To assess the relationship between mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) and clinical pyrimethamine-sulfadoxine resistance, polymerase chain reaction surveys and analyses for new mutations were conducted in four countries with increasing levels of pyrimethamine-sulfadoxine resistance: Mali, Kenya, Malawi, and Bolivia. Prevalence of mutations at DHFR codon 108 and a new mutation at DHPS 540 correlated with increased pyrimethamine-sulfadoxine resistance (P < .05). Mutations at DHFR 51, DHFR 59, and DHPS 437 correlated with resistance without achieving statistical significance. Mutations at DHFR 164 and DHPS 581 were common in Bolivia, where pyrimethamine-sulfadoxine resistance is widespread, but absent in African sites. Two new DHFR mutations, a point mutation at codon 50 and an insert at codon 30, were found only in Bolivia. DHFR and DHPS mutations occur in a progressive, stepwise fashion. Identification of specific sets of mutations causing in vivo drug failure may lead to the development of molecular surveillance methods for pyrimethamine-sulfadoxine resistance.

Plasmodium vivax is a major cause of illness in areas with low transmission of malaria in Latin America, Asia, and the Horn of Africa. However, pregnancy-associated malaria remains poorly characterized in such areas. Using a hospital-based survey of women giving birth and an antenatal survey, we assessed the prevalence rates of Plasmodium spp. infections in pregnant women in Bolivia, and evaluated the consequences of malaria during pregnancy on the health of mothers and newborns. P. vivax infection was detected in 7.9% of pregnant women attending antenatal visits, and placental infection occurred in 2.8% of deliveries; these rates did not vary with parity. Forty-two percent of all P. vivax malaria episodes were symptomatic. P. vivax–infected pregnant women were frequently anemic (6.5%) and delivered babies of reduced birthweight. P. vivax infections during pregnancy are clearly associated with serious adverse outcomes and should be considered in prevention strategies of pregnancy-associated malaria.

Despite many available treatments for schizophrenia, several unmet needs persist in treating individuals with this disorder, and the response rate to first-line antipsychotics remains relatively low. Clozapine has shown efficacy in treating schizophrenia patients who failed to respond to previous antipsychotics. However, side effects and the need for routine blood tests have limited its use as a first-line treatment. Cariprazine is a D 2 /D 3 partial agonist antipsychotic with a mechanism of action that differs from other antipsychotics due to its higher affinity for D 3 receptors. Several trials have demonstrated the efficacy of cariprazine on positive and negative symptoms of schizophrenia and have shown that it is a well-tolerated treatment. In this series, we present 3 cases of patients diagnosed with schizophrenia who were initially under treatment with clozapine. Despite some initial improvement, the patients showed persisting positive and negative symptoms or developed limiting side effects while in treatment with clozapine. Cariprazine treatment was titrated concurrently with clozapine tapering until its discontinuation. Significant improvement in both positive and negative symptoms was observed up to 14 months after starting cariprazine, and resolution of side effects was reported in all cases. Our case series supports cariprazine as an effective treatment for positive and negative symptoms in patients who failed to adequately respond or poorly tolerated treatment with clozapine, as well as a potential treatment in dual disorders, specifically psychotic disorders and cocaine use disorder.

SummaryWe assessed the efficacy of mefloquine monotherapy and mefloquine-artesunate (MQ-AS) combination therapy for the treatment of Plasmodium falciparum malaria at four sites in the Bolivian Amazon region.Patients with uncomplicated P. falciparum infections between 5 and 60 years of age were randomly assigned to be treated with either MQ (15 mg/kg in a single oral dose) or MQ (15 mg/kg) plus AS (4 mg/kg daily for 3 days). A total of 143 patients were enrolled and followed for 28 days. None of the 73 patients who received MQ alone or the 70 patients who received MQ-AS combination therapy had recurrences of parasitaemia during the 28-day follow-up period. Asexual parasite densities fell significantly more rapidly and the proportion of patients with gametocytes was significantly lower on days 7-28 in patients treated with MQ-AS than in those treated with MQ alone. All patients tolerated the medications well. After this study, the Bolivian Ministry of Public Health changed its treatment policy for uncomplicated P. falciparum malaria in the Amazon region to combination therapy with MQ-AS to slow or prevent the development of resistance.

Abstract. The World Health Organization (WHO) has developed guidelines for in vivo antimalarial drug efficacy testing for Plasmodium falciparum and Plasmodium vivax in areas with low-to-moderate transmission, such as the Americas. These guidelines are used widely by ministries of health and national malaria control programs to assess the efficacy of their first-line and second-line drugs for the treatment of malaria and to provide the information necessary to update national malaria treatment policies. Following the WHO guidelines, we have conducted in vivo efficacy trials with a variety of drugs and drug combinations against P. falciparum and P. vivax at 13 sites in Peru, Bolivia, and Ecuador. Based on these experiences, we have identified several modifications that we believe should be made in the WHO recommendations to make them more suitable to the relatively low levels of P. falciparum transmission in the Americas and to the logistic challenges of carrying out such studies in sparsely populated areas, such as the Amazon Basin. These include changes in inclusion and exclusion criteria, in enrollment and follow-up procedures, and in the measurement of study outcomes.

Intelligent well completion (IWC) or smart wells have been used in the industry for more than two decades. Numerous benefits from this technology have been reported in the literature. These benefits are associated with improved field development economics and better reservoir management. The field economics are mainly impacted by reduction of the well count and the increase of the estimated-ultimate recovery (EUR) and net-present value (NPV) by commingling different reservoirs. The reservoir management benefits are less tangible and more difficult to quantify. They have to rely on certain assumptions that may be controversial among the team members and management. Therefore, the IWC business case is usually supported only by the improved economics. A key input on the economics is the production forecast. The industry lacks a standard workflow to predict the production from an IWC. Reservoir engineers have to be creative using their available tools to model the performance of this complex well operation. The methods regularly used are simple inflow-performance relationships (IPR), nodal analysis, well modeling with pipeline-network simulators, and 3D reservoir simulators with multi-segment well capabilities. The latter is the most appropriate to capture the value for new developments, but still extensive customization is required to optimize the production forecast while honoring all the constraints in the field operational philosophy; the others are more suitable for routine production optimization. In our case, deepwater Gulf of Mexico (GOM), the operating philosophy is (1) use primary well-head choke to control well production, (2) limit the pressure drop across the inflow-control valves (ICV), and (3) limit the producing zone drawdown. In addition, the productivity index (PI) degradation mechanism has to be included in the forecast. None of the commercial reservoir simulators have these requirements built-in. This paper presents an approach that integrates detailed wellbore modeling, reservoir simulation, and the field operating philosophy. The workflow is based on a pipeline network simulator (GAP™) coupled to 3D reservoir simulation models in INTERSECT™. The IWC optimization under the operational philosophy is executed through a Python script—INTERSECT custom functionality—that manages the GAP network information obtained from OpenServer™ and the reservoir simulation data to select the ICV settings that optimize the well production while honoring all constraints. This workflow provides an accurate production forecast assuring all critical operating constraints are incorporated.

Productivity index (PI) degradation is a critical issue that negatively impacts hydrocarbon recovery. This problem is very common in deepwater environments such as Gulf of Mexico (GOM). In recent years, several publications have addressed this issue proposing integrated workflows to assess and mitigate this problem and providing interesting insights into the causes of this phenomenon. Our organization commissioned a study (Knobles et al. 2017) to understand the reasons for the high productivity declines observed across our assets in GOM and identify lessons learned and best practices to reduce the severity of the PI degradation in cased-hole-frac-pack (CHFP) completions in high-permeability reservoirs (50-1000 mD), which are the most common in our operations. These findings have contributed to improve our CHFP performance. This performance has been assessed based on a completion scorecard that grades and weights the key design and execution parameters of the CHFP completion and yields a score (0 to 100) for the completion execution and productivity. Knobles et al. established a correlation between the productivity score in the completion scorecard and a qualitative ranking of the well productivity performance, namely productivity tiers. The wells in scope were categorized in four groups, tier 1, tier 2, tier 3, and tier 4. Tier 1 is the highest performance level, i.e., low initial skin and low productivity degradation. Later, the completion scorecard was reviewed by a group of completion subject-matter experts (SME) to improve the correlation between the productivity score and the productivity tiers. The updated scorecard enhanced this relationship making it suitable as an indicator of long-term productivity. However, the use of this correlation in production forecasting is limited because of its categorical nature. The objective of this work is to quantify the relationship between the completion scorecard and the productivity performance and use the results to narrow down the productivity degradation uncertainty range in production forecasts. We use data science concepts and tools to analyze our well productivity database, Integral Well Productivity Tracker (IWPT), and develop a numeric correlation between the actual well productivity data observed in the field and the completion scorecard results from the post-job evaluations. The process includes IWPT data wrangling, modeling, and visualization. We performed regression analyses on the normalized productivity index and cumulative liquid production for approximately 120 wells in the IWPT dataset to calculate PI degradation rate for each well and combine them with the completion scorecard results. The results validate the conclusion from Knobles et al.'s work, i.e., a correlation exits between the productivity score from the completion scorecard and the productivity performance. The new, numerical relationship allows us to consider the improvements in completion quality. This quantitative correlation can inform the definition of the productivity-degradation-uncertainty ranges in the production forecast during planning and after the completion job when the completion scorecard results are available. Narrowing down the uncertainty in productivity degradation significantly impacts the estimated-ultimate recovery (EUR) of any GOM deepwater project.