Diagnostic markers of acute encephalitis syndrome and COVID-associated multisystem inflammatory syndrome in children from Southern India.

Acute encephalitis syndrome (AES) in children poses a significant public health challenge in India. This study aims to explore the utility of host inflammatory mediators and neurofilament (NfL) levels in distinguishing etiologies, assessing disease severity, and predicting outcomes in AES. We assessed 12 mediators in serum (n = 58) and 11 in cerebrospinal fluid (CSF) (n = 42) from 62 children with AES due to scrub typhus, viral etiologies, and COVID-associated multisystem inflammatory syndrome (MIS-C) in Southern India. Additionally, NfL levels in serum (n = 20) and CSF (n = 18) were examined. Clinical data, including Glasgow coma scale (GCS) and Liverpool outcome scores, were recorded. Examining serum and CSF markers in the three AES etiology groups revealed notable distinctions, with scrub typhus differing significantly from viral and MIS-C causes. Viral causes had elevated serum CCL11 and CCL2 compared with scrub typhus, while MIS-C cases showed higher HGF levels than scrub typhus. However, CSF analysis showed a distinct pattern with the scrub typhus group exhibiting elevated levels of IL-1RA, IL-1ß, and TNF compared with MIS-C, and lower CCL2 levels compared with the viral group. Modeling the characteristic features, we identified that age ≥3 years with serum CCL11 < 180 pg/mL effectively distinguished scrub typhus from other AES causes. Elevated serum CCL11, HGF, and IL-6:IL-10 ratio were associated with poor outcomes (p = 0.038, 0.005, 0.02). Positive CSF and serum NfL correlation, and negative GCS and serum NfL correlation were observed. Median NfL levels were higher in children with abnormal admission GCS and poor outcomes. Measuring immune mediators and brain injury markers in AES provides valuable diagnostic insights, with the potential to facilitate rapid diagnosis and prognosis. The correlation between CSF and serum NfL, along with distinctive serum cytokine profiles across various etiologies, indicates the adequacy of blood samples alone for assessment and monitoring. The association of elevated levels of CCL11, HGF, and an increased IL-6:IL-10 ratio with adverse outcomes suggests promising avenues for therapeutic exploration, warranting further investigation.

Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings.

BACKGROUND: Annual mortality from neonatal sepsis is an estimated 430 000-680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum ß-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting. OBJECTIVES: To assess the pharmacodynamics of flomoxef and amikacin in combination. METHODS: The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs. RESULTS: Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L. CONCLUSIONS: We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.

Cranioplasty with hydroxyapatite or acrylic is associated with a reduced risk of all-cause and infection-associated explantation.

OBJECTIVE: Cranioplasty remains an essential procedure following craniectomy but is associated with high morbidity. We investigated factors associated with outcomes following first alloplastic cranioplasty. METHODS: A single-centre, retrospective cohort study of patients undergoing first alloplastic cranioplasty at a tertiary neuroscience centre (01 March 2010-01 September 2021). Patient demographics and craniectomy/cranioplasty details were extracted. Primary outcome was all-cause explantation. Secondary outcomes were explantation secondary to infection, surgical morbidity and mortality. Multivariable analysis was performed using Cox proportional hazards regression or binary logistic regression. RESULTS: Included were 287 patients with a mean age of 42.9 years [SD = 15.4] at time of cranioplasty. The most common indication for craniectomy was traumatic brain injury (32.1%, n = 92). Cranioplasty materials included titanium plate (23.3%, n = 67), hydroxyapatite (22.3%, n = 64), acrylic (20.6%, n = 59), titanium mesh (19.2%, n = 55), hand-moulded PMMA cement (9.1%, n = 26) and PEEK (5.6%, n = 16). Median follow-up time after cranioplasty was 86.5 months (IQR 44.6-111.3). All-cause explantation was 12.2% (n = 35). Eighty-three patients (28.9%) had surgical morbidity. In multivariable analysis, the risk of all-cause explantation and explantation due to infection was reduced with the use of both hydroxyapatite (HR 0.22 [95% CI 0.07-0.71], p = .011, HR 0.22 [95% CI 0.05-0.93], p = .040) and acrylic (HR 0.20 [95% CI 0.06-0.73], p = .015, HR 0.24 [95% CI 0.06-0.97], p = .045), respectively. In addition, risk of explantation due to infection was increased when time to cranioplasty was between three and six months (HR 6.38 [95% CI 1.35-30.19], p = .020). Mean age at cranioplasty (HR 1.47 [95% CI 1.03-2.11], p = .034), titanium mesh (HR 5.36 [95% CI 1.88-15.24], p = .002), and use of a drain (HR 3.37 [95% CI 1.51-7.51], p = .003) increased risk of mortality. CONCLUSIONS: Morbidity is high following cranioplasty, with over a tenth requiring explantation. Hydroxyapatite and acrylic were associated with reduced risk of all-cause explantation and explantation due to infection. Cranioplasty insertion at three to six months was associated with increased risk of explantation due to infection.

Cardiovascular drugs and COVID-19 clinical outcomes: a systematic review and meta-analysis of randomized controlled trials.

AIMS: To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs). METHODS: More than 500 databases were searched between 1 November 2020 and 2 October 2021 to identify RCTs that were published after our baseline review. One reviewer extracted data with other reviewers verifying the extracted data for accuracy and completeness. RESULTS: After screening 22 414 records, we included 24 and 21 RCTs in the qualitative and quantitative syntheses, respectively. The most investigated drug classes were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and anticoagulants, investigated by 10 and 11 studies respectively. In meta-analyses, ACEI/ARBs did not affect hospitalization length (mean difference -0.42, 95% confidence interval [CI] -1.83; 0.98 d, n = 1183), COVID-19 severity (risk ratio/RR 0.90, 95% CI 0.71; 1.15, n = 1661) or mortality (risk ratio [RR] 0.92, 95% CI 0.58; 1.47, n = 1646). Therapeutic anticoagulation also had no effect (hospitalization length mean difference -0.29, 95% CI -1.13 to 0.56 d, n = 1449; severity RR 0.86, 95% CI 0.70; 1.04, n = 2696; and, mortality RR 0.93, 95% CI 0.77; 1.13, n = 5689). Other investigated drug classes were antiplatelets (aspirin, 2 trials), antithrombotics (sulodexide, 1 trial), calcium channel blockers (amlodipine, 1 trial) and lipid-modifying drugs (atorvastatin, 1 trial). CONCLUSION: Moderate- to high-certainty RCT evidence suggests that cardiovascular drugs such as ACEIs/ARBs are not associated with poor COVID-19 outcomes, and should therefore not be discontinued. These cardiovascular drugs should also not be initiated to treat or prevent COVID-19 unless they are needed for an underlying currently approved therapeutic indication.

Flomoxef and fosfomycin in combination for the treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance.

BACKGROUND: Neonatal sepsis is a serious bacterial infection of neonates, globally killing up to 680 000 babies annually. It is frequently complicated by antimicrobial resistance, particularly in low- and middle-income country (LMIC) settings with widespread resistance to the WHO's recommended empirical regimen of ampicillin and gentamicin. OBJECTIVES: We assessed the utility of flomoxef and fosfomycin as a potential alternative empirical regimen for neonatal sepsis in these settings. METHODS: We studied the combination in a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment and chequerboard assays. We further assessed the combination using clinically relevant regimens in the HFIM with six Enterobacterales strains with a range of flomoxef/fosfomycin MICs. RESULTS: Pharmacokinetic/pharmacodynamic modelling of the HFIM experimental output, along with data from chequerboard assays, indicated synergy of this regimen in terms of bacterial killing and prevention of emergence of fosfomycin resistance. Flomoxef monotherapy was sufficient to kill 3/3 strains with flomoxef MICs ≤0.5 mg/L to sterility. Three of three strains with flomoxef MICs ≥8 mg/L were not killed by fosfomycin or flomoxef monotherapy; 2/3 of these were killed with the combination of the two agents. CONCLUSIONS: These data suggest that flomoxef/fosfomycin could be an efficacious and synergistic regimen for the empirical treatment of neonatal sepsis in LMIC settings with prevalent antimicrobial resistance. Our HFIM results warrant further assessment of the flomoxef/fosfomycin combination in clinical trials.

External validation and recalibration of an incidental meningioma prognostic model - IMPACT: protocol for an international multicentre retrospective cohort study.

INTRODUCTION: Due to the increased use of CT and MRI, the prevalence of incidental findings on brain scans is increasing. Meningioma, the most common primary brain tumour, is a frequently encountered incidental finding, with an estimated prevalence of 3/1000. The management of incidental meningioma varies widely with active clinical-radiological monitoring being the most accepted method by clinicians. Duration of monitoring and time intervals for assessment, however, are not well defined. To this end, we have recently developed a statistical model of progression risk based on single-centre retrospective data. The model Incidental Meningioma: Prognostic Analysis Using Patient Comorbidity and MRI Tests (IMPACT) employs baseline clinical and imaging features to categorise the patient with an incidental meningioma into one of three risk groups: low, medium and high risk with a proposed active monitoring strategy based on the risk and temporal trajectory of progression, accounting for actuarial life expectancy. The primary aim of this study is to assess the external validity of this model. METHODS AND ANALYSIS: IMPACT is a retrospective multicentre study which will aim to include 1500 patients with an incidental intracranial meningioma, powered to detect a 10% progression risk. Adult patients ≥16 years diagnosed with an incidental meningioma between 1 January 2009 and 31 December 2010 will be included. Clinical and radiological data will be collected longitudinally until the patient reaches one of the study endpoints: intervention (surgery, stereotactic radiosurgery or fractionated radiotherapy), mortality or last date of follow-up. Data will be uploaded to an online Research Electronic Data Capture database with no unique identifiers. External validity of IMPACT will be tested using established statistical methods. ETHICS AND DISSEMINATION: Local institutional approval at each participating centre will be required. Results of the study will be reported through peer-reviewed articles and conferences and disseminated to participating centres, patients and the public using social media.

Modelling of longitudinal data to predict cardiovascular disease risk: a methodological review.

OBJECTIVE: The identification of methodology for modelling cardiovascular disease (CVD) risk using longitudinal data and risk factor trajectories. METHODS: We screened MEDLINE-Ovid from inception until 3 June 2020. MeSH and text search terms covered three areas: data type, modelling type and disease area including search terms such as "longitudinal", "trajector*" and "cardiovasc*" respectively. Studies were filtered to meet the following inclusion criteria: longitudinal individual patient data in adult patients with ≥3 time-points and a CVD or mortality outcome. Studies were screened and analyzed by one author. Any queries were discussed with the other authors. Comparisons were made between the methods identified looking at assumptions, flexibility and software availability. RESULTS: From the initial 2601 studies returned by the searches 80 studies were included. Four statistical approaches were identified for modelling the longitudinal data: 3 (4%) studies compared time points with simple statistical tests, 40 (50%) used single-stage approaches, such as including single time points or summary measures in survival models, 29 (36%) used two-stage approaches including an estimated longitudinal parameter in survival models, and 8 (10%) used joint models which modelled the longitudinal and survival data together. The proportion of CVD risk prediction models created using longitudinal data using two-stage and joint models increased over time. CONCLUSIONS: Single stage models are still heavily utilized by many CVD risk prediction studies for modelling longitudinal data. Future studies should fully utilize available longitudinal data when analyzing CVD risk by employing two-stage and joint approaches which can often better utilize the available data.

Population Pharmacokinetics and Pharmacodynamics of Itraconazole for Disseminated Infection Caused by Talaromyces marneffei.

First-line treatment of talaromycosis with amphotericin B deoxycholate (DAmB) is labor-intensive and toxic. Itraconazole is an appealing alternative antifungal agent. Pharmacokinetic data were obtained from 76 patients who were randomized to itraconazole in the Itraconazole versus Amphotericin B for Talaromycosis (IVAP) trial. Plasma levels of itraconazole and its active metabolite, hydroxyitraconazole, were analyzed alongside longitudinal fungal CFU counts in a population model. Itraconazole and hydroxyitraconazole pharmacokinetic variability was considerable, with areas under the concentration-time curve over 24 h (AUC24) of 3.34 ± 4.31 mg·h/liter and 3.57 ± 4.46 mg·h/liter (mean ± standard deviation), respectively. Levels of both analytes were low; itraconazole minimum concentration (Cmin) was 0.11 ± 0.16 mg/liter, and hydroxyitraconazole Cmin was 0.13 ± 0.17 mg/liter. The mean maximal rates of drug-induced killing were 0.206 and 0.208 log10 CFU/ml/h, respectively. There were no associations between itraconazole Cmin/MIC and time to sterilization of the bloodstream (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.99 to 1.03; P = 0.43), time to death (HR, 0.99; 95% CI, 0.96 to 1.02; P = 0.77), or early fungicidal activity (EFA) (coefficient, -0.004; 95% CI, -0.010 to 0.002; P = 0.18). Similarly, there was no relationship between AUC/MIC and time to sterilization of the bloodstream (HR, 1.00; 95% CI, 0.99 to 1.00; P = 0.50), time to death (HR, 1.00; 95% CI, 0.99 to 1.00; P = 0.91), or EFA (coefficient, -0.0001; 95% CI, -0.0003 to 0.0001; P = 0.19). This study raises the possibility that the failure of itraconazole to satisfy noninferiority criteria against DAmB for talaromycosis in the IVAP trial was a pharmacokinetic and pharmacodynamic failure.

The Atrial Fibrillation Better Care pathway for managing atrial fibrillation: a review.

The 2020 European Society of Cardiology guidelines endorse the Atrial Fibrillation Better Care (ABC) pathway as a structured approach for the management of atrial fibrillation (AF), addressing three principal elements: 'A' - avoid stroke (with oral anticoagulation), 'B' - patient-focused better symptom management, and 'C' - cardiovascular and comorbidity risk factor reduction and management. This review summarizes the definitions used for the ABC criteria in different studies and the impact of adherence/non-adherence on clinical outcomes, from 12 studies on seven different cohorts. All studies consistently showed statistically significant reductions in the risk of stroke, myocardial infarction, and mortality among those with ABC pathway adherent treatment. The ABC pathway provides a simple decision-making framework to enable consistent equitable care from clinicians in primary and secondary/tertiary care. Further research examining the impact of ABC pathway implementation in prospective cohorts utilizing consistent inclusion criteria and definitions of 'A', 'B', and 'C' adherent care is warranted.

Cardiovascular drugs and COVID-19 clinical outcomes: A living systematic review and meta-analysis.

AIMS: The aim of this study was to continually evaluate the association between cardiovascular drug exposure and COVID-19 clinical outcomes (susceptibility to infection, disease severity, hospitalization, hospitalization length, and all-cause mortality) in patients at risk of/with confirmed COVID-19. METHODS: Eligible publications were identified from more than 500 databases on 1 November 2020. One reviewer extracted data with 20% of the records independently extracted/evaluated by a second reviewer. RESULTS: Of 52 735 screened records, 429 and 390 studies were included in the qualitative and quantitative syntheses, respectively. The most-reported drugs were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) with ACEI/ARB exposure having borderline association with confirmed COVID-19 infection (OR 1.14, 95% CI 1.00-1.31). Among COVID-19 patients, unadjusted estimates showed that ACEI/ARB exposure was associated with hospitalization (OR 1.76, 95% CI 1.34-2.32), disease severity (OR 1.40, 95% CI 1.26-1.55) and all-cause mortality (OR 1.22, 95% CI 1.12-1.33) but not hospitalization length (mean difference -0.27, 95% CI -1.36-0.82 days). After adjustment, ACEI/ARB exposure was not associated with confirmed COVID-19 infection (OR 0.92, 95% CI 0.71-1.19), hospitalization (OR 0.93, 95% CI 0.70-1.24), disease severity (OR 1.05, 95% CI 0.81-1.38) or all-cause mortality (OR 0.84, 95% CI 0.70-1.00). Similarly, subgroup analyses involving only hypertensive patients revealed that ACEI/ARB exposure was not associated with confirmed COVID-19 infection (OR 0.93, 95% CI 0.79-1.09), hospitalization (OR 0.84, 95% CI 0.58-1.22), hospitalization length (mean difference -0.14, 95% CI -1.65-1.36 days), disease severity (OR 0.92, 95% CI 0.76-1.11) while it decreased the odds of dying (OR 0.76, 95% CI 0.65-0.88). A similar trend was observed for other cardiovascular drugs. However, the validity of these findings is limited by a high level of heterogeneity and serious risk of bias. CONCLUSION: Cardiovascular drugs are not associated with poor COVID-19 outcomes in adjusted analyses. Patients should continue taking these drugs as prescribed.

Sorafenib is associated with a reduced rate of tumour growth and liver function deterioration in HCV-induced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib has been the standard of care for patients with advanced hepatocellular carcinoma and although immunotherapeutic approaches are now challenging this position, it retains an advantage in HCV-seropositive patients. We aimed to quantify the rate of tumour progression in patients receiving sorafenib and relate this figure to survival, both overall, and according to viral status. METHODS: Using serial data from an international clinical trial we applied a joint model to combine survival and progression over time in order to estimate the rate of tumour growth as assessed by tumour burden and serum alpha-fetoprotein, and the impact of treatment on liver function. RESULTS: High tumour burden at baseline was associated with an increased risk of death. In patients still alive at the end of the study, the progression in relation to tumour burden was very low compared to those who died within the study. Overall, the change in mean tumour burden was 0.12 mm per day or an absolute growth rate of 3.6 mm/month. Median doubling time was 665 days. For those who progressed above 0.12 mm per day or the 12% rate, median survival was 234 days compared to 384 days if the rate was below 12%. Tumour growth rate and serum alpha-fetoprotein rise were significantly lower in those who were HCV seropositive as was the rate of decline in liver function. These results were replicated in 2 independent patient groups. CONCLUSION: Our analysis suggests that sorafenib treatment is associated with improved survival in patients with advanced hepatocellular carcinoma mainly by decreasing the rate of tumour growth and liver function deterioration among patients with HCV infection. LAY SUMMARY: Among patients receiving sorafenib for advanced hepatocellular carcinoma the rate of tumour growth (as assessed by changes in tumour size and the biomarker alpha-fetoprotein) and the deterioration of liver function is less in those who have the hepatitis C virus, than in those who do not.

Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance.

Antimicrobial resistance (particularly through extended-spectrum ß-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA < 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.

Procalcitonin, C-reactive protein, neutrophil gelatinase-associated lipocalin, resistin and the APTT waveform for the early diagnosis of serious bacterial infection and prediction of outcome in critically ill children.

OBJECTIVE: Bacterial Infections remains a leading cause of death in the Paediatric Intensive Care Unit (PICU). In this era of rising antimicrobial resistance, new tools are needed to guide antimicrobial use. The aim of this study was to investigate the accuracy of procalcitonin (PCT), neutrophil gelatinase-associated lipocalin (NGAL), resistin, activated partial thromboplastin time (aPTT) waveform and C-reactive protein (CRP) for the diagnosis of serious bacterial infection (SBI) in children on admission to PICU and their use as prognostic indicators. SETTING: A regional PICU in the United Kingdom. PATIENTS: Consecutive PICU admissions between October 2010 and June 2012. MEASUREMENTS: Blood samples were collected daily for biomarker measurement. The primary outcome measure was performance of study biomarkers for diagnosis of SBI on admission to PICU based on clinical, radiological and microbiological criteria. Secondary outcomes included durations of PICU stay and invasive ventilation and 28-day mortality. Patients were followed up to day 28 post-admission. MAIN RESULTS: A total of 657 patients were included in the study. 92 patients (14%) fulfilled criteria for SBI. 28-day mortality was 2.6% (17/657), but 8.7% (8/92) for patients with SBI. The combination of PCT, resistin, plasma NGAL and CRP resulted in the greatest net reclassification improvement compared to CRP alone (0.69, p<0.005) with 10.5% reduction in correct classification of patients with SBI (p 0.52) but a 78% improvement in correct classification of patients without events (p <0.005). A statistical model of prolonged duration of PICU stay found log-transformed maximum values of biomarkers performed better than first recorded biomarkers. The final model included maximum values of CRP, plasma NGAL, lymphocyte and platelet count (AUC 79%, 95% CI 73.7% to 84.2%). Longitudinal profiles of biomarkers showed PCT levels to decrease most rapidly following admission SBI. CONCLUSION: Combinations of biomarkers, including PCT, may improve accurate and timely identification of SBI on admission to PICU.

Pharmacodynamics of the Novel Metallo-ß-Lactamase Inhibitor ANT2681 in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae.

Enterobacteriaceae that produce metallo-ß-lactamases (MBLs) are an emerging threat to public health. The metallo-ß-lactamase inhibitor (MBLi) ANT2681 inhibits the enzymatic activity of MBLs through interaction with the dinuclear zinc ion cluster present in the active site that is common to these enzymes. ANT2681 is being codeveloped, with meropenem as the partner ß-lactam, as a novel combination therapy for infections caused by MBL-producing bacteria. The pharmacokinetics/pharmacodynamics of meropenem-ANT2681 were studied in a murine neutropenic thigh model of NDM-producing Enterobacteriaceae Dose-ranging studies were performed with both meropenem and ANT2681. Dose fractionation experiments were performed to identify the relevant pharmacodynamic index of ANT2681 when coadministered with meropenem. A background of meropenem at 50 mg/kg of body weight every 4 h (q4h) subcutaneously (s.c.) had minimal antibacterial effect. On this background, half-maximal effect was observed with an ANT2681 dose of 89 mg/kg q4h intravenously (i.v.). The dose fractionation study showed that area under the concentration-time curve (AUC) was the relevant pharmacodynamic index for the inhibitor. The magnitude of the meropenem-ANT2681 exposure required to achieve stasis was explored using 5 NDM-producing strains. A 3-dimensional surface fitted to the pharmacodynamic data from the 5 strains suggested that stasis was achieved with an fT > potentiated meropenem MIC of 40% and ANT2681 AUC of 700 mg · h/liter. These data and analyses provide the underpinning evidence for the combined use of meropenem and ANT2681 for clinical infections.

Population Pharmacokinetics of Praziquantel in Pregnant and Lactating Filipino Women Infected with Schistosoma japonicum.

An estimated 40 million women of reproductive age are infected with one of three species of the waterborne parasite Schistosoma spp. Treatment with praziquantel (PZQ) via mass drug administration (MDA) campaigns is the mainstay of schistosomiasis control for populations living in areas of endemicity. The World Health Organization recommends that pregnant and lactating women be included in schistosomiasis MDA programs, and several recent studies have evaluated the safety and efficacy of PZQ use during pregnancy. To date, there are no data describing PZQ pharmacokinetics (PK) during pregnancy or among lactating postpartum women. As part of a randomized controlled trial investigating the safety and efficacy of PZQ during human pregnancy, we examined the PK of this therapeutic drug among three distinct cohorts of women infected with S. japonicum in Leyte, Philippines. Specifically, we studied the PK properties of PZQ among early- and late-gestation pregnant women (n = 15 each) and lactating postpartum women (n = 15) with schistosomiasis. We found that women in early pregnancy had increased apparent clearance and lower area-under-the-curve (AUC0-24) values that may be related to physiological changes in drug clearance and/or changes in oral bioavailability. There was no relationship between body weight and apparent clearance. The mean ± standard deviation partition ratio of plasma to breast milk was 0.36. ± 0.13. The estimated median infant PZQ daily dose would be 0.037 mg/kg of body weight ingested from breast milk, which is significantly lower than the dosage required for antischistosomal activity and not known to be harmful to the infant. Our PK data do not support the suggestion to delay breastfeeding 72 h after taking PZQ. Results can help inform future drug efficacy studies in pregnant and lactating women with schistosomiasis.

Spatial and spatio-temporal statistical analyses of retinal images: a review of methods and applications.

BACKGROUND: Clinical research and management of retinal diseases greatly depend on the interpretation of retinal images and often longitudinally collected images. Retinal images provide context for spatial data, namely the location of specific pathologies within the retina. Longitudinally collected images can show how clinical events at one point can affect the retina over time. In this review, we aimed to assess statistical approaches to spatial and spatio-temporal data in retinal images. We also review the spatio-temporal modelling approaches used in other medical image types. METHODS: We conducted a comprehensive literature review of both spatial or spatio-temporal approaches and non-spatial approaches to the statistical analysis of retinal images. The key methodological and clinical characteristics of published papers were extracted. We also investigated whether clinical variables and spatial correlation were accounted for in the analysis. RESULTS: Thirty-four papers that included retinal imaging data were identified for full-text information extraction. Only 11 (32.4%) papers used spatial or spatio-temporal statistical methods to analyse images, others (23 papers, 67.6%) used non-spatial methods. Twenty-eight (82.4%) papers reported images collected cross-sectionally, while 6 (17.6%) papers reported analyses on images collected longitudinally. In imaging areas outside of ophthalmology, 19 papers were identified with spatio-temporal analysis, and multiple statistical methods were recorded. CONCLUSIONS: In future statistical analyses of retinal images, it will be beneficial to clearly define and report the spatial distributions studied, report the spatial correlations, combine imaging data with clinical variables into analysis if available, and clearly state the software or packages used.

Bayesian joint modelling of longitudinal and time to event data: a methodological review.

BACKGROUND: In clinical research, there is an increasing interest in joint modelling of longitudinal and time-to-event data, since it reduces bias in parameter estimation and increases the efficiency of statistical inference. Inference and prediction from frequentist approaches of joint models have been extensively reviewed, and due to the recent popularity of data-driven Bayesian approaches, a review on current Bayesian estimation of joint model is useful to draw recommendations for future researches. METHODS: We have undertaken a comprehensive review on Bayesian univariate and multivariate joint models. We focused on type of outcomes, model assumptions, association structure, estimation algorithm, dynamic prediction and software implementation. RESULTS: A total of 89 articles have been identified, consisting of 75 methodological and 14 applied articles. The most common approach to model the longitudinal and time-to-event outcomes jointly included linear mixed effect models with proportional hazards. A random effect association structure was generally used for linking the two sub-models. Markov Chain Monte Carlo (MCMC) algorithms were commonly used (93% articles) to estimate the model parameters. Only six articles were primarily focused on dynamic predictions for longitudinal or event-time outcomes. CONCLUSION: Methodologies for a wide variety of data types have been proposed; however the research is limited if the association between the two outcomes changes over time, and there is also lack of methods to determine the association structure in the absence of clinical background knowledge. Joint modelling has been proved to be beneficial in producing more accurate dynamic prediction; however, there is a lack of sufficient tools to validate the prediction.

Pharmacodynamics of Cefepime Combined with the Novel Extended-Spectrum-ß-Lactamase (ESBL) Inhibitor Enmetazobactam for Murine Pneumonia Caused by ESBL-Producing Klebsiella pneumoniae.

Klebsiella pneumoniae strains that produce extended-spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options, and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for the treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose-ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing the area under the concentration-time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime, given as 100 mg/kg of body weight every 8 h intravenously (q8h i.v.), had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam, a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. The dose fractionation study suggested both fT > threshold and fAUC:MIC are relevant PD indices. The AUCELF:AUCplasma ratio for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT > MIC of ≥20% and enmetazobactam fT > 2 mg/liter of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

Treatment Outcomes of Incidental Intracranial Meningiomas: Results from the IMPACT Cohort.

BACKGROUND: Incidental findings such as meningioma are becoming increasingly prevalent. There is no consensus on the optimal management of these patients. The aim of this study was to examine the outcomes of patients diagnosed with an incidental meningioma who were treated with surgery or radiotherapy. METHODS: Single-center retrospective cohort study of adult patients diagnosed with an incidental intracranial meningioma (2007-2015). Outcomes recorded were postintervention morbidity, histopathologic diagnosis, and treatment response. RESULTS: Out of 441 patients, 44 underwent treatment. Median age at intervention was 56.1 years (interquartile range [IQR], 49.6-66.5); patients included 35 women and 9 men. The main indication for imaging was headache (25.9%). Median meningioma volume was 4.55 cm3 (IQR, 1.91-8.61), and the commonest location was convexity (47.7%). Six patients underwent surgery at initial diagnosis. Thirty-eight had intervention (34 with surgery and 4 with radiotherapy) after a median active monitoring duration of 24 months (IQR, 11.8-42.0). Indications for treatment were radiologic progression (n = 26), symptom development (n = 6), and patient preference (n = 12). Pathology revealed World Health Organization (WHO) grade 1 meningioma in 36 patients and WHO grade 2 in 4 patients. The risk of postoperative surgical and medical morbidity requiring treatment was 25%. Early and late moderate adverse events limiting activities of daily living occurred in 28.6% of patients treated with radiotherapy. Recurrence rate after surgery was 2.5%. All meningiomas regressed or remained radiologically stable after radiotherapy. CONCLUSIONS: The morbidity after treatment of incidental intracranial meningioma is not negligible. Considering most operated tumors are WHO grade 1, treatment should be reserved for those manifesting symptoms or demonstrating substantial growth on radiologic surveillance.