Later Phases Of Development Research Articles

Artificial Intelligence and Machine Learning for Lead-to-Candidate Decision-Making and Beyond.

The use of artificial intelligence (AI) and machine learning (ML) in pharmaceutical research and development has to date focused on research: target identification; docking-, fragment-, and motif-based generation of compound libraries; modeling of synthesis feasibility; rank-ordering likely hits according to structural and chemometric similarity to compounds having known activity and affinity to the target(s); optimizing a smaller library for synthesis and high-throughput screening; and combining evidence from screening to support hit-to-lead decisions. Applying AI/ML methods to lead optimization and lead-to-candidate (L2C) decision-making has shown slower progress, especially regarding predicting absorption, distribution, metabolism, excretion, and toxicology properties. The present review surveys reasons why this is so, reports progress that has occurred in recent years, and summarizes some of the issues that remain. Effective AI/ML tools to derisk L2C and later phases of development are important to accelerate the pharmaceutical development process, ameliorate escalating development costs, and achieve greater success rates.

Improving recovery efficiency by CO2 injection at late stage of steam assisted gravity drainage

The high recovery performance of steam-assisted gravity drainage (SAGD) makes it a popular option for heavy oil resources. Currently, most of the heavy oil reservoirs developed by SAGD in China are in the late development phase, with high energy consumption due to reduced thermal efficiency. The use of SAGD wind-down processes involving CO2 in combination with steam for heavy oil recovery is considered as a viable alternative to limit energy consumption, and also reduce the amount of greenhouse gas emissions by leaving CO2 behind in the reservoir. Study reveals that the dissolution and demulsification of CO2 steam chamber temperature reaches 200 ◦C, the amount of solid phase deposition induced in crude oil can reduce the viscosity of emulsified heavy oil by more than 50%. When the by CO2 extraction is only 0.016 kg/m3 , the rock wettability changes from lipophilic to hydrophilic, and the higher the reservoir temperature, the stronger the hydrophilicity is, which reduces the adhesion power of the oil phase and facilitates the stripping of crude oil from the rock surface. Numerical simulation studies have been carried out utilizing STARS to obtain energy efficient utilization and improved steam chamber characteristics. Heat loss from SAGD baseline is 1.77 times that with CO2 injection process, but the recovery factor is only 2.48% higher. At the initial stage with CO2 injection, the steam chamber continues its lateral expanding, which increases the recovery factor at the initial stage of CO2 injection by about 6%. One year after CO2 injection, gas channeling results in lower recovery than traditional SAGD process, and 38.4% of the injected CO2 is stored in the reservoir from this study. Cited as: Gong, H., Yu, C., Jiang, Q., Su, N., Zhao, X., Fan, Z. Improving recovery efficiency by CO2 injection at late stage of steam assisted gravity drainage. Advances in Geo-Energy Research, 2022, 6(4): 276-285. https://doi.org/10.46690/ager.2022.04.02

Early timing analysis based on scenario requirements and platform models

Distributed, software-intensive systems (e.g., in the automotive sector) must fulfill communication requirements under hard real-time constraints. The requirements have to be documented and validated carefully using a systematic requirements engineering (RE) approach, for example, by applying scenario-based requirements notations. The resources of the execution platforms and their properties (e.g., CPU frequency or bus throughput) induce effects on the timing behavior, which may lead to violations of the real-time requirements. Nowadays, the platform properties and their induced timing effects are verified against the real-time requirements by means of timing analysis techniques mostly implemented in commercial-off-the-shelf tools. However, such timing analyses are conducted in late development phases since they rely on artifacts produced during these phases (e.g., the platform-specific code). In order to enable early timing analyses already during RE, we extend a scenario-based requirements notation with allocation means to platform models and define operational semantics for the purpose of simulation-based, platform-aware timing analyses. We illustrate and evaluate the approach with an automotive software-intensive system.

Modulation of Neuropathic Pain by Glial Regulation in the Insular Cortex of Rats.

The insular cortex (IC) is known to process pain information. However, analgesic effects of glial inhibition in the IC have not yet been explored. The aim of this study was to investigate pain alleviation effects after neuroglia inhibition in the IC during the early or late phase of pain development. The effects of glial inhibitors in early or late phase inhibition in neuropathic pain were characterized in astrocytes and microglia expressions in the IC of an animal model of neuropathic pain. Changes in withdrawal responses during different stages of inhibition were compared, and morphological changes in glial cells with purinergic receptor expressions were analyzed. Inhibition of glial cells had an analgesic effect that persisted even after drug withdrawal. Both GFAP and CD11b/c expressions were decreased after injection of glial inhibitors. Morphological alterations of astrocytes and microglia were observed with expression changes of purinergic receptors. These findings indicate that inhibition of neuroglia activity in the IC alleviates chronic pain, and that purinergic receptors in glial cells are closely related to chronic pain development.

Promise & challenges in discovering cellular immunotherapies &T cell engagers for solid tumor indications

David McCall, Editor, Cell & Gene Therapy Insights, speaks to Pallavur Sivakumar, Vice President and Head of Discovery at ImmunoOncology and Cell Therapy Thematic Research CenterPallavur Sivakumar is currently Vice President and Head of Discovery, in the ImmunoOncology and Cell Therapy Thematic Research Center in Seattle. In his current role, Pallavur leads the Discovery efforts for IO/CT and is responsible for the early pipeline across all modalities (biologics, small molecules and cell therapy). Pallavur also helps establish and execute on the broader IO/CT Strategy, including working to identify and work with key external partnerships. Pallavur joined Celgene in 2015. He has over 20 years of biotech/pharma experience spanning early to late phases of drug development in Inflammation, Oncology, Immuno-Oncology, Virology and Diabetic Complications. Pallavur was born in India and has an undergraduate degree in Pharmacy (B.Pharm) and Biology (MSc). After a PhD in Immunology at University of Texas Southwestern Medical Center in Dallas, where his work focused on development of NK cells and the NK cell receptor repertoire, he moved to Seattle and has been in Seattle biotech industry at Immunex, ZymoGenetics and Novo Nordisk. He also spent 2 years at Novo Nordisk Headquarters in Copenhagen where he was responsible for Novo’s Inflammation Portfolio and in establishing/executing strategy for the Inflammation area.

Scenario-Based Comparative Analysis for Coupling Electricity and Hydrogen Storage in Clean Oilfield Energy Supply System

In response to the objective of fully attaining carbon neutrality by 2060, people from all walks of life are pursuing low-carbon transformation. Due to the high water cut in the middle and late phases of development, the oilfield’s energy consumption will be quite high, and the rise in energy consumption will lead to an increase in carbon emission at the same time. As a result, the traditional energy model is incapable of meeting the energy consumption requirement of high water cut oilfields in their middle and later phases of development. The present wind hydrogen coupling energy system was researched and coupled with the classic dispersed oilfield energy system to produce energy for the oilfields in this study. This study compares four future energy system models to existing ones, computes the energy cost and net present value of an oilfield in Northwest China, and proposes a set of economic evaluation tools for oilfield energy systems. The study’s findings indicate that scenario four provides the most economic and environmental benefits. This scenario effectively addresses the issue of high energy consumption associated with aging oilfields at this point, significantly reduces carbon emissions, absorbs renewable energy locally, and reduces the burden on the power grid system. Finally, sensitivity analysis is utilized to determine the effect of wind speed, electricity cost, and oilfield gas output on the system’s economic performance. The results indicate that the system developed in this study can be applied to other oilfields.

A tissue-selective estrogen complex as treatment of osteoporosis in experimental lupus.

Osteoporosis is a common secondary complication in patients with systemic lupus erythematosus (SLE). Current osteoporosis treatment with bisphosphonates has some negative side effects and there is a lack of data regarding newer treatments options for SLE associated osteoporosis. The tissue-selective estrogen complex (TSEC) containing conjugated estrogens and the selective estrogen receptor modulator bazedoxifene (Bza) is approved for treatment of postmenopausal vasomotor symptoms and prevention of osteoporosis. However, it has not been evaluated for treatment of osteoporosis in postmenopausal SLE patients. Ovariectomized MRL/lpr mice constitute a model for postmenopausal lupus that can be used for osteoporosis studies. We used this model in a set of experiments where the mice were treated with different doses of 17β-estradiol-3-benzoate (E2), Bza, or TSEC (E2 plus Bza), administered in the early or late phases of disease development. The skeleton was analyzed by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and high-resolution microcomputed tomography. The lupus disease was assessed by determination of proteinuria, hematuria, and lupus disease markers in serum. Treatment with medium dose TSEC administered in early disease protected ovariectomized MRL/lpr mice from trabecular bone loss, while there were no differences in lupus disease parameters between treatments. This is the first experimental study to investigate TSEC as a potential new therapy for osteoporosis in postmenopausal SLE.

Tentacle patterning during Exaiptasia diaphana pedal lacerate development differs between symbiotic and aposymbiotic animals.

Exaiptasia diaphana, a tropical sea anemone known as Aiptasia, is a tractable model system for studying the cellular, physiological, and ecological characteristics of cnidarian-dinoflagellate symbiosis. Aiptasia is widely used as a proxy for coral-algal symbiosis, since both Aiptasia and corals form a symbiosis with members of the family Symbiodiniaceae. Laboratory strains of Aiptasia can be maintained in both the symbiotic (Sym) and aposymbiotic (Apo, without algae) states. Apo Aiptasia allow for the study of the influence of symbiosis on different biological processes and how different environmental conditions impact symbiosis. A key feature of Aiptasia is the ease of propagating both Sym and Apo individuals in the laboratory through a process called pedal laceration. In this form of asexual reproduction, small pieces of tissue rip away from the pedal disc of a polyp, then these lacerates eventually develop tentacles and grow into new polyps. While pedal laceration has been described in the past, details of how tentacles are formed or how symbiotic and nutritional state influence this process are lacking. Here we describe the stages of development in both Sym and Apo pedal lacerates. Our results show that Apo lacerates develop tentacles earlier than Sym lacerates, while over the course of 20 days, Sym lacerates end up with a greater number of tentacles. We describe both tentacle and mesentery patterning during lacerate development and show that they form through a single pattern in early stages regardless of symbiotic state. In later stages of development, Apo lacerate tentacles and mesenteries progress through a single pattern, while variable patterns were observed in Sym lacerates. We discuss how Aiptasia lacerate mesentery and tentacle patterning differs from oral disc regeneration and how these patterning events compare to postembryonic development in Nematostella vectensis, another widely-used sea anemone model. In addition, we demonstrate that Apo lacerates supplemented with a putative nutrient source developed an intermediate number of tentacles between un-fed Apo and Sym lacerates. Based on these observations, we hypothesize that pedal lacerates progress through two different, putatively nutrient-dependent phases of development. In the early phase, the lacerate, regardless of symbiotic state, preferentially uses or relies on nutrients carried over from the adult polyp. These resources are sufficient for lacerates to develop into a functional polyp. In the late phase of development, continued growth and tentacle formation is supported by nutrients obtained from either symbionts and/or the environment through heterotrophic feeding. Finally, we advocate for the implementation of pedal lacerates as an additional resource in the Aiptasia model system toolkit for studies of cnidarian-dinoflagellate symbiosis.

Региональное луговодство на основе арктополевицы широколистной сорта Приохотская

The article deals with the topical issue of the formation of the local livestock feed base and the preservation of the productive longevity of sown meadows, based on the variety of broad-leaved arktopolitsa Priokhotskaya (Arctagrostis latifolia), created in 2012 in the Magadan Research Institute of Agriculture (R.Br .) Griseb). The purpose of the research is to create a regional system of seed production of perennial grasses to reduce the volume of the market of imported seeds and the formation of an economically valuable crop of fodder grasses at the expense of their own. The results of research conducted by the Institute's staff for a number of years (from 2012 to the present) give an idea of the full characteristics of the variety, revealing the full potential for plant growth and development, changes in the biochemical composition of feed during the growing season, depending on the phases of development. In extreme soil and climatic conditions of agricultural lands of the Magadan region, located mainly on permafrost tundra soils, the variety has the maximum adaptation over the years to abiotic and biotic factors, which determines the effectiveness of its use in regional meadow farming. A tendency to increase the protein and fat content in the earing phase and a gradual decrease in these indicators in later phases of development due to increased nutrient intake by the plant due to a sharp increase in aboveground mass has been established. The content of fiber, ash and calcium in plant tissues increases gradually and reaches a maximum by the time of maturation. A change in the biochemical composition and a stable reaction to meteorological conditions regulating the duration of phenological phases indicates the unique properties of the development of the variety and its adaptive capabilities in the conditions of the Northeast.

Design and evaluation of an engine-in-the-loop environment for developing plug-in hybrid electric vehicle operating strategies at conventional test benches

Due to a large number of degrees of freedom and connected powertrain functionalities, the development of operating strategies for plug-in hybrid electric vehicles is an especially complex task. Besides optimizations of drivability, noise, vibrations and harshness as well as energy efficiency, the main challenge lies in ensuring emissions conformity. For this purpose, test vehicles are typically applied to achieve a realistic test and validation environment. However, operating strategy calibration using test vehicles has the drawbacks, that (i) it is very time consuming and cost intensive, (ii) it can only be conducted in late development phases and (iii) cannot be applied to reproducing driving loads for a valid comparison. To overcome these issues, this paper presents a consistent engine-in-the-loop approach combining real engine hardware and multiple software elements to represent PHEV behavior at the engine test bench. Thereby, an environment is created, which allows for realistic, flexible, cost efficient and reproducible testing. The effectiveness of the presented framework is evaluated by comparing relevant on-road measurements with their reproduction at the engine test bench. The results show that the vehicle on-road behavior can be replicated using the described testing environment. Particularly engine start/stop behavior and load levels—the core functionalities for operating strategy calibration—are matched. The proven level of realism in powertrain behavior enables further use cases beyond on-road measurement reproduction, i.e. varying individual component properties and observing real-world consequences at the test bench without the need for vehicle tests.

Making design decisions under uncertainties: probabilistic reasoning and robust product design

Making design decisions is characterized by a high degree of uncertainty, especially in the early phase of the product development process, when little information is known, while the decisions made have an impact on the entire product life cycle. Therefore, the goal of complexity management is to reduce uncertainty in order to minimize or avoid the need for design changes in a late phase of product development or in the use phase. With our approach we model the uncertainties with probabilistic reasoning in a Bayesian decision network explicitly, as the uncertainties are directly attached to parts of the design artifact′s model. By modeling the incomplete information expressed by unobserved variables in the Bayesian network in terms of probabilities, as well as the variation of product properties or parameters, a conclusion about the robustness of the product can be made. The application example of a rotary valve from engineering design shows that the decision network can support the engineer in decision-making under uncertainty. Furthermore, a contribution to knowledge formalization in the development project is made.

New horizons in early drugs development in solid cancers.

Drug development is the process of bringing new anticancer agents into clinical practice. From the basic research to clinical research each step is essential and intimately linked. The aim of this review is to describe emerging preclinical models and to provide an overview of selected drugs recently developed in oncology. Preclinical models reproducing human immune-tumor interactions, 3D cell cultures and microfluidic platforms are of great interest for the development of immunotherapies and combination therapies and offer the opportunity to better understand the interplay between cancer and stromal cells.Following a better biological understanding of cancer and advances in precision oncology, new exciting drugs (e.g. antibodies-drugs conjugates [ADCs], immunotherapeutic strategies, molecular-targeted therapies) have entered the field of clinical research and even clinical practice. Recent improvements in preclinical models will allow an accurate selection of drug candidates for clinical research. Innovative drugs are currently being developed from early to later phases of development. An important remaining challenge in drug development is to set up a new model of patient-centered clinical research to facilitate quick access to innovation and target-oriented trials.

Time-sequenced transcriptomes of developing distal mouse limb buds: A comparative tissue layer analysis.

The development of the amniote limb has been an important model system to study patterning mechanisms and morphogenesis. For proper growth and patterning, it requires the interaction between the distal sub-apical mesenchyme and the apical ectodermal ridge (AER) that involve the separate implementation of coordinated and tissue-specific genetic programs. Here, we produce and analyze the transcriptomes of both distal limb mesenchymal progenitors and the overlying ectodermal cells, following time-coursed dissections that cover from limb bud initiation to fully patterned limbs. The comparison of transcriptomes within each layer as well as between layers over time, allowed the identification of specific transcriptional signatures for each of the developmental stages. Special attention was given to the identification of genes whose transcription dynamics suggest a previously unnoticed role in the context of limb development and also to signaling pathways enriched between layers. We interpret the transcriptomic data in light of the known development pattern and we conclude that a major transcriptional transition occurs in distal limb buds between E9.5 and E10.5, coincident with the switch from an early phase continuation of the signature of trunk progenitors, related to the initial proximo distal specification, to a late intrinsic phase of development.

Recent advances and future perspectives in the pharmacological treatment of Candida auris infections

ABSTRACT Introduction Candida auris is responsible for hospital outbreaks worldwide. Some C. auris isolates may show concomitant resistance to azoles, echinocandins, and polyenes, thereby possibly leaving clinicians with few therapeutic options. Areas covered Antifungal agents both in early and in late phases of clinical development showing anti-C. auris activity. Expert opinion The research on antifungal agents active against C. auris has made important steps forward in recent years: (i) the development of drugs with novel mechanisms of action, such as ibrexafungerp and fosmanogepix, could provide a valid option against C. auris strains resistant to one or more older antifungals, including pan-resistant strains; (ii) rezafungin could allow once weekly administration of an active drug in the case of echinocandin-susceptible isolates, providing an effective outpatient treatment, while at the same time relieving selective pressure on novel classes; (iii) the development of oral formulations could allow step-down therapy and/or early discharge, or even to avoid hospitalization in mild or noninvasive diseases; (iv) according to available data, these novel agents show a good safety profile and a low potential for drug–drug interactions.

EFFICIENCY OF USING RARE OIL FOR BIOLOGIZATION OF FERTILIZATION SYSTEMS OF CERTAIN AGRICULTURAL CULTURES OF ESPC UKRAINIAN SCIENTIFIC-EDUCATIONAL CONSORTIUM

The article presents the results of studying the effectiveness of options for biologizing the fertilization system and related factors of the impact of options for using post-harvest green manure in the technology of growing grain corn on gray forest and chernozem soils. The effectiveness of the use of cruciferous green manure crops, such as white mustard, oil radish and spring rape, has been investigated. Evaluation of the effectiveness of green manure was carried out both by the species factor and by the method of sowing green manure plants, in particular, the usual row and wide-row methods. The features of the influence of late autumn post-harvest green manure on the formation of agrophysical soil properties, such as the duty cycle in its categories and soil density, taking into account the optimization of the air properties of the soil and the restoration of its structure in the technologies of adaptive cultivation of agricultural crops, have been studied. The role of green manure crops in providing herbicide-free control of the level of weed infestation was assessed both from the standpoint of controlling the number of various types of weeds and from the standpoint of regulating their development and prevalence. The formation of segetal vegetation in crops of corn for grain was investigated in the format of determining the effectiveness of the aftereffect of green manure on the formation of the level of weediness in the late phenological phases of growth and development of corn. The features of the formation of leafy mass of green manure were investigated, taking into account the temperature and moisture regime.Based on this, an assessment was made of the adaptability of various types of green manure crops depending on the limiting factors of moisture and low temperatures in the variant of summer-autumn use. Conclusions are made about the expediency of using this criterion of the studied cruciferous crops. The influence of green manure crops on the formation of corn yield for grain is shown, taking into account different types of soils and their fertility potential, as well as taking into account the method of sowing green manure. Increases in corn yield were determined in comparison with unfertilized control and their level was assessed in relation to a possible effective alternative replacement of existing options for fertilizing corn with grain. Conclusions are made about the most productive green manure option based on cruciferous species, and prospects for further research and problematic aspects of the use of cruciferous green manure plants are outlined.

Regulation of Fruit Growth in a Peach Slow Ripening Phenotype.

Consumers’ choices are mainly based on fruit external characteristics such as the final size, weight, and shape. The majority of edible fruit are by tree fruit species, among which peach is the genomic and genetic reference for Prunus. In this research, we used a peach with a slow ripening (SR) phenotype, identified in the Fantasia (FAN) nectarine, associated with misregulation of genes involved in mesocarp identity and showing a reduction of final fruit size. By investigating the ploidy level, we observed a progressive increase in endoreduplication in mesocarp, which occurred in the late phases of FAN fruit development, but not in SR fruit. During fruit growth, we also detected that genes involved in endoreduplication were differentially modulated in FAN compared to SR. The differential transcriptional outputs were consistent with different chromatin states at loci of endoreduplication genes. The impaired expression of genes controlling cell cycle and endocycle as well as those claimed to play a role in fruit tissue identity result in the small final size of SR fruit.

Pathways to Deviance: Exploring the Relationship between Peer Affiliation, Gang Membership and Youth Misconduct

Deviant peer affiliation and gang membership often act as a catalyst for maladaptive behaviour, as individuals in the late adolescent phase of lifespan development typically share stronger attachment to their peers than to their caregivers. An interrelationship also exists between delinquency and factors such as peer approval of deviance and peer pressure to transgress. This is particularly prevalent when exposed to challenges in the family or school, which typically perpetuate feelings of rejection, leading to a greater likelihood to seek out peers to gain a sense of belonging, support and camaraderie. Despite the importance of these interactions, exposure to antisocial peers or gangs exponentially increase the propensity to transgress, as maladaptive behaviour would be reinforced, thereby decreasing the efficacy of primary and secondary socialisation agents. Moreover, youths may become desensitised to violence, learn to rationalise unlawful behaviour and gain opportunities for crime. Accordingly, a qualitative study was conducted in South Africa to explore peer affiliation and gang membership as a pathway to deviance, based on the unique experiences of 20 detained male youths. The data were obtained through purposive sampling and analysed by frequency or percentage distributions, and also through narrative accounts from the participants. The findings identified deviant peer affiliation (75%) and gang involvement (65%) as key factors which motivated the participants to transgress. Furthermore, the association between peer affiliation, substance abuse, academic failure and truancy was apparent. It is thus envisaged that these findings will stimulate further research, contribute to the existing literature and aid in the development of strategies to manage deviant peer association and gang membership.

Developing an Aggregator Mechanism for Late-Stage Clinical Trials of Neglected Disease Product Candidates

There have been significant improvements in recent years in the early stage development of products for poverty-related and neglected diseases (PRNDs). However, there are still major challenges in the funding of late-stage clinical trials of candidate products for these diseases. For vaccine development specifically, Rappuoli and colleagues recently concluded that “these improvements in the early development process have revealed a new, and possibly more perilous, Valley of Death in the late vaccine development phase.” There are three major challenges in conducting phase III trials for PRND product development. First, such trials are expensive and companies often shy away from investing in them because there is no commercial market for most PRNDs. Second, there is poor coordination on late-stage trials across R&D initiatives. At present, there is no overarching global mechanism that is “steering the ship”—there is no universally agreed-upon process for prioritizing R&D investments for PRNDs, for selecting the most promising candidates, or for coordinating the multiple, overlapping research programs worldwide. The result is duplication, waste, and ultimately delays in the development of products. Third, current R&D efforts for PRNDs are “top-down”—they are controlled by high-income countries (HICs) and have generally done poorly at including decision-makers from high-burden countries. It is policymakers in low- and middle-income countries (LMICs) who are in the trenches when it comes to controlling PRNDs—yet they are often not at the table when it comes to deciding on what gets funded, where research is conducted, who gets access to intellectual property, and where and how the technologies end up being manufactured. All these steps need to be “globalized” if we are to develop and deploy new control tools.

Sustained glial reactivity induced by glutaric acid may be the trigger to learning delay in early and late phases of development: Involvement of p75NTR receptor and protection by N-acetylcysteine

Degeneration of striatal neurons and cortical atrophy are pathological characteristics of glutaric acidemia type I (GA-I), a disease characterized by accumulation of glutaric acid (GA). The mechanisms that lead to neuronal loss and cognitive impairment are still unclear. The purpose of this study was to verify if acute exposure to GA during the neonatal period is sufficient to trigger apoptotic processes and lead to learning delay in early and late period. Besides, whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Pups mice received a dose of GA (2.5 μmol/ g) or saline, 12 hs after birth, and were treated with NAC (250 mg/kg) or saline, up to 21th day of life. Although GA exhibited deficits in the procedural and working memories in 21 and 40-day-old mice, NAC protected against cognitive impairment. In striatum and cortex, NAC prevented glial cells activation (GFAP and Iba-1), decreased NGF, Bcl-2 and NeuN, the increase of lipid peroxidation and PARP induced by GA in both ages. NAC protected against increased p75NTR induced by GA, but not in cortex of 21-day-old mice. Thus, we showed that the integrity of striatal and cortical pathways has an important role for learning and suggested that sustained glial reactivity in neonatal period can be an initial trigger for delay of cognitive development. Furthermore, NAC protected against cognitive impairment induced by GA. This work shows that early identification of the alterations induced by GA is important to avoid future clinical complications and suggest that NAC could be an adjuvant treatment for this acidemia.

The role of new antimicrobials for Gram-negative infections in daily clinical practice.

To discuss a possible clinical reasoning for treating resistant Gram-negative bacteria (GNB) infections in daily clinical practice, as well as developing a research agenda for the field. Novel agents, both belonging to β-lactams and to other classes of antimicrobials, have recently become available, likely replacing polymyxins or polymyxin-based combination regimens as the preferred choices for the first-line treatment of severe resistant GNB infections in the near future. The peculiar characteristics of novel agents for severe resistant GNB infections have abruptly made the structure of previous therapeutic algorithms somewhat obsolete, in view of the differential activity of most of them against different classes of carbapenemases. Furthermore, other agents showing activity against resistant GNB are in late phase of clinical development. Optimizing the use of novel agents in order both to guarantee the best available treatment to patients and to delay the emergence and spread of resistance is an important task that cannot be postponed, especially considering the unavailability of well tolerated and fully efficacious options for treating resistant GNB infections that we faced in the last 15 years.