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BACKGROUND: Numerous surgical approaches exist for the treatment of pilonidal disease. Current literature on treatment is of poor quality, limiting the ability to define optimal intervention. The aim of this study was to provide real-world data on current surgical practice and report patient and risk-adjusted outcomes, informing future trial design. METHODS: This UK-wide multicentre prospective cohort study, including patients (aged over 16 years) who had definitive treatment for symptomatic pilonidal disease, was conducted between May 2019 and March 2022. Patient and disease characteristics, and intervention details were analysed. Data on patient-reported outcomes, including pain, complications, treatment failure, wound issues, and quality of life, were gathered at various time points up to 6 months after surgery. Strategies were implemented to adjust for risk influencing different treatment choices and outcomes. RESULTS: Of the 667 participants consenting, 574 (86.1%) were followed up to the study end. Twelve interventions were observed. Broadly, 59.5% underwent major excisional surgery and 40.5% minimally invasive surgery. Complications occurred in 45.1% of the cohort. Those who had minimally invasive procedures had better quality of life and, after risk adjustment, less pain (score on day 1: mean difference 1.58, 95% c.i. 1.14 to 2.01), fewer complications (difference 17.5 (95% c.i. 9.1 to 25.9)%), more rapid return to normal activities (mean difference 25.9 (18.4 to 33.4) days) but a rate of higher treatment failure (difference 9.6 (95% c.i. 17.3 to 1.9)%). At study end, 25% reported an unhealed wound and 10% had not returned to normal activities. CONCLUSION: The burden after surgery for pilonidal disease is high and treatment failure is common. Minimally invasive techniques may improve outcomes at the expense of a 10% higher risk of treatment failure.
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Seio Pilonidal , Humanos , Idoso , Resultado do Tratamento , Estudos Prospectivos , Seio Pilonidal/cirurgia , Qualidade de Vida , Recidiva Local de Neoplasia , Dor , RecidivaRESUMO
AIM: Pilonidal sinus disease is a common condition treated by colorectal surgeons. There is a lack of literature in the field to guide optimal management of this condition. As part of the PITSTOP study, we aimed to identify policy and research priorities to provide direction to the field. METHOD: Patients and surgeons were invited to participate. A 'So what, now what' exercise was conducted, informed by data from PITSTOP. This generated statements for research and practice priorities. A three-round online Delphi study was conducted, ranking statements based on policy and research separately. Statements were rated 1 (not important) to 9 (important). Statements that were rated 7-9 by more than 70% of participants were entered into the consensus meeting. Personalized voting feedback was shown between rounds. A face-to-face meeting was held to discuss statements, and participants were asked to rank statements using a weighted choice vote. RESULTS: Twenty-two people participated in the focus group, generating 14 research and 19 policy statements. Statements were voted on by 56 participants in round 1, 53 in round 2 and 51 in round 3. A total of 15 policy statements and 19 research statements were discussed in the consensus round. Key policy statements addressed treatment strategies and intensity, surgeon training opportunities, need for classification and the impact of treatment on return to work. Research recommendations included design of future trials, methodology considerations and research questions. CONCLUSION: This study has identified research and policy priorities in pilonidal sinus disease which are relevant to patients and clinicians. These should inform practice and future research.
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AIM: Research in pilonidal disease faces several challenges, one of which is consistent and useful disease classification. The International Pilonidal Society (IPS) proposed a four-part classification in 2017. The aim of this work was to assess the validity and reliability of this tool using data from the PITSTOP cohort study. METHOD: Face validity was assessed by mapping the items/domains in the IPS tool against tools identified through a systematic review. Key concepts were defined as those appearing in more than two-thirds of published tools. Concurrent and predictive validity were assessed by comparing key patient-reported outcome measures between groups at baseline and at clinic visit. The outcomes of interest were health utility, Cardiff Wound Impact Questionnaire (CWIQ) and pain score between groups. Significance was set at p = 0.05 a priori. Interrater reliability was assessed using images captured during the PITSTOP cohort. Ninety images were assessed by six raters (two experts, two general surgeons and two trainees), and classified into IPS type. Interrater reliability was assessed using the unweighted kappa and unweighted Gwet's AC1 statistics. RESULTS: For face validity items represented in the IPS were common to other classification systems. Concurrent and predictive validity assessment showed differences in health utility and pain between groups at baseline, and for some treatment groups at follow-up. Assessors agreed the same classification in 38% of participants [chance-corrected kappa 0.52 (95% CI 0.42-0.61), Gwet's AC1 0.63 (95% CI 0.56-0.69)]. CONCLUSION: The IPS classification demonstrates key aspects of reliability and validity that would support its implementation.
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Tuberculosis remains a significant global health pandemic. There is an urgent need for new anti-tubercular agents to combat the rising incidence of drug resistance and to offer effective and additive therapeutic options. High-throughput screening of a subset of the NatureBank marine fraction library (n = 2000) identified a sample derived from an Australian marine sponge belonging to the order Haplosclerida that displayed promising anti-mycobacterial activity. Bioassay-guided fractionation of the organic extract from this Haplosclerida sponge led to the purification of previously identified antimicrobial pyrrole alkaloids, axinellamines A (1) and B (2). The axinellamine compounds were found to have a 90% minimum inhibitory concentration (MIC90) of 18 µM and 15 µM, respectively. The removal of protein and complex carbon sources reduced the MIC90 of 1 and 2 to 0.6 and 0.8 µM, respectively. The axinellamines were not toxic to mammalian cells at 25 µM and significantly reduced the intracellular bacterial load by >5-fold. These data demonstrate that axinellamines A and B are effective anti-tubercular agents and promising targets for future medicinal chemistry efforts.
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Antituberculosos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Poríferos , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/isolamento & purificação , Animais , Mycobacterium tuberculosis/efeitos dos fármacos , Humanos , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Pirróis/farmacologia , Pirróis/química , Pirróis/isolamento & purificaçãoRESUMO
AIM: Pilonidal sinus is a common surgical condition which impacts a young and economically active population. There are limited data to guide treatment in this condition. The aim of this work was to assess current practice. METHOD: A survey was developed as part of the PITSTOP study. It included questions on volume of practice, treatment preferences and training. The survey was delivered to consultant surgeons with a UK practice through social media, specialty surgical societies and through PITSTOP sites. Descriptive statistics were reported. RESULTS: Of the 200 people who received a link to the questionnaire, 109 completed it (response rate 54.5%). Respondents treated a median of 15 patients per year, with 20% of these having recurrent disease. Estimates of recurrence were higher than reported in the literature and higher than in a survey 10 years ago. Nearly 50% of surgeons advocate nonsurgical treatment in some patients despite limited evidence. Two thirds practised interventions not favoured by guidelines, including excision and leave open and midline closure techniques. Invasive procedures tended to be favoured when minimally invasive procedures may be appropriate. Surgical training programmes were the key training setting for commonly offered procedures, with few other training opportunities reported. For some procedures, no formal training had been given. CONCLUSION: This survey highlights issues with quality in pilonidal surgery in the UK, with persistence of potentially outdated techniques, no consistent treatment escalation plan, a suggestion of under- or overtreatment of disease and a high perception of failure. This may relate to the current system of training and lack of evidence-based guidance.
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Seio Pilonidal , Cirurgiões , Humanos , Seio Pilonidal/cirurgia , Recidiva Local de Neoplasia , Inquéritos e Questionários , Reino Unido , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: A range of treatments are available for pilonidal sinus disease (PSD), each of which has a different risk/benefit profile. The aim of this study was to collect patient views on which interventions they would rather avoid and which outcomes they most value for PSD. METHOD: We conducted an online survey using the discrete choice experiment (DCE) method. DCE task involved participants choosing the best treatment option when presented with a set of competing hypothetical treatment profiles. Participants with symptomatic PSD, referred for elective surgery were recruited from 33 NHS trusts between 2020 and 2022. Collected DCE data were analysed using regression analyses. RESULTS: One hundred and eleven participants completed the survey. In the overall group, low risk of infection/persistence was the most important characteristic when making a treatment decision (attribute importance score of 70%), followed by treatments with shorter recovery time with an attribute importance score of 30%. The results demonstrated that patients are willing to accept trade-offs between treatment recovery time and risk of infection/persistence. Patients above 30 years old are willing to accept a higher chance of treatment failure in exchange for rapid treatment recovery (risk tolerance between 22.35 - 34.67 percentage points). Conversely, patients in the younger age groups, were risk averse, and were only willing to accept a small risk 1.51-2.15 in exchange for a treatment with faster recovery time. All patient groups appear to the reject the excision and leave open technique due to the need for protracted nursing care. CONCLUSION: This study highlights the need for shared decision making when it comes to surgery for PSD.
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BACKGROUND: Autophagy is an important mechanism for promoting Mycobacterium clearance from macrophages. Pathogenic and non-pathogenic mycobacterium can activate the mTOR pathway while simultaneously inducing autophagy. M. tuberculosis and M. bovis BCG inhibit autophagy and favor intracellular bacteria survival. RESULTS: We observed that pre-infection of live or heat-killed BCG could prevent autophagy induced by pharmacological activators or M. smegmatis, a strong autophagy-inducing mycobacterium. BCG-derived lipids are responsible for autophagy inhibition. However, post-infection with BCG could not stop the autophagy initiated by M. smegmatis, which increases further autophagy induction and mycobacteria clearance. Coinfection with BCG and heat killed M. smegmatis enhanced antigen specific CD4+ T cell responses and reduced mycobacterial survival. CONCLUSION: These results suggest that autophagy-inducing M. smegmatis could be used to promote better innate and consequential adaptive immune responses, improving BCG vaccine efficacy.
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Mycobacterium tuberculosis , Eficácia de Vacinas , Autofagia/fisiologia , Vacina BCG , MacrófagosRESUMO
BACKGROUND: When three SARS-CoV-2 vaccines came to market in Europe and North America in the winter of 2020-2021, distribution networks were in a race against a major epidemiological wave of SARS-CoV-2 that began in autumn 2020. Rapid and optimized vaccine allocation was critical during this time. With 95% efficacy reported for two of the vaccines, near-term public health needs likely require that distribution is prioritized to the elderly, health care workers, teachers, essential workers, and individuals with comorbidities putting them at risk of severe clinical progression. METHODS: We evaluate various age-based vaccine distributions using a validated mathematical model based on current epidemic trends in Rhode Island and Massachusetts. We allow for varying waning efficacy of vaccine-induced immunity, as this has not yet been measured. We account for the fact that known COVID-positive cases may not have been included in the first round of vaccination. And, we account for age-specific immune patterns in both states at the time of the start of the vaccination program. Our analysis assumes that health systems during winter 2020-2021 had equal staffing and capacity to previous phases of the SARS-CoV-2 epidemic; we do not consider the effects of understaffed hospitals or unvaccinated medical staff. RESULTS: We find that allocating a substantial proportion (>75%) of vaccine supply to individuals over the age of 70 is optimal in terms of reducing total cumulative deaths through mid-2021. This result is robust to different profiles of waning vaccine efficacy and several different assumptions on age mixing during and after lockdown periods. As we do not explicitly model other high-mortality groups, our results on vaccine allocation apply to all groups at high risk of mortality if infected. A median of 327 to 340 deaths can be avoided in Rhode Island (3444 to 3647 in Massachusetts) by optimizing vaccine allocation and vaccinating the elderly first. The vaccination campaigns are expected to save a median of 639 to 664 lives in Rhode Island and 6278 to 6618 lives in Massachusetts in the first half of 2021 when compared to a scenario with no vaccine. A policy of vaccinating only seronegative individuals avoids redundancy in vaccine use on individuals that may already be immune, and would result in 0.5% to 1% reductions in cumulative hospitalizations and deaths by mid-2021. CONCLUSIONS: Assuming high vaccination coverage (>28%) and no major changes in distancing, masking, gathering size, hygiene guidelines, and virus transmissibility between 1 January 2021 and 1 July 2021 a combination of vaccination and population immunity may lead to low or near-zero transmission levels by the second quarter of 2021.
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Vacinas contra COVID-19/provisão & distribuição , COVID-19 , Controle de Doenças Transmissíveis/organização & administração , Alocação de Recursos para a Atenção à Saúde/organização & administração , Alocação de Recursos/organização & administração , Cobertura Vacinal , Vacinação , Fatores Etários , COVID-19/epidemiologia , COVID-19/prevenção & controle , Humanos , Incidência , Massachusetts/epidemiologia , Modelos Teóricos , Saúde Pública/métodos , Saúde Pública/normas , Rhode Island/epidemiologia , SARS-CoV-2 , Vacinação/métodos , Vacinação/estatística & dados numéricos , Cobertura Vacinal/estatística & dados numéricos , Cobertura Vacinal/provisão & distribuiçãoRESUMO
AIM: Little is known about optimal management strategies for pilonidal sinus disease (PSD). We conducted a mixed-methods study to understand why patients make, and sometimes regret, treatment decisions. METHOD: We conducted longitudinal semi-structured interviews at the time of surgery and 6 months later with 20 patients from 13 UK hospitals. Framework analysis was performed, and themes were mapped to (1) the coping in deliberation framework and (2) an acceptability framework. Results were triangulated with those from structured survey instruments evaluating shared decision-making (SDM, best = 9) at baseline and decision regret (DR, most regret = 100) at 6 months. RESULTS: Nine of 20 patients were not offered a choice of treatment, but this was not necessarily seen as negative (SDM median 4; range 2-4). Factors that influenced decision-making included previous experience and anticipated recovery time. Median (range) DR was 5 (0-50). Those with the highest DR (scores 40-50) were, paradoxically, also amongst the highest scores on SDM (scores 4). Burden of wound care and the disparity between anticipated and actual recovery time were the main reasons for decision regret. CONCLUSION: To minimize regret about surgical decisions, people with PSD need better information about the burden of wound care and the risks of recurrence associated with different surgical approaches.
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Seio Pilonidal , Tomada de Decisões , Emoções , Humanos , Recidiva Local de Neoplasia , Participação do Paciente , Seio Pilonidal/cirurgiaRESUMO
The interaction of host cells with mycobacteria is complex and can lead to multiple outcomes ranging from bacterial clearance to progressive or latent infection. Autophagy is recognized as one component of host cell responses that has an essential role in innate and adaptive immunity to intracellular bacteria. Many microbes, including Mycobacterium tuberculosis, have evolved to evade or exploit autophagy, but the precise mechanisms and virulence factors are mostly unknown. Through a loss-of-function screening of an M. tuberculosis transposon mutant library, we identified 16 genes that contribute to autophagy inhibition, six of which encoded the PE/PPE protein family. Their expression in Mycobacterium smegmatis confirmed that these PE/PPE proteins inhibit autophagy and increase intracellular bacterial persistence or replication in infected cells. These effects were associated with increased mammalian target of rapamycin (mTOR) activity and also with decreased production of tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß). We also confirmed that the targeted deletion of the pe/ppe genes in M. tuberculosis resulted in enhanced autophagy and improved intracellular survival rates compared to those of wild-type bacteria in the infected macrophages. Differential expression of these PE/PPE proteins was observed in response to various stress conditions, suggesting that they may confer advantages to M. tuberculosis by modulating its interactions with host cells under various conditions. Our findings demonstrated that multiple M. tuberculosis PE/PPE proteins are involved in inhibiting autophagy during infection of host phagocytes and may provide strategic targets in developing therapeutics or vaccines against tuberculosis.
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Autofagia , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Macrófagos/metabolismo , Mycobacterium tuberculosis/genética , Tuberculose/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Biblioteca Gênica , Ensaios de Triagem em Larga Escala , Interações entre Hospedeiro e Microrganismos/genética , Imunidade Inata , Interleucina-1beta/metabolismo , Macrófagos/microbiologia , Camundongos , Mycobacterium smegmatis/fisiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Células RAW 264.7 , Serina-Treonina Quinases TOR/metabolismo , Tuberculose/genética , Tuberculose/microbiologia , Fator de Necrose Tumoral alfa/metabolismo , Fatores de Virulência/genéticaRESUMO
Melioidosis, caused by the bacterium Burkholderia pseudomallei, is an often severe infection that regularly involves respiratory disease following inhalation exposure. Intranasal (i.n.) inoculation of mice represents an experimental approach used to study the contributions of bacterial capsular polysaccharide I (CPS I) to virulence during acute disease. We used aerosol delivery of B. pseudomallei to establish respiratory infection in mice and studied CPS I in the context of innate immune responses. CPS I improved B. pseudomallei survival in vivo and triggered multiple cytokine responses, neutrophil infiltration, and acute inflammatory histopathology in the spleen, liver, nasal-associated lymphoid tissue, and olfactory mucosa (OM). To further explore the role of the OM response to B. pseudomallei infection, we infected human olfactory ensheathing cells (OECs) in vitro and measured bacterial invasion and the cytokine responses induced following infection. Human OECs killed >90% of the B. pseudomallei in a CPS I-independent manner and exhibited an antibacterial cytokine response comprising granulocyte colony-stimulating factor, tumor necrosis factor alpha, and several regulatory cytokines. In-depth genome-wide transcriptomic profiling of the OEC response by RNA-Seq revealed a network of signaling pathways activated in OECs following infection involving a novel group of 378 genes that encode biological pathways controlling cellular movement, inflammation, immunological disease, and molecular transport. This represents the first antimicrobial program to be described in human OECs and establishes the extensive transcriptional defense network accessible in these cells. Collectively, these findings show a role for CPS I in B. pseudomallei survival in vivo following inhalation infection and the antibacterial signaling network that exists in human OM and OECs.
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Cápsulas Bacterianas/imunologia , Burkholderia pseudomallei/imunologia , Interações Hospedeiro-Patógeno/imunologia , Melioidose/imunologia , Melioidose/microbiologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Animais , Cápsulas Bacterianas/genética , Carga Bacteriana , Burkholderia pseudomallei/genética , Células Cultivadas , Biologia Computacional/métodos , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunidade Inata , Melioidose/genética , Melioidose/metabolismo , Camundongos , Mutação , Infiltração de Neutrófilos , Neurônios Receptores Olfatórios/imunologia , Neurônios Receptores Olfatórios/metabolismo , Neurônios Receptores Olfatórios/microbiologia , Infecções Respiratórias/genética , Infecções Respiratórias/metabolismo , Transdução de Sinais , Virulência , Fatores de VirulênciaRESUMO
BACKGROUND: Knowledge of care practices among clinicians who annually treat <20 human immunodeficiency virus (HIV)-positive patients with antiretroviral therapy (ART) is insufficient, despite their number, which is likely to increase given shifting healthcare policies. We analyze the practices, distribution and quality of care provided by low-volume prescribers (LVPs) based on available data sources in New York State. METHODS: We communicated with 1278 (66%) of the LVPs identified through a statewide claims database to determine the circumstances under which they prescribed ART in federal fiscal year 2009. We reviewed patient records from 84 LVPs who prescribed ART routinely and compared their performance with that of experienced clinicians practicing in established HIV programs. RESULTS: Of the surveyed LVPs, 368 (29%) provided routine ambulatory care for 2323 persons living with HIV/AIDS, and 910 LVPs cited other reasons for prescribing ART. Although the majority of LVPs (73%) practiced in New York City, patients living upstate were more likely to be cared for by a LVP (odds ratio, 1.7; 95% confidence interval, 1.4-1.9). Scores for basic HIV performance measures, including viral suppression, were significantly higher in established HIV programs than for providers who wrote prescriptions for <20 persons living with HIV/AIDS (P < .01). We estimate that 33% of New York State clinicians who provide ambulatory HIV care are LVPs. CONCLUSIONS: Our findings suggest that the quality of care associated with providers who prescribe ART for <20 patients is lower than that provided by more experienced providers. Access to experienced providers as defined by patient volume is an important determinant of delivering high-quality care and should guide HIV workforce policy decisions.
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Assistência Ambulatorial/métodos , Assistência Ambulatorial/estatística & dados numéricos , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Qualidade da Assistência à Saúde , Humanos , New York , Competência ProfissionalRESUMO
Simple alkyl-sulfonylacetamides have potent antitubercular activity and significantly decrease mycolic acid levels in mycobacteria. Although these compounds were originally designed to inhibit the ketoacyl synthase domain of fatty acid synthase, structure-activity relationships and biochemical evidence do not fully support fatty acid synthase as the target. In 2004, an enzyme family involved in the activation and transfer of fatty acids as acyl-adenylates was identified in mycobacteria, separate from the universal acetyl-CoA carrier mechanism. These fatty acyl-AMP ligases (FAAL), encoded by the FadD family play important roles in the biosynthesis of mycolic acids along with fatty acid metabolism and are hypothesised here to be the molecular target of the sulfonylacetamides. Due to structural similarities with the ligase's natural substrate, it is believed these compounds are exerting action via competitive inhibition of these highly potent molecular targets. The primary aim of this investigation was to synthesize an extended library of sulfonylacetamide derivatives, building upon existing structural activity relations to validate the molecular mechanism with the aid of molecular modelling, while also attempting to explore novel structural isosteres for further drug design and development. Sulfonylacetamide derivatives were modified based on the putative molecular target resulting in derivatives with improved activities towards Mycobacteriumtuberculosis (H37Rv). The most active novel derivatives reported were 19, 22b, 22c and 46 displaying MIC90 levels of 1.4, 16.0, 13.0 and 5.9 µg/mL, respectively.
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Mycobacterium tuberculosis , Acetamidas/farmacologia , Antituberculosos/farmacologia , Ácidos Micólicos/metabolismo , Ácidos Graxos/metabolismo , Ácido Graxo SintasesRESUMO
The use of lead shotgun ammunition for shooting wildfowl has been restricted in England since 1999, but surveys finding lead shot in harvested birds show compliance with regulations has been low. Following the announcement in 2020 of a voluntary transition from lead to non-lead shot by UK shooting organizations, we investigated spatiotemporal variation in the composition of ammunition used for shooting mallards Anas platyrhynchos. We collected 176 harvested mallards during the 2021/22 shooting season and analyzed recent shot extracted from carcasses to determine shot composition. Using a separate collection of ducks of known provenance, we used stable isotope analysis as a means of differentiating captive-reared from wild mallards. This allowed us to understand how compliance might vary between driven game shooters, characterized by shooting birds that are flushed over a stationary line of shooters, and who primarily harvest captive-reared and released ducks, and wild duck shooters. Of 133 mallards containing recent shot, 92 (69%) had been illegally shot with lead. Analysis of this and five comparable surveys between 2001 and 2019 indicates regional and temporal variation in lead shot presence in England. In the North West and West Midlands, the likelihood of mallards containing lead shot decreased significantly over time, but no other regions showed significant changes. The use of non-lead shot types varied over time, with increases in steel shot use approximately matched by declines in bismuth shot. Mallards likely to be reared were more likely to have been shot with lead (75%) than those likely to be wild (48%). This suggests the use of lead shot is more frequent among driven game shooters than wild duck shooters. In England in 2021/22, most mallards continued to be shot with lead, suggesting that neither legislation nor voluntary approaches have been effective in substantially reducing illegal use of lead shot.
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Background: There is no consensus on optimal management of pilonidal disease. Surgical practice is varied, and existing literature is mainly single-centre cohort studies of varied disease severity, interventions and outcome assessments. Objectives: A prospective cohort study to determine: ⢠disease severity and intervention relationship ⢠most valued outcomes and treatment preference by patients ⢠recommendations for policy and future research. Design: Observational cohort study with nested mixed-methods case study. Discrete choice experiment. Clinician survey. Three-stage Delphi survey for patients and clinicians. Inter-rater reliability of classification system. Setting: Thirty-one National Health Service trusts. Participants: Patients aged > 16 years referred for elective surgical treatment of pilonidal disease. Interventions: Surgery. Main outcome measures: Pain postoperative days 1 and 7, time to healing and return to normal activities, complications, recurrence. Outcomes compared between major and minor procedures using regression modelling, propensity score-based approaches and augmented inverse probability weighting to account for measured potential confounding features. Results: Clinician survey: There was significant heterogeneity in surgeon practice preference. Limited training opportunities may impede efforts to improve practice. Cohort study: Over half of patients (60%; Nâ =â 667) had a major procedure. For these procedures, pain was greater on day 1 and day 7 (mean difference day 1 pain 1.58 points, 95% confidence interval 1.14 to 2.01 points, nâ =â 536; mean difference day 7 pain 1.53 points, 95% confidence interval 1.12 to 1.95 points, nâ =â 512). There were higher complication rates (adjusted risk difference 17.5%, 95% confidence interval 9.1 to 25.9%, nâ =â 579), lower recurrence (adjusted risk difference -10.1%, 95% confidence interval -18.1 to -2.1%, nâ =â 575), and longer time to healing (>34 days estimated difference) and time to return to normal activities (difference 25.9 days, 95% confidence interval 18.4 to 33.4 days). Mixed-methods analysis: Patient decision-making was influenced by prior experience of disease and anticipated recovery time. The burden involved in wound care and the gap between expected and actual time for recovery were the principal reasons given for decision regret. Discrete choice experiment: The strongest predictors of patient treatment choice were risk of infection/persistence (attribute importance 70%), and shorter recovery time (attribute importance 30%). Patients were willing to trade off these attributes. Those aged over 30 years had a higher risk tolerance (22.35-34.67%) for treatment failure if they could experience rapid recovery. There was no strong evidence that younger patients were willing to accept higher risk of treatment failure in exchange for a faster recovery. Patients were uniform in rejecting excision-and-leave-open because of the protracted nursing care it entailed. Wysocki classification analysis: There was acceptable inter-rater agreement (κâ =â 0.52, 95% confidence interval 0.42 to 0.61). Consensus exercise: Five research and practice priorities were identified. The top research priority was that a comparative trial should broadly group interventions. The top practice priority was that any interventions should be less disruptive than the disease itself. Limitations: Incomplete recruitment and follow-up data were an issue, particularly given the multiple interventions. Assumptions were made regarding risk adjustment. Conclusions and future work: Results suggest the burden of pilonidal surgery is greater than reported previously. This can be mitigated with better selection of intervention according to disease type and patient desired goals. Results indicate a framework for future higher-quality trials that stratify disease and utilise broad groupings of common interventions with development of a patient-centred core outcome set. Trial registration: This trial is registered as ISRCTN95551898. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/17/02) and is published in full in Health Technology Assessment; Vol. 28, No. 33. See the NIHR Funding and Awards website for further award information.
Pilonidal disease is caused by ingrowing hairs between the buttocks. It can cause pain and infection and may need surgery. We do not know which operation gives the best results, or who operations help. PITSTOP aimed to find out which operation is the best and what is important to patients when deciding on surgery, and to suggest ideas for better treatment and future research. We looked at what operations were done and their outcomes. We interviewed patients about their experiences. Some completed a survey to help us understand what operations they might prefer based on risks and outcomes. Surgeons completed a survey about their experiences, and we explored whether a new tool could help us tell the difference between 'mild' and 'bad' disease. We used findings from these studies to help patients and surgeons give priorities for future practice and research. Six hundred and sixty-seven patients joined PITSTOP. People who had a major operation had more pain and took longer to return to normal activities. Some were still affected 6 months after surgery. However, disease recurrence was lower than after a minor procedure. Patients based decisions about treatment on the likelihood of success and the time to recover. The study and the surgeons' survey both showed marked differences in practice. Surgeons tended to offer one or two operations learned during training. A classification tool put cases in similar groups, but this did not influence treatment choices. The consensus exercise identified five research priorities, the top one being to put types of surgery into two groups. Of the five practice priorities, the top one was that surgery should not make the patient worse than the disease. There is variation in the treatment of pilonidal disease. Wound issues and impact on daily living should be avoided. The highlighted research questions should be addressed to improve care.
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Seio Pilonidal , Humanos , Seio Pilonidal/cirurgia , Seio Pilonidal/terapia , Feminino , Masculino , Adulto , Estudos Prospectivos , Técnica Delphi , Recidiva , Pessoa de Meia-Idade , Adulto Jovem , Cicatrização , Dor Pós-Operatória , Preferência do Paciente , Índice de Gravidade de Doença , Adolescente , Reino UnidoRESUMO
Mycobacterium ulcerans is the causative agent of Buruli ulcer (BU), the third most common mycobacterial infection. Virulent M. ulcerans secretes mycolactone, a polyketide toxin. Most observations of M. ulcerans infection are described as an extracellular milieu in the form of a necrotic ulcer. While some evidence exists of an intracellular life cycle for M. ulcerans during infection, the exact role that mycolactone plays in this process is poorly understood. Many previous studies have relied upon the addition of purified mycolactone to cell-culture systems to study its role in M. ulcerans pathogenesis and host-response modulation. However, this sterile system drastically simplifies the M. ulcerans infection model and assumes that mycolactone is the only relevant virulence factor expressed by M. ulcerans. Here we show that the addition of purified mycolactone to macrophages during M. ulcerans infection overcomes the bacterial activation of the mechanistic target of rapamycin (mTOR) signaling pathway that plays a substantial role in regulating different cellular processes, including autophagy and apoptosis. To further study the role of mycolactone during M. ulcerans infection, we have developed an inducible mycolactone expression system. Utilizing the mycolactone-deficient Mul::Tn118 strain that contains a transposon insertion in the putative beta-ketoacyl transferase (mup045), we have successfully restored mycolactone production by expressing mup045 in a tetracycline-inducible vector system, which overcomes in-vitro growth defects associated with constitutive complementation. The inducible mycolactone-expressing bacteria resulted in the establishment of infection in a murine footpad model of BU similar to that observed during the infection with wild-type M. ulcerans. This mycolactone inducible system will allow for further analysis of the roles and functions of mycolactone during M. ulcerans infection.
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Toxinas Bacterianas , Úlcera de Buruli , Mycobacterium ulcerans , Animais , Toxinas Bacterianas/metabolismo , Úlcera de Buruli/microbiologia , Úlcera de Buruli/patologia , Macrolídeos/farmacologia , Camundongos , Mycobacterium ulcerans/metabolismoRESUMO
Antibiotic resistance poses a significant hurdle in combating global public health crises, prompting the development of novel therapeutics. Strategies to enhance the intracellular killing of mycobacteria by targeting host defense mechanisms offer numerous beneficial effects, which include reducing cytotoxicity caused by current lengthy anti-tubercular treatment regimens and slowing or circumventing the development of multidrug-resistant strains. The intracellular pathogen Mycobacterium tuberculosis infects macrophages and exploits host machinery to survive and multiply. Using a cell-based screen of FDA-approved drugs, we identified an antidepressant, Amoxapine, capable of inhibiting macrophage cytotoxicity during mycobacterial infection. Notably, this reduced cytotoxicity was related to the enhanced intracellular killing of Mycobacterium bovis BCG and M. tuberculosis within human and murine macrophages. Interestingly, we discovered that postinfection treatment with Amoxapine inhibited mTOR (mammalian target of rapamycin) activation, resulting in the induction of autophagy without affecting autophagic flux in macrophages. Also, inhibition of autophagy by chemical inhibitor 3-MA or knockdown of an essential component of the autophagic pathway, ATG16L1, significantly diminished Amoxapine's intracellular killing effects against mycobacteria in the host cells. Finally, we demonstrated that Amoxapine treatment enhanced host defense against M. tuberculosis in mice. In conclusion, our study identified Amoxapine as a novel host-directed drug that enhances the intracellular killing of mycobacteria by induction of autophagy, with concomitant protection of macrophages against death. IMPORTANCE The emergence and spread of multidrug-resistant (MDR) and extensive drug-resistant (XDR) TB urges the development of new therapeutics. One promising approach to combat drug resistance is targeting host factors necessary for the bacteria to survive or replicate while simultaneously minimizing the dosage of traditional agents. Moreover, repurposing FDA-approved drugs presents an attractive avenue for reducing the cost and time associated with new drug development. Using a cell-based screen of FDA-approved host-directed therapies (HDTs), we showed that Amoxapine inhibits macrophage cytotoxicity during mycobacterial infection and enhances the intracellular killing of mycobacteria within macrophages by activating the autophagy pathway, both in vitro and in vivo. These findings confirm targeted autophagy as an effective strategy for developing new HDT against mycobacteria.
Assuntos
Amoxapina , Mycobacterium tuberculosis , Tuberculose , Camundongos , Humanos , Animais , Amoxapina/metabolismo , Amoxapina/farmacologia , Vacina BCG , Mycobacterium tuberculosis/metabolismo , Macrófagos , Autofagia , Serina-Treonina Quinases TOR/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Mamíferos/metabolismoRESUMO
Autophagy is an ubiquitous homeostatic pathway in mammalian cells and plays a significant role in host immunity. Substantial evidence indicates that the ability of Mycobacterium tuberculosis (Mtb) to successfully evade immune responses is partially due to inhibition of autophagic pathways. Our previous screening of Mtb transposon mutants identified the PPE51 protein as an important autophagy-inhibiting effector. We found that expression of PPE51, either by infecting bacteria or by direct expression in host cells, suppressed responses to potent autophagy-inducing stimuli and interfered with bacterial phagocytosis. This phenotype was associated with reduced activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a key component of signaling pathways that stimulate autophagy. Multiple lines of evidence demonstrated that the effects of PPE51 are attributable to signal blocking by Toll-like receptor 2 (TLR2), a receptor with known involvement of activation of ERK1/2 and autophagy. Consistent with these results, mice with intact TLR2 signaling showed striking virulence attenuation for an Mtb ppe51 deletion mutant (Δ51) compared to wild-type Mtb, whereas infection of TLR2-deficient mice showed no such attenuation. Mice infected with Δ51 also displayed increased T cell responses to Mtb antigens and increased autophagy in infected lung tissues. Together, these results suggest that TLR2 activates relevant host immune functions during mycobacterial infection, which Mtb then evades through suppression of TLR2 signaling by PPE51. In addition to its previously identified function transporting substrates across the bacterial cell wall, our results demonstrate a direct role of PPE51 for evasion of both innate and adaptive immunity to Mtb. IMPORTANCE Tuberculosis is a significant global infectious disease caused by infection of the lungs with Mycobacterium tuberculosis, which resides and replicates mainly within host phagocytic cells. During coevolution with humans, Mtb has acquired various mechanisms to inhibit host cellular processes, including autophagy. Autophagy is a complex host cellular process that helps control intracellular infections by enhancing innate and adaptive immune responses. We identified the Mtb protein PPE51 as a mycobacterial effector that inhibits autophagy. We discovered TLR2 and mitogen-activated protein kinase signaling as the axis by which PPE51 mediates this effect. Autophagy regulation by PPE51, along with suppression of other TLR2-activated host cell functions, leads to increased bacterial survival in phagocytic cells and tissues of infected mice. A better understanding of how Mtb regulates autophagy and other host immune effectors could facilitate the design of new therapeutics or vaccines against tuberculosis.
Assuntos
Autofagia , Proteínas de Bactérias , Mycobacterium tuberculosis , Receptor 2 Toll-Like , Tuberculose , Animais , Proteínas de Bactérias/imunologia , Imunidade Inata/genética , Macrófagos/microbiologia , Camundongos , Mycobacterium tuberculosis/metabolismo , Receptor 2 Toll-Like/imunologia , Tuberculose/microbiologiaRESUMO
Many eye movement desensitization and reprocessing (EMDR) therapists moved their practice online during COVID-19. We conducted surveys and interviews to understand the implementation and acceptability of online EMDR therapy. From 17 June to 2nd August 2021 an online survey was open to EMDR therapists from the EMDR Association UK & Ireland and EMDR International Association email lists, and, through them, their clients. Questions related to determinants of implementation (for therapists) and acceptability (for clients) of online EMDR. Semi-structured interviews were conducted with a sample of therapist respondents to provide a deeper understanding of survey responses. Survey responses were received from therapists (n = 562) from five continents, and their clients (n = 148). 88% of clients responded as being extremely or very comfortable receiving EMDR therapy online. At the initial point of 'social distancing', 54% of therapists indicated strong or partial reluctance to deliver online EMDR therapy compared to 11% just over one year later. Four fifths of therapists intended to continue offering online therapy after restrictions were lifted. Free-text responses and interview data showed that deprivation and clinical severity could lead to exclusion from online EMDR. Internet connectivity could disrupt sessions, lead to cancellations, or affect the therapy process. Therapists benefited from training in online working. Online EMDR is generally acceptable to therapists and clients, with reservations about digital exclusion, case severity, poor internet connectivity and the need for training. Further research is needed to confirm that online EMDR is clinically non-inferior to in-person working. Supplementary Information: The online version contains supplementary material available at 10.1007/s40737-022-00260-0.
RESUMO
State-level reopenings in late spring 2020 facilitated the resurgence of severe acute respiratory syndrome coronavirus 2 transmission. Here, we analyze age-structured case, hospitalization, and death time series from three states-Rhode Island, Massachusetts, and Pennsylvania-that had successful reopenings in May 2020 without summer waves of infection. Using 11 daily data streams, we show that from spring to summer, the epidemic shifted from an older to a younger age profile and that elderly individuals were less able to reduce contacts during the lockdown period when compared to younger individuals. Clinical case management improved from spring to summer, resulting in fewer critical care admissions and lower infection fatality rate. Attack rate estimates through 31 August 2020 are 6.2% [95% credible interval (CI), 5.7 to 6.8%] of the total population infected for Rhode Island, 6.7% (95% CI, 5.4 to 7.6%) in Massachusetts, and 2.7% (95% CI, 2.5 to 3.1%) in Pennsylvania.