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Cut‐points and gray zones: The challenges of integrating Alzheimer's disease plasma biomarkers into clinical practice
Get PDFPlasma biomarkers for Alzheimer's disease (AD), such as plasma phosphorylated (p)‐tau217, offer a more accessible means of testing for the presence of AD pathology compared to cerebrospinal fluid (CSF) or positron emission tomography (PET) methods. They can support diagnostic assessment and determine patient eligibility for treatment with amyloid beta–lowering drugs in community settings where access to CSF examination and amyloid‐PET are limited. However, there are important challenges associated with interpreting and integrating plasma biomarker results in clinical practice. This article explores different approaches to interpreting plasma biomarker results in secondary care, important potential sources of uncertainty, and considerations for their clinical application.
Highlights
Plasma biomarkers such as phosphorylated tau‐217 (p‐tau217) offer a promising, accessible alternative to cerebrospinal fluid (CSF) and positron emission tomography (PET) for detecting Alzheimer's disease pathology, especially in settings with limited diagnostic resources.
Clinical integration of plasma biomarker testing presents challenges, particularly in interpreting results. This includes uncertainties around intermediate results and their role in patient management.
Clear frameworks and guidelines are essential to optimize the use of plasma biomarkers, supported by further research and education to ensure effective application in clinical practice
frizzled5 mutant zebrafish are genetically sensitised to developing microphthalmia and coloboma
Get PDFMicrophthalmia and coloboma are structural malformations of the eyes that arise from defective morphogenesis and are amongst the most severe defects associated with paediatric blindness. FZD5 is a Wnt receptor expressed in the developing eye and individuals with mutations in FZD5 exhibit microphthalmia/coloboma supporting a role for this receptor in human eye formation. Here we show that zebrafish fzd5 mutants homozygous for complete loss-of-function or predicted dominant-negative alleles, display no obvious eye defects during embryogenesis. Rather, they develop eye defects comparable to those described in humans only upon simultaneous abrogation of additional genes associated with ocular malformations. Thus, eye development can occur normally in the absence of Fzd5 in zebrafish but mutants are sensitised to developing eye malformations. By exploiting the sensitised nature of the fzd5 mutants we further identified aamp as a novel gene involved in eye morphogenesis. Overall, our study confirms the importance of considering multiple genetic contributions when searching for the molecular aetiology of ocular malformations in humans
Post-pulmonary tuberculosis lung function: a systematic review and meta-analysis
Get PDFBackground
Although post-tuberculosis lung disease poses a substantial threat to individuals who have recovered from pulmonary tuberculosis, data showing objective functional impairment in such people are scarce. We did a systematic review and meta-analysis to estimate respiratory impairment after pulmonary tuberculosis disease and examine differences in ventilatory defects.
Methods
We systematically searched Embase, MEDLINE, and CINAHL from Jan 1, 2000, to Dec 13, 2024. We included any study design with data on lung function tests in individuals with a previous diagnosis of pulmonary tuberculosis versus healthy controls. Outcomes extracted from eligible studies included forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1 as a percentage of the predicted value (FEV1%), FVC as a percentage of the predicted value (FVC%), and FEV1/FVC ratio. Pre-bronchodilator values were preferentially selected. Random effects mean difference models were used when possible and standardised mean difference where it was necessary to standardise to a single scale (ie, FEV1%, FVC%, and FEV1/FVC ratio). Between-study heterogeneity was estimated with I2. This study was prospectively registered with PROSPERO (CRD42021248838).
Findings
Of the 5594 publications found, data from 19 studies were included for meta-analyses, reporting on 75 960 individuals of whom 7447 had past pulmonary tuberculosis. All studies reporting absolute values, using various levels of adjustment or standardisation, showed that previous pulmonary tuberculosis had a negative effect across all spirometric values: FEV1 –0·41 L (95% CI –0·51 to –0·32, I2=90·4%), FVC –0·25 L (–0·33 to –0·17, I2=80·6%), and FEV1/FVC ratio –0·37 (–0·54 to –0·19, I2=92·0%). In those studies, using reference values to derive FEV1% and FVC %, prior pulmonary tuberculosis had a pooled standardised mean difference of –0·44 (–0·60 to –0·28, I2=95·6%) and –0·33 (–0·54 to –0·13, I2=91·3%), respectively, compared with controls.
Interpretation
People who recover from pulmonary tuberculosis have significantly decreased lung function compared with controls, with FEV1 more affected than FVC, giving a mixed obstructive and restrictive picture with predominantly airflow obstruction.
Funding
Breathing Matters
Clinical Grade of Obstetric Anal Sphincter Injuries and Prediction of Mode of Birth Recommendations: A 20‐Year Retrospective Analysis
Get PDFObjective
To determine whether assessment of symptoms and clinical grade of obstetric anal sphincter injuries (OASIs) is predictive of subsequent endoanal ultrasound (EAUS) and anal manometry (AM) findings to guide mode of birth recommendations.
Design
Twenty‐year retrospective analysis.
Setting
Tertiary urogynaecology unit.
Population or Sample
Women (n = 607) with a history of OASI in the second half of a subsequent pregnancy, 2002–2022.
Methods
A St Mark's Incontinence Score (SMIS), AM and EAUS were completed. An elective caesarean section (ELCS) was recommended if there was an external anal sphincter (EAS) defect and an incremental maximum squeeze pressure (IMSP) < 20 mmHg.
Main Outcome Measures
Accuracy, sensitivity, specificity, negative and positive predictive values (NPV and PPV) with 95% CI were calculated for the assessment of anorectal symptoms and clinical grade of tear relative to EAUS and AM findings.
Results
Accuracy of symptom assessment and clinical grade of tear in determining those with an EAS defect and IMSP < 20 was 75.4% (95% CI 69.3%), 69.6% (95% CI 63.8%–75.0%), 62.7% (95% CI 50.0–74.2) and 43.6% (95% CI 27.8%–60.4%) with 3a, 3b, 3c and fourth degree tears, respectively. 3a tears had the highest NPV for EAS defect and IMSP < 20 (100.0% [95% CI 97.9–100.0]), EAS defect alone (97.1% [95% CI 94.7%–98.4%]) and IMSP < 20 alone (93.5% [95% CI 90.1–82.1]).
Conclusions
Symptom assessment and clinical grade of OASI cannot be used solely to guide mode of delivery recommendations in a subsequent birth. Absence of symptoms in women with 3a tears has a high NPV, meaning these women can be recommended a vaginal birth
Two distinct subpopulations of human stem-like memory T cells exhibit complementary roles in self-renewal and clonal longevity
Get PDFT stem cell-like memory cells (TSCM cells) are considered to be essential for the maintenance of immune memory. The TSCM population has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single population has all these stem cell properties, instead the properties are distributed. We show that the human TSCM population consists of two distinct cell subpopulations which can be distinguished by the level of their CD95 expression (CD95int and CD95hi). Crucially, using long-term in vivo labelling of human volunteers, we establish that these are distinct populations rather than transient states of the same population. These two subpopulations have different functional profiles ex vivo, different transcriptional patterns, and different tissue distributions. They also have significantly different TREC content indicating different division histories and we find that the frequency of CD95hi TSCM increases with age. Most importantly, CD95hi and CD95int TSCM cells also have very different dynamics in vivo with CD95hi cells showing considerably higher proliferation but significantly reduced clonal longevity compared with CD95int TSCM. While both TSCM subpopulations exhibit considerable multipotency, no single population of TSCM cells has both the properties of self-renewal and clonal longevity. Instead, the “stemness” of the TSCM population is generated by the complementary dynamic properties of the two subpopulations: CD95int TSCM which have the property of clonal longevity and CD95hi TSCM which have the properties of expansion and self-renewal. We suggest that together, these two populations function as a stem cell population
Variation in Arterial Stiffness and Markers of Oxidative Stress in Patients with Type 2 Diabetes Mellitus from Different Ethnic Groups
Get PDFDiabetes is the world’s leading cause of renal and premature cardiovascular disease. There are marked differences between groups of patients with different ethnicities in their susceptibility to diabetes and its renal and cardiovascular complications. Novel markers of developing diabetes complications are related to disturbances in oxidative metabolism. In this cross-sectional study, we measured the arterial stiffness in patients of differing ethnicities with type 2 diabetes mellitus and assessed the relationship of their ethnicity with systemic markers of oxidative stress. Patients from black, African and Caribbean, and Asian minor ethnic groups were studied, with white patients with T2DM (n = 170) without evidence of cardiovascular disease (CVD). The vascular stiffness was measured by infrared finger-photoplethysmography. The oxidative stress burden was assessed by measuring the urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), activities of plasma glutathione peroxidase (GPx-3), superoxide dismutase (SOD) activities, and concentration of selenium. The vascular stiffness and 8-OHdG were higher in the white than in the Black patients (9.68 m/s vs. 9.26 m/s, p = 0.021 and 292.8 ng/mL vs. 200.9 ng/mL, p = 0.0027, respectively). Meanwhile, the GPx-3 and SOD activities and selenium were lower in the white than in the Black patients (283.3 U/L vs. 440.4 U/L, p < 0.0001; 37.5 U/L vs. 75.6 U/L, p = 0.0007; and 1.14 vs. 1.28 µmol/L, p = 0.0001, respectively). In regression modelling, the 8-OHdG/creatinine ratio was an independent predictor of vascular stiffness in the white patient group (β = 0.23 m/s per unit increase in ln(8-OHdG/creatinine) [95% CI, 0.03 to 0.42]; p = 0.021) but not in the Black patient group (p = 0.29). Increased vascular stiffness, lower endogenous antioxidant defense, and greater levels of oxidative damage were found in patients of white ethnicity, which could contribute to the higher incidence of CVD compared with patients from Black minor ethnic groups with diabetic renal disease
Cardiovascular screening of athletes
Get PDFThe sudden death of an athlete causes grave concern among the medical, sporting, and lay communities, considering athletes epitomise the healthiest segment of society. Most decedents are asymptomatic, therefore screening to identify vulnerable individuals seems appropriate, particularly since most aetiologies can be detected during life and several therapeutic interventions can be implemented to minimise the risk. Given the diversity of conditions implicated in exercise related SCD, no single test will detect all disorders. Furthermore, the low incidence of SCD allows for a cost-effective approach using the simplest and most readily available tools. The 12-lead electrocardiogram has emerged as the most effective tool for detecting electrical diseases and raising suspicion of cardiomyopathy. The international recommendations for ECG interpretation allows for physiological remodelling, substantially reducing false positive rates. Nonetheless, the challenge remains, since the ECG will fail to identify up to 20 % of diseases implicated in young sudden cardiac death and is of limited value in middle-aged and older athletes, in whom atherosclerotic coronary artery disease dominates. Therefore, mitigation of risk extends beyond screening to encompass timely resuscitation, universal defibrillator access, and education in cardiac awareness. The future of screening for cardiovascular disease in athletes is likely to combine traditional evaluation with artificial intelligence, including the use of wearable monitoring, and equal access for effective screening worldwide
Quantifying the experiences of Black and Dual Heritage young people in a forensic child and adolescent mental health service.
Get PDFBACKGROUND: Young people from racialised backgrounds are overrepresented in justice services. This study explored differences in community support offered to young people from racialised groups referred to a forensic child and adolescent mental health service. METHOD: We compared support offered to 427 young people, according to five ethnic groups. RESULTS: Over 20% of young people referred were Black (compared with 14% of the local population) and 15.8% were Dual White and Black Heritage (compared with 4% of the local population). Odds ratios showed that Black and Dual Heritage groups were more frequently involved with youth offending services (Black: 2.59, Dual Heritage: 2.88), gangs services (Black: 4.31, Dual Heritage: 7.13) and have a national referral mechanism (Black: 3.61, Dual Heritage: 4.01) than their White peers, but were less often in mainstream education compared with their Asian peers (Black: 0.26, Dual Heritage: 0.29). Black (odds ratio 0.35) and Dual Heritage (odds ratio 0.40) young people were less frequently diagnosed with a neurodevelopmental disorder than their White peers. CONCLUSIONS: Those from Black and Dual Heritage backgrounds were disproportionately disadvantaged
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