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CRISPR-mediated detection of Pneumocystis transcripts in bronchoalveolar, oropharyngeal, and serum specimens for Pneumocystis pneumonia diagnosis
Get PDFBACKGROUND.Pneumocystis jirovecii pneumonia (PCP) is a leading cause of fungal pneumonia, but its diagnosis primarily relies on invasive bronchoalveolar lavage (BAL) specimens that are difficult to obtain. Oropharyngeal swabs and serum could improve the PCP diagnostic workflow, and we hypothesized that CRISPR could enhance assay sensitivity to allow robust P. jirovecii diagnosis using swabs and serum. Herein we describe the development of an ultrasensitive RT-PCR-coupled CRISPR assay with high active-infection specificity in infant swabs and adult BAL and serum.
METHODS. Mouse analyses employed an RT-PCR CRISPR assay to analyze P. murina transcripts in wild-type and Rag2–/– mouse lung RNA, BAL, and serum at 2-, 4-, and 6-weeks post-infection. Human studies used an optimized RT-PCR CRISPR assay to detect P. jirovecii transcripts in infant oropharyngeal swab samples, adult serum, and adult BAL specimens from P. jirovecii-infected and P. jirovecii-non-infected patients.
RESULTS. The P. murina assays sensitively detected Pneumocystis RNA in the serum of infected mice throughout infection. Oropharyngeal swab CRISPR assay results identified infants infected with P. jirovecii with greater sensitivity (96.3% vs. 66.7%) and specificity (100% vs. 90.6%) than RT-qPCR compared to mtLSU standard marker, and CRISPR results achieved higher sensitivity than RT-qPCR results (93.3% vs. 26.7%) in adult serum specimens.
CONCLUSION. Since swabs are routinely collected in pediatric pneumonia patients and serum is easier to obtain than BAL, this assay approach could improve the accuracy and timing of pediatric and adult Pneumocystis diagnosis by achieving specificity for active infection and potentially avoiding the requirement for BAL specimens
Interrelation between anaesthesiology and intensive care medicine training in Europe: An ESAIC National Anaesthesiologists Societies Committee survey
No full textManagement of Legg-Calve-Perthes disease: a scoping review with advice on initial management.
Get PDFBACKGROUND: Legg-Calve-Perthes disease (LCPD) is a developmental disorder causing avascular necrosis of the femoral head in children, with long-term consequences that can extend into adulthood. Early diagnosis and management in primary care are crucial but challenging. AIM: This review aims to provide a concise overview of the presentation, differential diagnosis and management of LCPD, offering practical guidance for primary healthcare professionals. METHOD: Recent literature and expert opinions were reviewed to summarise the epidemiology, diagnosis and current management of LCPD. RESULTS: LCPD commonly presents as a painless limp in children aged between 2 and 14 years, with the diagnosis based on the clinical features and radiographic abnormalities. Management is individualised and includes non-operative care to surgery, which attempts to correct anatomical abnormalities and therefore delay the onset of osteoarthritis. The review highlights the importance of primary care in early detection, appropriate referral and interim management. CONCLUSION: LCPD is a rare condition that can lead to long-term disability, affecting a child's physical, mental and social development, often presenting as a painless limp. Diagnosis typically involves plain radiographs, with MRI or hip joint arthrography providing additional details for management, which may include both non-surgical (eg, physiotherapy) and surgical options. Early recognition by primary care providers is crucial for timely referral to orthopaedic services, along with interim support through physiotherapy, pain management and access to mental health and educational resources
Perioperative Medicine for Older People Undergoing Surgery Scale Up (POPS-SUp): study protocol
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Surgery provides definitive management of many age-related diseases, relieving symptoms or extending life. Age-related physiological decline, multimorbidity, and frailty predispose older people to postoperative complications and incomplete functional recovery, with resultant health and social care costs. These age-related conditions can be optimized using Comprehensive Geriatric Assessment (CGA), thus mitigating perioperative risk to improve clinical outcomes with cost-effectiveness. National organizations advocate CGA-based services for older surgical patients. However, there is variation in the provision of CGA-based perioperative medicine for older people undergoing surgery (POPS) services across the UK National Health Service, resulting in inequitable access for older surgical patients at higher risk, unnecessary deaths, complications, and financial cost. The aim of the POPS Scale Up (POPS-SUp) study is to determine whether CGA-based POPS services can be implemented at scale to cost-effectively improve clinical outcomes for older patients undergoing surgery.
Methods
A mixed-methods hybrid implementation–effectiveness interrupted time series study will examine the use of a coproduced implementation strategy to embed CGA-based POPS services at scale in the UK. Co-primary implementation–effectiveness outcomes will be used, namely reach and length of hospital stay, respectively. Evaluation will include an embedded process evaluation, quantitative evaluation of clinical effectiveness and cost-effectiveness, and qualitative appraisal of patient and staff experience. The proposed analysis is to embed a process evaluation using real-time framework analysis, enabling iterative refinement and evaluation of the implementation strategy. Accepted interrupted time series analysis will be used to examine and compare outcomes per participating site. A predefined dissemination strategy has been co-designed with patients/carers, clinical community of practice, and organizational bodies.
Conclusion
The anticipation is that POPS-SUp will have impact at the individual (patient and clinician), organizational, and policy levels in the perioperative setting, but with additional potential application to other clinical settings.
Registration numbers: ISRCTN 45327 (https://www.isrctn.com/); NIHR 157443 (https://www.nihr.ac.uk/)
Knowledge, Attitudes, Motivations, Expectations, and Systemic Factors Regarding Antimicrobial Use Amongst Community Members Seeking Care at the Primary Healthcare Level: A Scoping Review.
Get PDFBackground/objectivesAntimicrobial resistance (AMR) is a major global health challenge, particularly in low- and middle-income countries (LMICs). Understanding the knowledge, attitudes, motivations, and expectations of community members regarding antimicrobial use is essential for effective stewardship interventions. This scoping review aimed to identify key themes relating to the critical areas regarding antimicrobial use among community members in primary healthcare (PHC), with a particular focus on LMICs.MethodsOVID Medline, PubMed, and CINAHL databases were searched using Boolean operators and Medical Subject Headings (MeSH) terms relevant to antimicrobial use and community behaviors. The Population, Intervention, Comparison, Outcome, and Study Design (PICOS) framework guided study selection, which focused on community members seeking care in PHC in LMICs. Data management and extraction were facilitated using the Covidence platform, with the Critical Appraisal Skills Programme (CASP) qualitative checklist applied for qualitative studies. A narrative synthesis identified and grouped key themes and sub-themes.ResultsThe search identified 497 sources, of which 59 met the inclusion criteria, with 75% of the studies conducted in outpatient primary care settings. Four key themes were identified: (1) the 'patient' theme, highlighting beliefs, knowledge, and expectations, which was the most prominent (40.5%); (2) the 'provider' theme, emphasizing challenges related to clinical decision-making, knowledge gaps, and adherence to guidelines; (3) the 'healthcare systems' theme, highlighting resource limitations, lack of infrastructure, and policy constraints; and (4) the 'intervention/uptake' theme, emphasizing strategies to improve future antibiotic use and enhance access to and quality of healthcare.ConclusionsStewardship programs in PHC settings in LMICs should be designed to be context-specific, community-engaged, and accessible to individuals with varying levels of understanding, involving the use of information and health literacy to effectively reduce AMR
Development of a Physical Activity Maintenance intervention for people with PERsistent musculoskeletal pain (PAMPER): a mixed-methods study protocol
Get PDFIntroduction
Persistent musculoskeletal pain is a leading cause of disability and need for rehabilitation globally. Many people with the condition attend pain management programmes (PMPs) for rehabilitation and support with self-management. Physical activity (PA) is an essential self-management strategy facilitated on PMPs as it benefits symptoms, general health and well-being. PA needs to be maintained in the long term to continue to be beneficial. However, while many patients increase their PA during or immediately after a PMP, they commonly find it difficult to maintain it in the long term. This study aims to address this problem by developing an intervention to support PA maintenance after a PMP.
Methods and analysis
This mixed-methods study will be guided by the Medical Research Council guidelines for developing complex interventions and the Behaviour Change Wheel intervention development framework. Participants will be recruited from multiple UK National Health Service PMPs. Participants will include patients with persistent musculoskeletal pain who have completed PMPs, their PA partners (people who support them with PA) and healthcare professionals who facilitate PA on PMPs. The study will be conducted in three phases. In phase 1, qualitative interviews will explore the experiences, barriers and facilitators of PA maintenance after a PMP and potential characteristics for a PA maintenance intervention from patient, PA partner and healthcare professional perspectives. Phase 2 will consist of a prospective longitudinal pilot study to identify factors associated with PA maintenance after a PMP. Phase 3 will involve developing a logic model and co-designing the intervention with patient, PA partner and healthcare professional stakeholder groups.
Ethics and dissemination
The project received research ethics committee (REC) and Health Research Authority approval on 4 June 2024 (REC: North West—Liverpool Central, REC reference: 24/NW/0174, IRAS Project ID: 340674). Findings will be disseminated by peer-reviewed publications, conference presentations, social media and lay summaries for patients and the public
Recurrent invasive pneumococcal disease in children: A retrospective cohort study, England, 2006/07-2017/18
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Recurrent invasive pneumococcal disease (IPD) is rare in children and usually associated with underlying comorbidities. We aimed to assess the risk and describe the characteristics of children with recurrent IPD over a 12-year period covering the introduction of the 7-valent (PCV7), followed by the 13-valent (PCV13) pneumococcal conjugate vaccine (PCV) in the national childhood immunisation programme in England.
Methods
We used enhanced national surveillance data for England and included all laboratory-confirmed IPD cases in children (<15 years) during 2006/07–2017/18. We assessed the risk and rate of recurrent IPD, the serotypes responsible and the demographics, comorbidity status and prevalence, vaccination status, clinical presentation and outcomes in children with recurrent IPD compared to those with a single IPD episode.
Findings
There were 5158 IPD episodes reported in 5033 children over 12 years and 2.2% (105/4814) of those surviving their first IPD had at least one recurrence. Recurrence risk decreased with increasing age and over time. During 2015/16–2017/18, five years after PCV13 replaced PCV7, IPD recurrence rate was 229.0 (95% CI 154.8–339.0) per 100,000 person-years, with all recurrent cases caused by non-PCV13 serotypes. Where serotype information was available, recurrence was due to the same serotype in 25 cases, with a shorter median (IQR) interval of 88 (57–177) days between recurrent episodes, and in 60 cases due to different serotypes, with a median (IQR) interval of 223 (125–574) days (p=0.001). Compared to healthy children (103.0; 95%CI 63.1–168.1), recurrence rate per 100,000 person-years was 10 times higher in children with any comorbidity (1061.0; 95% CI 827.2–1360.9; 62/78 [79.5%] with available information had comorbidities), and almost 30 times higher in immunosuppressed children (2788.5; 95%CI 2029.0–3832.2; 38/78 [48.7%] were immunosuppressed). The 30-day case-fatality rate after recurrent IPD was 2.9% (3/105) compared to 4.4% (219/4928; p=0.63) after single-episode IPD.
Interpretation
Recurrent IPD is rare in children and occurs mainly in children with comorbidities, especially immunosuppression. Higher-valent PCVs have the potential to further reduce the risk of recurrent IPD in children
Essential components and validation of multi-specialty robotic surgical training curricula: a systematic review.
Get PDFINTRODUCTION: The rapid adoption of robotic surgical systems has overtook the development of standardised training and competency assessment for surgeons, resulting in an unmet educational need in this field. This systematic review aims to identify the essential components and evaluate the validity of current robotic training curricula across all surgical specialties. METHODS: A systematic search of MEDLINE, EMBASE, Emcare, and CINAHL databases was conducted to identify studies reporting on multi-specialty or specialty-specific surgical robotic training curricula, between January 2000 and January 2024. We extracted data according to Kirkpatrick's curriculum evaluation model and Messick's concept of validity. The quality of studies was assessed using the Medical Education Research Study Quality Instrument (MERSQI). RESULTS: From the 3,687 studies retrieved, 66 articles were included. The majority of studies were single-centre (n = 52, 78.8%) and observational (n = 58, 87.9%) in nature. The most commonly reported curriculum components included didactic teaching (n = 48, 72.7%), dry laboratory skills (n = 46, 69.7%), and virtual reality (VR) simulation (n = 44, 66.7%). Curricula assessment methods varied, including direct observation (n = 44, 66.7%), video assessment (n = 26, 39.4%), and self-assessment (6.1%). Objective outcome measures were used in 44 studies (66.7%). None of the studies were fully evaluated according to Kirkpatrick's model, and five studies (7.6%) were fully evaluated according to Messick's framework. The studies were generally found to have moderate methodological quality with a median MERSQI of 11. CONCLUSIONS: Essential components in robotic training curricula identified include didactic teaching, dry laboratory skills, and VR simulation. However, variability in assessment methods used and notable gaps in curricula validation remain evident. This highlights the need for standardised, evidence-based development, evaluation, and reporting of robotic curricula to ensure the effective and safe adoption of robotic surgical systems
Systematic identification of disease-causing promoter and untranslated region variants in 8040 undiagnosed individuals with rare disease
Get PDFBackground
Both promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown.
Methods
We present a framework for the identification and annotation of potentially deleterious proximal promoter and UTR variants in known dominant disease genes. We use this framework to annotate de novo variants (DNVs) in 8040 undiagnosed individuals in the Genomics England 100,000 genomes project, which were subject to strict region-based filtering, clinical review, and validation studies where possible. In addition, we performed region and variant annotation-based burden testing in 7862 unrelated probands against matched unaffected controls.
Results
We prioritised eleven DNVs and identified an additional variant overlapping one of the eleven. Ten of these twelve variants (82%) are in genes that are a strong match to the individual’s phenotype and six had not previously been identified. Through burden testing, we did not observe a significant enrichment of potentially deleterious promoter and/or UTR variants in individuals with rare disease collectively across any of our region or variant annotations.
Conclusions
Whilst screening promoters and UTRs can uncover additional diagnoses for individuals with rare disease, including these regions in diagnostic pipelines is not likely to dramatically increase diagnostic yield. Nevertheless, we provide a framework to aid identification of these variants
Factors Associated With Retinal Vessel Traits in the Canadian Longitudinal Study on Aging
Get PDFPURPOSE: To determine the factors cross-sectionally and longitudinally associated with retinal vessel diameter, total area, and tortuosity in the Canadian Longitudinal Study on Aging (CLSA). METHODS: Of the 30,097 adults between ages 45 and 85 years old in the CLSA Comprehensive Cohort, 26,076 had at least one retinal image gradable by QUARTZ, a deep-learning algorithm that automatically assessed image quality, distinguished between arterioles and venules, and estimated retinal vessel traits over the entire retina. Questions were asked about demographic, lifestyle, and medical factors. Blood pressure, cholesterol, and C-reactive protein were measured. Participants returned for follow-up 3 years later. Multiple linear regression was used to provide adjusted estimates. RESULTS: Current smoking was strongly associated with wider arteriolar and venular diameters and their widening over 3 years (P < 0.05). Current smoking was also associated with a larger arteriolar and venular area and a 3-year increase in venular area (P < 0.05). Obesity was positively associated with venular diameter, total venular area, 3-year change in total venular area, and venular tortuosity (P < 0.05). Diastolic blood pressure was negatively associated with both arteriolar and venular diameter, area, and tortuosity, both cross-sectionally and longitudinally (P < 0.05). Diabetes was associated with wider arteriolar diameters cross-sectionally, and type 1 diabetes was associated with 3-year widening of arteriolar diameters (P < 0.05). CONCLUSIONS: This work provides comprehensive information on the factors associated with retinal vessel traits and their change. Factors such as smoking, obesity, blood pressure, and diabetes were longitudinally related to retinal vessel traits, which play a role in the development of eye disease
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