QJM: An International Journal of Medicine最新文献

Background: Current noninvasive prenatal testing (NIPT) based on cell-free DNA (cfDNA) mainly targets the detection of chromosome aberrations but not dominant single-gene disorders (dSGDs).

Aim: This prospective pilot study aims to evaluate the clinical utility of a plasma cfDNA and targeted next-generation sequencing-based NIPT approach for dSGDs (NIPT-dSGD), with a particular focus on neurodevelopmental disorders (NDDs).

Methods: The NIPT-dSGD method targeted 34 genes, including 25 correlated to NDDs and nine correlated to Noonan spectrum, skeletal, craniosynostosis, and other syndromic disorders. Retrospective samples first validated NIPT-dSGD and then performed for a prospective cohort of 567 pregnant women seeking NIPT-dSGD. The testing results were compared to invasive prenatal or postnatal genetic diagnosis by whole-exome sequencing and Sanger sequencing.

Results: Of the 535 samples with qualified NIPT-dSGD analysis, 11 (2.1%) had one pathogenic or likely pathogenic variant in one of the 34 genes. Three of the 11 variants were paternally inherited, and eight were de novo. Five positive cases had normal ultrasound parameters, and three of them had disease-causing variants in NDD genes. Particularly, one family had two pregnancies with de novo variants of two different genes (GRIN2B: c.1606G>A and ARID1B: c.6100A>G). NIPT-dSGD did not generate any false-positive or negative results, achieving 100% of sensitivity (95% CI, 71.7%-100%) and 100% of specificity (95% CI, 99.0%-100%).

Conclusions: NIPT-dSGD provides accurate genetic testing for de novo and paternally inherited variants of dominant genes, including those that do not cause any ultrasound abnormalities, which could assist clinicians and families in better pregnancy management.

Background and aims: To establish an early and quick model for diagnosing infections in patients with acute-on-chronic liver disease (AoCLD).

Approach: This study analyzed 3,949 patients from two multicenter prospective cohorts of the Chinese Acute-on-Chronic Liver Failure (CATCH-LIFE) study. The dataset was randomly divided into training and validation cohorts in a 7:3 ratio. In the training cohort, logistic regression and least absolute shrinkage and selection operator regression analyses were used to identify predictive risk factors for infection in patients with AoCLD, and a simple nomogram was established. Two different cutoff values were determined to stratify infection risk in AoCLD patients.

Results: The developed diagnostic model included six variables: cirrhosis, ascites, neutrophil count (N), and total bilirubin, C-reactive protein (CRP), and blood sodium levels. The area under the receiver operating characteristic curve for the training and validation cohorts were 0.818 and 0.809, respectively, significantly higher than using CRP, procalcitonin, or N alone. Additionally, in the training cohort, we set a low cutoff value of 0.2028, resulting in a sensitivity of 80.15%, specificity of 68.25%, and a negative predictive value of 92.7% for rule-out diagnosis. A high cutoff value of 0.4045 resulting in a specificity of 90.1%, sensitivity of 52.7%, and a positive predictive value of 64% for rule-in diagnosis. These cutoff values were validated in the validation cohort.

Conclusions: We established a nomogram model to assist clinicians in diagnosing infections in patients with AoCLD, effectively improving the accuracy and timeliness of diagnosis.

Background: Variation in DNA is known to contribute to medication response, impacting both medicine effectiveness and incidence of adverse drug reactions (ADRs). However, clinical implementation of pharmacogenomics (PGx) has been slow, and the views of the public are not well understood.

Aim: To assess UK national public attitudes around pharmacogenetics.

Design and methods: The survey was co-designed with the Participant Panel at Genomics England and the data were collected by the National Centre for Social Research, using its nationally representative panel of UK adults. Multivariable logistic regression analyses were used to analyse relationships between selected survey reported variables, controlled for age and sex.

Results: The survey response rate was 58%. Two thousand seven hundred and nineteen responses were obtained. Most respondents (59%) had experienced either no benefit or a side effect. Forty-five per cent of respondents reported having experienced no benefit and 46% of respondents reported having experienced a side effect, with female respondents more likely to be in both groups (P < 0.0001). Despite variability in interindividual medicine response being well understood (89%), the involvement of DNA in predicting benefit or risk of a side effect is not (understood by 52% and 48%, respectively). Eighty-nine per cent would complete a PGx test, with 91% wanting direct access to this information. Eighty-five per cent of UK adults think that the NHS should offer PGx to those regularly taking many medicines. Respondents were not more worried overall about misuse of PGx data compared with other routine medical data. Experience with prescription medication impacted on views with those who were prescribed medication almost twice as likely to want a PGx test for any reason.

Conclusion: Most respondents reported experience with either a medication not working for them or ADRs. There was a high level of understanding of variable medication response but a relatively low level of awareness of the role genetics plays in that variability. Most respondents would want a PGx test, to have direct access to results, and think the NHS should offer this form of testing. Importantly, respondents were not more concerned about PGx data use than that of any other routinely generated medical data. Notably, this study highlights a relationship between individuals' experiences with prescription medications and their interest in PGx testing, underscoring the potential for personalized medicine to address public healthcare needs.