Northampton General Hospital NHS Trust

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: Rising demand for emergency and urgent care services is well documented, as are the consequences, for example, emergency department (ED) crowding, increased costs, pressure on services, and waiting times. Multiple factors have been suggested to explain why demand is increasing, including an aging population, rising number of people with multiple chronic conditions, and behavioral changes relating to how people choose to access health services. The aim of this systematic mapping review was to bring together published research from urgent and emergency care settings to identify drivers that underpin patient decisions to access urgent and emergency care. METHODS: Systematic searches were conducted across Medline (via Ovid SP), EMBASE (via Ovid), The Cochrane Library (via Wiley Online Library), Web of Science (via the Web of Knowledge), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; via EBSCOhost). Peer-reviewed studies written in English that reported reasons for accessing or choosing emergency or urgent care services and were published between 1995 and 2016 were included. Data were extracted and reasons for choosing emergency and urgent care were identified and mapped. Thematic analysis was used to identify themes and findings were reported qualitatively using framework-based narrative synthesis. RESULTS: Thirty-eight studies were identified that met the inclusion criteria. Most studies were set in the United Kingdom (39.4%) or the United States (34.2%) and reported results relating to ED (68.4%). Thirty-nine percent of studies utilized qualitative or mixed research designs. Our thematic analysis identified six broad themes that summarized reasons why patients chose to access ED or urgent care. These were access to and confidence in primary care; perceived urgency, anxiety, and the value of reassurance from emergency-based services; views of family, friends, or healthcare professionals; convenience (location, not having to make appointment, and opening hours); individual patient factors (e.g., cost); and perceived need for emergency medical services or hospital care, treatment, or investigations. CONCLUSIONS: We identified six distinct reasons explaining why patients choose to access emergency and urgent care services: limited access to or confidence in primary care; patient perceived urgency; convenience; views of family, friends, or other health professionals; and a belief that their condition required the resources and facilities offered by a particular healthcare provider. There is a need to examine demand from a whole system perspective to gain better understanding of demand for different parts of the emergency and urgent care system and the characteristics of patients within each sector.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

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.

The Silver-Russell syndrome (SRS) is characterised by severe intrauterine growth retardation, with a preserved head circumference, leading to a lean body habitus and short stature. Facial dysmorphism and asymmetry are considered typical features of the syndrome, although the range of phenotypic variance is unknown. Fifty seven subjects varying in age from 0.84 to 35.01 years, in whom the diagnosis of SRS had been considered definite or likely, were re-evaluated in a combined clinical and molecular study by a single observer (SMP). In 50 patients the clinical findings complied with a very broad definition of SRS. Notable additional findings included generalised camptodactyly seen in 11 (22%), many with distal arthrogryposis. Thirteen of the 25 males required genital surgery for conditions including hypospadias and inguinal hernia. Fourteen (36.8%) subjects above school age have received a statement of special educational needs. Molecular genetic analysis was performed in 42 subjects and has identified maternal uniparental disomy of chromosome 7 in four. The phenotype was generally milder with birth weights for one patient above and three below -2 SD from the mean. Two children had classical facial dysmorphic features, and two had a milder facial phenotype. Of relevance to the possible molecular mechanism underlying this condition, none of the four disomic patients had significant asymmetry.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

The association between tumor Epstein-Barr virus (EBV) status and clinical outcome in Hodgkin lymphoma (HL) is controversial. This population-based study assessed the impact of EBV status on survival in age-stratified cohorts of adults with classic HL (cHL). Data from 437 cases were analyzed with a median follow-up of 93 months. Overall survival (OS) was significantly better for EBV-negative compared with EBV-positive patients (P < .001), with 5-year survival rates of 81% and 66%, respectively; disease-specific survival (DSS) was also greater for EBV-negative patients (P = .03). The impact of EBV status varied with age at diagnosis. In patients aged 16 to 34 years, EBV-associated cases had a survival advantage compared with EBV-negative cases, but differences were not statistically significant (P = .21). Among patients 50 years or older, EBV positivity was associated with a significantly poorer outcome (P = .003). Excess deaths occurred in EBV-positive patients with both early- and advanced-stage disease. In multivariate analysis of OS in the older patients, EBV status retained statistical significance after adjusting for the effects of sex, stage, and B symptoms (P = .01). Impaired immune status may contribute to the development of EBV-positive cHL in older patients, and strategies aimed at boosting the immune response should be investigated in the treatment of these patients.

OBJECTIVE The FreeStyle Libre (FSL) flash glucose-monitoring device was made available on the U.K. National Health Service (NHS) drug tariff in 2017. This study aims to explore the U.K. real-world experience of FSL and the impact on glycemic control, hypoglycemia, diabetes-related distress, and hospital admissions. RESEARCH DESIGN AND METHODS Clinicians from 102 NHS hospitals in the U.K. submitted FSL user data, collected during routine clinical care, to a secure web-based tool held within the NHS N3 network. The t and Mann-Whitney U tests were used to compare the baseline and follow-up HbA1c and other baseline demographic characteristics. Linear regression analysis was used to identify predictors of change in HbA1c following the use of FSL. Within-person variations of HbA1c were calculated using . RESULTS Data were available for 10,370 FSL users (97% with type 1 diabetes), age 38.0 (±18.8) years, 51% female, diabetes duration 16.0 (±49.9) years, and BMI of 25.2 (±16.5) kg/m2 (mean [±SD]). FSL users demonstrated a −5.2 mmol/mol change in HbA1c, reducing from 67.5 (±20.9) mmol/mol (8.3%) at baseline to 62.3 (±18.5) mmol/mol (7.8%) after 7.5 (interquartile range 3.4–7.8) months of follow-up (n = 3,182) (P &amp;lt; 0.0001). HbA1c reduction was greater in those with initial HbA1c ≥69.5 mmol/mol (&amp;gt;8.5%), reducing from 85.5 (±16.1) mmol/mol (10%) to 73.1 (±15.8) mmol/mol (8.8%) (P &amp;lt; 0.0001). The baseline Gold score (score for hypoglycemic unawareness) was 2.7 (±1.8) and reduced to 2.4 (±1.7) (P &amp;lt; 0.0001) at follow-up. A total of 53% of those with a Gold score of ≥4 at baseline had a score &amp;lt;4 at follow-up. FSL use was also associated with a reduction in diabetes distress (P &amp;lt; 0.0001). FSL use was associated with a significant reduction in paramedic callouts and hospital admissions due to hypoglycemia and hyperglycemia/diabetic ketoacidosis. CONCLUSIONS We show that the use of FSL was associated with significantly improved glycemic control and hypoglycemia awareness and a reduction in hospital admissions.

Background Locally advanced cervical cancer is treated with chemoradiotherapy (standard of care), but many patients still relapse and die from metastatic disease. We investigated chemoradiotherapy with or without induction chemotherapy to determine whether induction chemotherapy improves both progression-free survival and overall survival. Methods The INTERLACE trial was a multicentre, randomised phase 3 trial done at 32 medical centres in Brazil, India, Italy, Mexico, and the UK. Adults (aged ≥18 years) with locally advanced cervical cancer (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, IIA, IIB, IIIB, or IVA disease) were randomly assigned (1:1), by minimisation, using a central electronic system, to standard cisplatin-based chemoradiotherapy (once-a-week intravenous cisplatin 40 mg/m 2 for 5 weeks with 45·0–50·4 Gy external beam radiotherapy delivered in 20–28 fractions plus brachytherapy to achieve a minimum total 2 Gy equivalent dose of 78–86 Gy) alone or induction chemotherapy (once-a-week intravenous carboplatin area under the receiver operator curve 2 and paclitaxel 80 mg/m 2 for 6 weeks) followed by standard cisplatin-based chemoradiotherapy. Stratification factors were recruiting site, stage, nodal status, three-dimensional conformal radiotherapy or intensity modulated radiotherapy, age, tumour size, and histology (squamous vs non-squamous). Primary endpoints were progression-free survival and overall survival within the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01566240, and EUDRACT, 2011-001300-35. Findings Between Nov 8, 2012, and Nov 17, 2022, 500 eligible patients were enrolled and randomly assigned to the chemoradiotherapy alone group (n=250) or the induction chemotherapy with chemoradiotherapy group. Of 500 patients, 354 (70%) had stage IIB disease and 56 (11%) stage IIIB disease. Pelvic lymph nodes were positive in 215 (43%) patients. 230 (92%) patients who received induction chemotherapy had at least five cycles. Median interval between induction chemotherapy and chemoradiotherapy was 7 days. Four or more cycles of cisplatin were given to 212 (85%) participants in the induction chemotherapy with chemoradiotherapy group and to 224 (90%) of participants in the chemoradiotherapy alone group. 462 (92%) participants received external beam radiotherapy and brachytherapy with a median overall treatment time of 45 days. After a median follow-up of 67 months, 5-year progression-free survival rates were 72% in the induction chemotherapy with chemoradiotherapy group and 64% in the chemoradiotherapy alone group with a hazard ratio (HR) of 0·65 (95% CI 0·46–0·91, p=0·013). 5-year overall survival rates were 80% in the induction chemotherapy with chemoradiotherapy group and 72% in the chemoradiotherapy alone group, with an HR of 0·60 (95% CI 0·40–0·91, p=0·015). Grade 3 or greater adverse events were reported in 147 (59%) of 250 individuals in the induction chemotherapy with chemoradiotherapy group versus 120 (48%) of 250 individuals in the chemoradiotherapy alone group. Interpretation Short-course induction chemotherapy followed by chemoradiotherapy significantly improves survival of patients with locally advanced cervical cancer. Funding Cancer Research UK and University College London–University College London Hospitals Biomedical Research Centre.

BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and are currently used as supportive therapy for multiple myeloma (MM). However, the exact clinical role of bisphosphonates in MM remains unclear. OBJECTIVES: This update of the first review published in 2002. We have also analyzed observational studies targeting osteonecrosis of jaw (ONJ). SEARCH STRATEGY: We searched the literature using the methods outlined in the previous review. We also searched observational studies or case reports examining ONJ. SELECTION CRITERIA: We selected RCTs with a parallel design related to the use of bisphosphonate in myeloma. We also selected observational studies or case reports examining bisphosphonates related to ONJ. DATA COLLECTION AND ANALYSIS: We have reported pooled data using either hazard ratio or risk ratio and, when appropriate, as absolute risk reduction and the number needed to treat to prevent or to cause a pathological event. We have assessed statistical heterogeneity and reported I(2) statistic. MAIN RESULTS: This review includes 17 trials with 1520 patients analyzed in bisphosphonates groups, and 1490 analyzed in control groups. In comparison with placebo/no treatment, the pooled analysis demonstrated the beneficial effect of bisphosphonates on prevention of pathological vertebral fractures (RR= 0.74 (95% CI: 0.62 to 0.89), P = 0.001), total skeletal related events (SREs) (RR= 0.80 (95% CI: 0.72 to 0.89), P < 0.0001) and on amelioration of pain (RR = 0.75 (95% CI: 0.60 to 0.95), P = 0.01). We found no significant effect of bisphosphonates on overall survival (OS), progression-free survival (PFS), hypercalcemia or on the reduction of non-vertebral fractures. The indirect meta-analyses did not find the superiority of any particular type of bisphosphonate over others. Only two RCTs reported ONJ. The identified observational studies suggested that ONJ may be a common event (range: 0% to 51%). AUTHORS' CONCLUSIONS: Adding bisphosphonates to the treatment of MM reduces pathological vertebral fractures, SREs and pain but not mortality. Assuming the baseline risk of 20% to 50% for vertebral fracture without treatment, we estimate that between eight and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming the baseline risk of 31% to 76% for pain amelioration without treatment, we estimate that between five to 13 MM patients should be treated to reduce pain in one patient. Also, with the baseline risk of 35% to 86% for SREs without treatment, we estimate that between six and 15 MM patients should be treated to prevent SRE(s) in one patient. No bisphoshphonate appears to be superior to others.

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883.

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.

Investigating the role of host genetic factors in COVID-19 severity and susceptibility can inform our understanding of the underlying biological mechanisms that influence adverse outcomes and drug development 1 , 2 . Here we present a second updated genome-wide association study (GWAS) on COVID-19 severity and infection susceptibility to SARS-CoV-2 from the COVID-19 Host Genetic Initiative (data release 7). We performed a meta-analysis of up to 219,692 cases and over 3 million controls, identifying 51 distinct genome-wide significant loci—adding 28 loci from the previous data release 2 . The increased number of candidate genes at the identified loci helped to map three major biological pathways that are involved in susceptibility and severity: viral entry, airway defence in mucus and type I interferon.

Joint replacement in HIV-positive patients remains uncommon, with most experience gained in patients with haemophilia. We analysed retrospectively the outcome of 102 replacement arthroplasties in 73 HIV-positive patients from eight specialist haemophilia centres. Of these, 91 were primary procedures. The mean age of the patients at surgery was 39 years, and the median follow-up was for five years. The overall rate of deep sepsis was 18.7% for primary procedures and 36.3% for revisions. This is a much higher rate of infection than that seen in normal populations. A total of 44% of infections resolved fully after medical and/or surgical treatment. The benefits of arthroplasty in haemophilic patients are well established but the rates of complications are high. As this large study has demonstrated, high rates of infection occur, but survivorship analysis strongly suggests that most patients already diagnosed with HIV infection at the time of surgery should derive many years of symptomatic relief after a successful joint replacement. Careful counselling and education of both patients and healthcare workers before operation are therefore essential.

Venous thromboembolism (VTE) is a clinically important complication for both hospitalised and ambulatory cancer patients. In the current study, the frequency, demographics and risk (according to tumour site) of VTE were examined among patients seen at outpatient DVT (deep-vein thrombosis) clinics. Of 10,015 VTE cases, 1,361 were diagnosed with cancer, for an overall rate of cancer-associated VTE of 13.6% in this outpatient population. Patients with cancer-associated VTE were significantly older than cancer-free VTE cases (66.4 +/- 12.7 vs. 58.8 +/- 18.5 years; p<0.0001). The frequency of cancer-associated VTE peaked earlier among females than males, occurring in the sixth (137/639, 21.4% vs. 98/851, 11.3%; p<0.001) and seventh decades (213/980, 21.7% vs. 197/1096, 18%; p=0.036). VTE was described most frequently in common cancers - breast, prostate, colorectal and lung (56.1% of cases). The risk of VTE varied widely across 17 cancer types. Calculating odds ratios (OR) to assess the effect size of cancer type on VTE risk, the highest odds were observed for patients with pancreatic cancer (OR 9.65, 95% confidence interval [CI] (5.51-16.91). Tumours of the head and neck had higher odds than previously reported (OR 8.24, 95% CI 5.06-13.42). Reduced risk estimates were observed for skin cancers (melanoma and non-melanoma: OR 0.89, 95% CI 0.42-1.87; OR 0.74, 95% CI, 0.32-1.69, respectively). We conclude that outpatients have a similar rate of cancer-associated VTE as VTE patient populations previously reported, that cancer-associated VTE occurs in an older age group and earlier in females and that outpatients exhibit distinct tumour site-specific risk from that described among hospitalised cancer patients.

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

AIMS: The epidemiological and pathological features of Hodgkin lymphoma (HL) are complex. The Epstein-Barr virus (EBV) is consistently associated with a proportion of cases, and these cases are thought to represent a distinct aetiological subgroup of HL. The aim of the present analysis was to determine the age and sex specific incidence of EBV associated and non-associated HL, analysed separately, using data derived from a population based study-the Scotland and Newcastle epidemiological study of Hodgkin's disease (SNEHD). This study also provided a unique opportunity to evaluate accuracy in the current diagnosis and classification of HL. METHODS: SNEHD analysed consecutive cases of HL diagnosed in the study area between 1993 and 1997. Diagnostic biopsy material was retrieved, EBV status of tumours was determined, and histological review was performed. RESULTS: In total, 622 cases were eligible for the study, and EBV studies and histopathological review were performed on biopsy material from 537 and 549 cases, respectively. Accuracy in the overall diagnosis of HL and classification of nodular sclerosis HL was good, but diagnosis of HL in the elderly and classification of other subtypes was less reliable. One third of classic HL cases were EBV associated, and age specific incidence curves for EBV associated and non-associated cases were distinct. CONCLUSIONS: Comparison of age specific incidence curves for EBV associated and non-associated HL supports the hypothesis that these are two distinct aetiological entities. Accuracy in the diagnosis of HL is generally good, but certain subgroups of cases continue to present diagnostic difficulties.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterised by recurrent painful boils in flexural sites, such as the axillae and groin, that affects about 1% of the population, with onset in early adulthood. OBJECTIVES: To assess the effects of interventions for HS in people of all ages. SEARCH METHODS: We searched the following databases up to 13 August 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (Issue 7, 2015), MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We also searched five trials registers and handsearched the conference proceedings of eight dermatology meetings. We checked the reference lists of included and excluded studies for further references to relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of all interventions for hidradenitis suppurativa. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and methodological quality and performed data extraction. Our primary outcomes were quality of life, measured by a validated dermatology-specific scale, and adverse effects of the interventions. MAIN RESULTS: Twelve trials, with 615 participants, met our inclusion criteria. The median number of participants in each trial was 27, and median trial duration was 16 weeks. The included studies were conducted over a 32-year time period, from 1983 to 2015. A single RCT that was underpowered to detect clinically meaningful differences investigated most interventions.There were four trials of anti-TNF-α (tumour necrosis factor-alpha) therapies, which included etanercept, infliximab, and adalimumab. Adalimumab 40 mg weekly improved the Dermatology Life Quality Index (DLQI) score in participants with moderate to severe HS by 4.0 points relative to placebo (95% confidence interval (CI) -6.5 to -1.5 points), an effect size approximately equal to the DLQI minimal clinically important difference. We reduced the evidence quality to 'moderate' because the effect size was based on the results of only one study. In a meta-analysis of two studies with 124 participants, standard dose adalimumab 40 mg every other week was ineffective compared with placebo (moderate quality evidence). In a smaller study of 38 participants, of whom only 33 provided efficacy data, infliximab 5 mg/kg treatment improved DLQI by 8.4 DLQI points after eight weeks. Etanercept 50 mg twice weekly was well tolerated but ineffective.In a RCT of 200 participants, no difference was found in surgical complications (week one: risk ratio (RR) 0.78, 95% CI 0.58 to 1.05, moderate quality evidence) or risk of recurrence (after three months: RR 0.96, 95% CI 0.68 to 1.34, moderate quality evidence) in those randomised to receive a gentamicin-collagen sponge prior to primary closure compared with primary closure alone.RCTs of other interventions, including topical clindamycin 1% solution; oral tetracycline; oral ethinylestradiol 50 mcg with either cyproterone acetate 50 mg or norgestrel 500 mcg; intense pulsed light; neodymium-doped yttrium aluminium garnet (Nd:YAG) laser; methylene blue gel photodynamic therapy; and staphage lysate, were relatively small studies, preventing firm conclusions due to imprecision. AUTHORS' CONCLUSIONS: Many knowledge gaps exist in RCT evidence for HS. Moderate quality evidence exists for adalimumab, which improves DLQI score when 40 mg is given weekly, twice the standard psoriasis dose. However, the 95% confidence interval includes an effect size of only 1.5 DLQI points, which may not be clinically relevant, and the safety profile of weekly dosing has not been fully established. Infliximab also improves quality of life, based on moderate quality evidence.More RCTs are needed in most areas of HS care, particularly oral treatments and the type and timing of surgical procedures. Outcomes should be validated, ideally, including a minimal clinically important difference for HS.

BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. METHODS AND RESULTS: Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. CONCLUSIONS: This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.

Abstract: Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.