CSF neopterin and quinolinic acid are biomarkers of neuroinflammation and neurotoxicity in FIRES and other infection-triggered encephalopathy syndromes.

OBJECTIVE: Infection-triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI neuroimaging phenotypes, there are otherwise few biomarkers of disease. Early detection to enable immune modulatory treatments could improve outcomes. METHODS: We measured CSF neopterin, quinolinic acid, kynurenine and kynurenine/tryptophan ratio using a liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) system. The CSF of 18 children with ITES were compared with acute encephalitis (n = 20), and three control groups, namely epilepsy (n = 20), status epilepticus (n = 18) and neurogenetic controls (n = 20). RESULTS: The main ITES phenotypes in 18 patients were acute encephalopathy with biphasic seizures and late restricted diffusion (AESD, n = 4), febrile infection-related epilepsy syndrome (FIRES n = 4) and other ITES phenotypes. Influenza A was the most common infectious trigger (n = 5), and 50% of patients had a preceding notable neurodevelopmental or family history. CSF neopterin, quinolinic acid and kynurenine were elevated in ITES group compared to the three control groups (all p < 0.0002). The ROC (area under curve) for CSF neopterin (99.3%, CI 98.1-100) was significantly better than CSF pleocytosis (87.3% CI 76.4-98.2) (p = 0.028). Elevated CSF neopterin could discriminate ITES from other causes of seizures, status epilepticus and febrile status epilepticus (all p < 0.0002). The elevated CSF metabolites normalised during longitudinal testing in two patients with FIRES. INTERPRETATION: CSF neopterin and quinolinic acid are neuroinflammatory and excitotoxic metabolites. This CSF metabolomic inflammatory panel can discriminate ITES from other causes of new onset seizures or status epilepticus, and rapid results (4 h) may facilitate early immune modulatory therapy.

CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.

BACKGROUND: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. METHODS: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1-17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). FINDINGS: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid (57%, CI 47-67), KYN/TRP ratio (47%, CI 36-56) and kynurenine (37%, CI 28-48). CSF pleocytosis had sensitivity of 53%, CI 42-64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0-97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5-90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups. INTERPRETATION: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University.

Urgent computed tomography angiography in paediatric stroke.

AIM: To improve delivery of acute therapies for acute ischaemic stroke (AIS). METHOD: We identified factors influencing the speed of diagnosis and delivery of acute therapies in a prospective cohort of 21 children with suspected AIS (eight with AIS, 13 stroke mimics) and explored them in a retrospective cohort with confirmed AIS. RESULTS: Approximately half of the prospective and total AIS cohorts presented with acute, sustained hemiparesis, and were diagnosed relatively quickly. AIS was suspected and diagnosed more slowly in the half presenting with symptoms other than sustained hemiparesis. Thirty-one out of 51 patients with AIS (19 females, 32 males, mean age 8 years 6 months, SD 5 years 4 months) had arterial abnormalities identified by computed tomography angiography (CTA) or magnetic resonance angiography (MRA): 11 with large vessel occlusion, six with dissection, five with moyamoya disease, nine with other arteriopathies. Among these patients, those initially imaged with CTA were diagnosed more quickly than those with initial magnetic resonance imaging/angiography, which facilitated thrombectomy and thrombolytic therapy. Twenty out of 51 had AIS without arterial abnormalities on CTA or MRA: eight with lenticulostriate vasculopathy and 12 with other small-vessel AIS. Among these patients, 80% were ineligible for thrombolysis for reasons beyond delay to diagnosis, and all showed good outcomes with supportive treatments alone. INTERPRETATION: Clinical features at presentation influence rapidity with which childhood AIS is suspected and diagnosed. Readily available CTA can direct thrombectomy in patients with large vessel occlusion and thrombolysis in most, but not all, eligible patients. WHAT THIS PAPER ADDS: Children with acute ischaemic stroke (AIS) commonly present with symptoms other than sustained hemiparesis. Stroke is more slowly recognized in these patients, which limits potential therapies. Computed tomography angiography (CTA) accurately identifies AIS with large vessel occlusion, enabling timely endovascular thrombectomy. CTA is sufficient to direct thrombolytic therapy in most eligible children. Most childhood AIS without arterial abnormalities identified by CTA had good outcomes.

The role of large cavity sinus surgery in the management of chronic rhinosinusitis in non-steroidal anti-inflammatory drug exacerbated respiratory disease: a single-centre experience and long-term outcomes.

OBJECTIVE: This study aimed to discuss the role of large cavity functional endoscopic sinus surgery in the management of chronic rhinosinusitis with nasal polyps in patients with non-steroidal anti-inflammatory drug exacerbated respiratory disease. METHODS: This was a retrospective review of patients undergoing large cavity functional endoscopic sinus surgery for non-steroidal anti-inflammatory drug exacerbated respiratory disease from January 2016 to March 2022. Population characteristics, pre- and post-operative number of functional endoscopic sinus surgical procedures, endoscopic polyp grade, Lund-Mackay score and nasal symptoms were recorded. RESULTS: Thirteen consecutive patients with a median age of 47 years were included. They all failed maximal medical treatment and/or conservative functional endoscopic sinus surgery and underwent large cavity sinus surgery followed by post-operative maximal medical therapy. All patients showed an improvement in nasal symptoms with improved Lund-Mackay scores post-operatively. The median length of follow up was 1.5 years. CONCLUSION: Large cavity functional endoscopic sinus surgery seems to halt the progression of chronic rhinosinusitis with nasal polyps in non-steroidal anti-inflammatory drug exacerbated respiratory disease. In this case series, large cavity functional endoscopic sinus surgery combined with optimal post-operative medical treatment appeared to switch off chronic rhinosinusitis with nasal polyps in patients with non-steroidal anti-inflammatory drug exacerbated respiratory disease.

Neural networks involved in nausea in adult humans: A systematic review.

Nausea is a common clinical symptom, poorly managed with anti-emetic drugs. To identify potential brain regions which may be therapeutic targets we systematically reviewed brain imaging in subjects reporting nausea. The systematic review followed PRISMA statements with methodological quality (MINORS) and risk of bias (ROBINS-I) assessed. Irrespective of the nauseagenic stimulus the common (but not only) cortical structures activated were the inferior frontal gyrus (IFG), the anterior cingulate cortex (ACC) and the anterior insula (AIns) with some evidence for lateralization (Left-IFG, Right-AIns, Right-ACC). Basal ganglia structures (e.g., putamen) were also consistently activated. Inactivation was rarely reported but occurred mainly in the cerebellum and occipital lobe. During nausea, functional connectivity increased, mainly between the posterior and mid- cingulate cortex. Limitations include, a paucity of studies and stimuli, subject demographics, inconsistent definition and measurement of nausea. Structures implicated in nausea are discussed in the context of knowledge of central pathways for interoception, emotion and autonomic control. Comparisons are made between nausea and other aversive sensations as multimodal aversive conscious experiences.

Molecular typing of enteroviruses: comparing 5'UTR, VP1 and whole genome sequencing methods.

Enteroviruses (EV) commonly cause hand, foot and mouth disease (HFMD), and can also cause potentially fatal neurological and systemic complications. In our laboratory, sequencing 5' untranslated region (UTR) of the viral genome has been the routine method of genotyping EVs. During a recent localised outbreak of aseptic meningitis, sequencing the 5'UTR identified the causative virus as EV-A71, which did not fit with the clinical syndrome or illness severity. When genotyped using a different target gene, VP1, the result was different. This led us to evaluate the accuracy of the two different target genome regions and compare them against whole genome sequencing (WGS). We aimed to optimise the algorithm for detection and characterisation of EVs in the diagnostic laboratory. We hypothesised that VP1 and WGS genotyping would provide different results than 5'UTR in a subset of samples. Clinical samples from around New South Wales which were positive for EV by commercial polymerase chain reaction (PCR) assays were genotyped by targeting three different viral genome regions: the 5'UTR, VP1 and WGS. Sequencing was performed by Sanger and next generation sequencing. The subtyping results were compared. Of the 74/118 (63%) samples that were successfully typed using both the 5'UTR and the VP1 method, the EV typing result was identical for 46/74 (62%) samples compared to WGS as the gold standard. The same EV group but different EV types were found in 22/74 (30%) samples, and 6/74 (8%) samples belonged to different EV groups depending on typing method used. Genotyping with WGS and VP1 is more accurate than 5'UTR. Genotyping by the 5'UTR method is very sensitive, but less specific.

Lessons from rhinology and facial plastic surgery clinical negligence claims in England 2013-2018.

OBJECTIVE: This study reviewed all rhinology clinical negligence claims in the National Health Service in England between 2013 and 2018. METHOD: All clinical negligence claims held by National Health Service Resolution relating to rhinology in England between 1 April 2013 and 1 April 2018 were reviewed. RESULTS: There were 171 rhinology related claims with a total estimated potential cost of £13.6 million. There were 119 closed claims (70 per cent) with a total cost of £2.3 million, of which 55 claims resulted in payment of damages. Over three quarters of all rhinology claims were associated with surgery (n = 132). Claims associated with endoscopic sinus surgery had the highest mean cost per claim (£172 978). Unnecessary pain (33.9 per cent) and unnecessary operation (28.1 per cent) were the most commonly cited patient injuries. CONCLUSION: Patient education and consent have been highlighted as key areas for improvement from this review of rhinology related clinical negligence claims. A shift in clinical practice towards shared decision making could reduce litigation in rhinology.

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.

OBJECTIVE: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. METHODS: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. RESULTS: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. INTERPRETATION: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284.

Intranasal sodium citrate in quantitative and qualitative olfactory dysfunction: results from a prospective, controlled trial of prolonged use in 60 patients.

OBJECTIVES: We have previously shown that treatment with intranasal sodium citrate may be beneficial in post-infectious olfactory dysfunction. Sodium citrate reduces free intranasal calcium and is, therefore, thought to prevent calcium-mediated feedback inhibition at the level of the olfactory receptor. We aimed to determine whether treatment with a 2-week course of intranasal sodium citrate improves quantitative olfactory function in patients with post-infectious impairment. We also aimed to determine whether sodium citrate is beneficial in treating qualitative olfactory dysfunction. METHODS: We performed a prospective, controlled study. Patients applied intranasal sodium citrate solution to the right nasal cavity for 2 weeks. The left nasal cavity was untreated and, therefore, acted as an internal control. Monorhinal olfactory function was assessed using the "Sniffin' Sticks" composite 'TDI' score, before and after treatment. The presence of parosmia and phantosmia was also assessed. RESULTS: Overall, there was a significant increase in TDI after treatment (using the best of right and left sides). Treatment with sodium citrate did not significantly improve quantitative olfactory function, compared to control. The proportion of patients reporting parosmia did not change significantly after treatment. However, there was a significant reduction in the proportion of patients reporting phantosmia, at the end of the study period. CONCLUSIONS: Treatment with intranasal sodium citrate for a period of 2 weeks does not appear to improve quantitative olfactory function in patients with post-infectious impairment, compared to control. It may, however, be beneficial in treating phantosmia, which should be further addressed in future work.

Predictive in silico modeling of emetic potency of liquid cleaning products using an historical in vivo database.

The induction of vomiting by activation of mechanisms protecting the body against ingested toxins is not confined to natural products but can occur in response to manmade medicinal and non-medicinal products such as liquid cleaning products where it is a commonly reported adverse effect of accidental ingestion. The present study examined the utility of an historic database (>30 years old) reporting emetic effects of 98 orally administered liquid cleaning formulations studied in vivo (canine model) to objectively identify the main pro-emetic constituents and to derive a predictive model. Data were analysed by categorizing the formulation constituents into 10 main groups followed by using multivariate correlation, partial least squares and recursive partitioning analysis. Using the ED50 we objectively identified high ionic strength, non-ionic surfactants (alcohol ethoxylate) and alkaline pH as the main pro-emetic factors. Additionally, a mathematical model was developed which allows prediction of the ED50 based on formulation. The limitations of the use of historic data and the model are discussed. The results have practical applications in new product formulation and safety but additionally the principles underpinning this in silico study have wider applicability in demonstrating the potential utility of such archival data in current research contributing to animal replacement.

Evaluation of historic in vivo data to characterise the emetic properties of liquid cleaning products and provide a framework for the development of an in silico predictive algorithm.

Accidental ingestion of household cleaning products frequently results in emesis but the physicochemical properties responsible are not known. To investigate whether data collected during in vivo animal studies performed >30 years ago could provide novel insights into the components responsible, we re-analysed original studies from a total of 74 liquid cleaning formulations. The incidence of emesis was dose-related with ED50 values between 0.012 and 8.4 ml/kg and 57% of formulations having an ED50 ≤ 1 ml/kg. The median latency for emesis was 10.0 min (95% CI, 8-12 min) and number of vomits in 60 min ranged from 1 to 10 (median 2). From the ED100, latency and number of vomits we derived a "vomiting index" (VI) for a subset of 15 formulations which revealed an association between a high VI, a high percentage of non-ionic surfactants/high ionic strength, and a pH of ~10 which we propose are causally linked with the possible mechanism(s) discussed. The limitations of using historic data are discussed but analysis of such data has provided novel insights into the emetic characteristics of this class of products and has informed the development of an in silico model to predict the emetic liability of novel formulations without additional in vivo studies.

Orthorhombic crystal structure and oxygen deficient cluster distribution model for YBa2Cu3-xAlxO6+δ superconductor.

Single crystal x-ray diffraction measurements on both as-grown as well as oxygenated single crystals of an aluminium doped high temperature superconductor YBa2Cu3-xAlxO6+δ revealed the crystal structure to be orthorhombic with space group Pmmm, in contrast to, tetragonal crystal structures corresponding to space group P4/mmm, previously reported for as-grown YBa2Cu3-xAlxO6+δ, and conflicting structures on oxygenated YBa2Cu3-xAlxO6+δ. The orthorhombic crystal structure was confirmed by powder x-ray diffraction that showed the presence of two peaks corresponding to (020) and (200) reflections associated with orthorhombic structures of space group Pmmm, instead of a single (200) reflection corresponding to tetragonal crystal structures with space group P4/mmm. All the as-grown crystals were found to be superconducting. An oxygen-vacancy cluster distribution model is proposed to explain the differences in the obtained magnetisation hysteresis loop and the broad superconducting transition temperature. The model proposes the existence of two oxygen deficient clusters of (Al-..-Cu-O-Cu)n and (Cu-O-Cu-..)n juxtaposed with each other whose number and size vary as the as-grown single crystals of YBa2Cu3-xAlxO6+δ are subjected to oxygenation. X-ray photoelectron spectroscopy measurements showed the existence of two distinct peaks in each of the spectrum of O, Cu, Y and Ba in YBa2Cu3-xAlxO6+δ crystals corresponding to the two different types of clusters. The relative intensities of each XPS peak was found to decrease in the oxygenated crystals as compared to the as-grown ones confirming the change in the number and size of clusters in the as-grown crystals after oxygenation.

Endovascular clot retrieval for acute ischaemic stroke due to basilar artery occlusion in childhood.

Endovascular clot retrieval (ECR) is an emerging therapy for treatment of acute ischaemic stroke (AIS) in adults, including basilar artery occlusion (BAO). Its role in children is not well established. We report four consecutive children with AIS due to BAO treated with ECR in Sydney, Australia. We reviewed the literature to characterize the 'natural course' of AIS due to BAO in children not treated with thrombolysis or ECR, and compared their outcome with our patients and reported children with BAO treated with ECR. Despite delays in diagnosis, ECR achieved recanalization in our four children. Three children had a good outcome (Paediatric Modified Rankin Score [PedmRS] 0-2). One child with acute leukaemia suffered recurrent basilar occlusion and died of brainstem dysfunction. Literature review identified 111 children exhibiting the natural course of AIS due to BAO, among whom 42% had good outcomes (PedmRS 0-2), 48% had significant residual disability (PedmRS 3-5), and 10% died. Of 34 children treated with ECR, 28 (82%) had good outcomes (PedmRS 0-2), five (15%) had significant residual disability (PedmRS 3-5), and one (3%) died. Complications of ECR were uncommon. These observations suggest ECR may be beneficial for children with AIS due to BAO. WHAT THIS PAPER ADDS: Children with acute ischaemic stroke (AIS) due to basilar artery occlusion (BAO) experience significant morbidity and mortality. Endovascular clot retrieval may be beneficial in children with AIS due to BAO.

Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts.

Mass extinctions occur frequently in natural history. While studies of animals that became extinct can be informative, it is the survivors that provide clues for mechanisms of adaptation when conditions are adverse. Here, we describe a survival pathway used by many species as a means for providing adequate fuel and water, while also providing protection from a decrease in oxygen availability. Fructose, whether supplied in the diet (primarily fruits and honey), or endogenously (via activation of the polyol pathway), preferentially shifts the organism towards the storing of fuel (fat, glycogen) that can be used to provide energy and water at a later date. Fructose causes sodium retention and raises blood pressure and likely helped survival in the setting of dehydration or salt deprivation. By shifting energy production from the mitochondria to glycolysis, fructose reduced oxygen demands to aid survival in situations where oxygen availability is low. The actions of fructose are driven in part by vasopressin and the generation of uric acid. Twice in history, mutations occurred during periods of mass extinction that enhanced the activity of fructose to generate fat, with the first being a mutation in vitamin C metabolism during the Cretaceous-Paleogene extinction (65 million years ago) and the second being a mutation in uricase that occurred during the Middle Miocene disruption (12-14 million years ago). Today, the excessive intake of fructose due to the availability of refined sugar and high-fructose corn syrup is driving 'burden of life style' diseases, including obesity, diabetes and high blood pressure.

Evolutionary basis for the human diet: consequences for human health.

The relationship of evolution with diet and environment can provide insights into modern disease. Fossil evidence shows apes, and early human ancestors were fruit eaters living in environments with strongly seasonal climates. Rapid cooling at the end of the Middle Miocene (15-12 Ma: millions of years ago) increased seasonality in Africa and Europe, and ape survival may be linked with a mutation in uric acid metabolism. Climate stabilized in the later Miocene and Pliocene (12-5 Ma), and fossil apes and early hominins were both adapted for life on ground and in trees. Around 2.5 Ma, early species of Homo introduced more animal products into their diet, and this coincided with developing bipedalism, stone tool technology and increase in brain size. Early species of Homo such as Homo habilis still lived in woodland habitats, and the major habitat shift in human evolution occurred at 1.8 Ma with the origin of Homo erectus. Homo erectus had increased body size, greater hunting skills, a diet rich in meat, control of fire and understanding about cooking food, and moved from woodland to savannah. Group size may also have increased at the same time, facilitating the transmission of knowledge from one generation to the next. The earliest fossils of Homo sapiens appeared about 300 kyr, but they had separated from Neanderthals by 480 kyr or earlier. Their diet shifted towards grain-based foods about 100 kyr ago, and settled agriculture developed about 10 kyr ago. This pattern remains for many populations to this day and provides important insights into current burden of lifestyle diseases.

Case report of a child bearing a novel deleterious splicing variant in PIGT.

RATIONALE: Trio family-based whole exome sequencing (WES) is a powerful tool in the diagnosis of rare neurodevelopmental diseases, even in patients with the unclear diagnosis. There have been previous reports of variants in the phosphatidylinositol glycan anchor biosynthesis class T (PIGT) gene associated with multiple congenital anomalies, with a total of 14 affected individuals across 8 families. PATIENT CONCERNS: An 18-month-old boy of Greek ancestry presented with global developmental delay, generalized tonic-clonic seizures, hypotonia, renal cysts, esotropia, bilateral undescended testes, bilateral vesicoureteric reflux, marked cardiac dextroposition, bilateral talipes equinovarus, and dysmorphic features. DIAGNOSIS: WES revealed 2 compound heterozygous variants in the PIGT gene, c.[494-2A>G]; [547A>C]/p.[Asp122Glyfs*35]; [Thr183Pro]. The splicing mutation was demonstrated to lead to the skipping of exon 4. INTERVENTIONS: Seizures, infections, and other main symptoms were treated. OUTCOMES: The patient died at 2 years of age before the molecular diagnosis was achieved. Genetic counseling has been offered to the family. LESSONS: Most of the clinical features of the patient are in agreement with the previously described PIGT cases corroborating the usefulness of WES as a diagnostic tool.

Rhinological interventions for obstructive sleep apnoea - a systematic review and descriptive meta-analysis.

OBJECTIVES: Obstructive sleep apnoea is a common chronic sleep disorder characterised by collapse of the upper airway during sleep. The nasal airway forms a significant part of the upper airway and any obstruction is thought to have an impact on obstructive sleep apnoea. A systematic review was performed to determine the role of rhinological surgical interventions in the management of obstructive sleep apnoea. METHODS: A systematic review of current literature was undertaken; studies were included if they involved comparison of a non-surgical and/or non-rhinological surgical intervention with a rhinological surgical intervention for treatment of obstructive sleep apnoea. RESULTS: Sixteen studies met the selection criteria. The pooled data suggest that there are reductions in the apnoea/hypopnea index and respiratory disturbance index following nasal surgery. However, the current body of studies is too heterogeneous for statistically significant meta-analysis to be conducted. CONCLUSION: Nasal surgery may have limited benefit for a subset of patients based on current evidence.

The internal nasal valve: a validated grading system and operative guide.

PURPOSE: Nasal obstruction is a highly subjective and commonly reported symptom. The internal nasal valve (INV) is the rate limiting step to nasal airflow. A static INV grading score was devised with regard to visibility of the middle turbinate. METHODS: A prospective study of all patients who underwent primary external functional septorhinoplasty in 2017 for nasal obstruction. All patients' INV score was assessed pre- and postoperatively in a blinded and independent fashion by surgeons of varying seniority. RESULTS: Twenty-eight patients were studied, with mean age 30.9 years and follow-up 18.8 weeks. Inter-rater and test-retest reliability of INV grading were excellent, with Cronbach's alpha 0.936 and 0.920, respectively. There was also statistically significant improvement in both subjective and objective postoperative outcome measures including nasal inspiratory peak flows. CONCLUSIONS: We demonstrate a novel, easy to interpret, clinically valuable grading system of the static internal nasal valve that is reliable and reproducible.

Structural Plasticity of the Primary and Secondary Olfactory cortices: Increased Gray Matter Volume Following Surgical Treatment for Chronic Rhinosinusitis.

Functional plasticity of the adult brain is well established. Recently, the structural counterpart to such plasticity has been suggested by neuroimaging studies showing experience-dependent differences in gray matter (GM) volumes. Within the primary and secondary olfactory cortices, reduced GM volumes have been demonstrated in patients with olfactory loss. However, these cross-sectional studies do not provide causal evidence for GM volume change, and thereby structural plasticity. Disorders of the peripheral olfactory system, such as chronic rhinosinusitis (CRS), provide an ideal model to study GM structural plasticity, given that patients may experience long periods of olfactory impairment, followed by near complete recovery with treatment. We therefore performed a prospective longitudinal study in patients undergoing surgical treatment for CRS. We used voxel-based morphometry (VBM) to investigate GM volume change in 12 patients (M:F = 7:5; 47.2 ±â€¯14.9 years), 3 months post-op. There was a significant improvement in olfactory function according to birhinal psychophysical testing. We performed a voxel-wise region of interest analysis, with significance corrected for number of regions (p < 0.0036corr). We found significantly increased post-operative GM volumes within the primary (left piriform cortex, right amygdala) and secondary (right orbitofrontal cortex, caudate nucleus, hippocampal-parahippocampal complex and bilateral temporal poles) olfactory networks, and decreased GM volumes within the secondary network only (left caudate nucleus and temporal pole, bilateral hippocampal-parahippocampal complex). As a control measure, we assessed GM change within V1, S1 and A1, where there were no suprathreshold voxels. To our knowledge, this is the first study to demonstrate GM structural plasticity within the primary and secondary olfactory cortices, following restoration of olfaction.

Targeted temperature management in patients with intracerebral haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke: consensus recommendations.

BACKGROUND: A modified Delphi approach was used to identify a consensus on practical recommendations for the use of non-pharmacological targeted temperature management in patients with intracerebral haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke with non-infectious fever (assumed neurogenic fever). METHODS: Nine experts in the management of neurogenic fever participated in the process, involving the completion of online questionnaires, face-to-face discussions, and summary reviews, to consolidate a consensus on targeted temperature management. RESULTS: The panel's recommendations are based on a balance of existing evidence and practical considerations. With this in mind, they highlight the importance of managing neurogenic fever using a single protocol for targeted temperature management. Targeted temperature management should be initiated if the patient temperature increases above 37.5°C, once an appropriate workup for infection has been undertaken. This helps prevent prophylactic targeted temperature management use and ensures infection is addressed appropriately. When neurogenic fever is detected, targeted temperature management should be initiated rapidly if antipyretic agents fail to control the temperature within 1 h, and should then be maintained for as long as there is potential for secondary brain damage. The recommended target temperature for targeted temperature management is 36.5-37.5°C. The use of advanced targeted temperature management methods that enable continuous, or near continuous, temperature measurement and precise temperature control is recommended. CONCLUSIONS: Given the limited heterogeneous evidence currently available on targeted temperature management use in patients with neurogenic fever and intracerebral haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke, a Delphi approach was appropriate to gather an expert consensus. To aid in the development of future investigations, the panel provides recommendations for data gathering.