Brighton Hospital

BACKGROUND: Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. METHODS: We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. RESULTS: The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57). CONCLUSIONS: Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).

Soft lithography, a set of techniques for microfabrication, is based on printing and molding using elastomeric stamps with the patterns of interest in basrelief. As a technique for fabricating microstructures for biological applications, soft lithography overcomes many of the shortcomings of photolithography. In particular, soft lithography offers the ability to control the molecular structure of surfaces and to pattern the complex molecules relevant to biology, to fabricate channel structures appropriate for microfluidics, and to pattern and manipulate cells. For the relatively large feature sizes used in biology (> or = 50 microns), production of prototype patterns and structures is convenient, inexpensive, and rapid. Self-assembled monolayers of alkanethiolates on gold are particularly easy to pattern by soft lithography, and they provide exquisite control over surface biochemistry.

BACKGROUND: Obstructive sleep apnea (OSA) is a common chronic disorder that often requires lifelong care. Available practice parameters provide evidence-based recommendations for addressing aspects of care. OBJECTIVE: This guideline is designed to assist primary care providers as well as sleep medicine specialists, surgeons, and dentists who care for patients with OSA by providing a comprehensive strategy for the evaluation, management and long-term care of adult patients with OSA. METHODS: The Adult OSA Task Force of the American Academy of Sleep Medicine (AASM) was assembled to produce a clinical guideline from a review of existing practice parameters and available literature. All existing evidence-based AASM practice parameters relevant to the evaluation and management of OSA in adults were incorporated into this guideline. For areas not covered by the practice parameters, the task force performed a literature review and made consensus recommendations using a modified nominal group technique. RECOMMENDATIONS: Questions regarding OSA should be incorporated into routine health evaluations. Suspicion of OSA should trigger a comprehensive sleep evaluation. The diagnostic strategy includes a sleep-oriented history and physical examination, objective testing, and education of the patient. The presence or absence and severity of OSA must be determined before initiating treatment in order to identify those patients at risk of developing the complications of sleep apnea, guide selection of appropriate treatment, and to provide a baseline to establish the effectiveness of subsequent treatment. Once the diagnosis is established, the patient should be included in deciding an appropriate treatment strategy that may include positive airway pressure devices, oral appliances, behavioral treatments, surgery, and/or adjunctive treatments. OSA should be approached as a chronic disease requiring long-term, multidisciplinary management. For each treatment option, appropriate outcome measures and long-term follow-up are described.

This special issue of Dalton Transactions is to mark the 60th birthday of Professor Dr. Annie K. Powell. The issue highlights advances in Modern Coordination Chemistry.

OBJECTIVES: To assess the literature on the accuracy of static computer-assisted implant surgery in implant dentistry. MATERIALS AND METHODS: Electronic and manual literature searches were conducted to collect information about the accuracy of static computer-assisted implant systems. Meta-regression analysis was performed to summarise the accuracy studies. RESULTS: From a total of 372 articles. 20 studies, one randomised controlled trial (RCT), eight uncontrolled retrospective studies and 11 uncontrolled prospective studies were selected for inclusion for qualitative synthesis. A total of 2,238 implants in 471 patients that had been placed using static guides were available for review. The meta-analysis of the accuracy (20 clinical) revealed a total mean error of 1.2 mm (1.04 mm to 1.44 mm) at the entry point, 1.4 mm (1.28 mm to 1.58 mm) at the apical point and deviation of 3.5°(3.0° to 3.96°). There was a significant difference in accuracy in favour of partial edentulous comparing to full edentulous cases. CONCLUSION: Different levels of quantity and quality of evidence were available for static computer-aided implant surgery (s-CAIS). Based on the present systematic review and its limitations, it can be concluded that the accuracy of static computer-aided implant surgery is within the clinically acceptable range in the majority of clinical situations. However, a safety marge of at least 2 mm should be respected. A lack of homogeneity was found in techniques adopted between the different authors and the general study designs.

Previous studies of the relative importance of industry and country factors in determining equity returns generally concluded that country factors dominate industry factors. We present evidence that industry factors have been growing in relative importance and may now dominate country factors. Furthermore, our evidence suggests that over the past five years, diversification across global industries has provided greater risk reduction than diversification by countries. These findings suggest that industry allocation is an increasingly important consideration for active managers of global equity portfolios and that investors may wish to reconsider home-biased equity allocation policies.

Recent reports have suggested that brain stem and cortical Lewy body formation may identify a neurodegenerative disorder in elderly demented individuals which accounts for up to 20% of cases of senile dementia coming to autopsy. Retrospective analysis of case notes of 21 autopsy patients with neuropathologically proven senile dementia of Lewy body type (SDLT) and 37 cases with neuropathologically proven Alzheimer's disease (AD) identified a characteristic clinical syndrome in SDLT. Fluctuating cognitive impairment; psychotic features including visual and auditory hallucinations, and paranoid delusions; depressive symptoms; falling and unexplained losses of consciousness were all seen significantly more often than in AD. Over half of the SDLT patients in this series who were given neuroleptics in standard dose showed acute and often irreversible adverse reactions indicative of a neuroleptic sensitivity syndrome. The survival time of drug treated patients was reduced by 50%. Operational criteria to aid in the clinical distinction between SDLT and AD patients are proposed and hypotheses regarding possible aetiology and treatment discussed.

OBJECTIVES: To estimate life expectancy for people with HIV undergoing treatment compared with life expectancy in the general population and to assess the impact on life expectancy of late treatment, defined as CD4 count <200 cells/mm(3) at start of antiretroviral therapy. DESIGN: Cohort study. SETTING: Outpatient HIV clinics throughout the United Kingdom. Population Adult patients from the UK Collaborative HIV Cohort (UK CHIC) Study with CD4 count ≤ 350 cells/mm(3) at start of antiretroviral therapy in 1996-2008. MAIN OUTCOME MEASURES: Life expectancy at the exact age of 20 (the average additional years that will be lived by a person after age 20), according to the cross sectional age specific mortality rates during the study period. RESULTS: 1248 of 17,661 eligible patients died during 91,203 person years' follow-up. Life expectancy (standard error) at exact age 20 increased from 30.0 (1.2) to 45.8 (1.7) years from 1996-9 to 2006-8. Life expectancy was 39.5 (0.45) for male patients and 50.2 (0.45) years for female patients compared with 57.8 and 61.6 years for men and women in the general population (1996-2006). Starting antiretroviral therapy later than guidelines suggest resulted in up to 15 years' loss of life: at age 20, life expectancy was 37.9 (1.3), 41.0 (2.2), and 53.4 (1.2) years in those starting antiretroviral therapy with CD4 count <100, 100-199, and 200-350 cells/mm(3), respectively. CONCLUSIONS: Life expectancy in people treated for HIV infection has increased by over 15 years during 1996-2008, but is still about 13 years less than that of the UK population. The higher life expectancy in women is magnified in those with HIV. Earlier diagnosis and subsequent timely treatment with antiretroviral therapy might increase life expectancy.

The ability to edit plant genomes through gene targeting (GT) requires efficient methods to deliver both sequence-specific nucleases (SSNs) and repair templates to plant cells. This is typically achieved using Agrobacterium T-DNA, biolistics or by stably integrating nuclease-encoding cassettes and repair templates into the plant genome. In dicotyledonous plants, such as Nicotinana tabacum (tobacco) and Solanum lycopersicum (tomato), greater than 10-fold enhancements in GT frequencies have been achieved using DNA virus-based replicons. These replicons transiently amplify to high copy numbers in plant cells to deliver abundant SSNs and repair templates to achieve targeted gene modification. In the present work, we developed a replicon-based system for genome engineering of cereal crops using a deconstructed version of the wheat dwarf virus (WDV). In wheat cells, the replicons achieve a 110-fold increase in expression of a reporter gene relative to non-replicating controls. Furthermore, replicons carrying CRISPR/Cas9 nucleases and repair templates achieved GT at an endogenous ubiquitin locus at frequencies 12-fold greater than non-viral delivery methods. The use of a strong promoter to express Cas9 was critical to attain these high GT frequencies. We also demonstrate gene-targeted integration by homologous recombination (HR) in all three of the homoeoalleles (A, B and D) of the hexaploid wheat genome, and we show that with the WDV replicons, multiplexed GT within the same wheat cell can be achieved at frequencies of ~1%. In conclusion, high frequencies of GT using WDV-based DNA replicons will make it possible to edit complex cereal genomes without the need to integrate GT reagents into the genome.

BACKGROUND: The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy. METHODS: Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis. RESULTS: A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]). CONCLUSIONS: In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

Importance: Large language models (LLMs) like ChatGPT appear capable of performing a variety of tasks, including answering patient eye care questions, but have not yet been evaluated in direct comparison with ophthalmologists. It remains unclear whether LLM-generated advice is accurate, appropriate, and safe for eye patients. Objective: To evaluate the quality of ophthalmology advice generated by an LLM chatbot in comparison with ophthalmologist-written advice. Design, Setting, and Participants: This cross-sectional study used deidentified data from an online medical forum, in which patient questions received responses written by American Academy of Ophthalmology (AAO)-affiliated ophthalmologists. A masked panel of 8 board-certified ophthalmologists were asked to distinguish between answers generated by the ChatGPT chatbot and human answers. Posts were dated between 2007 and 2016; data were accessed January 2023 and analysis was performed between March and May 2023. Main Outcomes and Measures: Identification of chatbot and human answers on a 4-point scale (likely or definitely artificial intelligence [AI] vs likely or definitely human) and evaluation of responses for presence of incorrect information, alignment with perceived consensus in the medical community, likelihood to cause harm, and extent of harm. Results: A total of 200 pairs of user questions and answers by AAO-affiliated ophthalmologists were evaluated. The mean (SD) accuracy for distinguishing between AI and human responses was 61.3% (9.7%). Of 800 evaluations of chatbot-written answers, 168 answers (21.0%) were marked as human-written, while 517 of 800 human-written answers (64.6%) were marked as AI-written. Compared with human answers, chatbot answers were more frequently rated as probably or definitely written by AI (prevalence ratio [PR], 1.72; 95% CI, 1.52-1.93). The likelihood of chatbot answers containing incorrect or inappropriate material was comparable with human answers (PR, 0.92; 95% CI, 0.77-1.10), and did not differ from human answers in terms of likelihood of harm (PR, 0.84; 95% CI, 0.67-1.07) nor extent of harm (PR, 0.99; 95% CI, 0.80-1.22). Conclusions and Relevance: In this cross-sectional study of human-written and AI-generated responses to 200 eye care questions from an online advice forum, a chatbot appeared capable of responding to long user-written eye health posts and largely generated appropriate responses that did not differ significantly from ophthalmologist-written responses in terms of incorrect information, likelihood of harm, extent of harm, or deviation from ophthalmologist community standards. Additional research is needed to assess patient attitudes toward LLM-augmented ophthalmologists vs fully autonomous AI content generation, to evaluate clarity and acceptability of LLM-generated answers from the patient perspective, to test the performance of LLMs in a greater variety of clinical contexts, and to determine an optimal manner of utilizing LLMs that is ethical and minimizes harm.

Small business and entrepreneurship has emerged as an important area of research over the past 40 years. Much of this development has been achieved by drawing on and adapting the theoretical frameworks of disciplines from outside. However, such diversity of disciplinary foundation does not necessarily result in a diversity of underlying meta-theoretical assumptions within an area. Other areas of the social sciences have benefited from the consideration of the meta-theoretical foundations of their research and as a consequence they have been able to extend their research into new agendas. There has been some meta-theoretic discussion of small business and entrepreneurial research, yet the review conducted for this project found no recent articles that provided a systematic analysis of contemporary research. This article will address this gap by employing Burrell and Morgan's (I1979) paradigmatic taxonomy to conduct a systematic meta-theoretical analysis of articles published in the year 2000 by leading authors in key small business and entrepreneurial journals. The analysis shows a dominance of the functionalist paradigm that pervades the elite discourse of research in leading journals and acts as a potential barrier to other perspectives. Whether a Hegelian or Kuhnian perspective on knowledge production is taken, it is clear that the health and future development of research in this area requires a broadening of perspectives to enable debate, friction, creativity and ultimately new theories and understandings.

This paper elaborates a concept of enrichment dynamics introduced in an earlier paper in which the author set out to find a labour saving technique for isolating salmonellac from sources other than faeces. Extensions to the concept are summarised in the Introduction. Explanations are given why a multiplicity of isolation procedures used in combination should normally yield more isolations than any one procedure alone. Since a limit must always be set on the number of different media and procedures which can be used during routine examinations, a corresponding limit has also to be set on the combined efficiency of the procedures used. Not even a very laborious combination of methods can be expected to yield quite 100% of the isolations that are technically possible. When this rather unpalatable conclusion is accepted, a way is opened up for compromises between endeavour and reward, in terms of salmonella isolations. Judicious application of principles and methods discussed in these papers might be expected sometimes to lead to modifications in techniques which increase their efficiency, and in other cases to modifications which reduce labour without diminishing efficiency.

values by an AlphaScreen competition assay. The follow-up libraries of four poised fragment hits improved potency into the sub-mM range while showing good ligand efficiency and detailed structural data.

The stability and the coating characteristics of a variety of organozirconium compounds have been investigated to coat ZrO 2 films on stainless steets for the improvement of heat resistance against oxidation. Zirconium tetraoctylate and zirconium tetrakis(acetylacetonate) were found to be more stable than zirconium alkoxides in an ambient atmosphere. The ZrO 2 films from zirconium alkoxides became white and discontinuous when the thickness of the films exceeded about 200 Å (20 nm). On the other hand, transparent ZrO 2 films were obtained from zirconium tetraoctylate and zirconium tetrakis(acetylacetonate). The IR spectra of the films showed that the heat treatment at 400°C for 5 min produced organic‐free ZrO 2 films. The heat resistance of stainless steel sheets against oxidation was improved by the ZrO 2 coating, depending on the film thickness.

Nonadherence to immunosuppressants in renal transplant recipients is a major factor affecting graft survival, but it is difficult to detect accurately in clinical practice. Adherence was measured in 153 adult renal transplant recipients using self-report questionnaires and interview, clinician rating, and cyclosporine levels. The sensitivity and specificity of these measures were determined by comparison with electronic monitoring in a randomly selected subsample of 58 subjects. Measures of adherence in current clinical use do not perform well when tested against electronic monitoring. Self-report at a confidential interview was the best measure of adherence for the detection of both missed doses and erratic timing of medication. However, the use of a confidential interview is not directly applicable to a clinical setting. Further research on how best to facilitate disclosure in clinical settings may be the best way to develop adherence measures for use in routine practice.

Background: Few randomized trials have compared bioprostheses for transcatheter aortic valve replacement, and no trials have compared bioprostheses with supra-annular design. The SCOPE 2 trial (Safety and Efficacy Comparison of Two TAVI Systems in a Prospective Randomized Evaluation 2) was designed to compare the clinical outcomes of the ACURATE neo and CoreValve Evolut bioprostheses for transcatheter aortic valve replacement. Methods: SCOPE 2 was a randomized trial performed at 23 centers in 6 countries between April 2017 and April 2019. Patients ≥75 years old with an indication for transfemoral transcatheter aortic valve replacement as agreed by the heart team were randomly assigned to receive treatment with either the ACURATE neo (n=398) or the CoreValve Evolut bioprostheses (n=398). The primary end point, powered for noninferiority of the ACURATE neo bioprosthesis, was all-cause death or stroke at 1 year. The key secondary end point, powered for superiority of the ACURATE neo bioprosthesis, was new permanent pacemaker implantation at 30 days. Results: Among 796 randomized patients (mean age, 83.2±4.3 years; mean Society of Thoracic Surgeons Predicted Risk of Mortality score, 4.6±2.9%), clinical follow-up information was available for 778 (98%) patients. Within 1 year, the primary end point occurred in 15.8% of patients in the ACURATE neo group and in 13.9% of patients in the CoreValve Evolut group (absolute risk difference, 1.8%, upper 1-sided 95% confidence limit, 6.1%; P =0.0549 for noninferiority). The 30-day rates of new permanent pacemaker implantation were 10.5% in the ACURATE neo group and 18.0% in the CoreValve Evolut group (absolute risk difference, –7.5% [95% CI, –12.4 to –2.60]; P =0.0027). No significant differences were observed in the components of the primary end point. Cardiac death at 30 days (2.8% versus 0.8%; P =0.03) and 1 year (8.4% versus 3.9%; P =0.01), and moderate or severe aortic regurgitation at 30 days (10% versus 3%; P =0.002) were significantly increased in the ACURATE neo group. Conclusions: Transfemoral transcatheter aortic valve replacement with the self-expanding ACURATE neo did not meet noninferiority compared with the self-expanding CoreValve Evolut in terms of all-cause death or stroke at 1 year, and it was associated with a lower incidence of new permanent pacemaker implantation. In secondary analyses, the ACURATE neo was associated with more moderate or severe aortic regurgitation at 30 days and cardiac death at 30 days and 1 year. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03192813.

Corporate social responsibility strategy and competitive advantage are important issues for the contemporary discussion on corporations in society when taking into account social and environmental impacts. Empirically, we can see that social responsibility strategies are associated with competitive advantages, such as attracting valuable employees as well as enhancing the company image and reputation. This paper presents a theoretical review that demonstrates the association between social strategy and competitive advantage through the formulation of social strategies that influence and are influenced by opportunities, resources, skills, corporation merits, industry structure and stakeholders. Based on the literature and a case study of Carrefour, a model is proposed for competitive advantages stemming from the formulation of social strategies, which are explained based on their elements and adaptation to societal expectations. This article seeks to enrich the discussion on the strategic management of social responsibility and contribute to the literature on Corporate Social Responsibility as well as Strategy and Competitive Advantage.

Experimental evidence from animal models has provided a framework for our current understanding of autoimmune disease pathogenesis and supports the importance of genetic predisposition, molecular mimicry, and immune dysregulation. However, only recently has evidence emerged to support the role of immune dysregulation in human organ-specific autoimmune disease. In the current study of the "late" manifestation of autoimmune thyroid disease (AITD) in a cohort of human immunodeficiency virus (HIV)-positive patients following highly active antiretroviral therapy (HAART), we discuss how immune dysregulation and factors associated with the immunopathology of HIV infection fit the current understanding of autoimmunity and provide a plausible basis for our clinical observations. De novo diagnoses of thyroid disease were identified between 1996 and 2002 in 7 HIV treatment centers (5/7 centers completed the study). Patients were diagnosed as clinical case entities and not discovered through thyroid function test screening. Paired plasma specimens were used to demonstrate sequential rise in thyroid antibodies. Seventeen patients were diagnosed with AITD (median age, 38 yr; 65% were of black African or black Caribbean ethnicity; and 82% were female). The median duration of immune reconstitution was 17 months. Graves disease (GD) was diagnosed in 15 of 17 patients. One patient developed hashithyrotoxicosis with atypically raised C-reactive protein, and another developed hypothyroidism. One GD patient had associated secondary hypoadrenalism. The estimated combined prevalence of GD for 4 treatment centers for female patients was 7/234 and for males was 2/1289. The denominator numbers were matched controls, from 4 centers able to provide data, who commenced HAART during the same time (January 1996 to July 2002) and who did not develop clinical AITD. The mean baseline pre-HAART CD4 count was 67 cells/mL, and the mean increase from nadir to AITD presentation was 355 cells/mL. AITD patients were more likely than controls (95% confidence interval, chi-square test) to be severely compromised at baseline (as defined by a CD4 count < 200 cells/mL or the presence of an acquired immunodeficiency syndrome [AIDS]-defining diagnosis), and to experience greater CD4 increments following HAART. AITD may be a late manifestation of immune reconstitution in HIV-positive patients taking HAART, and immune dysregulation may be an important factor.

ABSTRACT Teaching research methods to social science undergraduates presents a number of dilemmas, including the development of effective means of providing students with practical research experience and the difficulty of engaging the interest of students in a subject which for many is not intrinsically appealing and to which some have a long-standing aversion. One way of addressing these issues is to enable students to participate in a ‘real˚s research project, often commissioned by an external agency. Reports of this approach have demonstrated its benefits to student learning and have identified some logistical problems of project-based teaching. This paper reports on a project-based research methods course which has been running for 5 years and which has some distinctive features: unlike most such courses it is compulsory and is taken by a relatively large number of students; the research project is funded each year by a commissioning agency; considerable emphasis is placed upon the assessment of students' contributions to the research. These distinctive aspects of the course are discussed in relation to one particular project in which students participated, a patient satisfaction study of an accident and emergency department, funded by a Regional Health Authority. The results of a student evaluation of the learning benefits of involvement in this project are reported. It is concluded that project-based learning of research methods on courses that are larger than those reported in the literature and which are compulsory can be beneficial to both students and commissioners, and that through detailed planning of student participation and formal assessment of students' research activities, some of the problems reported by those running such courses can be resolved.