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Diagnosis and management of congenital Cytomegalovirus: Critical Appraisal of Clinical Practice Guidelines.
Get PDFOBJECTIVES: To review the currently available Clinical Practice Guidelines regarding the diagnosis and management of Cytomegalovirus (CMV) infection in pregnancy. METHODS: Medline, Turning Research into Practice (TRIP), Web of Science databases and scientific societies' websites were searched electronically up to April 2024. We included national and international Clinical Practice Guidelines regarding diagnosis, treatment and follow-up of CMV infection in pregnancy, published in English language. Quality assessment of the included guidelines was performed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. RESULTS: Ten Clinical Practice Guidelines and two expert consensus statements were included. The review showed agreement among national and international guidelines about the diagnostic criteria for primary maternal CMV infection and about the gold standard for confirmation of fetal infection. Regarding treatment, only two societies recommended routine administration of Valaciclovir in case of primary infection in the clinical practing setting. Fetal surveillance including ultrasound and magnetic resonance imaging (MRI) in case of confirmed infection was found to be heterogeneous among the recommendations. CONCLUSIONS: Although consensus was obtained regarding the diagnostic criteria for primary CMV infection in pregnancy, there was heterogeneity among Clinical Practice Guidelines with regards to other aspects of clinical management of CMV in pregnancy. In addition, some topics where not addressed in the current guidelines, including the treatment of non-confirmed fetal infection and the management of non-primary maternal infection. Recommendations regarding prevention of congenital CMV are rapidly evolving based on the new available evidence
Recent Antiretroviral Therapy Initiation Is Associated With Increased Mortality Risk in Human Immunodeficiency Virus-associated Cryptococcal Meningitis: An Analysis of Clinical Trial Data From Africa
Get PDFBackground
More than half of people diagnosed with human immunodeficiency virus–associated cryptococcal meningitis are antiretroviral therapy (ART)-experienced. The impact of recent ART initiation (≤14 days) on outcomes from cryptococcal meningitis, and how to optimally manage ART in this patient population, are unknown.
Methods
We analyzed data from the recent Ambisome Therapy Induction Optimisation (AMBITION) trial to (1) examine whether patients diagnosed with cryptococcal meningitis within 14 days of ART initiation are at higher risk of mortality and (2) determine the impact of ART interruption at diagnosis of cryptococcal meningitis. Combined data from the AMBITION trial and the earlier Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa trial were analyzed to describe baseline characteristics of patients according to ART status.
Results
Among the 810 AMBITION participants, adjusted 2-week mortality risk was 20.8% (95% confidence interval [CI]: 11.5–30.2; 26/120) in those on ART for 14 days or less at presentation, 10.4% (95% CI: 3.6–17.2; 18/130) on ART for >2 weeks to 2 months, 7.1% (95% CI: 0–14.9; 7/92) on ART for >2 months to 6 months, and 13.0% (95% CI: 8.5–17.6; 50/307) in those on ART for more than 6 months compared to 12.4% (95% CI: 9.2–15.5; 111/707) among individuals not on ART. In the combined dataset, baseline fungal burdens were lower and baseline CD4 counts were higher with increasing ART duration. Among individuals on ART for ≤14 days at presentation, 2-week mortality was 35% (8/23) in those continuing ART versus 14% (7/49) in those discontinuing ART.
Conclusions
Mortality from cryptococcal meningitis was higher in recent ART initiators. ART interruption in this group may lead to improved outcomes
Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder.
Get PDFPURPOSE: The TAOK proteins are a group of serine/threonine-protein kinases involved in signalling pathways, cytoskeleton regulation, and neuronal development. TAOK1 variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia and feeding difficulties. TAOK2 variants have been reported to be associated with autism and early-onset obesity. However, a distinct TAOK2-NDD has not yet been delineated. METHODS: We retrospectively studied the clinical and genetic data of individuals recruited from several centres with TAOK1 and TAOK2 variants that were detected through exome and genome sequencing. RESULTS: We report 50 individuals with TAOK1 variants with associated phenotypes including neurodevelopmental abnormalities (100%), macrocephaly (83%) and hypotonia (58%). We report male genital anomalies and hypoglycaemia as novel phenotypes. Thirty-seven unique TAOK1 variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report ten patients with TAOK2 variants with associated phenotypes including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%). CONCLUSION: We describe the largest cohort of TAOK1-NDD to date, expanding its phenotype and genotype spectrum with thirty novel variants. We delineate the phenotype of a novel TAOK2-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity
Evaluation of Perineal Descent Measurements on Pelvic Floor Imaging.
Get PDFObjectives: The aim of this study is to validate a uniform method for measuring perineal descent which can be used for different imaging methods, to establish cut-off values for this measurement, and to assess diagnostic test accuracy (DTA) of imaging techniques using these cut-off values. Secondly, the study aims to correlate perineal descent to symptoms, signs and imaging findings in women with obstructed defaecation syndrome (ODS) to assess its clinical relevance. Methods: Cross-sectional study of 131 women with symptoms of ODS. Symptoms and signs were assessed using validated methods. These women underwent evacuation proctography (EP), magnetic resonance imaging (MRI), transperineal ultrasound (TPUS) and endovaginal ultrasound (EVUS). Perineal descent was measured on EP and MRI as the position of anorectal junction (ARJ) with respect to the pubococcygeal line (PCL) at rest (i.e., static descent) and during evacuation (i.e., descent at Valsalva). Dynamic perineal descent was measured on all four imaging techniques as the difference between the position of the ARJ at rest and Valsalva. DTA of dynamic perineal descent was estimated using Latent Class Analysis in the absence of a reference standard. Results: Interobserver agreement of dynamic perineal descent measurements was good for MRI and EVUS (ICC 0.86 and 0.85) and moderate for EP and TPUS (ICC 0.61 and 0.59). The systematic differences in measurements between imaging techniques show the need for individual cut-off values. New established cut-off values for dynamic descent are for EP 20 mm, MRI 35 mm, TPUS 15 mm and EVUS 15 mm. Sensitivity was moderate for EP (0.78) and MRI (0.74), fair for TPUS (0.65) and poor for EVUS (0.58). Specificity was similar for all imaging techniques (0.73-0.77). Static perineal descent correlated with symptoms of pelvic organ prolapse (POP) (r = 0.19), prolapse of all three compartments (r = 0.19-0.36), presence of levator ani muscle avulsion (p = 0.01) and increased hiatal area (r = 0.51). Dynamic perineal descent correlated with excessive straining (r = 0.24) and use of laxatives (r = 0.24). Classic symptoms of ODS (incomplete evacuation and digitation) did not correlate with perineal descent measurements. Static and dynamic perineal descent were associated with presence of rectocele, enterocele, intussusception, and absence of anismus. Conclusions: Dynamic perineal descent is a reliable measurement that can be applied to different imaging techniques to allow standardisation. Static descent is more often present in women with POP and dynamic descent is more often present in women with constipation. Perineal descent does not correlate with typical symptoms of ODS. Specificity of TPUS and EVUS is comparable to EP and MRI, hence ultrasound could be used for the initial assessment of pelvic floor dysfunction
Levetiracetam dosing in continuous renal replacement therapy: A systematic review and development of a novel pharmacokinetic model to optimise dosing in critically ill patients. Do recommended doses achieve therapeutic drug concentrations?
Get PDFAim:
Levetiracetam is a widely used anti-epileptic in the critical care setting that is almost exclusively (>90%) renally excreted. The altered pharmacokinetics of levetiracetam have been widely studied in intermittent haemodialysis but the evidence and guidance on dosage in continuous renal replacement therapy is varied and poorly defined. Understanding this is critical as a significant number of critically unwell patients develop renal failure requiring continuous renal replacement therapy. The aim of this systematic review is to investigate the pharmacokinetics of levetiracetam in such patients and to understand the implications on dosing strategies.
Methods:
A systematic review of the available literature from 2000 to November 2022 was conducted. Seven articles were identified for inclusion from 54 records. A novel hybrid model was developed to evaluate the quality of pharmacokinetic and haemofiltration data. This data was used to develop a one-compartment model that simulated dosing strategies in 10,000 patients based on an assumed steady state of 72 hr and target trough concentrations of 12–46 mcg/mL.
Results:
From the seven articles included, pharmacokinetic data was retrieved for 24 individual patients. Total clearance was 3.49–4.63 L/hr (mean 3.55, S.D. 0.52). Elimination half-life was 5.66–12.88 hr (mean 9.41, S.D. 2.86). Volume of distribution was 0.45–0.73 L/kg. The proportion of total clearance attributable to continuous renal replacement therapy was 52%–73% (mean 54.7%, S.D. 13.5). Our simulations demonstrate that more than half of patients who received twice daily doses of 750 mg or greater without a loading dose achieved therapeutic drug concentrations. The time to achievement of therapeutic drug concentrations was greatly reduced by the addition of a 60 mg/kg loading dose (up to a maximum of 4.5 g). The use of a reduced loading dose or twice daily doses of 500 mg or less without loading were more likely to result in prolonged sub-therapeutic drug concentrations.
Conclusion:
Levetiracetam clearance in haemofiltration is similar to healthy adults with normal renal function (GFR > 90 mL/min). The use of reduced doses due to renal failure in critically ill patients may result in sub-therapeutic drug concentrations in a high number of patients. A twice daily dosing of 750–1000 mg with an initial loading dose of 60 mg/kg should be considered in such patients alongside therapeutic drug monitoring
Inequality in exposure to daily aircraft noise near heathrow airport: An empirical study.
Get PDFAircraft noise is an important source of environmental pollution and a burden on public health. We examined the association between three different area-level deprivation measures (Carstairs index 2011 only; yearly avoidable mortality rates 2014-2018 and yearly fuel poverty rates 2014-2018) and daily aircraft noise metrics (Lday, Leve, Lnight, and LAeq24) around London Heathrow Airport. Analyses were conducted for 2014-18 for ∼155,000 postcodes using a Random-Effects model with an autoregressive term for the temporal variability of daily noise. We found that the relationship between aircraft noise and deprivation was complex, varying by the measure of deprivation and aircraft noise metric. We observed gradient relationships between avoidable death rates and aircraft noise exposure for all noise metrics. For Carstairs index, a measure of area-based material deprivation, the least deprived quintile exhibited the lowest night-time noise levels, but no gradients were observed for this or other noise metrics. Similarly, we did not see clear patterns of association between fuel poverty and aircraft noise. When stratifying the data by % non-White population, the conclusions for avoidable death rates and fuel poverty remained similar, but an association of Carstairs index with noise metrics was seen in the two tertiles with the highest % non-white population. Our strengths include our large dataset with high temporal and spatial resolution, as well as use of multiple deprivation measures and daily noise metrics over five years, that can capture dynamic changes in noise exposure related to changes in flight paths and weather conditions. Limitations include that we looked at 2014-18 and noise levels have been changing over time due to action plans to reduce exposure, and activity changes due to the pandemic and post-pandemic periods. Heathrow Airport is sited near wealthy and densely inhabited communities so may not be representative of all airports
Whole-genome sequencing, strain composition, and predicted antimicrobial resistance of Streptococcus pneumoniae causing invasive disease in England in 2017–20: a prospective national surveillance study
Get PDFBackground
Surveillance of the invasive disease burden caused by Streptococcus pneumoniae in England is performed by the UK Health Security Agency (UKHSA). In 2017, UKHSA switched from phenotypic methods to whole-genome sequencing (WGS) approaches for pneumococcal surveillance. Here, we present the first results of national WGS surveillance, up to the start of the COVID-19 pandemic, with the aim of describing the population genomics of this important pathogen.
Methods
We examined prospective national surveillance data from England, using bacterial isolates from cases of invasive pneumococcal disease (IPD) submitted to the national reference laboratory at UKHSA. A bioinformatic pipeline was developed to quality control WGS data and routinely report species and serotype. We assembled isolate data, assigned global pneumococcal sequencing clusters (GPSCs), and predicted antimicrobial resistance (AMR) profiles for isolates that passed further quality control. We collected additional data on patient outcomes and characteristics using enhanced surveillance questionnaires completed by patients’ general practitioners. We used logistic regression analysis to assess the effects of various genomic and patient characteristics on the outcomes of IPD.
Findings
In England, between July 1, 2017, and Feb 29, 2020, there were 15 400 cases of IPD. From these cases, 13 749 (89·3%) isolates were sequenced, passed quality control, and were included in analyses. Serotype diversity was high during the study period, with 2751 (20%) isolates serotyped as 13-valent pneumococcal conjugate vaccine (PCV13) types, whereas serotype 8 was the most prevalent serotype (n=3074 [22·4%]) overall. There were 157 GPSCs within the collection, with GSPC3 the most common, encompassing 98·7% (3033 of 3074) of serotype 8 isolates. Most isolates (n=10 198 [74·2%]) did not contain AMR-associated genes. Resistance to co-trimoxazole was the most frequently predicted resistance (n=2331 [17%]), followed by resistance to tetracycline (n=1199 [8·7%]) and β-lactams (n=1149 [8·4%]). Logistic regression analysis found the presence of AMR-associated genes significantly increased the odds of patient death (odds ratio 1·18, 95% CI 1·01–1·38). Some GPSCs were also associated with a significant increase in the odds of patient death, such as GPSC12 (1·88, 1·48–2·38). Isolates from 2018 were associated with a significant increase in the odds of patient death (1·12, 1·00–1·25), whereas younger patient age was significantly associated with a reduction in the odds of patient death compared with being aged 85 years or older.
Interpretation
WGS-based surveillance has allowed us to interrogate country-wide population dynamics driving changes in pneumococcal serotype frequency. Here, we observe a stable but diverse population before the COVID-19 pandemic restrictions were enforced in England, with low rates of AMR. These findings will provide the baseline for pandemic and post-pandemic data, to collectively inform implementation and development of the vaccination programme within the country.
Funding
None
Heart Digital Twins Predict Features of Invasive Reentrant Circuits and Ablation Lesions in Scar-Dependent Ventricular Tachycardia
Get PDFBACKGROUND:
Catheter ablation of scar-dependent ventricular tachycardia (VT) is frequently hampered by hemodynamic instability, long procedure duration, and high recurrence rates. Magnetic resonance imaging-based personalized heart digital twins may overcome these challenges by noninvasively predicting VT circuits and optimum ablation lesion sites. In this combined clinical and digital twin study, we investigated the relationship between digital twin-predicted VTs and optimum ablation lesion sets with their invasively mapped counterparts during clinical VT ablation.
METHODS:
A total of 18 patients with scar-dependent VT underwent digital twin creation based on preprocedural, contrast-enhanced cardiac magnetic resonance imaging. Using rapid pacing protocols, VT was simulated and ablation targets were derived that would terminate all possible VTs in the models. Patients subsequently underwent invasive VT ablation, including targeting of diastolic activity and optimum entrainment sites. Digital twin-predicted VT circuits and ablation lesions were compared with their invasive clinical counterparts.
RESULTS:
Forty-three clinical VTs and 92 digital twin VTs were induced. Diastolic activity was seen in 16 of 43 (37.2%) clinical VTs. Sensitivity, specificity, positive predictive, and negative predictive values for the detection of critical VT sites by digital twins were 81.3%, 83.8%, 21.7%, and 98.8%, respectively. At an AHA-segment level, agreement between clinical VT critical sites and digital twin primary predicted sites was moderate, with a κ coefficient of 0.46 (±0.32; P≤0.001). Termination of VT with ablation was achieved at a digital twin-predicted site in 4 of 5 (80%) cases where attempted. A total of 426 of 709 (60.1%) lesions were within 5 mm of a predicted target site. In total, 54.0% (±28.9%) of the digital twin-predicted area was ablated per patient based on conventional mapping criteria.
CONCLUSIONS:
Heart digital twin VT circuits and ablation targets accurately predict many features of their respective clinical counterparts but have some limitations in spatial resolution. Our findings demonstrate the significant potential of digital twin technology in guiding catheter ablation for scar-dependent VT
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