Early Phase Of Test Research Articles

Novel immunotherapeutic approaches in lung cancer: driving beyond programmed death-1/programmed death ligand-1 and cytotoxic T-lymphocyte-associated Protein-4.

In this review, our aim is to highlight the latest novel immunotherapeutic approaches for advanced nonsmall cell lung cancer (NSCLC) beyond anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) and anti- cytotoxic T-lymphocyte-associated Protein-4 (CTLA4). Immune checkpoint inhibitors (ICIs) revolutionized the treatment of advanced NSCLC. Despite that, patients develop primary or acquired resistance to ICIs. The discovery of novel approaches represents both an unmet need and an opportunity to improve outcomes in these patients. We summarized the most relevant novel immune checkpoints, many of them in their early phase of testing, to provide a comprehensive overview of the state of the art of immunotherapy in NSCLC beyond PD-1/PD-L1 and CTL-4 inhibitors.

Optimization of surgical evaluation algorithms for living donor liver transplantation

BackgroundLiving donor liver transplantation (LDLT) is an established and endorsed alternative for deceased donor liver transplantation with better recipient outcomes. Nevertheless, while extensive evaluation of potential donors is crucial, evaluation algorithms differ between transplant centres and guidelines. MethodsWe included 317 individuals evaluated for LDLT between 07/2007–07/2022 in a retrospective analysis. The evaluation process was analysed to identify the key reasons for declining 77 potential donors. Additionally, 146 donors that underwent LDLT were analysed regarding risk factors for complications. ResultsThe main reasons for donor refusal were liver volumetry (40.3 %) and metabolic factors including obesity or steatotic liver disease (20.8 %). Contrast-enhanced computed tomography (CECT) identified 63.6 % of all declined donors; CECT combined with assessment of medical history, physical examination, blood testing and ultrasonography, identified 87.0 % of declined potential donors. Associated with this selection, complication rates in donors were low (≥II in 17.1 %; none with ≥IVb). Notably, higher age was a risk factor for developing a complication ≥II after hemi-hepatectomy (p = 0.0373). ConclusionsWe propose a progressive 4-step evaluation algorithm that begins with a very basic assessment combined with up-front CECT. This early phase of testing is expected to identify nearly 90 % of ineligible donors, thereby conserving critical resources, time and money, as well as minimising burden for potential donors. FundingJ.M.W. received funding by grant We-4675/6–1 from the Deutsche Forschungsgemeinschaft (DFG) in Bonn, Germany.

Inversion Effect of Hand Postures: Effect of Visual Experience Over Long and Short Term.

Some researchers argue that holistic processing is unique to face recognition supported by the face inversion effect. However, findings such as the body inversion effect challenge the face processing-specificity hypothesis, thus supporting the expertise hypothesis. Few studies have explored a possible hand inversion effect which could involve special processing similar to the face and body. We conducted four experiments to investigate the time course and flexibility of the hand posture inversion effect. We utilized a same/different discrimination task (Experiments 1 and 2), an identification task (Experiment 3), and a training paradigm involving the exposure of different hand orientations (Experiment 4). The results show the hand posture inversion effect (with fingers up as upright orientation) was not initially observed during the early phase of testing, but occurred in later phases. This suggests that both lifetime experience and recent exposure affect the hand posture inversion effect. We also found the hand posture inversion effect, once established, was stable across days and remained consistent across different tasks. In addition, the hand posture inversion effect for specific orientations could be obtained with short-term training of a given orientation, indicating the cognitive process is flexible.

From Research to the Real World: Moving Prostate Cancer Biomarkers into the Clinic.

Effective biomarkers provide the potential to significantly improve treatment decisions and outcomes in prostate cancer patients. While the literature is inundated with prostate cancer biomarkers in the early phases of testing, very few reach the clinic. Research should be focused on progressing effective biomarkers from discovery to clinical utility and implementation. Presented here is an overview of the biomarker development pathway and a discussion of the current issues impeding our efforts to deliver biomarkers that improve clinical outcomes in men with prostate cancer.

Quantitative Assessment of the Efficacy of Near-Infrared Photoimmunotherapy with Bioluminescence Imaging.

Near-infrared photoimmunotherapy (NIR-PIT) is a cell-specific cancer therapy in which antibody-photoabsorber conjugates (APCs) are activated by NIR light to induce rapid immunogenic cell death with minimal off-target effects. In preclinical settings, bioluminescence imaging (BLI) is useful to quantitatively assess the efficacy of NIR-PIT for both in vitro and in vivo experiments, especially in the early phase of testing. Here, we describe the detailed methods of the experiments for NIR-PIT and evaluation of its efficacy using BLI.

Application of robotic technologies in lower gastrointestinal tract endoscopy: A systematic review

BACKGROUNDConventional optical colonoscopy is considered the gold standard investigation for colorectal tract pathology including colorectal malignancy, polyps and inflammatory bowel disease. Inherent limitations exist with current generation endoscopic technologies, including, but not limited to, patient discomfort, endoscopist fatigue, narrow field of view and missed pathology behind colonic folds. Rapid developments in medical robotics have led to the emergence of a variety of next-generation robotically-augmented technologies that could overcome these limitations.AIMTo provide a comprehensive summary of recent developments in the application of robotics in lower gastrointestinal tract endoscopy.METHODSA systematic review of the literature was performed from January 1, 2000 to the January 7, 2021 using EMBASE, MEDLINE and Cochrane databases. Studies reporting data on the use of robotic technology in ex vivo or in vivo animal and human experiments were included. In vitro studies (studies using synthetic colon models), studies evaluating non-robotic technology, robotic technology aimed at the upper gastrointestinal tract or paediatric endoscopy were excluded. System ergonomics, safety, visualisation, and diagnostic/therapeutic capabilities were assessed.RESULTSInitial literature searching identified 814 potentially eligible studies, from which 37 were deemed suitable for inclusion. Included studies were classified according to the actuation modality of the robotic device(s) as electromechanical (EM) (n = 13), pneumatic (n = 11), hydraulic (n = 1), magnetic (n = 10) and hybrid (n = 2) mechanisms. Five devices have been approved by the Food and Drug Administration, however most of the technologies reviewed remain in the early phases of testing and development. Level 1 evidence is lacking at present, but early reports suggest that these technologies may be associated with improved pain and safety. The reviewed devices appear to be ergonomically capable and efficient though to date no reports have convincingly shown diagnostic or therapeutic superiority over conventional colonoscopy. CONCLUSIONSignificant progress in robotic colonoscopy has been made over the last couple of decades. Improvements in design together with the integration of semi-autonomous and autonomous systems over the next decade will potentially result in robotic colonoscopy becoming more commonplace.

Development of NIRS re-calibration model for ethiopian barley (Hordeum vulgare) lines traits to determine their brewing potential

Barley is one of the top five grain crops in Ethiopia, covering approximately 1 million hectares, and is grown for food, animal's feed and industrial purposes. Ethiopian Agricultural Research Institute (EIAR) is also conducting a barley research and breeding program with the aim of improving grain yield and resilience through screening lines. Sample materials used for the experiment were taken from 2018, 2019 and 2020 seasons to capture the variation in the growing year. As a result, the spectral data of the samples and the wet chemical data were generated using official international methods. Subsequently, a recalibration based on 280 samples of breeding lines of different genotypes, growing years and locations was developed in order to predict the protein, extract and friability content characteristics of important barley malt parameters. Wet chemical data were collected from processed/malted barley grains. A calibration model was created on the basis of the calibration software OPUS LAB 7.5 from Bruker Optics GmbH. The protein calibration (R 2 c = 0.90; RPD = 3.8) can be viewed as broadly applicable; the extract content (R 2 c = 0.88 and RPD = 2.8) and friability (R 2 c = 0.85 and RPD = 2.7) could be useful as well as a good predictive model for line screening. The calibration model was missing to predict long-range sample sources before the model range was expanded by recalibration process including different sample sources. Therefore, these NIRS models enable the selection of suitable food and malt barley genotypes at wide range. Since NIRS is fast and inexpensive, the barley improvement program can increase selection intensity, especially in the early testing phase. So the best precision of the NIRS recalibration discovered in this study enables to identify top candidate lines with a minimum of errors. • The aim was predicting grain barley quality trait using near infrared spectroscopy. • The 2018, 2019 and 2020 seasons of 280 barley genotypes were used for the study. • Models developed for protein, extract & friability from reference ^ spectral data. • Protein, extract & friability model predictive result is 3.8, 2.8 and 2.7 respectively. • A predictive model (>2.5) & (2–2.5) are excellent and good respectively.

Detecting bad actors in value-based payment models.

The U.S. federal government is spending billions of dollars to test a multitude of new approaches to pay for healthcare. Unintended consequences are a major consideration in the testing of these value-based payment (VBP) models. Since participation is generally voluntary, any unintended consequences may be magnified as VBP models move beyond the early testing phase. In this paper, we propose a straightforward unsupervised outlier detection approach based on ranked percentage changes to identify participants (e.g., healthcare providers) whose behavior may represent an unintended consequence of a VBP model. The only data requirements are repeated measurements of at least one relevant variable over time. The approach is generalizable to all types of VBP models and participants and can be used to address undesired behavior early in the model and ultimately help avoid undesired behavior in scaled-up programs. We describe our approach, demonstrate how it can be applied with hypothetical data, and simulate how efficiently it detects participants who are truly bad actors. In our hypothetical case study, the approach correctly identifies a bad actor in the first period in 86% of simulations and by the second period in 96% of simulations. The trade-off is that 9% of honest participants are mistakenly identified as bad actors by the second period. We suggest several ways for researchers to mitigate the rate or consequences of these false positives. Researchers and policymakers can customize and use our approach to appropriately guard VBP models against undesired behavior, even if only by one participant.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10742-021-00253-9.

Exploiting genotype × management interactions to increase rainfed crop production: a case study from south-eastern Australia.

Crop yield must increase to keep pace with growing global demand. Past increases in crop production have rarely been attributable to an individual innovation but have occurred when technologies and practices combine to form improved farming systems. Inevitably this has involved synergy between genotypic and management improvements. We argue that research focused on developing synergistic systems that overcome clear production constraints will accelerate increases in yield. This offers the opportunity to better focus and multiply the impact of discipline-focused research. Here we use the rainfed grain production systems of south-eastern Australia as a case study of how transformational change in water productivity can be achieved with research focused on genotype × management synergies. In this region, rainfall is low and variable and has declined since 1990. Despite this, growers have maintained yields by implementing synergistic systems combining innovations in (i) soil water conservation, (ii) crop diversity, (iii) earlier sowing, and (iv) matching nitrogen fertilizer to water-limited demand. Further increases are emerging from synergies between genetic improvements to deliver flowering time stability, adjusted sowing times, and potential dual-purpose use. Collaboration between agronomists, physiologists, and crop breeders has led to development of commercial genotypes with stable flowering time that are in early phases of testing and adoption.

Bisphenols exert detrimental effects on neuronal signaling in mature vertebrate brains

Bisphenols are important plasticizers currently in use and are released at rates of hundreds of tons each year into the biosphere1–3. However, for any bisphenol it is completely unknown if and how it affects the intact adult brain4–6, whose powerful homeostatic mechanisms could potentially compensate any effects bisphenols might have on isolated neurons. Here we analyzed the effects of one month of exposition to BPA or BPS on an identified neuron in the vertebrate brain, using intracellular in vivo recordings in the uniquely suited Mauthner neuron in goldfish. Our findings demonstrate an alarming and uncompensated in vivo impact of both BPA and BPS—at environmentally relevant concentrations—on essential communication functions of neurons in mature vertebrate brains and call for the rapid development of alternative plasticizers. The speed and resolution of the assay we present here could thereby be instrumental to accelerate the early testing phase of next-generation plasticizers.

Metabolomic networks and pathways associated with feed efficiency and related-traits in Duroc and Landrace pigs

Improving feed efficiency (FE) is a major goal of pig breeding, reducing production costs and providing sustainability to the pig industry. Reliable predictors for FE could assist pig producers. We carried out untargeted blood metabolite profiling in uncastrated males from Danbred Duroc (n = 59) and Danbred Landrace (n = 50) pigs at the beginning and end of a FE testing phase to identify biomarkers and biological processes underlying FE and related traits. By applying linear modeling and clustering analyses coupled with WGCNA framework, we identified 102 and 73 relevant metabolites in Duroc and Landrace based on two sampling time points. Among them, choline and pyridoxamine were hub metabolites in Duroc in early testing phase, while, acetoacetate, cholesterol sulfate, xanthine, and deoxyuridine were identified in the end of testing. In Landrace, cholesterol sulfate, thiamine, L-methionine, chenodeoxycholate were identified at early testing phase, while, D-glutamate, pyridoxamine, deoxycytidine, and L-2-aminoadipate were found at the end of testing. Validation of these results in larger populations could establish FE prediction using metabolomics biomarkers. We conclude that it is possible to identify a link between blood metabolite profiles and FE. These results could lead to improved nutrient utilization, reduced production costs, and increased FE.

COVID-19 battle: Measures implemented at a tertiary eye care center in South India

The spread of severe acute respiratory syndrome-coronavirus-2 has already taken on pandemic proportions, affecting over 100 countries in a matter of weeks. A global response to prepare health systems worldwide is imperative. Specific containment measures are needed to reduce the risk of spread while simultaneously maintaining the emergency health services. The purpose of this article is to propose the simple and effective measures implemented in our institution to ensure the minimum risk of COVID spread while taking care of the emergency patients. Effectiveness of these measures is still in the early phase of testing, but in view of lack of personal protective equipment for health caregivers, these measures could be implemented with ease and will be helpful in reducing the risk of exposure in both ophthalmic and nonophthalmic institutions.

Study of antinociceptive effect of ketamine in acute and neuropathic pain models in rats.

Glutamate N-methyl-D-aspartate (NMDA) receptors are known for their importance in the perseverance of chronic neuropathic pain. Ketamine, an intravenous anesthetic agent, is a non-competitive blocker of NMDA receptors. Applied in anesthetic doses, ketamine has anti-nociceptive effects in various animal pain models. The objective of this study was to investigate the anti-nociceptive effect of ketamine in acute and neuropathic pain models in rats. To study the anti-nociceptive effect of ketamine on acute pain, 40 Wistar rats were divided into 5 groups (n = 8): control, positive control group and 3 experimental groups treated intraperitoneally (ip.) with 30 mg/kg bw, 40 mg/kg bw and 50 mg/kg bw ketamine, respectively. The anti-nociceptive effect was evaluated in hot plate, analgesy-meter and formalin tests. The model of neuropathic pain was induced by left sciatic nerve ligation. Twenty-four Wistar rats were divided into 3 groups (n = 8): sham-control group, model group and ketamine-treated group subsequently tested in hot plate and analgesy-meter tests. In the hot plate test, the rats treated with ketamine presented increased reaction latency at the 120th min and 180th min compared to the controls. In the analgesy-meter test, ketamine produced an antinociceptive effect at the 60th min compared to the controls. In the formalin test, the paw licking time across the early phase of testing was reduced in the rats treated with the 2 higher doses of ketamine. In a neuropathic pain model, ketamine increased the reaction latency at the 120th min and 180th min compared with the model group in the hot plate test. In the analgesy-meter test, in the ketamine-treated animals the paw withdrawal threshold increased at the 60th min compared with the model group. Our results suggest that ketamine produces peripheral anti-nociceptive effect in an acute pain model. Also, it relieves thermal and mechanical allodynia after 14 days of treatment in a neuropathic pain model.

Epidemiology and causes of Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease and has agrowing socioeconomic impact due to demographic changes in the industrial nations. There are several forms of PD, afraction of which (<5%) are monogenic, i. e. caused by mutations in single genes. At present, six genes have been established for the clinically classical form of parkinsonism including three autosomal dominantly (SNCA, LRRK2, VPS35) and three autosomal recessively inherited ones (Parkin, PINK1, DJ-1). In addition, there are aplethora of genes causing atypical forms of parkinsonism. In contrast, idiopathic PD is of a multifactorial nature. Genome-wide association studies have established atotal of 26genetic loci for this form of the disease; however, for most of these loci the underlying functional genetic variants have not yet been identified and the respective disease mechanisms remain unresolved. Furthermore, there are anumber of environmental and life style factors that are associated with idiopathic PD. Exposure to pesticides and possibly a history of head trauma represent genuine risk factors. Other PD-associated factors, such as smoking and intake of coffee and alcohol may not represent risk factors per se and the cause-effect relationship has not yet been elucidated for most of these factors. Apatient with apositive family history and/or an early age of disease onset should undergo counseling with respect to apossible monogenic form of the disease. Disease prediction based on genetic, environmental and life style factors is not yet possible for idiopathic PD and potential gene-specific therapies are currently in the development or early testing phase.

A framework for scaling up health interventions: lessons from large-scale improvement initiatives in Africa.

BackgroundScaling up complex health interventions to large populations is not a straightforward task. Without intentional, guided efforts to scale up, it can take many years for a new evidence-based intervention to be broadly implemented. For the past decade, researchers and implementers have developed models of scale-up that move beyond earlier paradigms that assumed ideas and practices would successfully spread through a combination of publication, policy, training, and example.Drawing from the previously reported frameworks for scaling up health interventions and our experience in the USA and abroad, we describe a framework for taking health interventions to full scale, and we use two large-scale improvement initiatives in Africa to illustrate the framework in action. We first identified other scale-up approaches for comparison and analysis of common constructs by searching for systematic reviews of scale-up in health care, reviewing those bibliographies, speaking with experts, and reviewing common research databases (PubMed, Google Scholar) for papers in English from peer-reviewed and “gray” sources that discussed models, frameworks, or theories for scale-up from 2000 to 2014. We then analyzed the results of this external review in the context of the models and frameworks developed over the past 20 years by Associates in Process Improvement (API) and the Institute for Healthcare improvement (IHI). Finally, we reflected on two national-scale improvement initiatives that IHI had undertaken in Ghana and South Africa that were testing grounds for early iterations of the framework presented in this paper.ResultsThe framework describes three core components: a sequence of activities that are required to get a program of work to full scale, the mechanisms that are required to facilitate the adoption of interventions, and the underlying factors and support systems required for successful scale-up. The four steps in the sequence include (1) Set-up, which prepares the ground for introduction and testing of the intervention that will be taken to full scale; (2) Develop the Scalable Unit, which is an early testing phase; (3) Test of Scale-up, which then tests the intervention in a variety of settings that are likely to represent different contexts that will be encountered at full scale; and (4) Go to Full Scale, which unfolds rapidly to enable a larger number of sites or divisions to adopt and/or replicate the intervention.ConclusionsOur framework echoes, amplifies, and systematizes the three dominant themes that occur to varying extents in a number of existing scale-up frameworks. We call out the crucial importance of defining a scalable unit of organization. If a scalable unit can be defined, and successful results achieved by implementing an intervention in this unit without major addition of resources, it is more likely that the intervention can be fully and rapidly scaled. When tying this framework to quality improvement (QI) methods, we describe a range of methodological options that can be applied to each of the four steps in the framework’s sequence.

Evaluating a website to teach children safety with dogs.

Paediatric dog bites are a significant public health problem worldwide. Existing prevention programmes focused on altering children's risky behaviour with pet dogs tend to be atheoretical and only moderately effective. Test efficacy of a website to train young children in relevant cognitive skills to be safe with pet dogs in their home. Birmingham, Alabama, USA. A randomised trial will be conducted with an expected sample of two groups of 34 children (total N=68) ages 4-6 years. One group will engage in the newly designed website at home for 2 weeks and the other group will engage in a control website on transportation safety for an equivalent amount of time. All participants will complete a battery of laboratory-based tests to assess safety with dogs and cognitive functioning at baseline and postintervention. Primary analyses will be conducted through linear mixed models testing change over time. Children's cognitive functioning, knowledge about safety with dogs, and behaviour with dogs in simulation and in vivo will serve as the primary outcomes. This study is exempt from registry at the US government website, http://www.clinicaltrials.gov, based on being a behavioural trial in the early phases of testing.

Responses in growth and succession of the phytoplankton community to different N/P ratios near Dongtou Island in the East China Sea

In the present study, a microcosm experiment was conducted for 12days during the spring near Dongtou Island in the East China Sea with the aim of investigating the effects of different nitrogen-phosphorus (N/P) ratios (1N:1P, 4N:1P, 16N:1P, 64N:1P, and 256N:1P) on phytoplankton community growth and succession. The results indicated that the cell abundance, chlorophyll a (chl a) concentration, specific growth rate, diversity indices, and species composition of the phytoplankton community varied significantly with the N/P ratios. A higher growth rate (evaluated based on cell abundance and chl a) of the phytoplankton community was observed during the early phase of test (days 1 to 4) with high N/P ratio treatments and with low N/P ratio treatments during the late phase of test (after day 6). The H′ was most the sensitive among the diversity indices we used in the present study, and it decreased significantly in the low N/P ratio treatments on day 4 but increased in the low N/P ratio treatments on day 8 and day 12. On the other hand, a definite community succession order from diatoms (Skeletonema costatum) to dinoflagellates (Protoperidinium bipes and Prorocentrum donghaiense) was observed in all treatments. However, the proportion and occurrence time of the dominant species varied with different N/P treatments.

Prioritizing Program Elements: A Pretesting Effort to Improve Software Quality

Improving the efficiency of a testing process is a challenging task. Prior work has shown that often, a small number of bugs account for the majority of the reported software failures; and often, most bugs are found in a small portion of the source code of a program. First, prioritizing the code elements according to their criticality and then conducting testing, will promote to reveal the important bugs at the early phase of testing. Keeping it in view, we propose an efficient test effort prioritization method that give a chance to the tester to focus more on the parts of the source code that are highly influenced towards the system failures or in which, the failures have high impact on the system. We consider five important factors such as influence towards system failures, average execution time, structural complexity, severity, and business value associated with a component and estimates the criticality of the component within a system. We have experimentally proved that our proposed test effort prioritization approach is effective in revealing important bugs at the early phase of testing as it is linked to external measure of defect severity and business value, internal measure of frequency, complexity, and coupling.

A Theory-Based Primary Health Care Intervention for Women Who Have Left Abusive Partners

Although intimate partner violence is a significant global health problem, few tested interventions have been designed to improve women's health and quality of life, particularly beyond the crisis of leaving. The Intervention for Health Enhancement After Leaving is a comprehensive, trauma informed, primary health care intervention, which builds on the grounded theory Strengthening Capacity to Limit Intrusion and other research findings. Delivered by a nurse and a domestic violence advocate working collaboratively with women through 6 components (safeguarding, managing basics, managing symptoms, cautious connecting, renewing self, and regenerating family), this promising intervention is in the early phases of testing.

Role of nitric oxide in the rat hippocampal CA1 in morphine antinociception

In the present study, the effects of intra-hippocampal CA1 injections of l-arginine, a nitric oxide (NO) precursor and N G-nitro- l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on morphine-induced antinociception in rat formalin test were investigated. To induce inflammation pain, formalin (50 μl at 2.5%) was injected into the right hind-paw of male Wistar rats prior to testing. Morphine (3–9 mg/kg) was injected intraperitoneally (i.p.) 10 min before injection of formalin. The present study shows that administration of l-arginine (0.08, 0.15, 0.3, 1.0 and 3.0 μg/rat), but not L-NAME (0.15, 0.3 and 1.0 μg/rat), 5 min before formalin injection reversed morphine-induced antinociception at the early phase of formalin test. However, both drugs blocked morphine antinociception at the late phase of the test, but none of these drugs elicited any response by themselves at the tonic phase when injected alone. Moreover, the response to l-arginine was potentiated by L-NAME pre-treatment. It should be noted that a single injection of both l-arginine and L-NAME showed nociceptive effect at the early phase of the test. The present study reveals an expression of NADPH-diaphorase in the rat brain samples administered by l-arginine. Expression of NADPH-d is decreased in the samples which were pre-injected with L-NAME. This study suggests NO participation in the rat hippocampal CA1 area in morphine-induced antinociception.