James Paget University Hospitals NHS Foundation Trust

EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. no immunosuppressants IV D no nasal saline irrigation Ib, no data in single use D yes for symptomatic relief topical antibiotics no data D no anti-IL-5 no data D unclear phytotherapy no data D no decongestant topical / oral no data in single use D no mucolytics no data D no oral antihistamine in allergic patients no data D no antimycotics -topical Ia (-) ** A(-) no antimycotics -systemic Ib (-)# A(-) $ no anti leukotrienes Ib (-) A(-) no anti-IgE Ib (-) A(-) no * Some of these studies also included patients with CRS with nasal polyps. % short term antibiotics shows one positive and one negative study. Therefore recommendation C. oral antibiotic short term <4 weeks Ib(-) # A(-)* no intravenous antibiotics III(-) ## C(-) ** no # Ib (-): Ib study with a negative outcome.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

OBJECTIVES: To examine whether rate of reoperation after breast conserving surgery is associated with patients' characteristics and investigate whether reoperation rates vary among English NHS trusts. DESIGN: Cohort study using patient level data from hospital episode statistics. SETTING: English NHS trusts. PARTICIPANTS: Adult women who had breast conserving surgery between 1 April 2005 and 31 March 2008. MAIN OUTCOME MEASURE: Reoperation rates after primary breast conserving surgery within 3 months, adjusted using logistic regression for tumour type, age, comorbidity, and socioeconomic deprivation. Tumours were grouped by whether a carcinoma in situ component was coded at the time of the primary breast conserving surgery. RESULTS: 55,297 women had primary breast conserving surgery in 156 NHS trusts during the three year period. 11,032 (20.0%, 95% confidence interval 19.6% to 20.3%) women had at least one reoperation. 10,212 (18.5%, 18.2% to 18.8%) had one reoperation only; of these, 5943 (10.7%, 10.5% to 11.0%) had another breast conserving procedure and 4269 (7.7%, 7.5% to 7.9%) had a mastectomy. Of the 45,793 women with isolated invasive disease, 8229 (18.0%) had at least one reoperation. In comparison, 2803 (29.5%) of the 9504 women with carcinoma in situ had at least one reoperation (adjusted odds ratio 1.9, 95% confidence interval 1.8 to 2.0). Substantial differences were found in the adjusted reoperation rates among the NHS trusts (10th and 90th centiles 12.2% and 30.2%). CONCLUSION: One in five women who had breast conserving surgery in England had a reoperation. Reoperation was nearly twice as likely when the tumour had a carcinoma in situ component coded. Women should be informed of this reoperation risk when deciding on the type of surgical treatment of their breast cancer.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.

BACKGROUND: The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all-cause 30-day readmissions and complications in a prospective population-based cohort. METHODS: Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all-cause 30-day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two-level hierarchical structure with patients (level 1) nested within hospitals (level 2). RESULTS: Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. CONCLUSION: Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics.

INTRODUCTION: In this article we look at the aetiology of plantar fasciitis, the other common differentials for heel pain and the evidence available to support each of the major management options. We also review the literature and discuss the condition. METHODS: A literature search was performed using PubMed and MEDLINE(®). The following keywords were used, singly or in combination: 'plantar fasciitis', 'plantar heel pain', 'heel spur'. To maximise the search, backward chaining of reference lists from retrieved papers was also undertaken. FINDINGS: Plantar fasciitis is a common and often disabling condition. Because the natural history of plantar fasciitis is not understood, it is difficult to distinguish between those patients who recover spontaneously and those who respond to formal treatment. Surgical release of the plantar fascia is effective in the small proportion of patients who do not respond to conservative measures. New techniques such as endoscopic plantar release and extracorporeal shockwave therapy may have a role but the limited availability of equipment and skills means that most patients will continue to be treated by more traditional techniques.

Introduction Magseed is an alternative method of localising non-palpable breast lesions that has addressed many of the limitations of wire guided localisation (WGL). It consists of a paramagnetic seed that can be visualised on mammography and ultrasound. Intraoperative localisation of the seed is achieved with the use of the Sentimag probe. The aim of this study was to prospectively compare localisation in patients undergoing wide local excision (WLE) for non-palpable lesions between Magseed and WGL. Methods We prospectively collected data on all patients undergoing image-guided WLE between October 2017 and September 2018 in two academic breast units with a planned accrual of 100 consecutive patients undergoing Magseed localisation. Data was also collected on a cohort of 100 consecutive patients undergoing WGL in the same time period. Results Demographic and disease characteristics were well balanced between the two groups. 4/104 patients were converted preoperatively from Magseed to WGL (2 misplaced Magseeds; 2 undetected Magseeds). Intraoperative identification and excision of the localised lesion was successful in all patients as confirmed with specimen radiography. Overall no significant differences were observed in the proportion of patients requiring re-excision between the two groups (Magseed 16% vs. WGL 14% p = 0.692). Specimens size by weight and volume was similar for both groups (Magseed 39.6 g vs. WGL 44.5 g p = 0.206 and 90.1 cm 3 for Magseed vs. 95.6 cm 3 for WGL p = 0.579). Conclusions In our series Magseed localisation proved to be as reliable and effective as WGL in terms of lesion identification, excision with tumour free margins and specimen weight.

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

BACKGROUND: Common sinonasal disorders include chronic rhinosinusitis (CRS), allergic rhinitis (AR), and a deviated nasal septum (DNS), which often coexist with shared common symptoms including nasal obstruction, olfactory dysfunction, and rhinorrhea. Various objective outcome measures and patient-reported outcome measures (PROMs) are used to assess disease severity; however, there is limited evidence in the literature on the correlation between them. This systematic review aims to examine the relationship between them and provide recommendations. METHODS: A search of MEDLINE and EMBASE identified studies quantifying correlations between objective outcome measures and PROMs for the sinonasal conditions using a narrative synthesis. RESULTS: In total, 59 studies met inclusion criteria. For nasal obstruction, rhinomanometry shows a lack of correlation whereas peak nasal inspiratory flow (PNIF) shows the strongest correlation with PROMs (r > 0.5). The Sniffin' Stick test shows a stronger correlation with PROMs (r > 0.5) than the University of Pennsylvania Smell Identification Test (UPSIT) (r < 0.5). Computed tomography (CT) sinus scores show little evidence of correlation with PROMs and nasal endoscopic ratings (weak correlation, r < 0.5). CONCLUSION: Overall, objective outcome measures and PROMs assessing sinonasal symptoms are poorly correlated, and we recommend that objective outcome measures be used with validated PROMs depending on the setting. PNIF should be used in routine clinical practice for nasal obstruction; rhinomanometry and acoustic rhinometry may be useful in research. The Sniffin' Sticks test is recommended for olfactory dysfunction with UPSIT as an alternative. CT scores should be excluded as a routine CRS outcome measure, and endoscopic scores should be used in combination with PROMs until further research is conducted.

OBJECTIVE: The 'Sniffin' Sticks' olfactory test contains pen-like odour dispensing devices which are used to assess olfactory threshold, discrimination and identification. Odour identification is strongly dependent on familiarity with the odours and has an important cultural component which has limited the usefulness of other validated tests. The 'Sniffin' Sticks' test was developed in Germany and is validated in other countries but not in the UK. This study aims to validate the applicability of 'Sniffin' Sticks' in a local population. DESIGN: Prospective controlled study. SETTING: Rhinology or olfactory disorder clinic. PARTICIPANTS: About 82 subjects, 33 healthy volunteers with a reported normal sense of smell, and 49 patients with an impaired sense of smell presenting either at a rhinology or an olfactory disorder clinic. Each subject's olfactory function was assessed using the 'Sniffin' Sticks' test with a maximum score of 48. MAIN OUTCOME MEASURES: Threshold, discrimination and identification scores along with the combined olfactory score. RESULTS: The mean age of the subjects tested was 46.7 years; 46 female and 36 male. In the patient group 36 were hyposmic and 13 anosmic. In the healthy volunteers group all subjects were normosmic. In the control group the mean combined olfactory score was 34.5 (±2.5). The mean combined score in the patients group was 20.8 (±7.4). Odour threshold scores were 3.7(±2.8) for patients (hyposmics and anomics) and 8.3(±1.8) for controls. In the identification test the controls mean score was 13.6 (±1.2) for while the patients' mean score was 8.6 (±3.5). CONCLUSIONS: In our sample of the local population the combined olfactory and odour identification scores for healthy volunteers and patients with olfactory disorders are comparable with the normative data published on large samples of European populations. However, modification of a few of the distracters is recommended for British patients based on our findings.

OBJECTIVE: To assess perinatal outcomes for pregnancies affected by suspected or confirmed SARS-CoV-2 infection. METHODS: Prospective, web-based registry. Pregnant women were invited to participate if they had suspected or confirmed SARS-CoV-2 infection between 1st January 2020 and 31st March 2021 to assess the impact of infection on maternal and perinatal outcomes including miscarriage, stillbirth, fetal growth restriction, pre-term birth and transmission to the infant. RESULTS: Between April 2020 and March 2021, the study recruited 8239 participants who had suspected or confirmed SARs-CoV-2 infection episodes in pregnancy between January 2020 and March 2021. Maternal death affected 14/8197 (0.2%) participants, 176/8187 (2.2%) of participants required ventilatory support. Pre-eclampsia affected 389/8189 (4.8%) participants, eclampsia was reported in 40/ 8024 (0.5%) of all participants. Stillbirth affected 35/8187 (0.4 %) participants. In participants delivering within 2 weeks of delivery 21/2686 (0.8 %) were affected by stillbirth compared with 8/4596 (0.2 %) delivering ≥ 2 weeks after infection (95 % CI 0.3-1.0). SGA affected 744/7696 (9.3 %) of livebirths, FGR affected 360/8175 (4.4 %) of all pregnancies. Pre-term birth occurred in 922/8066 (11.5%), the majority of these were indicated pre-term births, 220/7987 (2.8%) participants experienced spontaneous pre-term births. Early neonatal deaths affected 11/8050 livebirths. Of all neonates, 80/7993 (1.0%) tested positive for SARS-CoV-2. CONCLUSIONS: Infection was associated with indicated pre-term birth, most commonly for fetal compromise. The overall proportions of women affected by SGA and FGR were not higher than expected, however there was the proportion affected by stillbirth in participants delivering within 2 weeks of infection was significantly higher than those delivering ≥ 2 weeks after infection. We suggest that clinicians' threshold for delivery should be low if there are concerns with fetal movements or fetal heart rate monitoring in the time around infection. The proportion affected by pre-eclampsia amongst participants was not higher than would be expected, although we report a higher than expected proportion affected by eclampsia. There appears to be no effect on birthweight or congenital malformations in women affected by SARS-CoV-2 infection in pregnancy and neonatal infection is uncommon. This study reflects a population with a range of infection severity for SARS-COV-2 in pregnancy, generalisable to whole obstetric populations.

BACKGROUND: This study is part of the Chronic Rhinosinusitis Epidemiology Study (CRES). The overarching aim is to determine factors that influence the onset and severity of chronic rhinosinusitis (CRS). The aim of this analysis is to determine whether those with CRS are more likely to report psychiatric morbidity and in particular mood disturbance compared with healthy controls. METHODS: CRES consists of a study-specific questionnaire regarding demographic and socioeconomic factors and past medical history as well as a nasal symptom score (SNOT-22) and SF-36 (QoL - quality of life tool). Both of these tools contain mental health or emotional well-being domains. Participants were specifically asked whether they had ever consulted with their General Practitioner for anxiety or depression. Questionnaires were distributed to patients with CRS attending ENT outpatient clinics at 30 centres across the United Kingdom from 2007-2013. Controls were also recruited at these sites. Patients were divided into subgroups of CRS according to the absence/presence of polyps (CRSsNPs/CRSwNPs) or allergic fungal rhinosinusitis (AFRS). RESULTS: Consultations with a family physician for depression or anxiety were higher amongst those with CRS than controls, but this was only significant for those with CRSsNPs. Odds ratio (OR) for CRSsNPs vs controls: 1.89; OR for CRSwNPs: 1.40. Patients with CRS showed significantly higher mental health morbidity than controls across the mental health and emotional wellbeing domains of the SF-36 and SNOT-22. Mean difference in the mental health domain of SF-36 was 8.3 for CRSsNPs and 5.3 for CRSwNPs. For the emotional domain of SNOT-22, differences were 7.7 and 6.3 respectively. CONCLUSIONS: Depression and anxiety are significantly more common in patients with CRS compared to healthy controls, especially in those with CRSsNPs. This added mental health morbidity needs consideration when managing these patients in primary and secondary care settings.

Sir, Acne keloidalis or folliculitis keloidalis is a chronic inflammatory, scarring dermatosis due to folliculitis and perifolliculitis of the hairs of the occipital scalp and nape of the neck, which is seen most commonly in young black males1 and is uncommon in caucasians. We report three caucasian males, treated with cyclosporin following organ transplantation, with acne keloidalis of the occipital scalp and nuchal neck. The first patient was a 46‐year‐old caucasian man with hypertensive chronic renal failure which necessitated cadaveric renal transplantation. He was treated with cyclosporin 500 mg daily, azathioprine 100 mg daily, prednisolone 20 mg daily, metoprolol, aspirin and nifedipine. Three years following transplantation, he was referred with an 18‐month history of pruritic papules affecting the posterior scalp. There was no preceding history of skin problems. On examination, he had multiple pink papules and nodules affecting the back of the neck and lower occipital scalp (Fig. 1). Skin biopsy showed a large intradermal and perifollicular abscess; there was neutrophilic inflammation of the hair shaft and perifollicular area with evidence of scar tissue formation. Skin swabs grew Staphylococcus aureus and mycological culture was negative. Treatment with flucloxacillin 500 mg twice daily for a month did not help him. His immunosuppressive treatment is under review by the nephrologists. Acne keloidalis affecting the nape of the neck and occipital scalp. The second patient, a 43‐year‐old caucasian man, had nephrotic syndrome and membranous glomerulonephritis which required cadaveric renal transplantation. He was treated with cyclosporin 400 mg daily, labetalol, nifedipine and frusemide and soon developed discrete papules on the back of the neck. Four years later, he was referred to a dermatologist with a diagnosis of molluscum contagiosum.2 Skin biopsy was suggestive of acne keloidalis and treatment was started with topical clindamycin 1% lotion followed by intralesional triamcinolone acetonide 15 mg. Response to treatment was not followed up as his general health later deteriorated and he died. The third patient was a 30‐year‐old caucasian man referred with an itchy, papular eruption on the nape of his neck and posterior scalp. He had undergone heart transplantation 3 years earlier and was treated with cyclosporin 425 mg daily, prednisolone 2·5 mg daily, azathioprine 50 mg daily, atorvastatin and amiloride. The eruption on the nape of his neck developed a few weeks after transplantation, and increased in size despite treatment with topical corticosteroids and systemic antibiotics. Examination showed multiple discrete flesh‐coloured follicular papules and one large area of hypertrophic tissue covered the whole of the posterior scalp. Skin biopsy showed infiltration with leucocytes, plasma cells, lymphocytes and histiocytes infiltrating around hair follicles and hair shafts with dermal fibrosis; the hypertrophic area showed no evidence of viral wart infection. Treatment with flucloxacillin for S. aureus infection and a trial of CO2 laser evaporation was unsuccessful. He was then referred to the department of plastic surgery to have the hypertrophic element excised. Skin diseases are a significant cause of morbidity in chronically immunosuppressed patients,3,4 who are prone to folliculitis and bacterial skin infections. Acne keloidalis most commonly occurs in young, black males and in one series of 38 affected males, S. aureus infection was the most common bacteria cultured from the lesions.5 It is of note that S. aureus was grown from 2/3 of our patients. The aetiology of acne keloidalis is likely to be multifactorial; the increased curvature of scalp hairs can be causative in pseudofolliculitis and keloid scarring.6 Others state that acne keloidalis may be a variant of lichen simplex chronicus.7 Cyclosporin has been implicated in a hyperplastic response to pseudofolliculitis barbae in a renal transplant recipient and this reaction was thought analagous to the relationship between gingivial hyperplasia and gingivitis that can occur due to cyclosporin.8 Acne keloidalis‐like lesions have also been described affecting the scalp in an epileptic patient on diphenylhydantoin and carbamazepine – the lesions only resolving on cessation of this drug combination.9 Both cyclosporin and diphenylhydantoin can cause hypertrichosis and this might suggest that increased hair growth was relevant to the aetiology of the acne keloidalis in these cases. Treatment of acne keloidalis is difficult but should firstly involve clearance of any bacterial infection with topical antiseptics and oral antibiotics; a number of other therapeutic options are available including topical or intralesional steroids and cryosurgery.10 Deep surgical excision of acne keloidalis with second intention healing has been reported11 and carbon dioxide laser excision treatment is an alternative therapeutic option.12 In summary, we have described three organ transplant patients showing similar clinical and histopathological features of acne keloidalis, whilst on cyclosporin. The aetiology in these cases is likely to be multifactorial, with bacterial infection, immunosuppression, cyclosporin‐induced hypertrichosis and pseudofolliculitis affecting the nape of the neck being the main factors. In many cases, acne keloidalis proves difficult to treat but particularly in organ‐transplant patients on cyclosporin, as this treatment cannot necessarily be altered.

OBJECTIVES: To explore patient views and perspectives of current management of chronic rhinosinusitis (CRS) in primary and secondary care. DESIGN: Semistructured qualitative telephone interviews as part of the MACRO programme (Defining best Management for Adults with Chronic RhinOsinusitis). SETTING: Primary care and secondary care ear, nose and throat outpatient clinics in the UK. PARTICIPANTS: Twenty-five patients consented to in-depth telephone interviews. Transcribed recordings were managed using NVivo software and analysed using inductive thematic analysis. RESULTS: CRS has a significant impact on patients' quality of life, affecting their ability to work effectively, their social interactions and daily living. Patients seek help when symptoms become unmanageable, but can become frustrated with the primary care system with difficulties obtaining an appointment, and lack of continuity of care. Patients perceive that general practitioners can be dismissive of CRS symptoms, and patients often prioritise other concerns when they consult. Health system barriers and poor communication can result in delays in accessing appropriate treatment and referral. Adherence to intranasal steroids is a problem and patients are uncertain about correct technique. Nasal irrigation can be time-consuming and difficult for patients to use. Secondary care consultations can appear rushed, and patients would like specialists to take a more 'holistic' approach to their management. Surgery is often considered a temporary solution, appropriate when medical options have been explored. CONCLUSIONS: Patients are frustrated with the management of their CRS, and poor communication can result in delays in receiving appropriate treatment and timely referral. Patients seek better understanding of their condition and guidance to support treatments decisions in light of uncertainties around the different medical and surgical options. Better coordinated care between general practice and specialist settings and consistency of advice has the potential to increase patient satisfaction and improve outcomes.

Homozygous variegate porphyria is a severe skin and neurologic disease manifesting in early infancy, and characterized by markedly reduced levels of the penultimate enzyme in the heme biosynthetic pathway, protoporphyrinogen oxidase. We investigated the molecular basis of variegate porphyria, usually an autosomal dominantly inherited trait, in a severely affected female proband and her parents. The mutation detection strategy included heteroduplex analysis, automated sequencing, and allele specific oligonucleotide hybridization. We identified two underlying missense mutations in the protoporphyrinogen oxidase gene, consisting of a G-to-A transition in exon 6 (G169E), and a G-to-A transition in exon 10 (G358R). Our study establishes the molecular basis of "homozygous" variegate porphyria for the first time, in demonstrating that this patient is a compound heterozygote for two different missense mutations in the protoporphyrinogen oxidase gene.

OBJECTIVE: A cholesteatoma is a mass of keratinising epithelium in the middle ear. It is a rare disorder that is associated with significant morbidity, and its causative risk factors are poorly understood; on a global scale, up to a million people are affected by this each year. We have conducted a systematic literature review to identify reports about the heritability of cholesteatoma or any constitutional genetic factors that may be associated with its aetiology. DATA SOURCES: A systematic search of MEDLINE (EBSCO) and two databases of curated genetic research (OMIM and Phenopedia) was conducted. STUDY SELECTION: The participants and populations of interest for this review were people treated for cholesteatoma and their family members. The studies of interest reported evidence of heritability for the trait, or any association with congenital syndromes and particular genetic variants. DATA EXTRACTION: The searches identified 449 unique studies, of which 35 were included in the final narrative synthesis. DATA SYNTHESIS: A narrative synthesis was conducted, and data were tabulated to record characteristics, including study design, genetic data and author conclusions. Most of the studies identified in the literature search, and described here, are case reports and so represent the lowest level of evidence. In a few case reports, congenital and acquired cholesteatomas have been shown to segregate within families in the pattern typical of a monogenic or oligogenic disorder with incomplete penetrance. Evidence from syndromic cases could suggest that genes controlling ear morphology may be risk factors for cholesteatoma formation. CONCLUSIONS: This is the first systematic review about the genetics of cholesteatoma, and we have identified a small body of relevant literature that provides evidence of a heritable component for its aetiology. Cholesteatoma is a complex and heterogeneous clinical phenotype, and it is often associated with chronic otitis media and with some rare congenital syndromes known to affect ear morphology and related pathologies.

Abstract Background The aims of this prospective population-based cohort study were to identify the patient and hospital characteristics associated with emergency cholecystectomy, and the influences of these in determining variations between hospitals. Methods Data were collected for consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing the performance of emergency cholecystectomy were analysed by means of multilevel, multivariable logistic regression modelling using a two-level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 4744 cholecystectomies from 165 hospitals. Increasing age, lower ASA fitness grade, biliary colic, the need for further imaging (magnetic retrograde cholangiopancreatography), endoscopic interventions (endoscopic retrograde cholangiopancreatography) and admission to a non-biliary centre significantly reduced the likelihood of an emergency cholecystectomy being performed. The multilevel model was used to calculate the probability of receiving an emergency cholecystectomy for a woman aged 40 years or over with an ASA grade of I or II and a BMI of at least 25·0 kg/m2, who presented with acute cholecystitis with an ultrasound scan showing a thick-walled gallbladder and a normal common bile duct. The mean predicted probability of receiving an emergency cholecystectomy was 0·52 (95 per cent c.i. 0·45 to 0·57). The predicted probabilities ranged from 0·02 to 0·95 across the 165 hospitals, demonstrating significant variation between hospitals. Conclusion Patients with similar characteristics presenting to different hospitals with acute gallbladder pathology do not receive comparable care.

BACKGROUND: Patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) often require repeat sinus surgery. Mepolizumab reduced the need for sinus surgery in the SYNAPSE trial; this analysis sought to provide a more in-depth assessment of surgery endpoints in SYNAPSE. METHODS: SYNAPSE was a double-blind Phase III trial (NCT03085797) in adults with recurrent, refractory, severe, CRSwNP eligible for repeat sinus surgery despite standard of care treatments and previous surgery. Patients were randomized (1:1) to mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 52 weeks. Time to first inclusion on a waiting list for sinus surgery and time to first actual sinus surgery (both up to week 52) were assessed; the latter endpoint was also analyzed post hoc according to time since last sinus surgery before study screening and baseline blood eosinophil count. RESULTS: Among 407 patients (mepolizumab: 206; placebo: 201), mepolizumab versus placebo reduced the risk of being included on a waiting list for sinus surgery (week 52 Kaplan-Meier probability estimate [95% confidence interval]: 13.9% [9.8%, 19.5%] vs. 28.5% [22.7%, 35.4%]). Mepolizumab versus placebo reduced the risk of sinus surgery irrespective of time (<3 vs ≥3 years) since patients' last sinus surgery prior to study screening (hazard ratios [95% confidence intervals] 0.28 [0.09, 0.84] and 0.50 [0.26, 0.98], respectively) and baseline blood eosinophil count. CONCLUSIONS: Mepolizumab reduced the risk of further sinus surgery in patients with recurrent, refractory, severe CRSwNP, irrespective of the patient baseline characteristics assessed.

BACKGROUND: The optimal timing of cholecystectomy for patients admitted with acute gallbladder pathology is unclear. Some studies have shown that emergency cholecystectomy during the index admission can reduce length of hospital stay with similar rates of conversion to open surgery, complications and mortality compared with a 'delayed' operation following discharge. Others have reported that cholecystectomy during the index acute admission results in higher morbidity, extended length of stay and increased costs. This study examined the cost-effectiveness of emergency versus delayed cholecystectomy for acute benign gallbladder disease. METHODS: Using data from a prospective population-based cohort study examining the outcomes of cholecystectomy in the UK and Ireland, a model-based cost-utility analysis was conducted from the perspective of the UK National Health Service, with a 1-year time horizon for costs and outcomes. Probabilistic sensitivity analysis was used to investigate the impact of parameter uncertainty on the results obtained from the model. RESULTS: Emergency cholecystectomy was found to be less costly (£4570 versus £4720; €5484 versus €5664) and more effective (0·8868 versus 0·8662 QALYs) than delayed cholecystectomy. Probabilistic sensitivity analysis showed that the emergency strategy is more than 60 per cent likely to be cost-effective across willingness-to-pay values for the QALY from £0 to £100 000 (€0-120 000). CONCLUSION: Emergency cholecystectomy is less costly and more effective than delayed cholecystectomy. This approach is likely to be beneficial to patients in terms of improved health outcomes and to the healthcare provider owing to the reduced costs.