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Comparative in vitro susceptibility of clinical Leishmania isolates to miltefosine and oleylphosphocholine
Get PDFCutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. It poses a significant global health burden, particularly because treatment options are limited. More effective and safer treatments are urgently needed. In previous studies, oleylphosphocholine (OlPC), a novel investigational compound structurally related to miltefosine, exhibited comparable activity to miltefosine in intramacrophage assays across various CL-causing laboratory strains and demonstrated superior efficacy in an experimental CL model. This study investigated the in vitro activity of OlPC against clinical isolates of Leishmania spp., comparing its activity with standard anti-leishmanial drugs, including miltefosine, amphotericin B, and pentavalent antimonial agents. Seventy ex vivo isolates (L. major and L. tropica) obtained directly from CL patients before any treatment were used to capture the diversity of drug susceptibilities in circulating parasite populations. Dose-response curves were fitted using a four-parameter log-logistic model to estimate EC50 and EC90 values. Additionally, a linear mixed-effects model was applied to examine the influence of drug type and species on EC50 values while accounting for within-isolate variability. Our findings indicate that OlPC exhibits potent in vitro anti-leishmanial activity, exceeding that of miltefosine in our in vitro intramacrophage model. To facilitate similar analyses, we provide a dedicated wrapper function in R designed to simplify curve fitting and parameter estimation, making the process more accessible to researchers
Adverse perinatal outcomes in twins: comparison of intertwin fetal size discordance vs singleton and twin fetal growth charts
Get PDFObjective
To compare the predictive performance of intertwin estimated fetal weight (EFW) discordance and EFW centile calculated according to either the Fetal Medicine Foundation (FMF) singleton or twin‐specific fetal growth charts for adverse perinatal outcome in dichorionic and monochorionic twin pregnancies.
Methods
This was a retrospective multicenter cohort study of twin pregnancies managed between January 2013 and December 2023 at three tertiary fetal medicine centers in the UK, Italy and Belgium. Twin pregnancies in which an obstetric ultrasound exam was performed to obtain fetal biometry within 2 weeks before live birth or diagnosis of intrauterine fetal demise of one or both twins were included. Cases with anastomotic complications were excluded. The primary outcome was a composite adverse perinatal outcome (CAPO), defined as stillbirth (intrauterine fetal demise ≥ 22 weeks) of at least one cotwin and/or iatrogenic early preterm birth (delivery < 34 weeks) for fetal indications. The predictive performance of intertwin EFW discordance and of the EFW centile of the smaller twin, calculated using either singleton or twin‐specific FMF fetal growth charts, was assessed for CAPO. Predictive models were developed using logistic regression analysis and evaluated using the area under the receiver‐operating‐characteristics curve (AUC); pairwise comparisons between models were performed using DeLong's test.
Results
The study analyzed 1294 dichorionic and 487 monochorionic twin pregnancies. For the prediction of CAPO, intertwin EFW discordance in dichorionic twins achieved an AUC of 0.93 (95% CI, 0.89–0.98), compared with 0.83 (95% CI, 0.77–0.90) (P = 0.001) and 0.87 (95% CI, 0.81–0.93) (P = 0.017) for EFW centile based on singleton and twin‐specific growth charts, respectively. Likewise, intertwin EFW discordance achieved an AUC of 0.95 (95% CI, 0.92–0.97) for predicting CAPO in monochorionic twins, outperforming EFW centile based on singleton charts (AUC, 0.80 (95% CI, 0.73–0.87); P < 0.001) and twin‐specific growth charts (AUC, 0.83 (95% CI, 0.76–0.90); P < 0.001). In clinical terms, at a 20% false‐positive rate (FPR), the sensitivity for CAPO in dichorionic twin pregnancies was 74%, 81% and 93% using singleton charts, twin‐specific charts and intertwin EFW discordance, respectively. Similarly, in monochorionic twin pregnancies, the sensitivity at a FPR of 20% was 75%, 79% and 98% using singleton charts, twin‐specific charts and intertwin EFW discordance, respectively.
Conclusions
Intertwin EFW discordance is a more reliable predictor of the composite outcome of stillbirth in at least one cotwin and/or iatrogenic early preterm birth in twin pregnancies than is EFW centile based on either singleton or twin‐specific growth charts. This approach addresses the limitations of using different fetal growth reference charts that rely on arbitrary cut‐offs. Following external validation, the use of intertwin EFW discordance prediction algorithms may potentially enhance risk stratification to improve clinical outcomes in twin pregnancies
Comparative effectiveness of educational interventions in neurological disease for healthcare workers and students: a systematic review
Get PDFObjectives
To assess the comparative effectiveness of educational interventions in neurological disease for healthcare workers and students.
Design
Systematic review.
Data sources
Medline, Embase and Cochrane through to 1 June 2025.
Eligibility criteria
Studies evaluating neurological disease educational interventions with a comparator group (observational cohort/randomised controlled trial (RCT)) were included.
Data extraction and synthesis
A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review was conducted (PROSPERO: CRD42023461838). Knowledge acquisition and educational methodologies were collected from each study. Study outcomes were classified using the Kirkpatrick and Kirkpatrick four-level model (learner reaction, knowledge acquisition, behavioural change, clinical outcome).1 Risk of bias was assessed using the Newcastle-Ottawa scale for non-randomised studies and the Cochrane Risk of Bias tool for RCTs.2 3
Results
A total of 67 studies involving 4728 participants were included. Of these, 36 were RCTs, and 31 were observational studies. Virtual interventions were the most common (67.2%, n=45 studies), primarily targeting either medical students (46.3%, n=31 studies) or specialists (40.3%, n=27 studies). Overall, 70.1% (n=47) of studies demonstrated outcomes in favour of the intervention. However, few studies used K&K level 3/4 outcomes, with two studies evaluating behaviour change (level 3) and three assessing clinical outcomes (level 4 combined with other levels). No study exclusively assessed level 4 outcomes. Meta-analysis of 22 RCTs with calculable standardised mean differences (SMDs) (n=1748) showed a significant benefit of interventions (SMD 0.75, 95% CI 0.22 to 1.27, p=0.0056).
Conclusions
This review highlights a growing body of research particularly focusing on virtual techniques, specialist audiences and treatment-oriented content. Few studies assessed changes in practice or patient care. Non-specialists remain underrepresented. Future studies should prioritise assessing the clinical impact of educational interventions within non-specialist audiences
Making medical education great again: analysing trainee feedback to identify key drivers of trainee satisfaction and improve experience.
Get PDFOBJECTIVES: The London School of Paediatrics (LSP) surveys trainees annually regarding their training placements. There is a wide variation in satisfaction. We explored the last 5 years of data to identify trends and determine predictors of overall trainee satisfaction. METHODS: The survey is distributed annually to all London paediatric trainees with response rates of 86-90%. It explores overall placement satisfaction, followed by key questions covering staffing, supervision, teaching, facilities and other facets. The survey blends both quantitative and qualitative feedback.Satisfaction levels were analysed using time series trend analysis. Overall levels were compared using t-tests. Associations between satisfaction and components of the survey were identified using a convergence of multiple regression and other multivariate analyses. RESULTS: Overall trainee satisfaction increased steadily until 2020. There was a considerable variation across sites, some having consistently higher or lower scores than the median, while others showed an upward or downward trend, or very variable pattern.By training levels, ST3 trainees consistently rated their placement below average and ST7 trainees above average. There was also a considerable variation in responses by training level with regard to perceived staffing levels and teaching.To understand the influences on overall satisfaction, regression coefficients were derived between specific metrics and overall satisfaction using multiple regression and then normalised to 100%. The explanatory power of this list to explain satisfaction overall is high at 82% R2.Trainee satisfaction was most strongly correlated with workplace atmosphere and consultant support. Staffing, educational supervision, facilities and wider MDT (Multidisciplinary Team) support are associated with overall satisfaction, but to a lesser degree. CONCLUSIONS: Trainee satisfaction is crucial, affecting patient safety, retention and trainee mental health. Our analysis identified significant associations with satisfaction including modifiable elements such as consultant engagement and team morale. Staffing levels were less related to satisfaction than expected.Experimental data exploring the components of clinical training in real-world situations are lacking. These data use the natural experiment of placing trainees in different training locations to explore the factors that relate to their overall experience
Diagnostic accuracy of cell-free fetal DNA in maternal blood in detecting chromosomal anomalies in twin pregnancy: systematic review and meta-analysis
No full textObjective
To report the diagnostic accuracy of cell-free fetal DNA (cfDNA) in maternal blood in detecting fetal chromosomal anomalies in twin pregnancy.
Methods
PubMed, MEDLINE, EMBASE and Cochrane databases were searched from inception to November 2023. The inclusion criteria were twin pregnancy undergoing cfDNA screening for trisomies 21, 18 and 13, monosomy X and/or other sex-chromosome aneuploidies (SCA). The index test was cfDNA screening. The reference standard was pre- or postnatal karyotyping (in the case of a positive cfDNA result) or neonatal phenotypic assessment (in case of a negative cfDNA result). The quality of included studies was assessed using the revised quality assessment of diagnostic accuracy studies (QUADAS-2) tool. Summary estimates of diagnostic accuracy were computed using a bivariate random-effects model.
Results
Thirty-five studies were included in the systematic review and meta-analysis. cfDNA had a high accuracy in detecting trisomy 21 in twin pregnancy, with a sensitivity of 98.8% (95% CI, 96.5–100%) and specificity of 100% (95% CI, 99.9–100%). Sensitivity and specificity were 94.9% (95% CI, 75.9–99.1%) and 100% (95% CI, 99.9–100%), respectively, for trisomy 18 and 84.6% (95% CI, 54.6–98.1%) and 100% (95% CI, 99.9–100%), respectively, for trisomy 13. We could not compute the diagnostic accuracy of cfDNA in detecting monosomy X, owing to an absence of positive cases, while cfDNA had a sensitivity of 100% (95% CI, 71.5–100%) and specificity of 99.8% (95% CI, 99.7–99.9%) for other SCA. The accuracy of cfDNA in detecting the common trisomies was similar in dichorionic and monochorionic twin pregnancies.
Conclusions
cfDNA has high diagnostic accuracy in detecting trisomies 21 and 18 in twin pregnancy, irrespective of chorionicity. Estimation of diagnostic accuracy for trisomy 13 and other SCA was limited by the small number of affected cases and the difficulty associated with detecting false-negative cases of other SCA, and thus requires confirmation in larger studies
Influence of drug infusion pumps compared with an electronic prescribing and medicines administration (ePMA) system on vancomycin pharmacokinetic model fit: implications for bacterial resistance breakpoints in critically ill adults and children
Get PDFFactors influencing UK arthroplasty surgeons' decision-making between total and medial unicompartmental knee surgery: A vignette-based behavioural experiment
Get PDFPurpose
Surgical options for end-stage knee osteoarthritis (OA) include total and medial unicompartmental knee replacement (TKR and UKR). Deciding which surgery to perform is complex and ill-defined, yet it has important implications for patients and the health service. The study aimed to identify clinical and surgeon factors predicting surgeons' preferences.
Methods
Based on a preliminary survey of 162 UK surgeons, we identified clinical features frequently considered when deciding between TKR and UKR. By systematically varying patient age, obesity, site of pain, anaesthetic risk and anterior cruciate ligament (ACL) integrity, we constructed 32 clinical vignettes. We used these in a new survey, where surgeons indicated which surgery they would recommend on an 11-point rating scale with end points anchored at ‘definitely TKR’ and ‘definitely medial UKR’. Data were analysed with mixed-effects linear regressions.
Results
Eighty-three UK arthroplasty surgeons completed the vignettes. Preference for UKR over TKR was significantly lower for patients over 50 years (b = −0.57 [−0.82 to −0.33], p < 0.001) with abnormal ACL (b = −1.93 [−2.17 to −1.68], p < 0.001) and severe systemic disease (b = −0.46 [−0.70 to −0.21], p < 0.001). Obesity was a weak and unreliable predictor, and we did not detect any influence of site of pain. The surgeons' habitual practice (proportion of UKRs over all knee replacements performed in a typical year) was the second strongest predictor after ACL (b = 1.26 [0.54–1.99], p = 0.001).
Conclusions
ACL integrity was the most important determinant of surgeons' preferences between TKR and UKR. Their habitual practice was also a strong predictor, outweighing most clinical factors in the vignettes.
Level of Evidence
Level II, prospective cohort study
Development and validation of a liquid chromatography-tandem mass spectrometry assay for the simultaneous analysis of isoniazid and pyrazinamide in cerebrospinal fluid
Get PDFFor the effective treatment of tuberculosis with first-line anti-tubercular drugs, drug concentrations need to be measured at the site of infection to determine drug exposure. To enable the measurement of the anti-tuberculosis drugs isoniazid and pyrazinamide in the nervous system of patients with tuberculous meningitis, an analytical method was developed and validated for the quantification of these drugs in human cerebrospinal fluid. Samples were prepared by solid phase extraction using Strata-X polymeric extraction plates. The analytes were separated by high-performance liquid chromatography on an Atlantis T3, 100 A, 3 µm, 2.1 mm × 100 mm analytical column with gradient elution, employing a mobile phase that consisted of acetonitrile-methanol-formic acid (50:50:0.1, v/v/v), at a flowrate of 0.25 mL/min. The total run time was 4.5 minutes, and the average retention times of isoniazid and pyrazinamide were 1.1 and 1.3 min, respectively. The analytes and their respective deuterated internal standards were detected on a Sciex API4000 triple quadrupole mass spectrometer applying positive electrospray ionization with multiple reaction monitoring as the detection mode. The method was validated according to the FDA and EMA guidelines. The method was demonstrated to be accurate, reproducible, and robust, showing the necessary sensitivity and specificity for the quantification of isoniazid and pyrazinamide in cerebrospinal fluid. The method was successfully applied to analyze clinical samples from the LASER-TBM and TBM-KIDS clinical studies
The Prediction of Intrapartum Fetal Compromise According to the Expected Fetal Weight.
Get PDFObjectives: To assess the predictive accuracy of the expected fetal weight in the third trimester (ExFW3t), based on the estimated fetal weight (EFW) at mid-trimester ultrasound scan, for the prediction of intrapartum fetal compromise (IFC) (an abnormal intrapartum fetal heart rate or intrapartum fetal scalp pH requiring urgent cesarean section). Methods: This retrospective study included 777 singleton pregnancies that underwent a 20-week study and a 3t scan. The extrapolated EFW at 20 weeks to the 3t or ExFW3t was considered a proxy of the potential growth. The percentage difference with the actual 3t EFW (%ExFW3t) was compared with other ultrasonographic and clinical parameters—EFW centile (EFWc), middle cerebral artery pulsatility index (MCA PI) in multiples of the median (MoM), umbilical artery (UA) PI MoM, cerebroplacental ratio (CPR) MoM, and maternal height—for the prediction of IFC by means of the area under the curve (AUC) and Akaike Information Criteria (AIC). Results: Pregnancies with IFC presented higher values of UA PI MoM (1.19 vs. 1.09, p = 0.0460) and lower values of population and Intergrowth EFWc (45.9 vs. 28.9, p < 0.0001, 48.4 vs. 33.6, p = 0.0004), MCA PI MoM (0.97 vs. 0.81, p < 0.0001), CPR MoM (1.01 vs. 0.79, p < 0.0001), %ExFW3t (89.9% vs. 97.5%, p = 0.0003), and maternal height (160.2 vs. 162.9, p = 0.0083). Univariable analysis selected maternal height, EFWc, %ExFW3t, and UA PI MoM as significant parameters. However, %ExFW3t did not surpass the prediction ability of cerebral Doppler. Finally, multivariable analysis showed that the best models for the prediction of IFC resulted from the combination of cerebral Doppler (MCA PI MoM or CPR MoM), fetal weight (%ExFW3t or EFWc), and maternal height (AUC 0.75/0.76, AIC 345, p < 0.0001). Conclusions: Fetal weight-related parameters, including %ExFW3t, a proxy of the proportion of potential growth achieved in the 3t, were less effective than fetal cerebral Doppler for the prediction of IFC. The best performance was achieved by combining hemodynamic, ponderal, and clinical data
A Dominant Mutation in Gαs-Protein Increases Hair Pigmentation
Get PDFWe have identified a chemically induced mouse mutation which increases the eumelanic hair pigmentation. We identify a coding mutation, A3533G, resulting in an amino acid substitution Y1133C, in the Gnas gene encoding the Gαs subunit of the tripartite G‐protein, consistent with an activation of signalling via MC1R. In addition heterozygous mutant females are significantly lighter than wild type littermates. In cultured melanocytes, derived from mutant mice crossed to C57BL6 mice carrying Cdkn2atm1Rdp, basal pigmentation is higher than wild type melanocytes derived from litter mates. However, the addition of exogenous NDP‐MSH does not increase pigmentation in mutant melanocytes in contrast to the pigmentation response of non‐mutant melanocytes. The mutant and wild type cells respond in the same way to agouti signalling protein (ASP), consistent with ASP signalling mediated through a pathway other than Gαs‐protein
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