Semorinemab Pharmacokinetics and The Effect on Plasma Total Tau Pharmacodynamics in Clinical Studies.

BACKGROUND: Semorinemab is a monoclonal antibody that targets the N-terminal domain of the tau protein that is in clinical development for the treatment of Alzheimer's disease. OBJECTIVES: To perform model-based evaluations of the observed pharmacokinetics in serum and the total plasma tau target-engagement dynamics from clinical studies evaluating semorinemab. DESIGN: The observed semorinemab pharmacokinetics and plasma tau target engagement from phase 1 and 2 clinical studies were modeled using a non-linear mixed effect target-mediated drug disposition model. The model was simulated to understand target engagement at clinical dose levels. SETTINGS AND PARTICIPANTS: The clinical studies testing semorinemab were evaluated in healthy volunteers, subjects with prodromal-to-mild Alzheimer's disease, and subjects with mild-to-moderate Alzheimer's disease. The data included a total of 8430 semorinemab serum concentrations and 4772 total tau protein plasma concentrations from 463 subjects treated with a range of single and multiple doses of semorinemab. MEASUREMENTS: Serum concentrations of semorinemab and the total plasma tau concentrations were measured after administration of a range of doses of semorinemab to subjects with Alzheimer's disease. A sensitivity analysis was performed wherein key target-mediated drug disposition model parameters were estimated separately between healthy volunteers, subjects with prodromal-to-mild Alzheimer's disease, and subjects with mild-to-moderate Alzheimer's disease. RESULTS: Serum concentrations of semorinemab were consistent across studies and showed a dose-proportional increase across the evaluated dose range. The pharmacokinetic profile was comparable between healthy volunteers and subjects with Alzheimer's disease. Total plasma tau concentrations increased in a dose-dependent non-linear manner upon semorinemab administration. The target-mediated drug disposition model adequately described the serum pharmacokinetics and protein dynamics with an estimated antibody-ligand binding strength, Kss, of 42.7 nM. The estimated values of clearance and central volume of distribution were 0.109 L/day/70 kg and 2.95 L/70 kg, respectively, and were consistent with typical values for IgG mAbs. In the sensitivity analysis, Kss (32 nM) and baseline tau protein (0.30 µM) were estimated to be lower for healthy volunteers compared to subjects with Alzheimer's disease but were comparable between subjects with Alzheimer's disease of different severities (Kss: 52-57 nM, baseline tau: 0.44-0.47 µM). The models suggested that peripheral target engagement was over 90% at the clinical doses in each of the diagnostic subgroups. CONCLUSION: Our target-mediated drug disposition model adequately described the serum pharmacokinetics and the peripheral non-linear increase with dose of the total tau. The model confirmed that these dose-response relationships were consistent across populations of healthy volunteers and subjects with different severities of Alzheimer's disease.

Human tumor suppressor protein Pdcd4 binds at the mRNA entry channel in the 40S small ribosomal subunit.

Translation is regulated mainly in the initiation step, and its dysregulation is implicated in many human diseases. Several proteins have been found to regulate translational initiation, including Pdcd4 (programmed cell death gene 4). Pdcd4 is a tumor suppressor protein that prevents cell growth, invasion, and metastasis. It is downregulated in most tumor cells, while global translation in the cell is upregulated. To understand the mechanisms underlying translational control by Pdcd4, we used single-particle cryo-electron microscopy to determine the structure of human Pdcd4 bound to 40S small ribosomal subunit, including Pdcd4-40S and Pdcd4-40S-eIF4A-eIF3-eIF1 complexes. The structures reveal the binding site of Pdcd4 at the mRNA entry site in the 40S, where the C-terminal domain (CTD) interacts with eIF4A at the mRNA entry site, while the N-terminal domain (NTD) is inserted into the mRNA channel and decoding site. The structures, together with quantitative binding and in vitro translation assays, shed light on the critical role of the NTD for the recruitment of Pdcd4 to the ribosomal complex and suggest a model whereby Pdcd4 blocks the eIF4F-independent role of eIF4A during recruitment and scanning of the 5' UTR of mRNA.

Genetic predisposition of BDNF (rs6265) gene is susceptible to Schizophrenia: A prospective study and updated meta-analysis / Asociación entre el gen BDNF (rs6265) y predisposición a la esquizofrenia: estudio prospectivo y metaanálisis actualizado

Introduction: Genetic polymorphism in the BDNF gene has been found to cause neuronal alterations and has been identified as a causal factor for many neuropsychiatric disorders. Therefore, various neurological case–control studies and meta-analyses have been conducted to find the possible link between BDNF and susceptibility to schizophrenia. Method: This meta-analysis gathered data from 25 case–control studies including a total of 8384 patients with schizophrenia and 8821 controls in order to identify the relationship between the rs6265 single nucleotide polymorphism and the disease, evaluating the combined odds ratio and 95% confidence intervals under 5 different genetic models. Validation followed the “Leave one out” method, and we used the Egger test and Begg's funnel plot to identify publication bias. Results: Research into the rs6265 (G/A) polymorphism revealed a non-significant association with schizophrenia in all 5 genetic models; in the subgroup analysis, no association was found between white and Asian populations, with a p value > .05. Conclusions: Overall, the updated meta-analysis revealed that rs6265 exonic polymorphisms do not increase susceptibility to this disease. However, to better understand the pathogenesis of the disease, there is a need for further case–control studies into the BDNF polymorphism including larger sample sizes and different ethnic groups.(AU)

Introducción: Se sabe que los polimorfismos del gen BDNF provocan alteraciones neuronales y parecen ser un factor causal en muchos trastornos neuropsiquiátricos. Es por ello que se han llevado a cabo varios metaanálisis y estudios de casos y controles con el objetivo de evaluar la posible relación entre BDNF y la esquizofrenia. Método: Realizamos un metaanálisis de 25 estudios de casos y controles, que incluyó un total de 8.384 pacientes con esquizofrenia y 8.821 controles. Se analizó la relación entre el polimorfismo de nucleótido simple rs6265 y la esquizofrenia mediante odds ratios combinados y sus intervalos de confianza del 95% con 5 modelos genéticos diferentes. Utilizamos el método de validación cruzada dejando uno fuera («leave one out»), la prueba de Egger y el gráfico en embudo de Begg para identificar posibles sesgos de publicación. Resultados: Los estudios sobre el polimorfismo rs6265 (G/A) muestran una asociación no significativa con la esquizofrenia en los 5 modelos genéticos. En el análisis por subgrupos, no se encontró relación con las poblaciones caucásica y asiática (p > 0,05). Conclusiones: La presencia de polimorfismos rs6265 no aumenta la predisposición a desarrollar esquizofrenia. Sin embargo, se deben realizar más estudios de casos y controles sobre polimorfismos de BDNF, con muestras más numerosas y con individuos de diferentes grupos étnicos, para comprender mejor los mecanismos patogénicos de la enfermedad.(AU)

Genetic predisposition of BDNF (rs6265) gene is susceptible to Schizophrenia: A prospective study and updated meta-analysis.

INTRODUCTION: Genetic polymorphism in the BDNF gene has been found to cause neuronal alterations and has been identified as a causal factor for many neuropsychiatric disorders. Therefore, various neurological case-control studies and meta-analyses have been conducted to find the possible link between BDNF and susceptibility to schizophrenia. METHOD: This meta-analysis gathered data from 25 case-control studies including a total of 8384 patients with schizophrenia and 8821 controls in order to identify the relationship between the rs6265 single nucleotide polymorphism and the disease, evaluating the combined odds ratio and 95% confidence intervals under 5 different genetic models. Validation followed the "Leave one out" method, and we used the Egger test and Begg's funnel plot to identify publication bias. RESULTS: Research into the rs6265 (G/A) polymorphism revealed a non-significant association with schizophrenia in all 5 genetic models; in the subgroup analysis, no association was found between white and Asian populations, with a p value>.05. CONCLUSIONS: Overall, the updated meta-analysis revealed that rs6265 exonic polymorphisms do not increase susceptibility to this disease. However, to better understand the pathogenesis of the disease, there is a need for further case-control studies into the BDNF polymorphism including larger sample sizes and different ethnic groups.

The structure of a human translation initiation complex reveals two independent roles for the helicase eIF4A.

Eukaryotic translation initiation involves recruitment of the 43S pre-initiation complex to the 5' end of mRNA by the cap-binding complex eIF4F, forming the 48S translation initiation complex (48S), which then scans along the mRNA until the start codon is recognized. We have previously shown that eIF4F binds near the mRNA exit channel of the 43S, leaving open the question of how mRNA secondary structure is removed as it enters the mRNA channel on the other side of the 40S subunit. Here we report the structure of a human 48S that shows that, in addition to the eIF4A that is part of eIF4F, there is a second eIF4A helicase bound at the mRNA entry site, which could unwind RNA secondary structures as they enter the 48S. The structure also reveals conserved interactions between eIF4F and the 43S, probaby explaining how eIF4F can promote mRNA recruitment in all eukaryotes.

The molecular basis of translation initiation and its regulation in eukaryotes.

The regulation of gene expression is fundamental for life. Whereas the role of transcriptional regulation of gene expression has been studied for several decades, it has been clear over the past two decades that post-transcriptional regulation of gene expression, of which translation regulation is a major part, can be equally important. Translation can be divided into four main stages: initiation, elongation, termination and ribosome recycling. Translation is controlled mainly during its initiation, a process which culminates in a ribosome positioned with an initiator tRNA over the start codon and, thus, ready to begin elongation of the protein chain. mRNA translation has emerged as a powerful tool for the development of innovative therapies, yet the detailed mechanisms underlying the complex process of initiation remain unclear. Recent studies in yeast and mammals have started to shed light on some previously unclear aspects of this process. In this Review, we discuss the current state of knowledge on eukaryotic translation initiation and its regulation in health and disease. Specifically, we focus on recent advances in understanding the processes involved in assembling the 43S pre-initiation complex and its recruitment by the cap-binding complex eukaryotic translation initiation factor 4F (eIF4F) at the 5' end of mRNA. In addition, we discuss recent insights into ribosome scanning along the 5' untranslated region of mRNA and selection of the start codon, which culminates in joining of the 60S large subunit and formation of the 80S initiation complex.

Primary lipofilling as an adjunct in transverse upper gracilis flap breast reconstruction.

In many centres, the myocutaneous transverse upper gracilis (TUG) flap represents an alternative choice in autologous breast reconstruction when abdominal tissue is unavailable. However, a single TUG flap may be volume deficient, particularly in the upper pole. We describe the application of simultaneous lipofilling to the pectoralis major muscle at the index procedure and present our decision-making algorithm, technique and outcomes. A retrospective review of all TUG flaps between January 2011 and May 2021 was conducted. Patient demographics, volume of primary and any subsequent fat grafting and complications were recorded. A total of 183 patients (242 TUG flaps) were included in this study. Of these; 130 patients were reconstructed with single TUG flaps, 16 patients received a single TUG flap with immediate lipofilling, and 37 patients underwent stacked, double TUG flap reconstructions. Of the 242 flaps, there were 2 flap losses (<1%), neither of which occurred in the immediate lipofilling cohort. Among the 130 single TUG patients, 28 (21.5%) required a cumulative total of 40, and a mean of 1.4, secondary lipofilling procedures. The immediate lipofilling patients were injected with a mean of 42 ml fat (range: 20-80 ml). In this group, only 2 of 16 patients required secondary lipofilling. The mean follow-up was 67 months (17-141). Primary lipofilling may reduce the need for secondary revisional procedures and appears safe at the index operation, adds little operative time and has negligible donor site morbidity. In patients where a second (stacked) flap would add unnecessary volume and complexity, it can be considered a useful adjunct.

Position paper on olfactory dysfunction: 2023

BACKGROUND: Since publication of the original Position Paper on Olfactory Dysfunction in 2017 (PPOD-17), the personal and societal burden of olfactory disorders has come sharply into focus through the lens of the COVID-19 pandemic. Clinicians, scientists and the public are now more aware of the importance of olfaction, and the impact of its dysfunction on quality of life, nutrition, social relationships and mental health. Accordingly, new basic, translational and clinical research has resulted in significant progress since the PPOD-17. In this updated document, we present and discuss currently available evidence for the diagnosis and management of olfactory dysfunction. Major updates to the current version include, amongst others: new recommendations on olfactory related terminology; new imaging recommendations; new sections on qualitative OD and COVID-19 OD; updated management section. Recommendations were agreed by all co-authors using a modified Delphi process. CONCLUSIONS: We have provided an overview of current evidence and expert-agreed recommendations for the definition, investigation, and management of OD. As for our original Position Paper, we hope that this updated document 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.

Developing a core outcome set for clinical trials in olfactory disorders: a COMET initiative.

STATEMENT OF PROBLEM: Evaluating the effectiveness of the management of Olfactory Dysfunction (OD) has been limited by a paucity of high-quality randomised and/or controlled trials. A major barrier is heterogeneity of outcomes in such studies. Core outcome sets (COS) - standardized sets of outcomes that should be measured/reported as determined by consensus-would help overcome this problem and facilitate future meta-analyses and/or systematic reviews (SRs). We set out to develop a COS for interventions for patients with OD. METHODS: A long-list of potential outcomes was identified by a steering group utilising a literature review, thematic analysis of a wide range of stakeholders' views and systematic analysis of currently available Patient Reported Outcome Measures (PROMs). A subsequent e-Delphi process allowed patients and healthcare practitioners to individually rate the outcomes in terms of importance on a 9-point Likert scale. RESULTS: After 2 rounds of the iterative eDelphi process, the initial outcomes were distilled down to a final COS including subjective questions (visual analogue scores, quantitative and qualitative), quality of life measures, psychophysical testing of smell, baseline psychophysical testing of taste, and presence of side effects along with the investigational medicine/device and patient's symptom log. CONCLUSIONS: Inclusion of these core outcomes in future trials will increase the value of research on clinical interventions for OD. We include recommendations regarding the outcomes that should be measured, although future work will be required to further develop and revalidate existing outcome measures.

Clinical Validation and Extension of an Automated, Deep Learning-Based Algorithm for Quantitative Sinus CT Analysis.

BACKGROUND AND PURPOSE: Sinus CT is critically important for the diagnosis of chronic rhinosinusitis. While CT is sensitive for detecting mucosal disease, automated methods for objective quantification of sinus opacification are lacking. We describe new measurements and further clinical validation of automated CT analysis using a convolutional neural network in a chronic rhinosinusitis population. This technology produces volumetric segmentations that permit calculation of percentage sinus opacification, mean Hounsfield units of opacities, and percentage of osteitis. MATERIALS AND METHODS: Demographic and clinical data were collected retrospectively from adult patients with chronic rhinosinusitis, including serum eosinophil count, Lund-Kennedy endoscopic scores, and the SinoNasal Outcomes Test-22. CT scans were scored using the Lund-Mackay score and the Global Osteitis Scoring Scale. CT images were automatically segmented and analyzed for percentage opacification, mean Hounsfield unit of opacities, and percentage osteitis. These readouts were correlated with visual scoring systems and with disease parameters using the Spearman ρ. RESULTS: Eighty-eight subjects were included. The algorithm successfully segmented 100% of scans and calculated features in a diverse population with CT images obtained on different scanners. A strong correlation existed between percentage opacification and the Lund-Mackay score (ρ = 0.85, P < .001). Both percentage opacification and the Lund-Mackay score exhibited moderate correlations with the Lund-Kennedy score (ρ = 0.58, P < .001, and ρ = 0.58, P < .001, respectively). The percentage osteitis correlated moderately with the Global Osteitis Scoring Scale (ρ = 0.48, P < .001). CONCLUSIONS: Our quantitative processing of sinus CT images provides objective measures that correspond well to established visual scoring methods. While automation is a clear benefit here, validation may be needed in a prospective, multi-institutional setting.

Microdermabrasion facilitates direct current stimulation by lowering skin resistance.

Background: Transcranial direct current stimulation (tDCS) is reported to induce irritating skin sensations and occasional skin injuries, which limits the applied tDCS dose. Additionally, tDCS hardware safety profile prevents high current delivery when skin resistance is high. Objective: To test if decreasing skin resistance can enable high-dose tDCS delivery without increasing tDCS-related skin sensations or device hardware limits. Methods: We compared the effect of microdermabrasion and sonication on 2 mA direct current stimulation (DCS) through forearm skin for 2-3 min on 20 subjects. We also surveyed the subjects using a questionnaire throughout the procedure. We used a linear mixed-effects model for repeated-measures and multiple logistic regression, with adjustments for age, race, gender and visit. Results: Microdermabrasion, with/out sonication, led to significant decrease in skin resistance (1.6 ± 0.1 kΩ or ∼32% decrease, p < 0.0001). The decrease with sonication alone (0.4 ± 0.1 kΩ or ∼7% decrease, p = 0.0016) was comparable to that of sham (0.3 ± 0.1 kΩ or ∼5% decrease, p = 0.0414). There was no increase in the skin-electrode interface temperature. The perceived DCS-related sensations did not differ across skin preparation procedures (p > 0.16), but microdermabrasion (when not combined with sonication) led to increased perceived sensation (p < 0.01). Conclusions: Microdermabrasion (with/out sonication) resulted in reduced skin resistance without increase in perceived skin sensations with DCS. Higher current can be delivered with microdermabrasion-pre-treated skin without changing the device hardware while reducing, otherwise higher voltage required to deliver the same amount of current.

Metal-Air Field Emission Devices - Nano Electrode Geometries Comparison of Performance and Stability.

Air-channel devices have a special advantage due to the promise of vacuum-like ballistic transport in air, radiation insensitivity, and nanoscale size. Here, achieving high current at low voltage along with considerable mechanical stability is a primary issue. The comparative analysis of four planar and metallic electrode-pair geometries at 10 nm channel length is presented. The impact of nano-electrode-pair geometries on overall device performance is investigated. Air-channel devices are operated at the ultra-low voltage of 5 mV to demonstrate the device dynamics of air-channel devices at low power. Investigations focus on the direct tunneling (DT) mechanism which is dominant in the low-voltage regime. Comparative analysis of different electrode-pair geometries reveals two orders of magnitude increment in the current just by modulating the electrode-pair structure. Theoretical analysis suggests that the emission current is directly related to the active junction area within the metal-air-metal interface at the direct tunneling regime. The geometry-dependent mechanical stability of different electrode pairs is compared by imaging biasing triggered nanoscale structural changes and pulsed biasing stress analysis. The results and claims are confirmed and consolidated with the statistical analysis. Experimental investigations provide strong directions for high-performance and stable devices. In-depth theoretical discussions will enable the accurate modeling of emerging low-power, high-speed, radiation-hardened nanoscale vacuum electronics.

Experimental investigation of anomalous molecular probe diffusion in entangled polymer melts.

Investigations on the diffusion of small molecules or particles in polymeric materials are important to numerous technologies and can also be used to gain insight on polymer chain dynamics. Systems where the probe size is comparable to (or smaller than) a characteristic length of the polymer chain, the tube diameter for example, are of particular interest because the diffusion coefficient of the probe can be orders of magnitude larger than the value predicted by the Stokes-Einstein relation. In the present study, we employ the optical technique known as forced Rayleigh scattering to study the diffusion of a molecular probe (dye) in several entangled polymer melts over a wide range of length and time scales. The probe size is much smaller than the tube diameter for the systems studied. We find the diffusion coefficient is larger by four to five orders of magnitude than the Stokes-Einstein prediction. More interestingly, we observe anomalous, non-Fickian, diffusion where the value of the measured diffusion coefficient can abruptly change by as much as 50%. We suggest that this unexpected behavior occurs when the time scale for diffusion is larger than the relaxation time associated with the constraint release mechanism for polymer chain dynamics.

Quantitative Diffusion and Spectroscopic Neuroimaging Combined with a Novel Early-Developmental Assessment Improves Models for 1-Year Developmental Outcomes.

BACKGROUND AND PURPOSE: Preterm infants are at risk for overt and silent CNS injury, with developmental consequences that are difficult to predict. The novel Specific Test of Early Infant Motor Performance, administered in preterm infants at term age, is indicative of later developmental gross motor and cognitive scores at 12 months. Here, we assessed whether functional performance on this early assessment correlates with CNS integrity via MR spectroscopy or diffusional kurtosis imaging and whether these quantitative neuroimaging methods improve predictions for future 12-month developmental scores. MATERIALS AND METHODS: MR spectroscopy and quantitative diffusion MR imaging data were acquired in preterm infants (n = 16) at term. Testing was performed at term and 3 months using the Specific Test of Early Infant Motor Performance and the Bayley Scales of Infant and Toddler Development, Third Edition, at 12 months. We modeled the relationship of MR spectroscopy and diffusion MR imaging data with both test scores via multiple linear regression. RESULTS: MR spectroscopy NAA ratios at a TE of 270 ms in the frontal WM and basal ganglia and kurtosis metrics in major WM tracts correlated strongly with total Specific Test of Early Infant Motor Performance scores. The addition of MR spectroscopy and diffusion separately improved the functional predictions of 12-month outcomes. CONCLUSIONS: Microstructural integrity of the major WM tracts and metabolism in the basal ganglia and frontal WM strongly correlate with early developmental performance, suggesting that the Specific Test of Early Infant Motor Performance reflects CNS integrity after preterm birth. This study demonstrates that combining quantitative neuroimaging and early functional movement improves the prediction of 12-month outcomes in premature infants.

Visualizing formation of the active site in the mitochondrial ribosome.

Ribosome assembly is an essential and conserved process that is regulated at each step by specific factors. Using cryo-electron microscopy (cryo-EM), we visualize the formation of the conserved peptidyl transferase center (PTC) of the human mitochondrial ribosome. The conserved GTPase GTPBP7 regulates the correct folding of 16S ribosomal RNA (rRNA) helices and ensures 2'-O-methylation of the PTC base U3039. GTPBP7 binds the RNA methyltransferase NSUN4 and MTERF4, which sequester H68-71 of the 16S rRNA and allow biogenesis factors to access the maturing PTC. Mutations that disrupt binding of their Caenorhabditis elegans orthologs to the large subunit potently activate mitochondrial stress and cause viability, development, and sterility defects. Next-generation RNA sequencing reveals widespread gene expression changes in these mutant animals that are indicative of mitochondrial stress response activation. We also answer the long-standing question of why NSUN4, but not its enzymatic activity, is indispensable for mitochondrial protein synthesis.

Comparison of PEAK PlasmaBlade™ to conventional diathermy in abdominal-based free-flap breast reconstruction surgery-A single-centre double-blinded randomised controlled trial.

BACKGROUND: Electrosurgery makes dissection with simultaneous haemostasis possible. The produced heat can cause injury to the surrounding tissue. The PEAK PlasmaBlade™(PPB) is a new electrosurgery device which may overcome this by having the ability to operate on a lower temperature, therefore reducing collateral thermal damage. METHOD: A single-centre, double-blinded, randomised controlled trial (RCT) was conducted which included 108 abdominal-based free-flap breast reconstruction patients who had their flap raise performed using either the PPB (n = 56) or the conventional diathermy (n = 52). Data were collected during their in-patient stay and out-patient appointments. The primary outcome value was the number of days the abdominal drains were required. RESULTS: Baseline characteristics were similar between the groups, except a significantly lower flap weight in the PPB group. The median number of days the drains were required did not differ significantly (p = 0.48; 6.0 days for the diathermy and 5.0 days for the PPB). The total drain output (p = 0.68), the inflammatory cytokine in the drain fluid (p>0.054) and complications (p>0.24) did not differ significantly between the two groups. At the 2-week follow-up appointment, there was a trend towards less abdominal seromas on abdominal ultrasound (p = 0.09) in the PPB group which were significantly smaller (p = 0.04). CONCLUSION: The use of the PPB did not result in a significant reduction of drain requirement, total drain output or inflammatory cytokines but did reduce the size of seroma collections at the 2-week follow-up appointment. Therefore, the use of the PPB device could reduce early seroma formation after drain removal.

Safety of major reconstructive surgery during the peak of the COVID-19 pandemic in the United Kingdom and Ireland - multicentre national cohort study.

BACKGROUND: The safety of surgery during and after the coronavirus disease-2019 (COVID-19) pandemic is paramount. Early reports of excessive perioperative mortality in COVID-positive patients promoted the widespread avoidance of operations. However, cancelling or delaying operations for cancer, trauma, or functional restitution has resulted in increased morbidity and mortality. METHODS: A national multicentre cohort study of all major reconstructive operations carried out over a 12-week period of the 'COVID-19 surge' in the United Kingdom and Ireland was performed. Primary outcome was 30-day mortality and secondary outcome measures were major complications (Clavien-Dindo grade ≥3) and COVID-19 status of patients and healthcare professionals before and after surgery. RESULTS: A total of 418 patients underwent major reconstructive surgery with a mean operating time of 7.5 hours and 12 days' inpatient stay. Cancer (59.8%) and trauma (29.4%) were the most common indications. COVID-19 infection was present in 4.5% of patients. The 30-day post-operative mortality was 0.2%, reflecting the death of one patient who was COVID-negative. Overall complication rate was 20.8%. COVID status did not correlate with major or minor complications. Eight healthcare professionals developed post-operative COVID-19 infection, seven of which occurred within the first three weeks. CONCLUSIONS: Major reconstructive operations performed during the COVID-19 crisis have been mostly urgent cases involving all surgical specialties. This cohort is a surrogate for all major operations across all surgical specialties. Patient safety and surgical outcomes have been the same as in the pre-COVID era. With adequate precautions, major reconstructive surgery is safe for patients and staff. This study helps counsel patients of COVID-19 risks in the perioperative period.

The Olfactory Cleft Endoscopy Scale: a multi-institutional validation study in chronic rhinosinusitis.

BACKGROUND: Olfactory dysfunction (OD) associated with chronic rhinosinusitis (CRS) remains quite challenging. Instruments to precisely assess olfactory cleft anatomy and their association with olfaction are needed. METHODS: The olfactory cleft endoscopy scale (OCES) was used to assess the olfactory cleft in healthy control subjects and a cohort of patients with CRS. Psychophysical and psychosocial olfactory function were assessed and correlations with OCES scores were measured. RESULTS: Control subjects and subjects with CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) were enrol- led. OCES correlated with both psychophysical and psychosocial olfaction, as measured by threshold, discrimination and identi- fication (TDI) scores and Questionnaire on Olfactory Disorders (QOD-NS) scores for all case and control subjects combined. OCES improved in both CRS groups postoperatively with the highest correlation seen in postoperative olfaction in CRSwNP patients. CRS patients who achieve near perfect OCES and sinus endoscopy scores after surgery have olfactory metrics that are indistin- guishable from controls regardless of polyp status. CONCLUSIONS: The OCES is a valid olfactory-specific measure that demonstrates strong validity and provides complimentary infor- mation to traditional sinus endoscopy to aid in our understanding of OD associated with CRS.

St Andrew's COVID-19 surgery safety (StACS) study: Elective plastic surgery, trauma & burns.

INTRODUCTION: This study evaluates COVID-19 related patient risk, when undergoing management within one of the largest specialist centres in Europe, which rapidly implemented national COVID-19 safety guidelines. METHOD: A prospective cohort study was undertaken in all patients who underwent surgical (n = 1429) or non-operative (n = 191) management during the UK COVID-19 pandemic peak (April-May 2020); all were evaluated for 30-day COVID-19 related death. A representative sample of elective/trauma/burns patients (surgery group, n = 729) were selected and also sub-analysed within a controlled cohort study design. Comparison was made to a random selection of non-operatively managed (non-operative group, n = 100) or waiting list (control group, n = 250) patients. These groups were prospectively followed-up and telephoned from the end of June (control group) or at 30 days post-first assessment (non-operative group)/post-operatively (surgery group). RESULTS: Complex general (9.2%, 136/1483) or regional (5.0%, 74/1483) anaesthesia cases represented 14.2% (210/1483) of operations undertaken. There were no 30-day post-operative (0/1429)/first assessment (0/191) COVID-19 related deaths. Neither the three sub-speciality plastic surgery, or non-operative groups, displayed increases in post-operative/first assessment symptoms in comparison to each other, or to control. The proportion of COVID-19 positive tests were: 7.1% (1/14) (non-operative), 5.9% (2/34) (burns) and 3.0% (3/99) (trauma); there were however no significant differences between these groups, the elective (0%, 0/54) and control (0%, 0/24) groups (p = 0.236). CONCLUSION: We demonstrate that even heterogeneous sub-speciality patient groups, who required operative/non-operative management, did not incur an increased COVID-19 risk compared to each other or to control. These highly encouraging results were achieved with described, rapidly implemented service changes that were tailored to protect each patient group and staff.