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Background. Human-Immunodeficiency-Virus- (HIV-) related Kaposi's sarcoma (KS) has a high prevalence in Africa; however, there is minimal published data on treatment and outcomes in this population. Objective and Design. This was a prospective study of 50 patients, aiming to assess the impact of vincristine therapy on tumour response and survival and to assess palliative care outcomes in patients with HIV-related KS. Methods. 50 consecutive patients were recruited during 2008. Vincristine therapy and highly active antiretroviral therapy (HAART) were given. Tumour response, survival, and chemotherapy-related toxicities were documented. Palliative care outcomes were assessed using the African Palliative Care Association (APCA) Palliative Outcome Scale (POS). Results. The majority of patients were male, and the median age was 33 years. At baseline assessment, the median CD4 T-cell count was 263, and 50% patients had evidence of peripheral neuropathy. The overall response rate was 64% at 6 weeks, and median progression-free survival was 30 weeks. Treatment was generally well tolerated, with peripheral neuropathy the main dose-limiting toxicity. Conclusion. The combination of vincristine and HAART is feasible and effective in a low resource setting, although peripheral neuropathy is a dose-limiting factor. This patient group carries a high mortality and as such adequate access to palliative care is crucial.

Aim: The Ovarian Cancer Retrospective European (O'CaRE) study assessed the cumulative impact of high-risk factors on progression-free survival (PFS) and overall survival (OS) following first-line treatment in patients diagnosed with advanced ovarian cancer. Patients & methods: Medical records were collected from five European countries (2014 and 2015). Patients were grouped by number of high-risk factors: stage IV diagnosis, no known BRCA mutation , interval debulking surgery or no surgery, or visible residual disease. Results: Our analysis included 405 patients grouped based on having one (20.4%); two (32.3%); three (33.7%) or four (11.9%) high-risk factors. Increasing cumulative numbers of high-risk factors were associated with numerically shorter PFS and OS. Conclusion: Risk profiles should be carefully considered when planning clinical care.

Background: The NOVA study (NCT01847274) compared niraparib with placebo as a maintenance treatment for patients with recurrent ovarian cancer (OC) but was not powered to detect an overall survival (OS) improvement., Objective: To compare OS in a real-world population of patients with BRCA wild-type ( BRCA wt) recurrent OC who received second-line maintenance (2LM) niraparib monotherapy versus active surveillance (AS)., Design: A retrospective study using a US-based nationwide deidentified electronic health record-derived database., Methods: Patients diagnosed with epithelial OC (January 1, 2011-May 31, 2021) who completed second-line (2L) therapy (January 1, 2017-March 2, 2022) and were BRCA wt were included. A NOVA study-like subpopulation included patients with an Eastern Cooperative Oncology Group performance status score of 0-1 and platinum-sensitive disease. Patients were assigned to 2LM niraparib or AS cohorts. Follow-up was measured from the index date (2L non-maintenance therapy end) until the first of study end (May 31, 2022), last clinical activity, or death. Median OS (mOS) and hazard ratios were estimated with an emulated trial methodology., Results: The overall population comprised 199 patients in the 2LM niraparib monotherapy cohort and 707 patients in the AS cohort; the NOVA study-like subpopulation included 123 patients in the 2LM niraparib monotherapy cohort and 143 in the AS cohort. Demographic and clinical characteristics were similar in both populations. Overall, adjusted mOS was 24.1 months for the 2LM niraparib monotherapy cohort versus 18.4 months for the AS cohort (hazard ratio, 0.8; 95% confidence interval [CI]: 0.7-0.9). In the NOVA study-like subpopulation, adjusted mOS was 28.1 months for the 2LM niraparib monotherapy cohort versus 21.5 months for the AS cohort (hazard ratio, 0.6; 95% CI: 0.5-0.9)., Conclusion: These results provide important real-world OS data for patients with recurrent BRCA wt OC who received niraparib monotherapy compared with patients receiving AS., (© The Author(s), 2024.)

Artemisinin-based combination therapy (ACT) is the first-line recommended treatment for uncomplicated malaria. Pharmacokinetic (PK) properties in pregnant women are often based on small studies and need to be confirmed and validated in larger pregnant patient populations. This study aimed to evaluate the PK properties of amodiaquine and its active metabolite, desethylamodiaquine, and piperaquine in women in their second and third trimester of pregnancy with uncomplicated P. falciparum infections. Eligible pregnant women received either artesunate-amodiaquine (200/540 mg daily, n = 771) or dihydroartemisinin-piperaquine (40/960 mg daily, n = 755) for 3 days (NCT00852423). Population PK properties were evaluated using nonlinear mixed-effects modeling, and effect of gestational age and trimester was evaluated as covariates. 1071 amodiaquine and 1087 desethylamodiaquine plasma concentrations, and 976 piperaquine plasma concentrations, were included in the population PK analysis. Amodiaquine concentrations were described accurately with a one-compartment disposition model followed by a two-compartment disposition model of desethylamodiaquine. The relative bioavailability of amodiaquine increased with gestational age (1.25% per week). The predicted exposure to desethylamodiaquine was 2.8%-32.2% higher in pregnant women than that reported in non-pregnant women, while day 7 concentrations were comparable. Piperaquine concentrations were adequately described by a three-compartment disposition model. Neither gestational age nor trimester had significant impact on the PK of piperaquine. The predicted exposure and day 7 concentrations of piperaquine were similar to that reported in non-pregnant women. In conclusion, the exposure to desethylamodiaquine and piperaquine was similar to that in non-pregnant women. Dose adjustment is not warranted for women in their second and their trimester of pregnancy., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: This retrospective real-world study compared overall survival (OS) between patients with BRCA wild-type (BRCAwt) recurrent epithelial ovarian cancer (OC) who received niraparib second-line maintenance (2LM) versus active surveillance (AS) using target trial emulation, cloning, inverse probability of censoring weighting (IPCW) methodology to minimize immortal time bias., Methods: Eligible patients from a United States-based, deidentified, electronic health record-derived database were diagnosed with epithelial OC (January 1, 2011-May 31, 2021), were BRCAwt, and completed second-line (2L) therapy (January 1, 2017-March 2, 2022). Patient data were cloned at index (2L last treatment date), assigned to niraparib 2LM and AS cohorts, and censored when treatment deviated from clone assignment. Follow-up was measured from index to earliest of study end (May 31, 2022), last activity, or death. Median OS (mOS) and hazard ratios were estimated from stabilized IPCW Kaplan-Meier curves and Cox regression models., Results: Overall, 199 patients received niraparib 2LM, and 707 had their care managed with AS. Key characteristics were balanced across cohorts after cloning and stabilized IPCW. Median follow-up was 15.6- and 9.3-months pre-cloning. IPCW mOS was 24.1 months (95% CI: 20.9-29.5) and 18.4 months (95% CI: 15.1-22.8) in niraparib 2LM and AS cohorts, respectively (hazard ratio, 0.77; 95% CI: 0.66-0.89)., Conclusions: This real-world study provides supportive evidence of an OS benefit for patients with BRCAwt recurrent OC who received 2LM niraparib monotherapy compared with those whose care was managed with AS. The analytic strategies implemented were useful in minimizing immortal time bias and measured confounding., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Introduction: Clinical trials have demonstrated prolonged survival associated with niraparib first-line maintenance (1LM) therapy, compared with placebo, for patients with ovarian cancer (OC). However, data are limited on real-world 1LM niraparib monotherapy use, particularly as switch 1LM, following first-line (1L) combination chemotherapy plus bevacizumab. This real-world study aimed to describe patient demographics, clinical characteristics, and clinical outcomes of patients with OC receiving 1LM niraparib monotherapy following 1L combination chemotherapy plus bevacizumab., Methods: This retrospective observational study used data from a US-based nationwide database of deidentified, electronic health record-derived data. Patients diagnosed with OC during the study period (1 January 2011-30 November 2022, inclusive) were eligible if they received 1L chemotherapy plus bevacizumab treatment followed by 1LM niraparib monotherapy, initiated between 1 January 2017 (inclusive) and 2 September 2022. Patients were followed from index date (initiation of niraparib 1LM) until the first occurrence of death, end of follow-up, or end of study. Clinical outcomes were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Kaplan-Meier curves were used to estimate TTD, TTNT, and 95% confidence intervals (CIs)., Results: Among 93 patients selected, median age at index was 67 years (interquartile range [IQR] 60-72 years). Most patients had BRCA wild-type/homologous recombination (HR)-proficient or BRCA wild-type/HR unknown disease (75.3%). In all, 18 (19.4%) patients had HR-deficient disease. Five (5.4%) patients had unknown test results for both BRCA and HR deficiency status. Median follow-up time was 16.3 months (IQR 8.7-25.4 months), and median time from end of 1L therapy to 1LM initiation was 35.0 days (IQR 25.0-53.9 days). Median TTD was 9.3 months (95% CI 6.1-11.3 months). Median TTNT was 12.9 months (95% CI 11.5-19.0 months)., Conclusions: This real-world study provided insights into switch maintenance with 1LM niraparib monotherapy, which may be a viable treatment option for patients with advanced OC., (© 2024. The Author(s).)

Background: Residual disease following cytoreductive surgery in patients with ovarian cancer has been associated with poorer survival outcomes compared with no residual disease. We performed a meta-analysis to assess the impact of varying levels of residual disease status on survival outcomes in patients with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery in the setting of new therapies for this disease., Methods: Medline, Embase, and Cochrane databases (January 2011 - July 2020) and grey literature, bibliographic and key conference proceedings, were searched for eligible studies. Fixed and random-effects meta-analyses compared progression and survival by residual disease level across studies. Heterogeneity between comparisons was explored via type of surgery, disease stage, and type of adjuvant chemotherapy., Results: Of 2832 database and 16 supplementary search articles screened, 50 studies were selected; most were observational studies. The meta-analysis showed that median progression-free survival and overall survival decreased progressively with increasing residual disease (residual disease categories of 0 cm, > 0-1 cm and > 1 cm). Compared with no residual disease, hazard ratios (HR) for disease progression increased with increasing residual disease category (1.75 [95% confidence interval: 1.42, 2.16] for residual disease > 0-1 cm and 2.14 [1.34, 3.39] for residual disease > 1 cm), and also for reduced survival (HR versus no residual disease, 1.75 [ 1.62, 1.90] for residual disease > 0-1 cm and 2.32 [1.97, 2.72] for residual disease > 1 cm). All comparisons were significant (p < 0.05). Subgroup analyses showed an association between residual disease and disease progression/reduced survival irrespective of type of surgery, disease stage, or type of adjuvant chemotherapy., Conclusions: This meta-analysis provided an update on the impact of residual disease following primary or interval cytoreductive surgery, and demonstrated that residual disease was still highly predictive of progression-free survival and overall survival in adults with ovarian cancer despite changes in ovarian cancer therapy over the last decade. Higher numerical categories of residual disease were associated with reduced survival than lower categories., (© 2024. The Author(s).)

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BJR has received consulting or advisory fees from Deep6AI, AstraZeneca, and Tesaro, a GSK company; DMC declares advisory/consultancy for AstraZeneca, GSK, Clovis Oncology; speaker bureaus for AstraZeneca, GSK; and travel/accommodation/expenses from AstraZeneca, GSK; JP is an employee of GSK and holds stock/shares at GSK and Boston Scientific; AKG, JAH, and LK are employees of GSK; AAG is a former GSK employee; EXD, TW, and JS are employees of Analysis Group, which received consulting fees from GSK; RS reports honoraria from Arcus, Clovis, Genentech, GSK, Immunogen, Instil Bio, Merck, and Seagen; and advisory fees from Genentech; BJM reports consulting fees from Amgen, Aravive AstraZeneca, Clovis, GOG Foundation, Gradalis ImmunoGen Laekna Health Care, Merck, Mersana Myriad, Nucana Oncomed Oncoquest Pfizer, Roche/Genentech, GSK), speakers’ bureau fees (Clovis, Merck, Roche/Genentech, GSK), honoraria (Amgen, Aravive AstraZeneca, Clovis, GOG Foundation, Gradalis ImmunoGen Laekna Health Care, Merck, Mersana Myriad, Nucana Oncomed Oncoquest Pfizer, Roche/Genentech, GSK)., (© 2024 GSK.)

Objectives: This analysis aimed to better define the relationship between progression-free survival and overall survival in adult patients with ovarian cancer (including fallopian tube or primary peritoneal cancer) following primary cytoreductive surgery or interval cytoreductive surgery., Methods: A systematic literature review was carried out across the Medline, Embase, and Cochrane Central databases on 7 July 2020 (date limits 1 January 2011 to 7 July 2020) to identify studies with the following eligibility criteria: clinical trials/observational studies including >200 patients with ovarian cancer aged ≥18 years, evaluating overall survival/progression-free survival following cytoreductive surgery by residual disease status in the United States, Europe, Japan, or China. Weighted linear regression models were used to assess any correlation between median progression-free survival and overall survival, and between logHR for progression-free survival and logHR for overall survival. Risk of bias was assessed for all included studies., Results: Of the 50 studies reported, 43 were observational studies (41 retrospective and two prospective cohort studies), and seven were reporting for randomized clinical trials-of which four were retrospective data analyses. For analyses of the relationship between overall survival and progression-free survival, 21 studies were eligible. The weighted linear regression model showed a strong positive association between the two survival endpoints. Goodness-of-fit analysis measured the adjusted R 2 as 0.84 (p<0.001); a positive association was also observed between logHRs for overall survival and progression-free survival in the included studies., Conclusions: Median progression-free survival was predictive of median overall survival. This correlation between progression-free survival and overall survival after primary treatment for ovarian cancer highlights the validity of progression-free survival as a primary endpoint. Observational studies contributed most data, with limited information on disease stage and histology., Competing Interests: Competing interests: DC reports speakers’ bureau fees and/or advisory roles from GSK, AstraZeneca, Seagen, Eisai, Takeda, Clovis, Roche, and Merck. AM, DAS, and NH have no conflict of interest to disclose. LK is an employee of GSK., (© IGCS and ESGO 2023. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

This systematic review with embedded meta-analysis aimed to evaluate the clinical utility of circulating tumor DNA (ctDNA) in lung cancer. After screening and review of the Embase database search, 111 studies from 2015 to 2020 demonstrated ctDNA's value in prognostication/monitoring disease progression, mainly in patients with advanced/metastatic disease and non-small cell lung cancer. ctDNA positivity/detection at any time point was associated with shorter progression-free survival and overall survival, whereas ctDNA clearance/decrease during treatment was associated with a lower risk of progression and death. Validating these findings and addressing challenges regarding ctDNA testing integration into clinical practice will require further research.

Objective: This study used real-world population data to assess the trends of first-line (1L) poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment uptake and outcomes in patients with primary advanced ovarian cancer (AOC)., Methods: Patients diagnosed with AOC between January 1, 2017, and June 30, 2021, who completed 1L chemotherapy were selected from a real-world database. Descriptive analyses were performed to evaluate patient demographics, clinicopathological characteristics, and 1L treatment patterns. Time to next treatment or death was used as a proxy for real-world progression-free survival (rwPFS). Kaplan-Meier methods and Cox models were used for statistical analyses., Results: Of 705 patients who completed 1L chemotherapy, 166 received PARPi monotherapy and 539 underwent active surveillance (AS). Median follow-up was 10.9 months for PARPi monotherapy and 20.6 months for AS. PARPi monotherapy use increased from 6% in 2017 to 53% in 2021. Overall, patients receiving PARPi monotherapy had longer rwPFS than those who underwent AS (not reached vs 9.53 mo) respectively. rwPFS was also longer in patients who received PARPi monotherapy compared with AS in patients with BRCA- mutated disease (not reached vs 11.4 mo), BRCA- wild-type disease (13.5 vs 9.1 mo), homologous recombination-deficient tumors (not reached vs 10.2 mo), and homologous recombination-proficient or unknown status tumors (13.5 vs 9.3 mo)., Conclusions: Our real-world analysis suggested that 47% of patients with primary AOC did not receive PARPi maintenance in the year 2021. PARPi use was associated with significantly improved outcomes compared with AS., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

In areas of moderate to intense Plasmodium falciparum transmission, malaria in pregnancy remains a significant cause of low birth weight, stillbirth, and severe anaemia. Previously, fetal sex has been identified to modify the risks of maternal asthma, pre-eclampsia, and gestational diabetes. One study demonstrated increased risk of placental malaria in women carrying a female fetus. We investigated the association between fetal sex and malaria in pregnancy in 11 pregnancy studies conducted in sub-Saharan African countries and Papua New Guinea through meta-analysis using log binomial regression fitted to a random-effects model. Malaria infection during pregnancy and delivery was assessed using light microscopy, polymerase chain reaction, and histology. Five studies were observational studies and six were randomised controlled trials. Studies varied in terms of gravidity, gestational age at antenatal enrolment and bed net use. Presence of a female fetus was associated with malaria infection at enrolment by light microscopy (risk ratio 1.14 [95% confidence interval 1.04, 1.24]; P = 0.003; n = 11,729). Fetal sex did not associate with malaria infection when other time points or diagnostic methods were used. There is limited evidence that fetal sex influences the risk of malaria infection in pregnancy., (© 2023. The Author(s).)

Introduction: We evaluated real-world outcomes in patients with advanced ovarian cancer (AOC) based on their cumulative risk profile and maintenance therapy (MT) status following first-line (1L) treatment., Methods: This retrospective observational study of a nationwide electronic health record-derived de-identified database included adult patients diagnosed with stage III/IV OC from January 1, 2011 to February 28, 2021, who received 1L therapy and had ≥ 12 weeks of follow-up after the index date (end of 1L therapy). Patients were grouped according to whether they received MT or active surveillance (AS) following 1L treatment and by the cumulative number of risk factors (RF) present (stage IV disease; no surgery/treated with neoadjuvant therapy and interval debulking surgery; had postoperative visible residual disease; and had BRCA wild-type disease/unknown BRCA status). Time to next treatment (TTNT) and overall survival (OS) were assessed with a cloning and inverse probability of censoring (IPC)-weighted Kaplan-Meier method., Results: Among 1920 patients, 22.2% received MT and 77.8% received AS. Median IPC-weighted TTNT and OS were 13.3 months (95% CI 11.7-15.8) and 39.1 months (95% CI 32.5-48.6) in the MT cohort, respectively, and 8.6 months (95% CI 8.0-9.5) and 38.4 months (95% CI 36.4-41.0) in the AS cohort, respectively. Almost all patients had ≥ 1 RF (MT 95.3%; AS 96.7%). Median IPC-weighted TTNT was shorter among patients with more RF in both cohorts (MT: 1 RF, 19.3 months, 95% CI 13.5-37.8; 2 RF, 17.2 months, 95% CI 12.8-20.2; 3 RF, 11.0 months, 95% CI 8.2-13.8; 4 RF, 7.0 months, 95% CI 6.2-8.8; AS: 1 RF, 17.7 months, 95% CI 13.5-22.3; 2 RF, 10.2 months, 95% CI 9.1-11.5; 3 RF, 6.5 months, 95% CI 5.8-7.4; 4 RF, 4.1 months, 95% CI 3.5-4.5)., Conclusion: Regardless of RF number, MT was associated with longer TTNT in real-world patients with AOC., (© 2023. The Author(s).)

Purpose: To identify risk factors for disease progression or death and assess outcomes by risk categories in real-world patients with advanced ovarian cancer., Methods: This retrospective study included adult patients from a nationwide electronic health record-derived deidentified database with stage III/IV ovarian cancer who received first-line therapy and had ≥12 weeks of follow-up after index date (end of first-line therapy). Factors predictive of time to next treatment and overall survival (OS) were assessed. Patients were grouped according to the cumulative number of high-risk factors present (stage IV disease, no debulking surgery or neoadjuvant therapy and interval debulking surgery, visible residual disease after surgery, and breast cancer gene [ BRCA ] wild-type disease/unknown BRCA status), and time to next treatment and OS were assessed., Results: Region of residence, disease stage, histology, BRCA status, surgery modality, and visible residual disease were significant predictors of time to next treatment; age, Eastern Cooperative Oncology Group performance status, disease stage, BRCA status, surgery modality, visible residual disease, and platelet levels were significant predictors of OS (N = 1,920). Overall, 96.4%, 74.1%, and 40.3% of patients had at least 1, 2, or 3 high-risk factors, respectively; 15.7% of patients had all four high-risk factors. Observed median time to next treatment was 26.4 months (95% CI, 17.1 to 49.2) in patients with no high-risk factors and 4.6 months (95% CI, 4.1 to 5.7) in patients with four high-risk factors. Observed median OS was shorter among patients with more high-risk factors., Conclusion: These results underscore the complexity of risk assessment and demonstrate the importance of assessing a patient's cumulative risk profile rather than the impact of individual high-risk factors. They also highlight the potential for bias in cross-trial comparisons of median progression-free survival because of differences in risk-factor distribution among patient populations.

Preterm birth is a leading cause of death in children under five years of age. We hypothesized that sequential disruptions to inflammatory and angiogenic pathways during pregnancy increase the risk of placental insufficiency and spontaneous preterm labor and delivery. We conducted a secondary analysis of inflammatory and angiogenic analytes measured in plasma samples collected across pregnancy from 1462 Malawian women. Women with concentrations of the inflammatory markers sTNFR2, CHI3L1, and IL18BP in the highest quartile before 24 weeks gestation and women with anti-angiogenic factors sEndoglin and sFlt-1/PlGF ratio in the highest quartile at 28-33 weeks gestation had an increased relative risk of preterm birth. Mediation analysis further supported a potential causal link between early inflammation, subsequent angiogenic dysregulation detrimental to placental vascular development, and earlier gestational age at delivery. Interventions designed to reduce the burden of preterm birth may need to be implemented before 24 weeks of gestation., Competing Interests: The authors declare no competing interests., (Crown Copyright © 2023.)

The propensity score has become a standard tool to control for large numbers of variables in healthcare database studies. However, little has been written on the challenge of comparing large-scale propensity score analyses that use different methods for confounder selection and adjustment. In these settings, balance diagnostics are useful but do not inform researchers on which variables balance should be assessed or quantify the impact of residual covariate imbalance on bias. Here, we propose a framework to supplement balance diagnostics when comparing large-scale propensity score analyses. Instead of focusing on results from any single analysis, we suggest conducting and reporting results for many analytic choices and using both balance diagnostics and synthetically generated control studies to screen analyses that show signals of bias caused by measured confounding. To generate synthetic datasets, the framework does not require simulating the outcome-generating process. In healthcare database studies, outcome events are often rare, making it difficult to identify and model all predictors of the outcome to simulate a confounding structure closely resembling the given study. Therefore, the framework uses a model for treatment assignment to divide the comparator population into pseudo-treatment groups where covariate differences resemble those in the study cohort. The partially simulated datasets have a confounding structure approximating the study population under the null (synthetic negative control studies). The framework is used to screen analyses that likely violate partial exchangeability due to lack of control for measured confounding. We illustrate the framework using simulations and an empirical example., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Acute kidney injury is an expected adverse drug reaction listed in the European Union (EU) Summary of Product Characteristics (SmPC) for levetiracetam, one of the most widely used modern antiseizure medications (ASMs)., Objective: We conducted a voluntary post-authorization safety study to characterize the rate of acute renal failure (ARF) in patients exposed to levetiracetam versus other ASMs., Methods: New users of ASMs without prior renal dysfunction were identified and followed for 30 days in the IBM ® MarketScan ® database (USA, January 2008-December 2017). ARF was defined as a diagnosis on inpatient or emergency department claims. We estimated adjusted incidence rates, incidence rate ratios (IRRs), and incidence rate differences (IRDs) of ARF in patients initiating levetiracetam versus other ASMs., Results: Overall, 110,336 patients were eligible for the monotherapy cohort and 96,215 were eligible for the polytherapy cohort. The overall crude rate of ARF following a new ASM was 6.0 and 6.5 per 10,000 patients for the 'monotherapy' and 'polytherapy' cohorts, respectively, in the first 30 days after the index date. In the monotherapy cohort, the IRR for ARF was 1.37 (95% confidence interval [CI] 0.80-2.34) and the corresponding IRD was 2.0 (95% CI - 1.12 to 5.12) additional ARFs per 10,000 patient-months. In the polytherapy cohort, the adjusted IRR for ARF was 0.94 (95% CI 0.51-1.74) and the corresponding IRD was - 0.42 cases per 10,000 patient-months (95% CI - 4.01 to 3.17)., Conclusions: The rate of ARFs in ASM new users was very low. In patients without prior ASMs, the estimated difference in risk of ARF associated with initiation of levetiracetam versus initiation of other ASMs was small, with 95% CIs compatible with small protective or harmful effects. In patients receiving polytherapy, the difference was compatible with the null and the 95% CI with small protective or harmful effects., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Malaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes., Methods: Using samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1 +/- mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes., Findings: Decreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1 +/- ), to worsen birth outcomes by impeding vascular remodeling required for placental function., Interpretation: Collectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes., Funding: This work was supported by the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and Toronto General Research Institute Postdoctoral Fellowship Award. The parent trial was supported by the European & Developing Countries Clinical Trials Partnership and the Malaria in Pregnancy Consortium, which was funded by the Bill & Melinda Gates Foundation. The funders had no role in design, analysis, or reporting of these studies., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections., Methods: We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental Plasmodium falciparum at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789., Findings: Five trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where dhfr/dhps quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I 2 =67.0 %) and patent infection (RR=1.02, 0.61-1.16, I 2 =0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I 2 =0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I 2 =54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57)., Interpretation: ISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections., Funding: Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network., Competing Interests: All authors declare no competing interests.

Background: Annually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring., Methods and Findings: Between April 2014 and April 2015, we followed 421 Malawian mother-baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur-Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], -7.53 [-13.04, -2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], -8.57 [-13.09, -4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies., Conclusions: This mother-baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children., Competing Interests: The authors have declared that no competing interests exist. Author Steven R Meshnick was unable to confirm their authorship contributions. On their behalf, the corresponding author has reported their contributions to the best of their knowledge.

BACKGROUND: The cost of epilepsy is usually reported as total expenditure over a certain period. However, with the increased availability of acute treatments for use in the community setting, intermittent, single-seizure treatment is now possible in addition to the chronic epilepsy drug treatment paradigm. Data on the cost of discrete health care encounters are needed to substantiate the cost-benefit of these new treatments. OBJECTIVE: To estimate the health plan-paid costs of discrete epilepsy-related health care encounters in patients with epilepsy. METHODS: This retrospective cohort study utilized IBM MarketScan Commercial Claims, Medicare Supplemental and Coordination of Benefits (Medicare patients with supplemental insurance), and Multi-State Medicaid research databases. The primary analysis determined health plan-paid cost (adjudicated claims) of discrete epilepsy-related health care encounters, defined as having a primary diagnosis code of epilepsy or convulsion, from 2013 to 2018, in patients with epilepsy aged ≥ 12 years. Costs were adjusted to 2018 prices. Epilepsy cases were defined using ICD-CM codes. We excluded patients on capitated insurance plans as their cost per health care encounter is unknown. RESULTS: In total, 353,530 commercially insured, 378,051 Medicaid, and 69,176 Medicare plus supplemental insurance patients with epilepsy were included. More than 160,000 epilepsy-related emergency transportations, 225,000 emergency department (ED) visits, 49,000 hospitalizations, 700 urgent care visits, and ~2.5 million office visits were analyzed. 37.4% of epilepsy-related hospitalizations included care in the intensive care unit (ICU). In commercially insured patients, epilepsy-related health care encounters had median health plan-paid costs of $22,305 (Q1-Q3 = $14,336-$36,096, hospitalization); $3,375 ($565-$9,095, ICU visit); $1,913 ($417-$4,163, ED visit); $687 ($415-$1,083, emergency transportation); $95 ($23-$232, office visit); and $57 ($0-$171, urgent care visit). The median length of stay for epilepsy-related hospitalizations in working age, commercially insured patients was 4 (Q1-Q3 = 2-5) days. CONCLUSIONS: This is the first study to report health plan-paid cost per epilepsy-related health care encounter. These data can serve as a basis for more granular cost-benefit analyses of not only chronic but also acute treatments of epilepsy. DISCLOSURES: This analysis was funded by UCB Pharma. The sponsor had a role in the identification, design, conduct, and reporting of the analysis. Borghs, Beaty, Boudiaf, and Loewendorf are employees of UCB Pharma. Kalilani and Parekh were employees of UCB Pharma at the time of the analysis. Borghs, Beaty, and Loewendorf have received UCB Pharma stock from their employment. Kalilani and Parekh had received UCB Pharma stock at the time of employment, but no longer hold any. This work was presented in part as a poster at the 73rd Annual Meeting of the American Epilepsy Society; December 7, 2019; Baltimore, MD.

Background: Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women., Methods: We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013., Findings: Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57-14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14-0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34-0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18-0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29-23·82)., Interpretation: Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation., Funding: The Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.

Background: Sulfadoxine-pyrimethamine (SP) is used as intermittent preventive therapy in pregnancy (IPTp) for malaria in sub-Saharan Africa. The resistance marker dhps A581G has been associated with reduced IPTp-SP efficacy and enhanced morbidity in SP recipients., Methods: We measured SP-resistance allele frequencies in Malawian women participating in a trial comparing IPTp with SP against intermittent screening by rapid diagnostic tests (ISTp). We genotyped polymerase chain reaction-detected parasites using deep sequencing of SP-resistance alleles., Results: Among 125 placental infections, A581G-bearing parasites were associated with reduced birth weight (mean difference [MD], 252 g; 95% confidence interval [CI], 46-457; P = .017). Relative to ISTp, IPTp-SP was associated with higher birth weights in women with wild-type parasites (MD, 116 g; 95% CI, -40 to 272; P = .142) and lower birth weights in women with A581G-bearing parasites (MD, 192 g; 95% CI, -264 to 648; P = .385) (Pinteraction = .033). Similar associations were noted on gestational age (Pinteraction = .075). Amongst only IPTp-SP recipients, relative to women who last received SP > 4 weeks before delivery, recent SP receipt was associated with lower birth weight in women with wild-type parasites (MD, 118 g; 95% CI, -376 to 139; P = .361) and higher birth weight in women with A581G-bearing parasites (MD, 783 g; 95% CI, -20 to 1586; P = .054) (Pinteraction = .005)., Conclusions: The effectiveness in birth weight of IPTp-SP is compromised by A581G-bearing parasites, but there was no evidence that the adverse effects of these parasites are exacerbated by antenatal SP., Isrctn Registry: www.isrctn.com/ISRCTN69800930., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection., Methods: A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and < 37.0 weeks), small for gestational age (SGA, birthweight of < 10th percentile), and placental malaria (defined as deposition of malaria pigment in the placenta with or without parasites) after different treatments of uncomplicated falciparum malaria were assessed by mixed-effects logistic regression, using artemether-lumefantrine, the most used antimalarial, as the reference standard. Registration PROSPERO: CRD42018104013., Results: Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p < 0.001)., Conclusions: The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.

Objective: To examine the factors and reasons influencing treatment initiation decisions in patients with newly diagnosed epilepsy., Methods: We assessed antiseizure medication initiation decisions in adults with newly diagnosed epilepsy seen at first seizure clinics in Western Australia between 1999 and 2016 and followed to 2018., Results: Of 610 patients (median age 40 years, 61.0% male), 426 (69.8%) were diagnosed after two or more seizures and 184 (30.2%) after a single seizure with risk factors for recurrence. Treatment was commenced in 427 patients (70.0%) at diagnosis, 112 (18.4%) during follow-up, mostly after further seizures, whereas 71 (11.6%) remained untreated at last follow-up. Elders (≥65 years, odds ratio [OR] = 3.06, 95% confidence interval [CI]: 1.62-5.80), more seizures (OR = 3.48, 95% CI: 2.03-5.96), and epileptogenic lesions on neuroimaging (OR = 2.15, 95% CI: 1.26-3.68) had a higher likelihood of treatment at diagnosis. Patients with less than one seizure per year within the preceding year (OR = 0.40, 95% CI: 0.21-0.73) and of higher socioeconomic status (OR = 0.985, 95% CI: 0.977-0.994) were less likely to be treated. For 93 patients (15.2%), treatment was not recommended at diagnosis, most commonly because only a single seizure had occurred. Ninety patients (14.8%) declined recommended treatment, mostly because they were unconvinced of the need for treatment or the diagnosis., Significance: Thirty percent of adults with newly diagnosed epilepsy were not immediately treated. Treatment initiation in this real-world cohort was influenced by age, number of seizures prior to diagnosis, imaging findings, patient preferences, and socioeconomic status., (Wiley Periodicals, Inc. © 2020 International League Against Epilepsy.)

Objectives: The objective of the study was to describe treatment patterns in patients newly diagnosed with Parkinson's disease (PD) in the United States (US) and the United Kingdom (UK)., Methods: This retrospective cohort study used the US IBM MarketScan database (2012-2017) and the UK Clinical Practice Research Datalink (CPRD) (2004-2015) database to describe treatment patterns in incident PD cases. Patients fulfilling the case definition of PD, ≥30 years, with a 2-year baseline period prior to the index date (date of PD diagnosis), and ≥90 days of follow-up were included in the study. Treatment was classified as monotherapy (one PD medication for ≥60 continuous days), polytherapy (at least two PD medications concurrently for ≥60 days), or untreated (no PD medication prescription). Treatment patterns described included type of medication, duration and outcome of treatment., Results: There were 11,280 patients in IBM MarketScan and 7775 patients in CPRD who fulfilled the study criteria. The proportion of treated patients was 62.4% (US) and 78.6% (UK). The majority of patients were prescribed monotherapy as first-line treatment (US: 85.2%, UK: 68.5%). Levodopa was the most frequently prescribed first-line medication (US: 70.1%, UK: 29.0%). There were 57.9% in the US and 23.8% in the UK who remained on the first monotherapy treatment till the end of the study., Conclusion: The study has highlighted the current treatment practices in the US and UK, and underscored differences in the two regions impacted by treatment policies and guidelines., Competing Interests: Linda Kalilani is an employee of UCB Pharma. David Friesen (Friesen Limited, Ascot, UK) and Nada Boudiaf (Chiltern International, Slough, UK) were paid consultants for UCB Pharma on this study. Mahnaz Asgharnejad is a former employee of UCB Pharma. This does not alter the authors' adherence to the PLOS ONE policies on data sharing and materials.

Purpose: Describe treatment patterns in patients from the United States with new-onset epilepsy, comparing those with and without lesional epilepsy., Methods: In this observational study we used Truven Health MarketScan databases derived from commercial health insurance, Medicare and Medicaid claims covering at least 5 years, commencing in 2008. We identified incident epilepsy cases based on International Classification of Diseases, Ninth Revision, Clinical Modification codes indicating epilepsy or recurrent seizures, taking into account antiepileptic drug (AED) claims, consistent with International League Against Epilepsy Commission on Epidemiology recommendations. We identified patients with lesional epilepsy when associated diagnoses indicated central nervous system infection, neoplasm, traumatic brain injury, stroke, senile dementia and static encephalopathy. Lesional and nonlesional cohorts were matched 1:1 on baseline characteristics of age, sex and insurance type for group comparisons., Results: In unmatched cohorts lesional epilepsy patients (N = 15,302) were more commonly older (mean age 48.7 years) compared with nonlesional epilepsy patients (N = 15,970; mean age 18.5 years). Among lesional patients <20 years of age, the leading putative etiology was static encephalopathy, while among ages ≥20 years and older, the leading putative etiology was stroke or cerebrovascular disease. In matched cohorts (7063 patients each), those with lesional epilepsy were significantly less likely to be untreated at 1 year versus those with nonlesional epilepsy (37.2% vs 56.1%). In children and adults among matched cohorts, levetiracetam was the most common AED prescribed for initial AED therapy for the lesional (39.5%) and nonlesional (32.1%) groups. Lesional epilepsy patients on monotherapy were only slightly less likely than nonlesional epilepsy patients to be on the same AED 1 year after treatment initiation (55.6% vs 59.7%)., Significance: Compared with patients with lesional epilepsy, a higher proportion of patients with nonlesional epilepsy remain untreated 1 year after diagnosis. There were differences in AED selection by epilepsy etiology; levetiracetam is the most commonly prescribed drug for both cohorts., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Malaria in pregnancy is associated with adverse birth outcomes. However, the underlying mechanisms remain poorly understood. Tight regulation of angiogenic, metabolic, and inflammatory pathways are essential for healthy pregnancies. We hypothesized that malaria disrupts these pathways leading to preterm birth (PTB)., Methods and Findings: We conducted a secondary analysis of a randomized trial of malaria prevention in pregnancy conducted in Malawi from July 21, 2011, to March 18, 2013. We longitudinally assessed circulating mediators of angiogenic, metabolic, and inflammatory pathways during pregnancy in a cohort of HIV-negative women (n = 1,628), with a median age of 21 years [18, 25], and 562 (35%) were primigravid. Pregnancies were ultrasound dated, and samples were analyzed at 13 to 23 weeks (Visit 1), 28 to 33 weeks (Visit 2), and/or 34 to 36 weeks (Visit 3). Malaria prevalence was high; 70% (n = 1,138) had PCR-positive Plasmodium falciparum infection at least once over the course of pregnancy and/or positive placental histology. The risk of delivering preterm in the entire cohort was 20% (n = 304/1506). Women with malaria before 24 weeks gestation had a higher risk of PTB (24% versus 18%, p = 0.005; adjusted relative risk [aRR] 1.30, 95% confidence interval [CI] 1.04-1.63, p = 0.021); and those who were malaria positive only before week 24 had an even greater risk of PTB (28% versus 17%, p = 0.02; with an aRR of 1.67, 95% CI 1.20-2.30, p = 0.002). Using linear mixed-effects modeling, malaria before 24 weeks gestation was associated with altered kinetics of inflammatory (C-Reactive Protein [CRP], Chitinase 3-like protein-1 [CHI3L1], Interleukin 18 Binding Protein [IL-18BP], soluble Tumor Necrosis Factor receptor II [sTNFRII], soluble Intercellular Adhesion Molecule-1 [sICAM-1]), angiogenic (soluble Endoglin [sEng]), and metabolic mediators (Leptin, Angiopoietin-like 3 [Angptl3]) over the course of pregnancy (χ2 > 13.0, p ≤ 0.001 for each). Limitations include being underpowered to assess the impact on nonviable births, being unable to assess women who had not received any antimalarials, and, because of the exposure to antimalarials in the second trimester, there were limited numbers of malaria infections late in pregnancy., Conclusions: Current interventions for the prevention of malaria in pregnancy are initiated at the first antenatal visit, usually in the second trimester. In this study, we found that many women are already malaria-infected by their first visit. Malaria infection before 24 weeks gestation was associated with dysregulation of essential regulators of angiogenesis, metabolism, and inflammation and an increased risk of PTB. Preventing malaria earlier in pregnancy may reduce placental dysfunction and thereby improve birth outcomes in malaria-endemic settings., Competing Interests: The authors have declared that no competing interests exist.

Objective: The objective of this study was to describe antiepileptic drug (AED) treatment patterns in patients with epilepsy, with and without psychiatric comorbidities., Methods: This was a retrospective claims-based cohort study using Truven Health MarketScan databases (Commercial and supplemental Medicare, calendar years 2012-2017; Medicaid, 2012-2016). Persons met epilepsy diagnostic criteria, had an index date (first epilepsy diagnosis) with a preceding 2-year baseline (<1 year for persons of 1 to <2 years of age; none for persons <1 year), and continuous medical and pharmacy enrolment without epilepsy/seizure diagnosis or AED prescription during baseline. Based on presence/absence of psychiatric diagnosis codes in the baseline period, persons were classified into two cohorts: with or without psychiatric comorbidities. Outcomes included percentage of treated persons (AED prescription), type, duration, and outcome of first-line AED treatment., Results: There were 18,062 persons in each cohort with and without psychiatric comorbidities, matched by age, sex, and insurance type, who met selection (or inclusion) criteria. More patients with psychiatric comorbidities were prescribed an AED after diagnosis (57.6% vs. 52.8%), and had at least two AEDs prescribed during follow-up (16.7% vs. 11.4%) than patients without psychiatric comorbidities. Most patients with and without psychiatric comorbidities prescribed AED monotherapy as first-line treatment (73.0% vs. 78.7%). Levetiracetam was the most common AED prescribed less frequently in patients with than without psychiatric comorbidities (40.8% vs. 56.7%). More patients with psychiatric comorbidities changed first-line AED treatment than patients without psychiatric comorbidities., Conclusion: The presence of psychiatric comorbidities may impact treatment decisions in newly diagnosed persons with epilepsy to optimize patient outcomes., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)