Worthing Hospital

Survey research is sometimes regarded as an easy research approach. However, as with any other research approach and method, it is easy to conduct a survey of poor quality rather than one of high quality and real value. This paper provides a checklist of good practice in the conduct and reporting of survey research. Its purpose is to assist the novice researcher to produce survey work to a high standard, meaning a standard at which the results will be regarded as credible. The paper first provides an overview of the approach and then guides the reader step-by-step through the processes of data collection, data analysis, and reporting. It is not intended to provide a manual of how to conduct a survey, but rather to identify common pitfalls and oversights to be avoided by researchers if their work is to be valid and credible.

The race to produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK, B.1.1.7; South Africa, B.1.351; and Brazil, P.1. These variants have multiple changes in the immunodominant spike protein that facilitates viral cell entry via the angiotensin-converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here, we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K, although K417N and N501Y act together against some important antibody classes. In a number of cases, it would appear that convalescent and some vaccine serum offers limited protection against this variant.

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.

Journal Article The concept of dissolution efficiency Get access K A Khan K A Khan Beecham Pharmaceuticals, Clarendon Road, Worthing, Sussex. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 27, Issue 1, January 1975, Pages 48–49, https://doi.org/10.1111/j.2042-7158.1975.tb09378.x Published: 12 April 2011 Article history Received: 19 July 1974 Published: 12 April 2011

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.

SARS-CoV-2 has caused over 2 million deaths in little over a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of the pandemic and error-prone virus replication is leading to the appearance of mutant viruses and potentially escape from antibody responses. Variant B.1.1.7, now dominant in the UK, with increased transmission, harbors 9 amino acid changes in the spike, including N501Y in the ACE2 interacting surface. We examine the ability of B.1.1.7 to evade antibody responses elicited by natural SARS-CoV-2 infection or vaccination. We map the impact of N501Y by structure/function analysis of a large panel of well-characterized monoclonal antibodies. B.1.1.7 is harder to neutralize than parental virus, compromising neutralization by some members of a major class of public antibodies through light-chain contacts with residue 501. However, widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed.

5 Background: In estrogen-receptor-positive (ER+) early breast cancer, 5 years of tamoxifen reduces breast cancer death rates by about a third throughout years 0-14. It has been uncertain how 10 years of tamoxifen compares with this. Methods: During 1991-2005, 6,953 women with ER+ (n=2755), or ER untested (4198, estimated 80% ER+ if status known) invasive breast cancer from 176 UK centres were, after 5 years of tamoxifen, randomized to stop tamoxifen or continue to year 10. Annual follow-up recorded compliance, recurrence, mortality, and hospital admissions. Results: Allocation to continue tamoxifen reduced breast cancer recurrence (580/3468 vs 672/3485, p=0.003). This reduction was time dependent: rate ratio 0.99 during years 5-6 [95%CI 0.86-1.15], 0.84 [0.73-0.95] during years 7-9, and 0.75 [0.66-0.86] later. Longer treatment also reduced breast cancer mortality (392 vs 443 deaths after recurrence, p=0.05), rate ratio 1.03 [0.84-1.27] during years 5-9 and 0.77 [0.64-0.92] later; and overall mortality (849 vs 910 deaths, p=0.1), rate ratio 1.05 [0.90-1.22] during years 5-9 and 0.86 [0.75-0.97] later. Non-breast-cancer mortality was little affected (457 vs 467 deaths, rate ratio 0.94 [0.82-1.07]). There were 102 vs 45 endometrial cancers RR=2.20 (1.31-2.34, p<0.0001) with 37 (1.1%) vs 20 (0.6%) deaths (absolute hazard 0.5%, p=0.02). Combining the similar results of aTTom and its international counterpart ATLAS (Lancet 2013) enhances statistical significance of recurrence (p<0.0001), breast cancer mortality (p=0.002) and overall survival (p=0.005) benefits. Conclusions: aTTom confirms that, in ER+ disease, continuing tamoxifen to year 10 rather than just to year 5 produces further reductions in recurrence, from year 7 onward, and breast cancer mortality after year 10. Taken together with the reduction in breast cancer deaths seen in trials of 5 years of tamoxifen vs none, these results indicate that 10 years of adjuvant tamoxifen, compared to no tamoxifen, reduces breast cancer mortality by about one third in the first 10 years following diagnosis and by a half subsequently. Clinical trial information: ISRCTN17222211.

< 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.

OBJECTIVES: To examine the quality of response rate reporting and to identify methodological factors influencing response rates in published patient satisfaction studies. DESIGN: Examination and analysis of 210 studies from 200 papers published in 1994 in 141 different health journals. Papers were located in the following databases: British Nursing Index, CINAHL, EMBASE, MedLine, Popline, and PsycLIT. MAIN MEASURES: Reported and calculated response rates, collection and recruitment procedures of published studies, and type of instruments used for data collection. RESULTS: Forty-eight per cent of studies reported a response rate. The mean response rate was 72.1%. There was no association between response rate and the type of instrument used for data collection. Studies which used a face-to-face approach to either subject recruitment (mean response rate, 76.7%) or data collection (mean response rate, 76.9%) were associated with significantly higher response rates than those in which subjects were recruited by mail (mean response rate, 66.5%) or data were collected by mail (mean response rate, 67%). Response rate was not related to questionnaire length. CONCLUSION: Patient satisfaction studies generally show poor awareness of the importance of methodological issues relevant to response rate. Far more attention to this aspect is needed if findings in this field are to be accepted as valid and useful.

Forty-one patients with anorexia nervosa, admitted to the Maudsley Hospital between 1959 and 1966, were followed up after a mean of 20 years. An assessment of general outcome (based on the Morgan-Russell scales) yielded three outcome categories: 'good' (n = 12), 'intermediate' (n = 13) and 'poor' (n = 15). Six patients (15%) had died from causes related to anorexia nervosa; at least 15% had developed bulimia nervosa. There was a general consistency between the follow-up at 20 years and that previously conducted five years after admission, although with a few individual patients there were serious prognostic errors at the earlier follow-up. A poorer outcome was associated with a later age of onset, a history of neurotic and personality disturbances, disturbed relationships in the family and a longer duration of illness.

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.

BACKGROUND: Breast-cancer-related lymphoedema is a chronic condition with estimates of incidence ranging from 6 to 83%. Lymphoedema has been associated with a variety of risk factors. However, this evidence has suffered from methodological weaknesses, and so has had little impact upon clinical practice. AIM: To examine incidence and risk factors [hospital skin puncture, surgical procedure, Body Mass Index (BMI), age, axillary node status, number of axillary nodes removed, radiotherapy and surgery on dominant side] for breast cancer-related arm lymphoedema. DESIGN: Prospective observational study, with measurement of limbs pre-operatively and at regular intervals post-operatively. METHODS: We recruited 251 women who had surgical treatment for breast cancer that involved sampling, excision or biopsy of axillary nodes, aged > or = 18 years, and free of advanced disease and psychological co-morbidities. Of these, 188 (74.9%) were available for 3-year follow-up. RESULTS: At follow-up, 39 (20.7%) had developed lymphoedema. Hospital skin puncture (vs. none) (RR 2.44, 95%CI 1.33-4.47), mastectomy (vs. wide local excision or lumpectomy) (RR 2.04, 95%CI 1.18-3.54), and BMI > or = 26 (vs. BMI 19-26) (RR 2.02, 95%CI 1.11-3.68) were the only significant risk factors. DISCUSSION: Lymphoedema remains a significant clinical problem, with 1:5 women in this sample developing the condition following treatment for breast cancer. Risk factors are identified in the development of lymphoedema that should be taken into account in clinical practice.

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.

We have identified a t(8;9)(p21-23;p23-24) in seven male patients (mean age 50, range 32-74) with diverse hematologic malignancies and clinical outcomes: atypical chronic myeloid leukemia/chronic eosinophilic leukemia (n = 5), secondary acute myeloid leukemia (n = 1), and pre-B-cell acute lymphoblastic leukemia (n = 1). Initial fluorescence in situ hybridization studies of one patient indicated that the nonreceptor tyrosine kinase Janus-activated kinase 2 (JAK2) at 9p24 was disrupted. Rapid amplification of cDNA ends-PCR identified the 8p22 partner gene as human autoantigen pericentriolar material (PCM1), a gene encoding a large centrosomal protein with multiple coiled-coil domains. Reverse transcription-PCR and fluorescence in situ hybridization confirmed the fusion in this case and also identified PCM1-JAK2 in the six other t(8;9) patients. The breakpoints were variable in both genes, but in all cases the chimeric mRNA is predicted to encode a protein that retains several of the predicted coiled-coil domains from PCM1 and the entire tyrosine kinase domain of JAK2. Reciprocal JAK2-PCM1 mRNA was not detected in any patient. We conclude that human autoantigen pericentriolar material (PCM1)-JAK2 is a novel, recurrent fusion gene in hematologic malignancies. Patients with PCM1-JAK2 disease are attractive candidates for targeted signal transduction therapy.

<ns3:p> <ns3:bold>Background:</ns3:bold> The COVID-19 pandemic caused &gt;1 million infections during January-March 2020. There is an urgent need for reliable antibody detection approaches to support diagnosis, vaccine development, safe release of individuals from quarantine, and population lock-down exit strategies. We set out to evaluate the performance of ELISA and lateral flow immunoassay (LFIA) devices. </ns3:p> <ns3:p> <ns3:bold>Methods:</ns3:bold> We tested plasma for COVID (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) IgM and IgG antibodies by ELISA and using nine different LFIA devices. We used a panel of plasma samples from individuals who have had confirmed COVID infection based on a PCR result (n=40), and pre-pandemic negative control samples banked in the UK prior to December-2019 (n=142). </ns3:p> <ns3:p> <ns3:bold>Results:</ns3:bold> ELISA detected IgM or IgG in 34/40 individuals with a confirmed history of COVID infection (sensitivity 85%, 95%CI 70-94%), vs. 0/50 pre-pandemic controls (specificity 100% [95%CI 93-100%]). IgG levels were detected in 31/31 COVID-positive individuals tested ≥10 days after symptom onset (sensitivity 100%, 95%CI 89-100%). IgG titres rose during the 3 weeks post symptom onset and began to fall by 8 weeks, but remained above the detection threshold. Point estimates for the sensitivity of LFIA devices ranged from 55-70% versus RT-PCR and 65-85% versus ELISA, with specificity 95-100% and 93-100% respectively. Within the limits of the study size, the performance of most LFIA devices was similar. </ns3:p> <ns3:p> <ns3:bold>Conclusions:</ns3:bold> Currently available commercial LFIA devices do not perform sufficiently well for individual patient applications. However, ELISA can be calibrated to be specific for detecting and quantifying SARS-CoV-2 IgM and IgG and is highly sensitive for IgG from 10 days following first symptoms. </ns3:p>

Summary The method of adjusting plot values by covariance on neighbouring plots in randomized field experiments, suggested by Papadakis in 1937, is re-examined theoretically for both one-dimensional and two-dimensional layouts, making use of Markovian and autonormal models. The gain in efficiency over orthodox randomized block analysis can be appreciable when the number of treatments is fairly large, and can be increased by iterating the analysis; this also reduces the discrepancy between the apparent accuracy from the residual sum of squares, and the true accuracy of the treatment comparisons after adjustment. Some illustrative examples are included.

Dengue is a mosquito-transmitted virus infection that causes epidemics of febrile illness and hemorrhagic fever across the tropics and subtropics worldwide. Annual epidemics are commonly observed, but there is substantial spatiotemporal heterogeneity in intensity. A better understanding of this heterogeneity in dengue transmission could lead to improved epidemic prediction and disease control. Time series decomposition methods enable the isolation and study of temporal epidemic dynamics with a specific periodicity (e.g., annual cycles related to climatic drivers and multiannual cycles caused by dynamics in population immunity). We collected and analyzed up to 18 y of monthly dengue surveillance reports on a total of 3.5 million reported dengue cases from 273 provinces in eight countries in Southeast Asia, covering ∼ 10(7) km(2). We detected strong patterns of synchronous dengue transmission across the entire region, most markedly during a period of high incidence in 1997-1998, which was followed by a period of extremely low incidence in 2001-2002. This synchrony in dengue incidence coincided with elevated temperatures throughout the region in 1997-1998 and the strongest El Niño episode of the century. Multiannual dengue cycles (2-5 y) were highly coherent with the Oceanic Niño Index, and synchrony of these cycles increased with temperature. We also detected localized traveling waves of multiannual dengue epidemic cycles in Thailand, Laos, and the Philippines that were dependent on temperature. This study reveals forcing mechanisms that drive synchronization of dengue epidemics on a continental scale across Southeast Asia.

The purpose of this study was to examine a variety of mathematical volume formulae and their respective validity in establishing limb volume in monitoring and evaluation of treatment for lymphoedema. Using a random sample of treatment records from the Day Ward, Worthing Hospital, it is shown that the formula most commonly used at present, that for a cylinder, produces imprecise volume data. A simplified formula derived from the formula for a frustum is tested, and is found to produce more accurate data. The paper proposes that the frustum formula is more appropriate in establishing limb volume, and should be adopted by practitioners.

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 ).

AIMS: The staining pattern of the recently described antibody melan-A was compared with those of S100 protein and HMB-45 in a variety of melanocytic lesions to assess the specificity and sensitivity of these antibodies. METHODS AND RESULTS: Immunohistochemical staining of paraffin sections of a range of melanocytic lesions was carried out following a high temperature antigen retrieval technique. The pattern and intensity of staining was semiquantitatively scored. S100 remains the most sensitive marker of melanocytic differentiation being diffusely positive in all benign and all primary and secondary malignant lesions including naevoid melanomas, and in most desmoplastic/spindle cell melanomas. Of the two more specific melanocytic markers melan-A stains the majority of benign and malignant lesions diffusely but with occasional patchy positivity only in some secondary melanoma deposits and with little staining of desmoplastic/spindle cell melanomas. HMB-45 is the least sensitive of the three showing little positivity of benign mature naevus cells, only variable patchy positivity of primary and secondary melanoma cells and limited positivity in naevoid, desmoplastic and metastatic melanomas. CONCLUSIONS: Melan-A is a useful addition to antibody panels as it is apparently specific for melanocytic lesions and is more sensitive than HMB-45; however, it has less value than S100 in the detection of spindle cell and desmoplastic melanomas.