage of GHR to cell signaling pathways. As a result, the catabolic actions of GH, GLU, GLP, LEP, and SS prevail, mobilizing stored energy reserves. Coordinate regulation involves relative abundances of blood-borne hormones as well as the ability to adjust responsiveness to hormones (via receptor and post-receptor events) in a cell-/tissue-specific manner that results from genetic and epigenetic programming and modulation by the local milieu of hormones, nutrients, and autocrine/paracrine interactions. The proposed model of coordinate regulation demonstrates how feeding, metabolism, and growth are integrated with each other and with other processes, such as reproduction, and how adaptive adjustments can be made to energy allocation during an animal's life history and/or in response to changes in environmental conditions.

Environmental estrogens inhibit the expression of insulin-like growth factor mRNAs in rainbow trout in vitro by altering activation of the JAK-STAT, AKT-PI3K, and ERK signaling pathways.

Environmental estrogens (EE) have been found to disrupt a host of developmental, reproductive, metabolic, and osmoregulatory process in a wide-range of animals, particularly those in aquatic ecosystems where such compounds concentrate. Previously, we showed that EE inhibited post-embryonic organismal growth of rainbow trout in vivo, but the precise mechanism(s) through which EE exert their growth inhibiting effects remain unknown. In this study, we used rainbow trout (Oncorhynchus mykiss) as a model to investigate the direct effects of 17ß-estradiol (E2), ß-sitosterol (ßS), and 4-n-nonylphenol (NP) on the synthesis of insulin-like growth factors (IGFs) and to elucidate the mechanism(s) by which EEs exert such effects. E2, ßS, and NP significantly inhibited the expression of both IGF-1 and IGF-2 mRNAs in liver and gill in a time- and concentration-related manner. Although the response evoked by each EEs on the expression of IGF mRNAs was similar, the potency and efficacy varied with EE; the rank order potency/efficacy was as follows: E2 > NP > ßS. The effects of EEs on the expression of IGF mRNAs was blocked by the estrogen receptor (ER) antagonist, ICI 182780. The mechanism(s) through which EEs inhibit IGF mRNA expression were investigated in isolated liver cells in vitro. EE treatment deactivated JAK, STAT, ERK, and AKT. Moreover, blockade of growth hormone (GH)-stimulated IGF expression by EE was accompanied by deactivation of JAK, STAT, ERK, and AKT. EEs also increased the expression of suppressor of cytokine signaling 2 (SOCS-2), a known inhibitor of JAK-2--an action that also was blocked by ICI 182780. These results indicate that EEs directly inhibit the expression of IGF mRNAs by disrupting GH post-receptor signaling pathways (e.g., JAK, STAT, ERK, and AKT) in an ER-dependent manner.

Sport-Related Structural Brain Injury and Return to Play: Systematic Review and Expert Insight.

BACKGROUND: Sport-related structural brain injury (SRSBI) is intracranial pathology incurred during sport. Management mirrors that of non-sport-related brain injury. An empirical vacuum exists regarding return to play (RTP) following SRSBI. OBJECTIVE: To provide key insight for operative management and RTP following SRSBI using a (1) focused systematic review and (2) survey of expert opinions. METHODS: A systematic literature review of SRSBI from 2012 to present in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a cross-sectional survey of RTP in SRSBI by 31 international neurosurgeons was conducted. RESULTS: Of 27 included articles out of 241 systematically reviewed, 9 (33.0%) case reports provided RTP information for 12 athletes. To assess expert opinion, 31 of 32 neurosurgeons (96.9%) provided survey responses. For acute, asymptomatic SRSBI, 12 (38.7%) would not operate. Of the 19 (61.3%) who would operate, midline shift (63.2%) and hemorrhage size > 10 mm (52.6%) were the most common indications. Following SRSBI with resolved hemorrhage, with or without burr holes, the majority of experts (>75%) allowed RTP to high-contact/collision sports at 6 to 12 mo. Approximately 80% of experts did not endorse RTP to high-contact/collision sports for athletes with persistent hemorrhage. Following craniotomy for SRSBI, 40% to 50% of experts considered RTP at 6 to 12 mo. Linear regression revealed that experts allowed earlier RTP at higher levels of play (ß = -0.58, 95% CI -0.111, -0.005, P = .033). CONCLUSION: RTP decisions following structural brain injury in athletes are markedly heterogeneous. While individualized RTP decisions are critical, aggregated expert opinions from 31 international sports neurosurgeons provide key insight. Level of play was found to be an important consideration in RTP determinations.

Transcranial Doppler-derived indices of cerebrovascular haemodynamics are independent of depth and angle of insonation.

Continuous measurement of cerebral blood flow velocity (CBFV) of the middle cerebral artery (MCA) using transcranial Doppler (TCD) and arterial blood pressure (ABP) monitoring enables assessment of cerebrovascular haemodynamics. Further indices describing cerebrovascular function can be calculated from ABP and CBFV, such as the mean index (Mxa) of cerebrovascular autoregulation, the 'time constant of the cerebral arterial bed' (tau), the 'critical closing pressure' (CrCP) and a 'non-invasive estimator of ICP' (nICP). However, TCD is operator-dependent and changes in angle and depth of MCA insonation result in different readings of CBFV. The effect of differing CBFV readings on the calculated secondary indices remains unknown. The aim of this study was to investigate variation in angle and depth of MCA insonation on these secondary indices. In eight patients continuous ABP and ipsilateral CBFV monitoring was performed using two different TCD probes, resulting in four simultaneous CBFV readings at different angles and depths per patient. From all individual recordings, the K-means clustering algorithm was applied to the four simultaneous longitudinal measurements. The average ratios of the between-clusters, sum-of-squares and total sum-of-squares were significantly higher for CBFV than for the indices Mxa, tau and CrCP (p < 0.001, p = 0.007 and p = 0.016) but not for nICP (p = 0.175). The results indicate that Mxa, tau and CrCP seemed to be not affected by depth and angle of TCD insonation, whereas nICP was.

Independent replication of classic trials in neurosurgery: A missing validation practice.

A concerning phenomenon has been identified within the scientific literature. In multiple fields, systematic efforts to replicate peer reviewed studies have been successful in fewer than half of the originals attempted. Currently it is unclear how many influential neurosurgical trials have undergone direct replication. In this study we conducted a publication search to estimate the proportion of classic trials (>400 citations) to have undergone independent direct replication. Published replications would then be assessed for agreement with the original study findings. Our search included all journal articles in the Web of Science written in English and published between 1900 and 2019. This yielded 110 highly-cited trials published in 28 medical journals. Screening of the citation index for these classic studies (113,387 articles) identified 4632 articles to be scrutinised for evidence of replication. Review of these articles did not find any self-identified direct replication studies. This apparent absence of direct replication of classic trials in neurosurgery raises questions about the strength of the evidence base for widespread neurosurgical practices. Direct replication studies must be attempted and published in order to confirm the robustness of influential findings from neurosurgical research.

The Role of Liquid Biopsies in Detecting Molecular Tumor Biomarkers in Brain Cancer Patients.

Glioblastoma multiforme (GBM) is one of the most lethal primary central nervous system cancers with a median overall survival of only 12-15 months. The best documented treatment is surgical tumor debulking followed by chemoradiation and adjuvant chemotherapy with temozolomide, but treatment resistance and therefore tumor recurrence, is the usual outcome. Although advances in molecular subtyping suggests GBM can be classified into four subtypes, one concern about using the original histology for subsequent treatment decisions is that it only provides a static snapshot of heterogeneous tumors that may undergo longitudinal changes over time, especially under selective pressure of ongoing therapy. Liquid biopsies obtained from bodily fluids like blood and cerebro-spinal fluid (CSF) are less invasive, and more easily repeated than surgery. However, their deployment for patients with brain cancer is only emerging, and possibly suppressed clinically due to the ongoing belief that the blood brain barrier prevents the egress of circulating tumor cells, exosomes, and circulating tumor nucleic acids into the bloodstream. Although brain cancer liquid biopsy analyses appear indeed challenging, advances have been made and here we evaluate the current literature on the use of liquid biopsies for detection of clinically relevant biomarkers in GBM to aid diagnosis and prognostication.

Divergent genes encoding the putative receptors for growth hormone and prolactin in sea lamprey display distinct patterns of expression.

Growth hormone receptor (GHR) and prolactin receptor (PRLR) in jawed vertebrates were thought to arise after the divergence of gnathostomes from a basal vertebrate. In this study we have identified two genes encoding putative GHR and PRLR in sea lamprey (Petromyzon marinus) and Arctic lamprey (Lethenteron camtschaticum), extant members of one of the oldest vertebrate groups, agnathans. Phylogenetic analysis revealed that lamprey GHR and PRLR cluster at the base of gnathostome GHR and PRLR clades, respectively. This indicates that distinct GHR and PRLR arose prior to the emergence of the lamprey branch of agnathans. In the sea lamprey, GHR and PRLR displayed a differential but overlapping pattern of expression; GHR had high expression in liver and heart tissues, whereas PRLR was expressed highly in the brain and moderately in osmoregulatory tissues. Branchial PRLR mRNA levels were significantly elevated by stage 5 of metamorphosis and remained elevated through stage 7, whereas levels of GHR mRNA were only elevated in the final stage (7). Branchial expression of GHR increased following seawater (SW) exposure of juveniles, but expression of PRLR was not significantly altered. The results indicate that GHR and PRLR may both participate in metamorphosis and that GHR may mediate SW acclimation.

Rare case of double migration of thoracic intradural schwannoma.

Mobile or migratory intradural extramedullary schwannoma have been reported many times in the lumbar levels, however only twice in cervical spine and six times in thoracic spine. Double migration was reported only once. The exact cause of the migration of a schwannoma arising from the nerve sheath of a spinal nerve root is unclear and especially mysterious in cervical and thoracic spine. We report a 49 year old male who presented with multiple sclerosis confirmed on brain MRI and CSF showing oligoclonal bands, with concomitant spinal myelopathy from a thoracic intradural extramedullary lesion. Serial MRIs showed rostral migration of lesion initially from T10 level to T6 and then caudally to T9 level on day of surgery. Intra operatively it was mobile with respirations and disconnected from any neural or vascular attachments. Histopathology confirmed a benign schwannoma with areas of necrosis. This is the rare occurrence of double migration of thoracic intradural schwannoma with possibility of tumor disconnection due to high dose steroid therapy for multiple sclerosis.