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Success in septorhinoplasty surgery can be difficult to assess due to a lack of objective and measurable outcomes. If patients' expectations are not met, it places surgeons performing septorhinoplasty at risk of litigation which can be stressful and costly. The National Institute of health (NHS) Resolution is a government-funded organization in the United Kingdom that provides expertise to the NHS on resolving patient concerns. Data were requested from NHS Resolution for claims involving septorhinoplasty surgery over a period of 5 years between April 2015 and April 2020. Rhinoplasty claims performed by all specialties were included. Data included the claim status, incident details, alleged injury, damages claimed, and damages paid. A total of 31 claims were identified by the study, equating to a total cost of £1,347,336.10. Of the 31 claims for rhinoplasty or septorhinoplasty, 9 cases were open (29%, £962,361.00) and 22 cases were closed (71%, £384,975.10). The common causes for claims were “intraoperative problems (32%),” “failure to warn–informed consent (19%),” and “foreign body left in situ (13%).” The most common injuries were “cosmetic disfigurement (39%),” “unnecessary pain (29%),” and “additional/ unnecessary operation (29%).” This study highlights the need for improved awareness of clinical negligence claims among surgeons who perform septorhinoplasty. Results are applicable to all specialties who perform the procedure. The study highlights the importance of assessing patients' motives and expectations prior to surgery and emphasizes the need for a well-documented rigorous consent process.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, highlighting the unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDO) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBC). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven, basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, this study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and tailored treatment options.Significance:A comprehensive analysis of patient-derived organoids of TNBC provides insights into cellular heterogeneity and mechanisms of tumorigenesis at the single-cell level.

Supplementary Data from Patient-Derived Triple-Negative Breast Cancer Organoids Provide Robust Model Systems That Recapitulate Tumor Intrinsic Characteristics

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, highlighting the unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDO) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBC). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven, basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, this study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and tailored treatment options. Significance: A comprehensive analysis of patient-derived organoids of TNBC provides insights into cellular heterogeneity and mechanisms of tumorigenesis at the single-cell level.

ObjectiveThis study reviewed all rhinology clinical negligence claims in the National Health Service in England between 2013 and 2018.MethodAll clinical negligence claims held by National Health Service Resolution relating to rhinology in England between 1 April 2013 and 1 April 2018 were reviewed.ResultsThere 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.ConclusionPatient 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.

Background: European health-care systems are faced with a backlog of surgical procedures following the suspension of routine surgery during the COVID-19 crisis. Routine rhinology surgery under general anaesthetic (GA) is now faced with significant challenges which include limited theatre capacity, the negative ramifications of surgical prioritization, reduced patient throughput in secondary care, and additional personal protective equipment requirements. Delayed surgery in rhinology, particularly with regards to chronic rhinosinusitis, has previously been shown to have poorer surgical outcomes, a detrimental effect on quality of life and long-term negative health socio-economic effects. Awake rhinology surgery under local anaesthetic (LA) provides an ideal alternative to GA. It provides a means of operating on patients in a setting alternative to currently oversubscribed main theatres, by utilizing satellite facilities, while ensuring identical surgical outcomes for patients who may otherwise have been forced to wait a long time for their procedure. It also confers additional benefits in terms of shorter recovery time and hospital stay for patients. Objectives: We have developed a set of recommendations that are intended to help support clinicians and managers to better adopt LA rhinology protocols and minimize the risk to the patient and health-care professionals involved. Methodology: International roundtable forums were conducted and supplemented by individual interviews. The international board consisted of 12 rhinologists experienced in awake rhinology surgery. Feedback was analysed and shared to develop a consensus of best practice. Recommendations: Local and national guidelines need to be adhered to with specific focus on patient and clinician safety. When performing awake rhinology procedures in the COVID-19 recovery process, consider implementing specific safety measures and workflow practices to safeguard patients and staff and minimize the risk of infection. Conclusion: Awake surgery potentially provides quicker access to routine rhinology surgery in the post-COVID-19 recovery phase, ensuring patients are treated in a timely matter, thereby avoiding higher downstream costs, and improving outcomes.

Olfactory dysfunction (OD) is more common than hearing loss, partial blindness, or blindness and can have a significant impact on the quality of life. Moreover, unexplained OD is an early biomarker in neurodegenerative diseases and increases 5-year mortality risk. Structural alterations in olfactory eloquent brain regions may represent the neuroanatomical correlates of OD. Previous studies have demonstrated reduced gray matter (GM) volume in areas of presumed olfactory relevance in patients with OD. However, being cross-sectional in nature, these studies do not provide evidence of causality, for which longitudinal work is required. At present, however, longitudinal studies addressing olfactory structural plasticity are limited, both in number and methodological approach: to our knowledge, such work has not included parallel functional imaging to confirm the relevance of structural change. We therefore performed a longitudinal multimodal neuroimaging study investigating structural and functional plasticity in 24 patients undergoing surgical treatment for chronic rhinosinusitis, compared with 17 healthy controls. We demonstrated functionally significant structural plasticity within the orbitofrontal, anterior cingulate and insular cortices, and temporal poles in patients 3 months after surgery. Of interest, GM volume decreased in these regions, in association with increased psychophysical scores and BOLD signal. To our knowledge, this is the first study to demonstrate both structural and functional plasticity of the central olfactory networks, thereby confirming these areas as neuroanatomical correlates of olfactory function/dysfunction.

Short-read sequencers provide highly accurate reads at very low cost. Unfortunately, short reads are often inadequate for important applications such as assembly in complex regions or phasing across distant heterozygous sites. In this study, we describe novel bench protocols and algorithms to obtain haplotype-phased sequence assemblies with ultra-low error for regions 10 kb and longer using short reads only. We accomplish this by imprinting each template strand from a target region with a dense and unique mutation pattern. The mutation process randomly and independently converts ∼50% of cytosines to uracils. Sequencing libraries are made from both mutated and unmutated templates. Using de Bruijn graphs and paired-end read information, we assemble each mutated template and use the unmutated library to correct the mutated bases. Templates are partitioned into two or more haplotypes, and the final haplotypes are assembled and corrected for residual template mutations and PCR errors. With sufficient template coverage, the final assemblies have per-base error rates below 10–9. We demonstrate this method on a four-member nuclear family, correctly assembling and phasing three genomic intervals, including the highly polymorphic HLA-B gene.

Ever since the introduction of the concept of Procedures of Limited Clinical Value (PoLCV), procedures such as functional septorhinoplasty have been subject to additional funding restrictions within the British National Health Service. Recent publications have suggested that 10% of Clinical Commissioning Groups in the United Kingdom no longer fund septorhinoplasty surgery irrespective of the indications, including congenital malformations or post-trauma, and despite the strong evidence available in the literature in treating a range of health conditions. Thus, inequity exists across the country. At present functional septorhinoplasty surgery is frequently but incorrectly grouped together with aesthetic rhinoplasty, both of which are deemed to be cosmetic interventions. Moreover, as we exit the peak of the current coronavirus disease 2019 (COVID-19) pandemic, procedures deemed to be of lower clinical priority will potentially be at risk throughout Europe. The purpose of this review is twofold; the first is to put forward the evidence to commissioners in favor of functional septorhinoplasty surgery on patient well-being and mental health; the second is to demonstrate why functional septorhinoplasty surgery is a distinct procedure from aesthetic rhinoplasty and why it ought not to be classified as a procedure of limited clinical value.

Olfactory dysfunction (OD) has been described in patients with antineutrophil cytoplasmic antibody-associated vasculitides (AAV), but the underlying mechanisms are not completely understood. The causes of altered smell function can generally be divided into conductive, sensorineural or others. To date no specific treatment is available for AAV-related OD and the efficacy of currently available options has not been explored. The aim of this review is to provide an overview of the causes that may lead to OD in patients with AAV. Current available treatments for OD and possible options in patients with AAV presenting with smell impairment are also mentioned.

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.

Chromosomal microarray testing is indicated for patients with diagnoses including unexplained developmental delay or intellectual disability, autism spectrum disorders, and multiple congenital anomalies. The short multiply aggregated sequence homologies (SMASH) genomic assay is a novel next-generation sequencing technology that performs copy number analysis at resolution similar to high-coverage whole genome sequencing but requires far less capacity. We benchmarked the performance of SMASH on a panel of genomic DNAs containing known copy number variants (CNVs). SMASH was able to detect pathogenic copy number variants of ≥10 kb in 77 of 77 samples. No pathogenic events were seen in 32 of 32 controls, indicating 100% sensitivity and specificity for detecting pathogenic CNVs >10 kb. Repeatability (interassay precision) and reproducibility (intra-assay precision) were assessed with 13 samples and showed perfect concordance. We also established that SMASH had a limit of detection of 20% for detection of large mosaic CNVs. Finally, we analyzed seven blinded specimens by SMASH analysis and successfully identified all pathogenic events. These results establish the efficacy of the SMASH genomic assay as a clinical test for the detection of pathogenic copy number variants at a resolution comparable to chromosomal microarray analysis.

Sixty years ago, the geneticist James Neel proposed that the epidemics of obesity and diabetes today may have evolutionary roots. Specifically, he suggested that our ancestors may have accumulated mutations during periods of famine that provided a survival advantage at that time. However, the presence of this "thrifty genotype" in today's world, where food is plentiful, would predispose us to obesity and diabetes. The "thrifty gene" hypothesis, attractive to some, has been challenged over the years. The authors have previously postulated that the loss of the uricase gene, resulting in a rise in serum and intracellular uric acid levels, satisfies the criteria of a thrifty genotype mutation. This paper reviews and brings up-to-date the evidence supporting the hypothesis and discusses the current arguments that challenge this hypothesis. Although further studies are needed to test the hypothesis, the evidence supporting a loss of uricase as a thrifty gene is substantial and supports a role for evolutionary biology in the pathogenesis of the current obesity and diabetes epidemics.

Purpose Aspirin treatment after desensitization (ATAD) represents an effective therapeutic option suitable for NSAID-exacerbated respiratory disease (N-ERD) patients with recalcitrant disease. Intranasal administration of lysine-aspirin (LAS) has been suggested as a safer and faster route than oral ATAD but evidence for its use is less strong. We investigated nasal LAS therapy long-term efficacy based on objective outcomes, smell function, polyp recurrence and need for surgery or rescue therapy. Clinical biomarkers predicting response to intranasal LAS, long-term side effects and consequences of discontinuing treatment have been evaluated. Methods A retrospective analysis of a database of 60 N-ERD patients seen between 2012 and 2020 was performed in March 2021. They were followed up at 3-months, 1-, 2- and 3-years with upper and lower airway functions assessed at each follow-up. Results Higher nasal airflow and smell scores were found at each follow-up in patients taking LAS (p p = 0.048 respectively). No influence of LAS on pulmonary function measurements was observed. Patient on intranasal LAS showed a lower rate of revision sinus surgery when compared to those who discontinued the treatment (p Conclusion Our study demonstrates the clinical effectiveness of long-term intranasal LAS in the management of N-ERD in terms of improved nasal airflow and olfaction and a reduced need for revision sinus surgery. Intranasal LAS is safe, being associated with a lower rate of side effects when compared to oral ATAD. However, discontinuation of the treatment at any stage is associated with a loss of clinical benefit.

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.

Wonderwerk Cave, in South Africa, is an exceptional site that has yielded a large collection of small mammal fossils in a stratigraphic sequence reaching back ca. 2 million years. Taphonomic studies undertaken to date, show that Tytonidae (likely Tyto alba) was the dominant predator during the Earlier Stone Age. They produced masses of pellets that formed a dense carpet-like surface that covered the cave floor at intervals throughout the sequence. This paper compares the taphonomic signatures of five different Earlier Stone Age small mammal assemblages from Wonderwerk Cave, including assemblages not studied before, as well as a modern pellet assemblage collected from inside the cave. These samples were examined using taphonomic signatures, bone density and spatial distribution which confirm that the main predator in all periods of cave occupation were members of the Family Tytonidae, most likely Barn owls. The Wonderwerk small mammals have enabled us to clarify site formation processes and confirm that there was no transport or mixing of fossils, neither spatially (re-sedimentation) nor chronologically (reworking). This has confirmed the integrity of the stratigraphic sequence in the cave, reinforcing interpretations of palaeoecology, and elucidating intensity of occupation by hominins versus predators, and the behaviour of the predators vis a vis their prey., This research was supported by a Leakey Foundation grant to YFJ.

Background Recent studies suggest that fructose, as well as its metabolite, uric acid, have been associated with increased risk for both cancer incidence and growth. Both substances are known to cause oxidative stress to mitochondria and to reduce adenosine triphosphate (ATP) production by blocking aconitase in the Krebs cycle. The uricase mutation that occurred in the Miocene has been reported to increase serum uric acid and to amplify the effects of fructose to stimulate fat accumulation. Here we tested whether the uricase mutation can also stimulate tumor growth. Methods Experiments were performed in mice in which uricase was inactivated by either knocking out the gene or by inhibiting uricase with oxonic acid. We also studied mice transgenic for uricase. These mice were injected with breast cancer cells and followed for 4 weeks. Results The inhibition or knockout of uricase was associated with a remarkable increase in tumor growth and metastases. In contrast, transgenic uricase mice showed reduced tumor growth. Conclusion A loss of uricase increases the risk for tumor growth. Prior studies have shown that the loss of the mutation facilitated the ability of fructose to increase fat which provided a survival advantage for our ancestors that came close to extinction from starvation in the mid Miocene. Today, however, excessive fructose intake is rampant and increasing our risk not only for obesity and metabolic syndrome, but also cancer. Obesity-associated cancer may be due, in part, to a mutation 15 million years ago that acted as a thrifty gene.

Autism arises in high and low-risk families. De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the simplex families than in their unaffected siblings. But the extent of contribution in low-risk families cannot be determined solely from simplex families as they are a mixture of low and high-risk. The rate of de novo mutation in nearly pure populations of high-risk families, the multiplex families, has not previously been rigorously determined. Moreover, rates of de novo mutation have been underestimated from studies based on low resolution microarrays and whole exome sequencing. Here we report on findings from whole genome sequence (WGS) of both simplex families from the Simons Simplex Collection (SSC) and multiplex families from the Autism Genetic Resource Exchange (AGRE). After removing the multiplex samples with excessive cell-line genetic drift, we find that the contribution of de novo mutation in multiplex is significantly smaller than the contribution in simplex. We use WGS to provide high resolution CNV profiles and to analyze more than coding regions, and revise upward the rate in simplex autism due to an excess of de novo events targeting introns. Based on this study, we now estimate that de novo events contribute to 52–67% of cases of autism arising from low risk families, and 30–39% of cases of all autism., Yoon, Munoz, et al. investigate the rate of de novo coding and non-coding variants in families with high- and low-risk for autism using whole-genome sequence data from collections of families with autism. They demonstrate that de novo intronic variants increase the risk of autism, that the contribution of de novo variants is significantly larger in low-risk families, and that de novo variants contribute to 30-39% of cases of all autism.

Tandem repeats of simple sequence motifs, also known as microsatellites, are abundant in the genome. Because their repeat structure makes replication error-prone, variant microsatellite lengths are often generated during germline and other somatic expansions. As such, microsatellite length variations can serve as markers for cancer. However, accurate error-free measurement of microsatellite lengths is difficult with current methods precisely because of this high error rate during amplification. We have solved this problem by using partial mutagenesis to disrupt enough of the repeat structure of initial templates so that their sequence lengths replicate faithfully. In this work, we use bisulfite mutagenesis to convert a C to a U, later read as T. Compared to untreated templates, we achieve three orders of magnitude reduction in the error rate per round of replication. By requiring agreement from two independent first copies of an initial template, we reach error rates below one in a million. We apply this method to a thousand microsatellite loci from the human genome, revealing microsatellite length distributions not observable without mutagenesis.

In this narrative review, we present the hypothesis that key mutations in two genes, occurring 15 and 10 million years ago, were individually and then collectively adaptive for ancestral humans during periods of starvation, but are maladaptive in modern civilization (i.e., “thrifty genes”), with the consequence that these genes not only increase our risk today for obesity, but also for alcoholism. Both mutations occurred when ancestral apes were experiencing loss of fruit availability during periods of profound climate change or environmental upheaval. The silencing of uricase (urate oxidase) activity 15 million years ago enhanced survival by increasing the ability for fructose present in dwindling fruit to be stored as fat, which was a consequence of enhanced uric acid production during fructose metabolism that stimulated lipogenesis and blocked fatty acid oxidation. Likewise, a mutation in class IV alcohol dehydrogenase (ADH4) ~10 million years ago resulted in a remarkable 40-fold increase in the capacity to oxidize ethanol, which allowed our ancestors to ingest fallen, fermenting fruit. In turn, the ethanol ingested could activate aldose reductase that stimulates the conversion of glucose to fructose, while uric acid produced during ethanol metabolism could further enhance fructose production and metabolism. By aiding survival, these mutations would have allowed our ancestors to generate more fat, primarily from fructose, to survive changing habitats due to the Middle Miocene disruption and also during the late-Miocene aridification of East Africa. Unfortunately, the enhanced ability to metabolize and utilize ethanol may now be acting to increase our risk for alcoholism, which may be yet another consequence of once-adaptive thrifty genes.

Wireless and precise stimulation of deep brain structures could have important applications to study intact brain circuits and treat neurological disorders. Herein, we report that magnetoelectric nanoparticles (MENs) can be guided to a targeted brain region to stimulate brain activity with a magnetic field. We demonstrated the nanoparticles’ capability to reliably evoke fast neuronal responses in cortical slices ex vivo. After fluorescently labeled MENs were intravenously injected and delivered to a targeted brain region by applying a magnetic field gradient, a magnetic field of low intensity (350–450 Oe) applied to the mouse head reliably evoked cortical activities, as revealed by two-photon and mesoscopic imaging of calcium signals and by an increased number of c-Fos expressing cells after stimulation. Neither brain delivery of MENs nor the magnetic stimulation caused significant increases in astrocytes and microglia. Thus, MENs could enable a non-invasive and contactless deep brain stimulation without the need of genetic manipulation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01071-0.

The aim of this national survey is to assess the current practice of functional septorhinoplasty (SRP) surgery in the UK and better inform future practice. An ENT-UK approved questionnaire was sent out to all 135 consultant members of the British Society of Facial Plastic Surgery (BSFPS). Data was collected on numbers of functional SRPs performed on the NHS, use of outcome measures, psychology and photography support, antibiotic use, referral base and consenting practice. The response rate was 38.5%, with 52 out of 135 completed. The median number of annual SRP cases per surgeon was 40. Most surgeons (95%) used clinical photography as an outcome measure. However, 27% of the respondents use a subjective outcome measurement and 3% of them use an objective outcome measurement. Only 34% had access to psychology support and 60% receive their referrals from primary care. All surgeons counsel patients for aesthetic change, 15% mention CSF leak and 38% mention olfactory disturbance. The key comment from our respondents was to relabel the rhinoplasty procedure as a functional SRP procedure with the aim to remove it from the Procedures of Limited Clinical Value (PoLCV) list. The majority of our respondents perform a large proportion of the SRP surgeries in the UK with each of the respondents performing an average of 40 SRP surgeries per year. There is a need to recatergorise functional septorhinoplasty as a functional operation and recommend functional SRP surgery to be removed from the PoLCV list.