East Sussex Healthcare NHS Trust

PURPOSE: This article introduces the new 5-level EQ-5D (EQ-5D-5L) health status measure. METHODS: EQ-5D currently measures health using three levels of severity in five dimensions. A EuroQol Group task force was established to find ways of improving the instrument's sensitivity and reducing ceiling effects by increasing the number of severity levels. The study was performed in the United Kingdom and Spain. Severity labels for 5 levels in each dimension were identified using response scaling. Focus groups were used to investigate the face and content validity of the new versions, including hypothetical health states generated from those versions. RESULTS: Selecting labels at approximately the 25th, 50th, and 75th centiles produced two alternative 5-level versions. Focus group work showed a slight preference for the wording 'slight-moderate-severe' problems, with anchors of 'no problems' and 'unable to do' in the EQ-5D functional dimensions. Similar wording was used in the Pain/Discomfort and Anxiety/Depression dimensions. Hypothetical health states were well understood though participants stressed the need for the internal coherence of health states. CONCLUSIONS: A 5-level version of the EQ-5D has been developed by the EuroQol Group. Further testing is required to determine whether the new version improves sensitivity and reduces ceiling effects.

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.

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

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.

BACKGROUND: Recreational drug use in men who have sex with men (MSM) is of concern because it might be linked to the transmission of HIV and other sexually transmitted infections. Evidence about drug use in HIV-diagnosed MSM in the UK is limited by representativeness of the study populations. We describe patterns of drug use and associations with sexual behaviours in HIV-diagnosed MSM in the UK. METHODS: We used data from the cross-sectional ASTRA study, which recruited participants aged 18 years or older with HIV from eight HIV outpatient clinics in the UK between Feb 1, 2011, and Dec 31, 2012. We examined data for MSM, assessing the prevalence of recreational drug use and polydrug use in the previous 3 months and associations with sociodemographic and HIV-related factors. We examined the association of polydrug use with measures of condomless sex in the previous 3 months and with other sexual behaviours. FINDINGS: Our analysis included data for 2248 MSM: 2136 (95%) were gay, 1973 (89%) were white, 1904 (85%) were on antiretroviral treatment (ART), and 1682 (76%) had a viral load of 50 copies per mL or lower. 1138 (51%) used recreational drugs in the previous 3 months; 608 (27%) used nitrites, 477 (21%) used cannabis, 460 (21%) used erectile dysfunction drugs, 453 (20%) used cocaine, 280 (13%) used ketamine, 258 (12%) used 3,4-methylenedioxy-N-methylamphetamine (MDMA), 221 (10%) used gamma-hydroxybutyrate or gamma-butyrolactone, 175 (8%) used methamphetamine, and 162 (7%) used mephedrone. In the 1138 individuals who used drugs, 529 (47%) used three or more drugs and 241 (21%) used five or more. Prevalence of injection drug use was 3% (n = 68). Drug use was independently associated with younger age (p < 0·0001), not being religious (p = 0·001), having an HIV-positive stable partner (p = 0·0008), HIV-serostatus disclosure (p = 0·009), smoking (p < 0·0001), evidence of harmful alcohol drinking (p = 0·0001), and ART non-adherence (p < 0·0001). Increasing polydrug use was associated with increasing prevalence of condomless sex (prevalence range from no drug use to use of five or more drugs was 24% to 78%), condomless sex with HIV-seroconcordant partners (17% to 69%), condomless sex with HIV-serodiscordant partners (10% to 25%), and higher-HIV-risk condomless sex after taking viral load into account (4% to 16%; p ≤ 0·005 for all). Associations were similar after adjustment for sociodemographic and HIV-related factors. Methamphetamine was more strongly associated with higher-HIV-risk condomless sex than were other commonly used drugs. INTERPRETATION: Polydrug use is prevalent in HIV-diagnosed MSM and is strongly associated with condomless sex. Specialist support services for MSM with HIV who use recreational drugs might be beneficial in the reduction of harm and prevention of ongoing transmission of HIV and other sexually transmitted infections. FUNDING: National Institute for Health Research.

Chronic kidney disease (CKD) is a complex disease which affects approximately 13% of the world's population. Over time, CKD can cause renal dysfunction and progression to end-stage kidney disease and cardiovascular disease. Complications associated with CKD may contribute to the acceleration of disease progression and the risk of cardiovascular-related morbidities. Early CKD is asymptomatic, and symptoms only present at later stages when complications of the disease arise, such as a decline in kidney function and the presence of other comorbidities associated with the disease. In advanced stages of the disease, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. With limited treatment options available, an increasing prevalence of both the elderly population and comorbidities associated with the disease, the prevalence of CKD is set to rise. This review discusses the current challenges and the unmet patient need in CKD.

In a landmark move, the UK Department of Health (DH) has introduced the routine collection of patient-reported outcome measures (PROMs) to measure the performance of health-care providers. From April 2009, generic (EQ-5D) and condition-specific PROMs are being collected from patients before and after four surgical procedures; eventually this will be extended to include a wide range of other NHS services. The aim of this article is to report analysis of the EQ-5D data generated from a pilot study commissioned by the DH and to consider the implications for the use of EQ-5D data in performance indicators and measures of patient benefit. We present two new methods that we have developed for analysing and displaying EQ-5D profile data: a Paretian Classification of Health Change and a health profile grid. We show that EQ-5D profile data can be readily analysed to generate insights into the nature of changes in patient-reported health that would be obscured by summarising these profiles by their index scores, or focusing just on the post operative outcomes. Our methods indicate differences between providers and between sub-groups of patients. Our results also show striking differences in changes in EQ-5D profiles between surgical procedures, which require further investigation.

BACKGROUND: Complete rectal prolapse is a life-style altering disability that commonly affects older people. The range of surgical methods available to correct the underlying pelvic floor defects in complete rectal prolapse suggests that there is no agreement about the choice of the best operation. OBJECTIVES: To determine the effects of surgery on the treatment of rectal prolapse in adults. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Register (searched 10 January 2008), the Cochrane Colorectal Cancer Group Trials Register (searched 10 January 2008), CENTRAL (Issue 1, 2008), PubMed (1 January 1950 to 10 January 2008) and EMBASE (1 January 1998 to 10 January 2008). The British Journal of Surgery (January 1995 to January 2008) and the Diseases of the Colon and Rectum (January 1995 to January 2008) were specifically hand searched. The proceedings of the Association of Coloproctology meetings held from 1999 to 2007 were perused. Reference lists of all relevant articles were searched for further trials. SELECTION CRITERIA: All randomised or quasi-randomised trials of surgery in the management of adult rectal prolapse. DATA COLLECTION AND ANALYSIS: Three reviewers independently selected studies from the literature searches, assessed the methodological quality of eligible trials and extracted data. The four primary outcome measures were: number of patients with recurrent rectal prolapse, number of patients with residual mucosal prolapse, and number of patients with faecal incontinence or constipation. MAIN RESULTS: Twelve randomised controlled trials including 380 participants were identified and included in this review. One trial compared abdominal with perineal approaches to surgery, three trials compared fixation methods, three trials looked at the effects of lateral ligament division, one trial compared techniques of rectosigmoidectomy, two trials compared laparoscopic with open surgery and two trials compared resection with no resection rectopexy.The heterogeneity of the trial objectives, interventions and outcomes made analysis difficult. Many review objectives were covered by only one or two studies with small numbers of participants. With these caveats in mind there is insufficient data to say which of the abdominal and perineal approaches has a better outcome. There were no detectable differences between the methods used for fixation during rectopexy. Division, rather than preservation, of the lateral ligaments was associated with less recurrent prolapse but more post-operative constipation. Laparoscopic rectopexy was associated with fewer post-operative complications and shorter hospital stay than open rectopexy. Bowel resection during rectopexy was associated with lower rates of constipation. AUTHORS' CONCLUSIONS: The small sample size of included trials together with their methodological weaknesses severely limit the usefulness of this review for guiding practice. It is impossible to identify or refute clinically important differences between the alternative surgical operations. Larger rigorous trials are needed to improve the evidence with which to define optimum surgical treatment for rectal prolapse: the results of one such trial are awaited.

What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article introduced the revised format of the British National Formulary (BNF) and explained how the information it contains may be accessed. It discussed the importance of developing healthcare professionals' knowledge and understanding of the BNF to enable safe and effective prescribing, dispensing, administration and monitoring of medicines.

Frailty is a health condition leading to many adverse clinical outcomes. The relationship between frailty and advanced age, multimorbidity and disability has a significant impact on healthcare systems. Frailty increases cardiovascular (CV) morbidity and mortality both in patients with or without known CV disease. Though the recognition of this additional risk factor has become increasingly clinically relevant in CV diseases, uncertainty remains about operative definitions, screening, assessment, and management of frailty. Since the burdens of frailty components and domains may vary in the various CV diseases and clinical settings, the relevance of specific frailty-related aspects may be different. Understanding these issues may allow general cardiologists a clearer focus on frailty in CV diseases and thereby make more tailored clinical decisions and therapeutic choices in outpatients. Guidance on identification and management of frailty are sparse and an international consensus document on frailty in general cardiology is lacking. Moreover, new options linked with eHealth are going to better define and manage frailty. This consensus document on definition, assessment, clinical implications, and management of frailty provides an input to integrate strategies pre- and post-acute CV events with a comprehensive view including out of hospital, office-based diagnostic and therapeutic choices, and based on a multidisciplinary team approach (general cardiologists, nurses, and general practitioners).

INTRODUCTION: Suprapubic catheter (SPC) insertion is a common urological procedure, which is often referred to as safe and simple even in inexperienced hands. There is, however, very little published evidence on the safety of this procedure. Our study aimed to provide evidence on the associated morbidity and mortality and provide guidance for practising clinicians. PATIENTS AND METHODS: A total of 219 patients who underwent SPC insertion under cystoscopic guidance at two urology institutions between 1994 and 2002 were identified and their case notes reviewed. RESULTS: The intra-operative complication rate was 10% and the 30-day complications rate was 19%. Mortality rate was 1.8%. Long-term complications included recurrent UTIs (21%), catheter blockage (25%) resulting in multiple accident and emergency attendance (43%). Despite this, the satisfaction rate was high (72%) and most patients (89%) prefer the SPC over the urethral catheter. CONCLUSIONS: SPC bladder drainage results in a high patient satisfaction rate. Patients and clinicians should be aware of the potential complications associated with SPC insertion.

BACKGROUND: As part of EUROCAT's surveillance of congenital anomalies in Europe, a statistical monitoring system has been developed to detect recent clusters or long-term (10 year) time trends. The purpose of this article is to describe the system for the identification and investigation of 10-year time trends, conceived as a "screening" tool ultimately leading to the identification of trends which may be due to changing teratogenic factors. METHODS: The EUROCAT database consists of all cases of congenital anomalies including livebirths, fetal deaths from 20 weeks gestational age, and terminations of pregnancy for fetal anomaly. Monitoring of 10-year trends is performed for each registry for each of 96 non-independent EUROCAT congenital anomaly subgroups, while Pan-Europe analysis combines data from all registries. The monitoring results are reviewed, prioritized according to a prioritization strategy, and communicated to registries for investigation. Twenty-one registries covering over 4 million births, from 1999 to 2008, were included in monitoring in 2010. CONCLUSIONS: Significant increasing trends were detected for abdominal wall anomalies, gastroschisis, hypospadias, Trisomy 18 and renal dysplasia in the Pan-Europe analysis while 68 increasing trends were identified in individual registries. A decreasing trend was detected in over one-third of anomaly subgroups in the Pan-Europe analysis, and 16.9% of individual registry tests. Registry preliminary investigations indicated that many trends are due to changes in data quality, ascertainment, screening, or diagnostic methods. Some trends are inevitably chance phenomena related to multiple testing, while others seem to represent real and continuing change needing further investigation and response by regional/national public health authorities.

Diet interventions have suggested an association between plant-based diets and improvements in psychological well-being, quality of life and glycated hemoglobin (HbA1c) control in populations with diabetes. The aims of this review are to systematically analyze the available literature on plant-based diet interventions targeting diabetes in adults and to clearly define the benefits on well-being of such interventions. This is a systematic review of controlled trials. A computerized systematic literature search was conducted in the following electronic databases: Allied and Complementary Medicine, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, E-Journals, Excerpta Medica Database, MEDLINE, Health Management Information Consortium, PsycARTICLES, PsycINFO, PubMed, SocINDEX and Web of Science. The search strategy retrieved 1240 articles, of which 11 met the inclusion criteria (n=433; mean sample age 54.8 years). Plant-based diets were associated with significant improvement in emotional well-being, physical well-being, depression, quality of life, general health, HbA1c levels, weight, total cholesterol and low-density lipoprotein cholesterol, compared with several diabetic associations' official guidelines and other comparator diets. Plant-based diets can significantly improve psychological health, quality of life, HbA1c levels and weight and therefore the management of diabetes.

Worldwide, each year more than 7 million people experience myocardial infarction, in which one-year mortality rates are now in the range of 10%, but vary with patient characteristics. The consequences are even more dramatic: among patients who survive, 20% suffer a second cardiovascular event in the first year and approximately 50% of major coronary events occur in those with a previous hospital discharge diagnosis of ischaemic heart disease. The people behind these numbers spur this call for action. Prevention after myocardial infarction is crucial to reduce risk and suffering. Evidence-based interventions include optimal medical treatment with anti-platelets and statins, achievement of blood pressure, lipid and blood glucose targets, and appropriate lifestyle changes. The European Society of Cardiology and its constituent bodies are determined to embrace this challenge by developing a consensus document in which the existing gaps for secondary prevention strategies are reviewed. Effective interventions in relation to the patients, healthcare providers and healthcare systems are proposed and discussed. Finally, innovative strategies in hospital as well as in outpatient and long-term settings are endorsed.

The welfare state is based on a life course that no longer matches current experience. It assumes that people, or at least men and unmarried women, spend their early years in education and then go on to a long period in work followed by a short period in retirement, when they live off the pension accumulated while in work or, more usually, the tax and pension contributions of those still in work. At a time when many people did not survive to draw their pensions or, if they did, survived for only a few more years, welfare systems coped reasonably well. It is less clear whether they will be able to do so in the future. The scale of the challenge is shown by a single stark statistic. If there is no change in work and retirement patterns, the ratio of workers to older inactive persons in the countries that were European Union member states in May 2004 (the EU-25), now at 3:1, is projected to increase to 1:1 in 2050.

Whereas multiple national, international, and trial registries for heart failure have been created, international standards for clinical assessment and outcome measurement do not currently exist. The working group's objective was to facilitate international comparison in heart failure care, using standardized parameters and meaningful patient-centered outcomes for research and quality of care assessments. The International Consortium for Health Outcomes Measurement recruited an international working group of clinical heart failure experts, researchers, and patient representatives to define a standard set of outcomes and risk-adjustment variables. This was designed to document, compare, and ultimately improve patient care outcomes in the heart failure population, with a focus on global feasibility and relevance. The working group employed a Delphi process, patient focus groups, online patient surveys, and multiple systematic publications searches. The process occurred over 10 months, employing 7 international teleconferences. A 17-item set has been established, addressing selected functional, psychosocial, burden of care, and survival outcome domains. These measures were designed to include all patients with heart failure, whether entered at first presentation or subsequent decompensation, excluding cardiogenic shock. Sources include clinician report, administrative data, and validated patient-reported outcome measurement tools: the Kansas City Cardiomyopathy Questionnaire; the Patient Health Questionnaire-2; and the Patient-Reported Outcomes Measurement Information System. Recommended data included those to support risk adjustment and benchmarking across providers and regions. The International Consortium for Health Outcomes Measurement developed a dataset designed to capture, compare, and improve care for heart failure, with feasibility and relevance for patients and clinicians worldwide.

This review considers whether research shows a process of spiritual change or development associated with ageing. Spirituality was understood as that which is central to a sense of meaning and purpose in an individual's life and pertains to the sacred or transcendent. Electronic literature searches were conducted to find research published 1985-2003 aimed at understanding spiritual change, themes and tasks in later life. A total of 13 studies were reviewed that looked at changes in spirituality over time, spiritual themes and tasks in a lifespan development context and Tornstam's (Torstam, L. (1996). Gerotranscendence--a theory about maturing into old age. Journal of Aging & Identity, 1, 37-50) theory of gerotranscendence. The research reviewed suggested that some aspects of spirituality remain stable into old age but that there are identifiable spiritual tasks, needs and changes associated with ageing. Some common spiritual themes identified across the research were integrity, humanistic concern, changing relationships with others and concern for younger generations, relationship with a transcendent being or power, self transcendence, and coming to terms with death. These were not related to age per se, but to some of the challenges that age presents, and were mediated by cultural factors and individual differences. The findings and their limitations were discussed.

Plain language summary available online The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of cutaneous squamous cell carcinoma (cSCC). The document aims to The guideline is presented as a detailed review with highlighted recommendations for practical use in primary, secondary and tertiary care, in the clinic and in the appropriate skin cancer multidisciplinary team (MDT) meetings (see section 3.0). These may be either local skin MDTs (LSMDTs) or specialist skin cancer MDTs (SSMDTs), depending on the clinicopathological features of the SCC. Clinicians treating people with cSCC should be core members of the appropriate MDT or sanctioned by the MDT to treat the tumour.1 There is also an updated patient information leaflet available on the BAD website (https://www.skinhealthinfo.org.uk/a-z-conditions-treatments/). The guideline does not cover This set of guidelines has been developed using the BAD’s recommended methodology;5 further information can be found in Appendix J (see Supporting Information) with reference to the AGREE II instrument (www.agreetrust.org)6 and GRADE (https://www.gradeworkinggroup.org). Recommendations were developed for implementation in the UK National Health Service (NHS). The guideline development group (GDG) consisted of seven consultant dermatologists (representing England, Northern Ireland, Scotland and Wales), two consultant clinical oncologists (radiation oncologists), a consultant plastic surgeon, a consultant maxillofacial surgeon, a dermatopathologist, a general practitioner, a Macmillan dermatology clinical nurse specialist, two patient representatives and a technical team (consisting of an information scientist, a guideline research fellow and a project manager providing methodological and technical support). The GDG established several clinical questions pertinent to the scope of the guideline and a set of outcome measures of importance to patients, ranked according to the GRADE methodology7 (see section 2.1; and Appendix A; see Supporting Information). The GDG agreed to adopt the Royal College of Pathologists dataset for the histological reporting of cSCC.8 Along with Public Health England, this endorses the Union for International Cancer Control 8th edition (UICC8)9 (Tables 1 and 2), rather than the American Joint Committee on Cancer 8th edition cancer staging manual, which covers only head and neck cSCC.10 The GDG agreed that risk is part of a spectrum and not dichotomous, and the evidence from the literature searches supported a division based on low-, high- and very high-risk status. As shown in Figure 1, this division was achieved by integrating clinical, pathological, tumour–nodes–metastasis (TNM) staging and margin criteria. A systematic literature search of the PubMed, MEDLINE, Embase and Cochrane databases was conducted by the technical team to identify key articles on cSCC from 1 January 2007 to 30 January 2020; the search terms and strategies are detailed in Appendix K (see Supporting Information). Additional references relevant to the topic were also isolated from citations in the reviewed literature and the previous versions of the guidelines.11, 12 Data extraction, critical appraisal and data synthesis were performed by the technical team, who prepared the evidence summaries, lists of excluded studies and PRISMA diagram. Evidence from included studies was rated according to the GRADE system (high, moderate, low or very low quality). Recommendations are based on evidence drawn from systematic reviews of the literature pertaining to the clinical questions identified, following discussions with the entire GDG and factoring in all four factors that would affect their strength ratings according to the GRADE approach (i.e. balance between desirable and undesirable effects, quality of evidence, patient values and preferences, and resource allocation). All GDG members contributed towards drafting and/or reviewing the narratives and information in the guideline and supporting information documents. When there was insufficient evidence from the literature, informal consensus was reached based on the experience of the GDG. The summary of findings with forest plots (Appendix B), clinical evidence summary (Appendix C), tables Linking the Evidence To the Recommendations (LETR) (Appendix D), GRADE evidence profiles indicating the quality of evidence (Appendix E), summary of included studies (Appendix F), narrative findings for noncomparative studies (Appendix G), PRISMA flow diagram (Appendix H) and list of excluded studies (Appendix I) are detailed in the Supporting Information. The strength of recommendation is expressed by the wording and symbols shown in Table 3. The GDG established a number of clinical questions pertinent to the scope of the guideline (for a full review protocol see Appendix A in the Supporting Information). The GDG also established a set of outcome measures of importance to patients for each clinical question, which were ranked according to the GRADE methodology7 by the patient representatives. This uses a nine-point scale, with outcomes ranked 9 being those the patient representatives considered most important. Outcomes ranked 9, 8 or 7 are critical for decision-making; those ranked 6, 5 or 4 are important but not critical for decision-making; and those ranked 3, 2 or 1 are the least important for decision-making. Data on these outcome measures were extracted from the included studies (Appendixes B, C, E, F and G; see Supporting Information). Review question 1: treatment In people with ‘higher-risk’ primary cSCC, how clinically effective are surgical (standard and Mohs) and nonsurgical treatments (radiotherapy and electrochemotherapy) compared with each other? Review question 2: treatment In people with low-risk primary cSCC how clinically effective are surgical (standard excision, Mohs, curettage and cautery, cryosurgery and carbon dioxide laser) and nonsurgical treatments (topical therapies, photodynamic therapy or radiotherapy) compared with each other or with no treatment (observation)? (Radiotherapy includes brachytherapy where appropriate.) Review question 3: surgical margin In people with cSCC who undergo standard surgical excision, what surgical margin and surgical plane should be used? Review question 4: involved margins In people with cSCC who undergo excision of the primary tumour and where histological analysis shows either one or more involved or clear-but-close margins (< 1 mm), what is the appropriate subsequent management? Review question 5: adjuvant radiotherapy In people with primary cSCC following surgical excision with clear histological margins, what is the role of adjuvant radiotherapy in reducing the risk of local recurrence? [‘Adjuvant’ in the guidelines refers to any treatment (radiotherapy) after primary treatment (surgery).] Review question 6: metastatic squamous cell carcinoma In people with any metastasis from cSCC how clinically effective are standard surgical and nonsurgical treatments (chemotherapeutic therapy, radiotherapy, immunotherapy) compared with each other or with no treatment (observation)? (Radiotherapy includes brachytherapy where appropriate.) Review question 7: follow-up In people with a diagnosed higher-risk cSCC what is the appropriate follow-up period following treatment? Note: in Mohs surgery the tumour is curetted or surgically debulked, and the defect usually excised with a small (1–2 mm) margin of surrounding skin. The patient waits with a dressed wound pending histological confirmation by the Mohs surgeon that the tumour has been completely removed. If residual tumour is identified, a further layer of tissue is removed, and the process repeated until the surgical wound is confirmed to be tumour free. The wound is then repaired by conventional surgical techniques. There are few randomized controlled trials (RCTs) to support the following guidelines for the management of cSCC. The following recommendations and ratings were agreed upon unanimously by the core members of the GDG and patient representatives. The recommendations cover suspected and diagnosed cSCC. All recommendations would also generally relate to children, young people and adults, unless specified otherwise. Those under 24 years of age with cSCC should be managed by the SSMDT but must additionally be referred to the appropriate children’s, teenagers’ or young adults’ service for their specific expertise. These guidelines do not include specific recommendations for subungual or periungual SCCs. For further information on the wording used for recommendations and strength of recommendation ratings see Table 3. The evidence for recommendations is based on the studies as listed (for details and discussion of the evidence see Appendixes B–F in the Supporting Information). The GDG recommendations relating to referral pathways are based on discussion and clinical experience, as evidence-based details are not available at the time of writing. The GDG is aware of the lack of high-quality evidence for some of these recommendations, and therefore strong recommendations with an asterisk (*) are based on available evidence, as well as consensus and specialist experience. Good practice point (GPP) recommendations are derived from informal consensus. R1 (↑↑) Obtain histological confirmation of cSCC lesions in the event of diagnostic uncertainty, before planning definitive treatment. This must be a representative sample of the tumour; in most instances, this will be a full-thickness incisional biopsy ideally incorporating both the peripheral and the deep margins. R2 (GPP) Offer discussion on the risks and benefits of all treatment options (outcomes, function, cosmesis) to people with cSCC and their families or carers and make the treatment decision together. R3 (↑↑) Record the maximum clinical cSCC lesion dimension prior to any diagnostic or treatment procedure (usually diameter, in millimetres), the plane of the deep-excision margin, whether it is a recurrent tumour or in field of previous radiotherapy, and the immune status of the patient, on the specimen request form for the pathologist. R4 (GPP) Take a good-quality clinical photograph of the cSCC lesion for the patient record to aid future management and assessment of the area after healing. In multisite disease the lesions to be treated should ideally be marked on the photograph to limit the risk of wrong-site procedures. R5 (↑↑) Offer* standard surgical excision as the first-line treatment option to people with resectable primary cSCC. R6 (↑↑) Peripheral tumour margins should be determined under bright lighting and magnification or dermoscopy. Excise* with a clinical peripheral surgical margin of For definition of the levels of risk see Figure 1.13-18 R7 (↑↑) Ensure at least a 1-mm histological clearance of cSCC excisions at all margins by including sufficient peripheral and deep tissues (see R6 for appropriate standard surgical excision margins). R8 (↑↑) Manage and report excised cSCC specimens according to the Royal College of Pathologists dataset.8 R9 (GPP) Document the risk status of cSCC tumour as low risk, high risk or very high risk in the patient notes (Figure 1). R10 (↓↓) T1 cSCC tumours excised with histologically clear margins of at least 1 mm, in the absence of other high-risk factors, do not need routine discussion at an MDT (Figure 1). R11 (↑↑) Review the histology of people with cSCC with one or more involved or clear-but-close margins (< 1 mm) at an appropriate skin MDT (Figure 1). R12 (↑) Consider the risk factors for the patient and the margin, site and tumour stage in people with cSCC with one or more clear-but-close margins (< 1 mm). Consider observation in immunocompetent people with cSCC with a low-risk tumour (Figure 1). R13 (↑↑) Offer further wide local excision (with likely delayed reconstruction), Mohs micrographic surgery, or adjuvant radiotherapy to people with cSCC with one or more involved margins, or close margins (< 1 mm), where patient or tumour factors confer higher risk. R14 (GPP) Offer active treatment to immunosuppressed people with cSCC with one or more clear-but-close (< 1 mm) or involved margins with structured follow-up and surveillance. R15 (↑↑) Discuss at an SSMDT people with cSCC with symptomatic perineural invasion and/or radiological evidence of perineural invasion. If discussed at a skin MDT, skull base or head and neck MDT opinion may be required. Aggressive surgical excision of the involved nerve should be the first step, where technically possible, followed by consideration of adjuvant radiotherapy. R16 (↑) Consider Mohs micrographic surgery in selected people with cSCC following SSMDT discussion, particularly where tumour margins are difficult to delineate or in sites where tissue conservation is important for function. R17 (↑↑) Discuss people with histologically proven cSCC being considered for radiotherapy at an MDT (LSMDT or SSMDT) with a clinical oncologist present. R18 (↑↑) Offer primary radiotherapy R19 (↑) Consider adjuvant radiotherapy in people with cSCC R20 (↑↑) Offer adjuvant radiotherapy to people with incompletely excised cSCC, where further surgery is not possible (or is not chosen by the patient) and in those at high risk of local recurrence R21 (↓↓) Do not offer postoperative radiotherapy to people with completely excised T1 or T2 cSCC and with microscopic, dermal-only, nerve diameter < 0·1 mm perineural invasion. R22 (↑) Consider conformal radiotherapy including the entire course of the involved nerve in people with cSCC with symptomatic perineural invasion and/or radiological evidence of perineural invasion when surgery is inappropriate, after carefully weighing the benefits and side-effects from radiotherapy to such an extensive radiotherapy treatment field. R23 (GPP) Inform younger people with cSCC (age < 60 years), especially if they are an organ transplant recipient, of the very low risk of radiation-induced, in-field malignancy in the future. Take this risk into account when making any treatment decision. R24 (↑) Consider curettage and cautery with curative intent in immunocompetent people with small (< 1 cm), well-defined, nonrecurrent, clinically low-risk cSCC. R25 (GPP) Review the histology of cSCC removed by curettage and cautery to identify high-risk or very high-risk features. If these are identified, the case should be discussed at an appropriate MDT regarding further management. R26 (GPP) Do not routinely offer imaging of the draining to people with cSCC in the absence of suspected or clinically high-risk such as or cSCC, a high risk of metastasis and consideration can be to of the in the clinically (↑↑) an and imaging treatment for people (GPP) assessment of the of a primary cSCC including in the (GPP) biopsy for high-risk of primary cSCC in the of a clinical or SSMDT (GPP) Offer to people with cSCC with clinically If they are and this can be core or histology may be required. (GPP) imaging of the involved area in people with cSCC with in metastasis or perineural invasion of Discuss with a if is metastasis is a of metastasis in which skin cancer a and to between the area of previous treatment and the (↑↑) Offer to people with head and neck cSCC with is a surgical procedure in which the that the site of the tumour are removed to an that has rather than diagnostic or The tissue is under the for of is to the of and to identify metastatic disease see The head and neck imaging should include or and imaging of the as a The surgery should be performed by a surgeon who is a core of the SSMDT and with (↑↑) Offer to people with and neck cSCC with in or other peripheral draining is to the of and to identify metastatic disease see In the imaging should include the and as a and the surgery should include levels In the imaging should include the and to and the surgery should include and deep (↑↑) Offer adjuvant radiotherapy following to people with cSCC with high-risk two or more and by as (GPP) Consider surgical (with or adjuvant radiotherapy) or primary radiotherapy in people with recurrent cSCC. (GPP) Consider or in selected people with cSCC for disease in the of especially in those treatment. (↑) Consider immune treatment in people with cSCC where curative surgery or radiotherapy is not or those with metastatic cSCC, patients with organ or those who (↑) Consider or in people with metastatic cSCC with to immune are generally and is in and and consideration for should be are for cSCC in the (GPP) Consider in people with cSCC in if other local or are not (↑↑) Offer to a key to people with cSCC, ideally a clinical nurse specialist, as part of an treatment information on the and management of cSCC. (GPP) people with cSCC by the skin and and with any other appropriate clinical (GPP) people with cSCC on and and by providing appropriate and information (GPP) Offer people with low-risk cSCC a where to skin and and patient on and of at the information on the risk of further cSCC and on how to a including the into the system if they a (GPP) Offer people with high-risk cSCC when several risk factors follow-up at for 12 then at for a further 12 The follow-up should be with to skin and patient on may be with other to and skin according to local by the appropriate skin (GPP) Offer people with very high-risk cSCC follow-up at for 24 then at for a further 12 The follow-up should be with to skin and patient on may be with other to and skin according to local by the appropriate skin who a high risk of further primary cSCC, such as organ transplant should under skin surveillance. (GPP) Offer people with metastatic cSCC follow-up at for 24 then at for a further with review on patient should be performed on the of clinical with SSMDT discussion if There is insufficient evidence to support any recommendation for or in the treatment of cSCC. The following list future research recommendations should identify which clinicopathological or factors which a system for risk. need to include more people with cSCC, with of the by risk skin cancer clinical studies need to outcomes by (i.e. or cell and for primary cSCC reporting recurrence quality of and and effects, including and All future cSCC need to report outcome measures time to to and of data A the and resource of treatment options for people with cSCC in the UK strategies for people with cSCC, not to radiotherapy, or metastatic cSCC in immune are There is a need for a review of the treatments of cSCC in those who are at risk of those with or The role of biopsy in the staging of very high-risk cSCC the of these tumours to The recommendations, discussions in the (Appendix see Information) and consensus specialist experience were used to the and of 2 and cutaneous squamous cell carcinoma is a tumour that from the of the or is and has the to The of skin cancer is at least higher than that of the most tumour in the which is evidence that this is an for skin cancer to cSCC is the most cancer in the and to not only in the UK but also in other This will an on planning for and on is usually to and is therefore especially in people with and may also be for the of these may as a of previous to and or such as or or or from lesions such as in 24 A high of cSCC is found in with where it is a of In the of cSCC is not with immune function, for those following organ or for and those with or are at risk of this are with The risk of cSCC with the (for or has to be There is evidence with that from the use of and to support use of and effective in the of and These measures are particularly important for people who therapy for skin may also be at higher cSCC may also in patients who are being treated with for with organ are at high risk of cSCC. to and and measures to cSCC, should be part of their routine In patients with or high-risk consideration should be to and the use of which may also be in other high-risk should also be considered in this such as and and photodynamic may in skin and therefore the risk of skin in high-risk transplant but evidence is usually as an or tumour that may or it may as an evidence of All patients in there is a of a cSCC should be referred to an specialist who is to an usually in their local dermatology skin cancer The of skin cancer specimens and their and reporting should to the Royal College of Pathologists dataset for primary cSCC.8 The Royal College of Pathologists and Public Health for the staging of and skin In the patients with cSCC is there clear for or evidence of the The surgical margins of excision and see Note: these are 4 mm for mm for high-risk and mm for very high-risk cSCC. margins in all following standard surgical Note: these are as clear 1 mm), clear but close (< 1 mm) or involved mm). follow-up and see by members of the MDT, including clinical nurse Note: follow-up are one for and a follow-up 4 in the first then in the and very a follow-up 4 in the first and then in the The recommendation of is to in the to a patient and between (Appendix see Supporting Information). The document and Supporting were available to the BAD the Royal College of the Royal College of Pathologists the Royal College of the of and the of and the of and the for the the of Cancer and the The were considered by the GDG. further the was for review by the of the BAD of the prior to for This document has been prepared on of the BAD and is based on the data available when the document was is that under it may be to from the guidelines and that the of future studies may some of the recommendations to be to to these guidelines should not be considered should to these recommendations a a of the review to and references was a decision but the this may some important information in other The for this set of recommendations is for where important will be updated on the BAD are very to for on the and and for their at the of these the patient representatives and for their in the clinical of the reviewing the evidence and the recommendations, as well as all of those who on the the Data Data Data Data Data Data Data Data J Data Data Data Data A Data Data analysis The following were the of the guideline Cancer and and research and for of the and of the guidelines development group for cSCC of the skin cancer of the skin cancer has in a general of the Cancer of the of the skin cancer clinical for appraisal of for cSCC for of the of the skin cancer Cancer prior to on for Royal College of Pathologists on Cancer and they no of Appendix A Review Appendix Appendix evidence Appendix Linking Evidence To Recommendations Appendix GRADE evidence Appendix F of included Appendix findings for Appendix PRISMA Appendix excluded from Appendix J Appendix K Appendix data and data The is not for the or of any supporting information by the than should be to the for the

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.

Background: There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. Methods: We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. Results: Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], –4.0 to 45.5; P =0.100) with no interaction of FFR ( P interaction =0.318) or iFR ( P interaction =0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70–1.44; P &lt;0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR ( P interaction &lt;0.00001) and decreasing iFR ( P interaction &lt;0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96–2.80; P =0.072) with no detectable evidence of interaction with FFR ( P interaction =0.849) or iFR ( P interaction =0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30–4.72; P =0.006) but neither FFR ( P interaction =0.693) nor iFR ( P interaction =0.761) modified this effect. Conclusions: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02062593.