Ashford Hospital

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.

This paper reviews recent developments on the epoxidation of alkenes using hydrogen peroxide as an environmentally friendly oxidant. The activation of hydrogen peroxide takes place in the presence of a homogeneous metal catalyst such as tungten, manganese, iron and rhenium or through addition of stoichiometric amounts of auxiliaries, which convert hydrogen peroxide to a more active oxidant. Hydrogen peroxide has also been used with solids catalysts such as mixed oxides, redox zeolites, layered materials and supported metal catalysts. Heterogeneous catalysts, however, suffer generally from lower activity and stability compared to the homogeneous catalysts.

Three-dimensional printing (3DP) has demonstrated great potential for multi-material fabrication because of its capability for printing bespoke and spatially separated material conformations. Such a concept could revolutionise the pharmaceutical industry, enabling the production of personalised, multi-layered drug products on demand. Here, we developed a novel stereolithographic (SLA) 3D printing method that, for the first time, can be used to fabricate multi-layer constructs (polypills) with variable drug content and/or shape. Using this technique, six drugs, including paracetamol, caffeine, naproxen, chloramphenicol, prednisolone and aspirin, were printed with different geometries and material compositions. Drug distribution was visualised using Raman microscopy, which showed that whilst separate layers were successfully printed, several of the drugs diffused across the layers depending on their amorphous or crystalline phase. The printed constructs demonstrated excellent physical properties and the different material inclusions enabled distinct drug release profiles of the six actives within dissolution tests. For the first time, this paper demonstrates the feasibility of SLA printing as an innovative platform for multi-drug therapy production, facilitating a new era of personalised polypills.

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.

Introduction: Three-dimensional (3D) printing is a relatively new, rapid manufacturing technology that has found promising applications in the drug delivery and medical sectors. Arguably, never before has the healthcare industry experienced such a transformative technology. This review aims to discuss the state of the art of 3D printing technology in healthcare and drug delivery.Areas covered: The current and future applications of printing technologies within drug delivery and medicine have been discussed. The latest innovations in 3D printing of customized medical devices, drug-eluting implants, and printlets (3D-printed tablets) with a tailored dose, shape, size, and release characteristics have been covered. The review also covers the state of the art of 3D printing in healthcare (covering topics such as dentistry, surgical and bioprinting of patient-specific organs), as well as the potential of recent innovations, such as 4D printing, to shape the future of drug delivery and to improve treatment pathways for patients.Expert opinion: A future perspective is provided on the potential for 3D printing in healthcare, covering strategies to overcome the major barriers to integration that are faced today.

from the procedure, just as this is the main risk of carotid surgery.Only randomized comparison between carotid surgery and angioplasty can determine how these two procedures compare.The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) is the only ongoing randomized trial.The study now has 20 centres in the UK, Europe and North America.Our Monitoring Committee reported in November 1996, after analysing the data on over 300 patients, that there was no reason to stop the trial.We therefore plan to continue randomizing and will be carrying out an analysis with a minimum of 6 months' follow-up in 400 patients in October 1997.We hope that when we have the data available we will be able to answer some of the unanswered questions posed by

The popularity of machine learning (ML) across drug discovery continues to grow, yielding impressive results. As their use increases, so do their limitations become apparent. Such limitations include their need for big data, sparsity in data, and their lack of interpretability. It has also become apparent that the techniques are not truly autonomous, requiring retraining even post deployment. In this review, we detail the use of advanced techniques to circumvent these challenges, with examples drawn from drug discovery and allied disciplines. In addition, we present emerging techniques and their potential role in drug discovery. The techniques presented herein are anticipated to expand the applicability of ML in drug discovery.

The relationship between molecular structure and odor has fascinated and puzzled chemists for more than a century. Despite a great deal of research on structure-odor relationships, prediction of the odor of a novel molecule remains a statistical exercise and models only provide a probability of the character, threshold, and intensity. Surprises are still commonplace, and serendipity continues to be an important factor in the discovery of novel fragrant molecules. Recent advances in our understanding of the mechanism of olfaction provide an explanation for this and suggest that our ability to predict odor properties of molecules will not improve significantly in the near future.

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor (CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.

Purpose To illustrate the potential danger of applying “lean thinking” discretely and indiscriminantly in a project environment with high levels of complexity and uncertainty. Design/methodology/approach Insights are presented from two case studies of private residential construction projects which the authors believe are indicative of recent efforts to reduce the cost of construction activities. Findings Evidence was found of attempts to remove capacity in transportation, stockholding and on‐site labour. Some of these attempts were logical and resulted in cost‐savings but others were illogical and resulted in reduced levels of responsiveness and flexibility to respond to the uncertainty which is a characteristic of most construction projects. Research limitations/implications Further research is required to quantify the impact of discrete improvements in functional aspects of supply chain projects and the conditions in which lean thinking can be put to best effect. Practical implications Firms operating in the construction sector need to pay greater attention to the impact on the effectiveness of supply chain projects of achieving cost savings in discrete activities. Originality/value This paper challenges conventional thinking with respect to the application of lean principles to the construction industry and calls for greater awareness of the project‐centric nature of the construction industry and the application of lean thinking therein.

AIMS AND OBJECTIVES: The European Position Paper on Rhinosinusitis and Nasal Polyps provides treatment algorithms based on the mild/moderate/severe (MMS) classification. To date there has been no statistically validated stratification of the SNOT-22 score according to this classification. METHODS: 65 consecutive patients diagnosed with CRS completed a SNOT-22, VAS and rated their symptoms according to MMS and impact on quality of life. RESULTS: The median SNOT 22 scores varied between the 3 MMS categories. The interquartile ranges for the respective MMS groups were: Mild 8-17, Moderate 22.5-48, Severe 54-83. Median values for the respective MMs groups were: Mild 12, Moderate 36 and Severe 66. 15.38% of patients in the Mild category, 95.24% in the Moderate category and 100% in the Severe category feel their QoL is affected. There was a strongly positive correlation between the SNOT-22 and VAS scores. CONCLUSION: We propose a statistically validated definition for stratification of the SNOT-22, with Mild being defined on the SNOT-22 score as 8-20 inclusive, Moderate as >20-50 and Severe as >50.

Purpose To review published case studies, and some unpublished results, to identify the benefits actually achieved by implementing an electronic records management system or an electronic document management system (ERMS, or EDMS). Design/methodology/approach Draws on the literature and unpublished results of work undertaken by the authors’ organisation. Findings Few case studies were found in which clear, quantitative benefits are described. The reasons for this are discussed. Those studies that did show clear benefits with good evidence for them demonstrated five principles: (1) the “system” must include the people (policy makers and users); (2) the EDRMS must be integrated with the processes of the organisation; (3) frequently the role of records managers is to educate, advise and support the users; (4) a continuum model covering documents and records gives clearer benefits than separate document and record lifecycles; and (5) there is no single magic bullet to solve information management problems. Practical implications An organisation which is planning to implement an EDRMS, or which is planning to upgrade or modify an existing EDRMS, can be confident that real benefits and an acceptable return on investment are possible. Originality/value This paper identifies benefits that have been realised in practice from EDRMS implementations.

RuIV-CoIII (1:1.5) binary oxide, prepared by co-precipitation, is a highly efficient solid catalyst for the oxidation of primary alcohols to aldehydes with O2 (76-95% selectivity at 54-100% conversion) in a liquid phase under atmospheric pressure.

Body packing or internal concealment used by drug dealers to smuggle illicit substances, puts the body packer at risk of both imprisonment and death. We report our experience over a 4 year period from January 1996 to December 1999 of suspects presenting to our hospital (the largest series in Europe). A total of 572 cases were assessed radiographically and 180 were shown to be carrying foreign bodies. The commonest reasons for admission were suspected overdose or gastrointestinal obstruction. Thirty-six cases were admitted, of whom 7 required surgical intervention. No deaths occurred. Of all people detained for smuggling by internal concealment into Britain during this period, 27% were seen in our hospital. These cases may present alone or escorted by Her Majesty's Customs and Excise personnel, and one must be aware of this possibility even when situated away from a port of entry.

PURPOSE: We present our 4-year experience with the thermo-expandable shape memory alloy Memokath 051 stent (Engineers and Doctors of Copenhagen, Copenhagen, Denmark) for managing long-term ureteral obstruction. MATERIALS AND METHODS: We used a nickel-titanium shape memory alloy ureteral stent to treat 28 patients 29 to 86 years old (mean age 59.2). Ureteral obstruction was caused by malignancy in 18 cases and by recurrent benign disease in 10. A total of 37 stents were inserted from November 1996 to November 2000 using general anesthesia. Mean followup was 19.3 months (range 3 to 35). RESULTS: Upper tract decompression was achieved in all cases. Currently 15 stents are functional in 13 patients, while 8 patients died with a total of 13 functioning stents in place. In 7 patients 9 stents were removed for various reasons. There has been no radiological evidence of encrustation to date. No patient has been rehospitalized with stent related sepsis pain or hematuria, resulting in improved quality of life. CONCLUSIONS: This stent seems to provide a significant benefit over conventional Double-J (Medical Engineering Corp., New York, New York) and other metallic stents. Its remarkable thermal memory permits removal, a feature that until recently was not available in any other metallic ureteral stent. Durable and complication-free decompression of the upper tract can be achieved with the Memokath 051.

This study was undertaken to examine the feasibility of breast volume estimation as a predictor of cosmetic outcome. We looked at the cosmetic result of conservative surgery related to the percentage of breast tissue removed. The breast tissue excised was calculated by comparing the breast volume, calculated from the mammogram, and the specimen volume. A total of 24 patients were recalled to a special clinic and were assessed for their cosmetic result by the clinician, independent observer and the patient. The assessment was based on a scale of 1 to 4 (poor to excellent). Our results show that if less than 20% of the breast was removed, all assessors felt that the cosmetic result was at least fair. If more than 20% of the breast was removed, the cosmetic score was poor as assessed by the clinician and independent observer. When excision of greater than 20% of breast tissue is anticipated, then a breast reconstruction procedure should be considered, if cosmetic outcome is to be enhanced.

OBJECTIVE: To assess the ease on insertion, patient tolerance, undesirable side-effects, degree of encrustation and duration of upper tract decompression with a new thermo-expandable shape memory alloy ureteric stent. PATIENTS AND METHODS: From November 1996 to October 1998, 15 patients with ureteric strictures were treated with a new nickel-titanium shape-memory alloy stent, the Memokath 051 (Engineers & Doctors A/S, Hornbaek, Denmark). A total of 22 insertions were carried out. Ureteric obstruction was caused by recurrent colorectal carcinoma in four patients; two patients each with transitional cell carcinoma of the bladder, iatrogenic injury or ischaemia at the uretero-ileal anastomosis; and one patient each with metastatic lymph nodes from prostatic carcinoma, radiation-induced fibrosis, pelvi-ureteric junction obstruction, metastatic carcinoma of the vagina and extra-luminal endometriosis. The stent has a shaft diameter of 9 F and its proximal end expands to 17 F. The first three patients were treated with the original version, which expanded to 14 F. The unexpanded stent is inserted into the ureter after initial dilatation of the stricture to 12 F. The stent is expanded by injection with sterile water preheated to 50 degrees C. The procedures were carried out under a general anaesthetic and patients were allowed home the next day. The follow-up protocol included initial intravenous urography (IVU) at 6 weeks, with assessment of a mid-stream urine sample and renal function tests. These were repeated at 3-monthly intervals. Isotopic renography was performed when indicated. RESULTS: The mean (range) follow-up was 10.6 (2-21) months; there was complete relief of upper tract obstruction in all patients. No stent-related symptoms, e.g. pain, sepsis, haematuria or frequency, were noted and no encrustation has occurred so far. The stent migrated in the first three patients with the original smaller diameter of stent but decompression of the upper tracts was maintained. None of the modified wider stents have migrated. The return of peristalsis in the proximal ureter was detected during IVU. There was no apparent endothelial growth through the stent material and no re-admissions for stent-related complications. CONCLUSION: Early experience with this new stent is very encouraging. All patients have maintained satisfactory decompression of their upper tracts with no need for repeated hospitalization for stent changes. There have been no untoward side-effects so far. This stent appears to have a valuable place in the long-term management of ureteric strictures; it is probably most suited for malignant ureteric obstruction. It should be considered in the management of selected benign strictures that require long-term JJ stenting.

We compared the outcome of patients treated for an intertrochanteric fracture of the femoral neck with a locked, long intramedullary nail with those treated with a dynamic hip screw (DHS) in a prospective randomised study. Each patient who presented with an extra-capsular hip fracture was randomised to operative stabilisation with either a long intramedullary Holland nail or a DHS. We treated 92 patients with a Holland nail and 98 with a DHS. Pre-operative variables included the Mini Mental test score, patient mobility, fracture pattern and American Society of Anesthesiologists grading. Peri-operative variables were anaesthetic time, operating time, radiation time and blood loss. Post-operative variables were time to mobilising with a frame, wound infection, time to discharge, time to fracture union, and mortality. We found no significant difference in the pre-operative variables. The mean anaesthetic and operation times were shorter in the DHS group than in the Holland nail group (29.7 vs 40.4 minutes, p < 0.001; and 40.3 vs 54 minutes, p < 0.001, respectively). There was an increased mean blood loss within the DHS group versus the Holland nail group (160 ml vs 78 ml, respectively, p < 0.001). The mean time to mobilisation with a frame was shorter in the Holland nail group (DHS 4.3 days, Holland nail 3.6 days, p = 0.012). More patients needed a post-operative blood transfusion in the DHS group (23 vs seven, p = 0.003) and the mean radiation time was shorter in this group (DHS 0.9 minutes vs Holland nail 1.56 minutes, p < 0.001). The screw of the DHS cut out in two patients, one of whom underwent revision to a Holland nail. There were no revisions in the Holland nail group. All fractures in both groups were united when followed up after one year. We conclude that the DHS can be implanted more quickly and with less exposure to radiation than the Holland nail. However, the resultant blood loss and need for transfusion is greater. The Holland nail allows patients to mobilise faster and to a greater extent. We have therefore adopted the Holland nail as our preferred method of treating intertrochanteric fractures of the hip.

Prevention of further cardiovascular events in patients with established coronary heart disease is a priority for public health. 1 Previous studies have addressed such issues and have showed that there is considerable room for improvement. 2-4 The Healthwise survey was conducted in primary care throughout Britain to identify the prevalence of recorded coronary disease and to examine whether progress had been made in secondary preventive measures. Smoking, blood pressure, recording of cholesterol concentrations, and the specific use of the four lifesaving classes of cardiac drugs-aspirin, blockers, angiotensin converting enzyme inhibitors, and statins-were studied. (Other lifestyle issues, such as dietary assessment and exercise, were variably noted in practice records and are not shown.)

A scientific workshop held in the UK explored the potential contribution of traditional dried fruits to public health, identified gaps in the evidence and addressed priorities for research. Presentations considered the categorisation and composition of dried fruits; dried fruit and gastrointestinal health; the polyphenol content of dried fruits and their potential contribution to health; dried fruit and appetite in relation to the psychology of snacking and obesity; dried fruit and dental health including its role as a snack; and conflicts in public health advice for dried fruits. A round table discussion explored the contribution of dried fruit to "five a day" fruit and vegetable intake and fibre intake, whether dried fruits have equivalence with fresh in terms of dietary advice, advice on snacking in relation to dental health and appetite control, informing the public about different types of dried fruits and avoiding consumer confusion, and future research requirements.