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.

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.

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.

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.

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.

ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.

Although mitochondrial disorders are clinically heterogeneous, they frequently involve the central nervous system and are among the most common neurogenetic disorders. Identifying the causal genes has benefited enormously from advances in high-throughput sequencing technologies; however, once the defect is known, researchers face the challenge of deciphering the underlying disease mechanism. Here we characterize large biallelic deletions in the region encoding the ATAD3C, ATAD3B and ATAD3A genes. Although high homology complicates genomic analysis of the ATAD3 defects, they can be identified by targeted analysis of standard single nucleotide polymorphism array and whole exome sequencing data. We report deletions that generate chimeric ATAD3B/ATAD3A fusion genes in individuals from four unrelated families with fatal congenital pontocerebellar hypoplasia, whereas a case with genomic rearrangements affecting the ATAD3C/ATAD3B genes on one allele and ATAD3B/ATAD3A genes on the other displays later-onset encephalopathy with cerebellar atrophy, ataxia and dystonia. Fibroblasts from affected individuals display mitochondrial DNA abnormalities, associated with multiple indicators of altered cholesterol metabolism. Moreover, drug-induced perturbations of cholesterol homeostasis cause mitochondrial DNA disorganization in control cells, while mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann-Pick type C disease further corroborates the interdependence of mitochondrial DNA organization and cholesterol. These data demonstrate the integration of mitochondria in cellular cholesterol homeostasis, in which ATAD3 plays a critical role. The dual problem of perturbed cholesterol metabolism and mitochondrial dysfunction could be widespread in neurological and neurodegenerative diseases.

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.

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.

Peak nasal inspiratory flow correlates with quality of life in functional endoscopic sinus surgery.

OBJECTIVES: Whilst nasal function and airflow improve subjectively following functional endoscopic sinus surgery (FESS), a clinically useful and objective tool for quantifying such improvement is lacking. The peak nasal inspiratory flow (PNIF) metre offers convenient and objective measures of nasal patency. However, it has not yet been established whether changes in PNIF after surgery reflect changes in subjective disease burden. In this study we aimed to determine whether changes in PNIF correlate with commonly used subjective symptom and quality of life outcome measures following FESS for chronic rhinosinusitis (CRS). DESIGN: Prospective cohort. SETTING: Royal National Throat Nose and Ear Hospital. PARTICIPANTS: Thirty-seven patients undergoing FESS for CRS, with or without polyps (21 male, mean age 48.8). MAIN OUTCOME MEASURES: PNIF, "SNOT-22", "NOSE" and "VAS" questionnaires were performed before and after surgery. RESULTS: In all patients, there was a strong negative correlation between change in PNIF and change in "SNOT-22" score following surgery (Pearson r=-.64, P<.0001). Strong negative correlations were also seen during subgroup analysis of patients with and without polyps (r=-.57, P=.006 and r=-.67, P=.005, respectively). Change in PNIF correlated significantly with change in "NOSE" score following surgery in all patients and those without polyps (r=-.54, P=.0005 and r=-.68, P=.003). There were no significant correlations between PNIF and VAS (nasal obstruction). CONCLUSIONS: Changes in PNIF after FESS appear to best reflect improvements in quality of life in CRS as measured using the "SNOT-22" questionnaire.

The effect of intranasal sodium citrate on olfaction in post-infectious loss: results from a prospective, placebo-controlled trial in 49 patients.

OBJECTIVES: Free calcium plays an integral role in peripheral olfactory processing, including feedback inhibition. It has therefore been suggested that reduction of intranasal free calcium with buffer solutions such as sodium citrate may improve olfactory function in patients with smell impairment. Several previous studies have supported this hypothesis, particularly in post-infectious olfactory loss. We therefore aimed to determine whether treatment with intranasal sodium citrate improves olfactory function in patients with post-infectious impairment. DESIGN: Prospective, single-blind, placebo-controlled trial. SETTING: Interdisciplinary Smell and Taste Clinic, TU Dresden (tertiary referral centre). PARTICIPANTS: Forty-nine adult participants with post-infectious olfactory impairment (M : F = 11 : 38, mean age 58.71 ± 11.03 years). MAIN OUTCOME MEASURES: Olfactory function (odour threshold and identification) before and after treatment as determined using "Sniffin' Sticks". Patients were treated monorhinally with 1 mL sodium citrate solution. The contralateral nasal cavity was treated with 1 mL physiological sodium chloride solution, which acted as internal control. Clinical improvement was assumed where threshold or identification score increased by ≥2.5 or 3 points, respectively, or ≥5.5 points together. RESULTS: We demonstrated a statistically significant improvement in composite threshold + identification scores following treatment with sodium citrate, compared with placebo. This was true for all patients (mean improvement 0.87 ± 2.68 points, P = 0.04), and on subgroup analysis in those with hyposmia (mean improvement 1.15 ± 2.37 points, P = 0.02). However, the effect size did not reach clinical significance. CONCLUSIONS: Further basic and clinical work is required to fully delineate the effect of intranasal sodium citrate in the treatment of post-infectious olfactory loss.

Body dysmorphic disorder in patients undergoing septorhinoplasty surgery: should we be performing routine screening?

OBJECTIVE: Body dysmorphic disorder (BDD) is defined as having a preoccupation with a perceived flaw in one's appearance, which appears slight to others and significantly interferes with a person's functioning. When undetected in septorhinoplasty patients, it will often lead to poor outcomes. DESIGN: We performed a prospective cohort study to determine the prevalence of BDD in our patients and whether surgical correction could be considered. SETTING AND PARTICIPANTS: We recruited 34 patients being considered for septorhinoplasty in a tertiary referral rhinology clinic and a control group of 50 from the otology clinic giving a total of 84. MAIN OUTCOME MEASURES: Participants completed the Body Dysmorphic Disorder Questionnaire (BDDQ), the sino-nasal outcome test-23 (SNOT-23) and underwent nasal inspiratory peak flow (NIPF). Those found to be at high risk for BDD were referred to a clinical psychologist. RESULTS: Of the septorhinoplasty patients, 11 (32%) were high risk for BDD. Following psychological assessment, 7 (63%) patients were felt to be unsuitable for surgery and were offered psychological therapy. SNOT-23 scores were significantly higher in the BDD group indicating a negative impact on quality of life. NIPF readings were not significantly different in the BDD group compared to the control group. CONCLUSIONS: The BDDQ is a valid tool for identifying patients at risk of BDD. A close working relationship with clinical psychology has been advantageous to help the selection process of candidates for surgery when there is a high risk of BDD.

Early Changes in Brain Oxygen Tension May Predict Outcome Following Severe Traumatic Brain Injury.

We report on the change in brain oxygen tension (PbtO2) over the first 24 h of monitoring in a series of 25 patients with severe traumatic brain injury (TBI) and relate this to outcome. The trend in PbtO2 for the whole group was to increase with time (mean PbtO2 17.4 [1.75] vs 24.7 [1.60] mmHg, first- vs last-hour data, respectively; p = 0.002). However, a significant increase in PbtO2 occurred in only 17 patients (68 %), all surviving to intensive care unit discharge (p = 0.006). Similarly, a consistent increase in PbtO2 with time occurred in only 13 patients, the correlation coefficient for PbtO2 versus time being ≥0.5 for all survivors. There were eight survivors and four non-survivors, with low correlation coefficients (<0.5). Significantly more patients with a correlation coefficient ≥0.5 for PbtO2 versus time survived in intensive care (p = 0.039). The cumulative length of time that PbtO2 was <20 mmHg was not significantly different among these three groups. In conclusion, although for the cohort as a whole PbtO2 increased over the first 24 h, the individual trends of PbtO2 were related to outcome. There was a significant association between improving PbtO2 and survival, despite these patients having cumulative durations of hypoxia similar to those of non-survivors.

Position paper on olfactory dysfunction.

BACKGROUND: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: - Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. - Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. - Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. - Comprehensive chemosensory assessment should include gustatory screening. - Smell training can be helpful in patients with olfactory loss of several aetiologies. CONCLUSIONS: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

Outcomes in endoscopic sinus surgery: olfaction, nose scale and quality of life in a prospective cohort study.

OBJECTIVES: To determine the efficacy of endoscopic sinus surgery (ESS) on olfactory function in chronic rhinosinusitis patients with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) and to compare the nasal obstruction and symptom evaluation (NOSE) scale before and after surgery. DESIGN: A prospective cohort study SETTING: Royal National Throat and Nose and Ear Hospital, London UK. PARTICIPANTS: One hundred and thirteen patients with CRS; 60 CRSwNP and 53 CRSsNP. OUTCOME MEASUREMENTS: Olfaction was measured using both the University of Pennsylvania Smell Investigation Test (UPSIT) and the 'sense of smell' visual analogue scale (VAS). The NOSE scale, the sinonasal outcome test (SNOT 22) and the Lund-Kennedy (LK) surgeon reported scores were also measured pre- and postoperatively at 6 months. RESULTS: The UPSIT psychophysical measurement significantly improved following ESS in the CRSwNP subgroup as did the patients perceived VAS sense of smell. However, in the CRSsNP subgroup, the improved VAS and UPSIT measurements were not significant. The NOSE, SNOT 22 and LK scores all improved significantly. The olfactory improvement as measured by the UPSIT correlated to the SNOT-22, but a correlation between the NOSE score and UPSIT was not found. CONCLUSIONS: Endoscopic sinus surgery significantly improved the patient's perceived and measured sense of smell in the CRSwNP subgroup which is the most surgically responsive CRS subgroup. Additionally, improved olfaction in the CRSwNP subgroup is most likely to improve the patient's quality of life. Endoscopic sinus surgery significantly improved the NOSE scale in both CRS subgroups at 6 months following surgery.

The outcome of septorhinoplasty surgery on olfactory function.

OBJECTIVES: To assess olfactory outcomes in patients undergoing septorhinoplasty surgery in our unit. DESIGN: Prospective cohort study. SETTING: The Royal National Throat Nose and Ear Hospital, London. PARTICIPANTS: Forty-three patients undergoing functional septorhinoplasty (Males = 26; mean age = 34.1 ± 12.2) were recruited into the study. MAIN OUTCOME MEASURES: The primary outcome of olfactory function was assessed using 'Sniffin sticks'. Our secondary outcomes were assessment of patient quality of life using the disease specific Sino-nasal Outcome Test-23 questionnaire (SNOT-23) and a visual analogue scale for sense of smell. These measures were repeated at 12 weeks post operatively. RESULTS: There was a significant change in the Sniffin' sticks score post-operatively (8.3 versus 9.6; P < 0.001). The SNOT-23 score also showed a significant improvement post-operatively (53.5 versus 40.4; P < 0.001). A significant improvement was not found in the smell/taste question (question 21) of the SNOT-23 questionnaire as well as the visual analogue scale for sense of smell. A difference in olfactory outcome was not found between open versus closed approaches, primary versus revision surgery and traumatic versus non traumatic cases. CONCLUSIONS: The results show a measured significant improvement in olfaction following functional Septorhinoplasty but not a subjective improvement in the patients perception of their sense of smell and hence not a clinically significant difference. The reasons for the measured improvement are not clear and are likely to be multifactorial.

A retrospective study of root canal therapy in non-vital primary molars.

AIM: This study was performed to assess the clinical and radiographic success rates of a formocresol and zinc oxide eugenol (ZOE) primary molar root canal therapy (RCT) technique. The effects of this treatment on the permanent successors and on exfoliation times were also investigated. MATERIALS AND METHODS: Study design: the retrospective study included 161 patients with 211 primary molars treated by RCT by a single operator in a private paediatric dental office in the Toronto area. Data were coded and entered into a Microsoft Excel database and analysis undertaken using SPSS software. Predominantly non-parametric tests were used to evaluate statistical differences (p < 0.05). RESULTS: A clinical success rate of 90% (190/211) and a radiographic success rate of 77.3% (136/176) were obtained. Following RCT in a primary molar, enamel defects were found in 6.8% (7/103) of premolars, all of which occurred in first premolars, and in patients treated at a mean age of 54.1 months (p < 0.005). Treated molars exfoliated on average 7.6 months sooner than contralateral teeth (p < 0.005). CONCLUSION: This formocresol and ZOE RCT is a viable treatment for necrotic primary molars and yielded very high clinical and acceptable radiographic success rates.

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is a disorder caused by recessive mutations in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. Recent observations indicate that the phenotypic range of the disease is much wider than initially thought. Currently, no treatment is available. The aims of our study were (i) to explore a possible genotype-phenotype correlation; and (ii) to identify potential therapeutic agents that modulate the splice site mutations in intron 2 of DARS2, present in almost all patients. A cross-sectional observational study was performed in 78 patients with two DARS2 mutations in the Amsterdam and Helsinki databases up to December 2012. Clinical information was collected via questionnaires. An inventory was made of the DARS2 mutations in these patients and those previously published. An assay was developed to assess mitochondrial aspartyl-tRNA synthetase enzyme activity in cells. Using a fluorescence reporter system we screened for drugs that modulate DARS2 splicing. Clinical information of 66 patients was obtained. The clinical severity varied from infantile onset, rapidly fatal disease to adult onset, slow and mild disease. The most common phenotype was characterized by childhood onset and slow neurological deterioration. Full wheelchair dependency was rare and usually began in adulthood. In total, 60 different DARS2 mutations were identified, 13 of which have not been reported before. Except for 4 of 42 cases published by others, all patients were compound heterozygous. Ninety-four per cent of the patients had a splice site mutation in intron 2. The groups of patients sharing the same two mutations were too small for formal assessment of genotype-phenotype correlation. However, some combinations of mutations were consistently associated with a mild phenotype. The mitochondrial aspartyl-tRNA synthetase activity was strongly reduced in patient cells. Among the compounds screened, cantharidin was identified as the most potent modulator of DARS2 splicing. In conclusion, the phenotypic spectrum of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is wide, but most often the disease has a relatively slow and mild course. The available evidence suggests that the genotype influences the phenotype, but because of the high number of private mutations, larger numbers of patients are necessary to confirm this. The activity of mitochondrial aspartyl-tRNA synthetase is significantly reduced in patient cells. A compound screen established a 'proof of principle' that the splice site mutation can be influenced. This finding is promising for future therapeutic strategies.

Does time to endoscopic sinus surgery impact outcomes in chronic rhinosinusitis? Retrospective analysis using the UK clinical practice research data.

BACKGROUND: Patients with chronic rhinosinusitis (CRS) refractory to medical management may elect endoscopic sinus surgery (ESS). Recent data showed that clinical outcomes of patients treated earlier outperformed those of patients treated later in the disease continuum. In this study, CRS-related healthcare utilisation of patients treated early versus late was analysed using the UK-based Clinical Practice Research Database. METHODS: Two cohorts ("Early Cohort": ESS within 12 months of first CRS diagnosis, versus "Late Cohort": ≥ 5 years from diagnosis to ESS) were matched for age, gender, asthma, polyposis. Healthcare needs related to CRS were analysed post-operatively for 5 years. RESULTS: Patients in the Late cohort used significantly more CRS-related care than patients in the Early cohort visits and 0.54 prescriptions per patient per year. A sub-analysis of patients with and without asthma indicated that patients in the Late cohort without asthma had healthcare needs equivalent to patients in the Early cohort with asthma. CONCLUSION: Delayed surgical intervention for CRS is associated with greater post-operative healthcare needs than ESS within 12 months of first CRS diagnosis.

The need for an objective measure in septorhinoplasty surgery: are we any closer to finding an answer?

OBJECTIVES: To assess the reliability of nasal inspiratory peak flow (NIPF) in providing a clinically accurate objective measure following functional septorhinoplasty by comparing it to the validated disease-specific quality-of-life questionnaire, SNOT-22. Studies so far have demonstrated poor correlation between bilateral NIPF and symptom-specific nasal questionnaires following septorhinoplasty. DESIGN: To perform a prospective comparative analysis between NIPF and the validated disease-specific quality-of-life questionnaire SNOT-22 and to determine whether a correlation exists following septorhinoplasty surgery. SETTING: The Royal National Throat Nose and Ear Hospital, London. PARTICIPANTS: A total of 122 patients (78 males, 44 females; mean age 33.5 ± 12.2 years) were recruited from the senior authors rhinology clinic and underwent functional septorhinoplasty surgery. MAIN OUTCOME MEASURES: Preoperative and postoperative nasal inspiratory peak flow (NIPF) measurements were performed in addition to the completion of three subjective quality-of-life and symptom assessment tool questionnaires; Sinonasal Outcome Test 22 (SNOT-22), Nasal Obstruction Symptom Evaluation (NOSE) and Visual Analogue Scale (VAS: 0-10). RESULTS: The mean preoperative NIPF was 88.2 L/min, and the postoperative value was 101.6 L/min and showed a significant improvement following surgery (P = 0.0064). The mean total SNOT-22 score improved significantly from 48.6 to 26.6 (P < 0.0001); the NOSE score from 14.1 to 6.6 (P < 0.0001); and the Visual Analogue Scale (VAS) blockage score from 6.9 to 3.2 (P < 0.0001). All individual domains assessed showed improvements postoperatively, but no correlation was found between the NIPF and SNOT-22 score. Equally, we did not find a correlation between NIPF and the symptom-specific NOSE questionnaire and the nasal blockage domain on the Visual Analogue Scale (VAS) scale. CONCLUSION: We have demonstrated that NIPF does not correlate with the SNOT-22 disease-specific questionnaire, although both outcomes significantly improve postoperatively. At present, we are still lacking a clinically accurate objective measure of nasal function for the evaluation of patients undergoing septorhinoplasty surgery.