Miracle-dz/UniFAR-FTUs huggingface dataset:
Preclinical Pharmacokinetic and Pharmacodynamic Data To Support Cefoxitin Nebulization for the Treatment of Mycobacterium abscessus

Mycobacterium abscessus is responsible for difficult-to-treat chronic pulmonary infections in humans. Current regimens, including parenteral administrations of cefoxitin (FOX) in combination with amikacin and clarithromycin, raise compliance problems and are frequently associated with high failure and development of resistance. ABSTRACT Mycobacterium abscessus is responsible for difficult-to-treat chronic pulmonary infections in humans. Current regimens, including parenteral administrations of cefoxitin (FOX) in combination with amikacin and clarithromycin, raise compliance problems and are frequently associated with high failure and development of resistance. Aerosol delivery of FOX could be an interesting alternative. FOX was administered to healthy rats by intravenous bolus or intratracheal nebulization, and concentrations were determined in plasma and epithelial lining fluid (ELF) by liquid chromatography-tandem mass spectrometry. After intrapulmonary administration, the FOX area under the curve within ELF was 1,147 times higher than that in plasma, indicating that this route of administration offers a biopharmaceutical advantage over intravenous administration. FOX antimicrobial activity was investigated using time-kill curves combined with a pharmacokinetic/pharmacodynamic (PK/PD) type modeling approach in order to account for its in vitro instability that precludes precise determination of MIC. Time-kill data were adequately described by a model including in vitro degradation, a sensitive (S) and a resistant (R) bacteria subpopulation, logistic growth, and a maximal inhibition-type growth inhibition effect of FOX. Median inhibitory concentrations were estimated at 16.2 and 252 mg/liter for the S and R subpopulations, respectively. These findings suggest that parenteral FOX dosing regimens used in patients for the treatment of M. abscessus are not sufficient to reduce the bacterial burden and that FOX nebulization offers a potential advantage that needs to be further investigated.
Which Moral Foundations Predict Willingness to Make Lifestyle Changes to Avert Climate Change in the USA?

Jonathan Haidt’s Moral Foundations Theory identifies five moral axes that can influence human motivation to take action on vital problems like climate change. The theory focuses on five moral foundations, including compassion, fairness, purity, authority, and ingroup loyalty; these have been found to differ between liberals and conservatives as well as Democrats and Republicans. Here we show, based on the Cornell National Social Survey (USA), that valuations of compassion and fairness were strong, positive predictors of willingness to act on climate change, whereas purity had a non-significant tendency in the positive direction (p = 0.07). Ingroup loyalty and authority were not supported as important predictor variables using model selection (ΔAICc__). Compassion and fairness were more highly valued by liberals, whereas purity, authority, and in-group loyalty were more highly valued by conservatives. As in previous studies, participants who were younger, more liberal, and reported greater belief in climate change, also showed increased willingness to act on climate change. Our research supports the potential importance of moral foundations as drivers of intentions with respect to climate change action, and suggests that compassion, fairness, and to a lesser extent, purity, are potential moral pathways for personal action on climate change in the USA.
Does automated white-box test generation really help software testers?

Automated test generation techniques can efficiently produce test data that systematically cover structural aspects of a program. In the absence of a specification, a common assumption is that these tests relieve a developer of most of the work, as the act of testing is reduced to checking the results of the tests. Although this assumption has persisted for decades, there has been no conclusive evidence to date confirming it. However, the fact that the approach has only seen a limited uptake in industry suggests the contrary, and calls into question its practical usefulness. To investigate this issue, we performed a controlled experiment comparing a total of 49 subjects split between writing tests manually and writing tests with the aid of an automated unit test generation tool, EvoSuite. We found that, on one hand, tool support leads to clear improvements in commonly applied quality metrics such as code coverage (up to 300% increase). However, on the other hand, there was no measurable improvement in the number of bugs actually found by developers. Our results not only cast some doubt on how the research community evaluates test generation tools, but also point to improvements and future work necessary before automated test generation tools will be widely adopted by practitioners.
Localization of Phonological and Semantic Contributions to Reading

Reading involves the rapid extraction of sound and meaning from print through a cooperative division of labor between phonological and lexical–semantic processes. Whereas lesion studies of patients with stereotyped acquired reading deficits contributed to the notion of a dissociation between phonological and lexical–semantic reading, the neuroanatomical basis for effects of lexicality (word vs pseudoword), orthographic regularity (regular vs irregular spelling–sound correspondences), and concreteness (concrete vs abstract meaning) on reading is underspecified, particularly outside the context of strong behavioral dissociations. Support vector regression lesion–symptom mapping (LSM) of 73 left hemisphere stroke survivors (male and female human subjects) not preselected for stereotyped dissociations revealed the differential contributions of specific cortical regions to reading pseudowords (ventral precentral gyrus), regular words (planum temporale, supramarginal gyrus, ventral precentral and postcentral gyrus, and insula), and concrete words (pars orbitalis and pars triangularis). Consistent with the primary systems view of reading being parasitic on language-general circuitry, our multivariate LSM analyses revealed that phonological decoding depends on perisylvian areas subserving sound–motor integration and that semantic effects on reading depend on frontal cortex subserving control over concrete semantic representations that aid phonological access from print. As the first study to localize the differential cortical contributions to reading pseudowords, regular words, and concrete words in stroke survivors with variable reading abilities, our results provide important information on the neurobiological basis of reading and highlight the insights attainable through multivariate, process-based approaches to alexia. SIGNIFICANCE STATEMENT Whereas fMRI evidence for neuroanatomical dissociations between phonological and lexical–semantic reading is abundant, evidence from modern lesion studies establishing the differential contributions of specific brain regions to specific reading processes is lacking. Our application of multivariate lesion–symptom mapping revealed that effects of lexicality, orthographic regularity, and concreteness on reading differentially depend on areas subserving auditory–motor integration and semantic control. Phonological decoding of print relies on a dorsal perisylvian network supporting auditory and articulatory representations, with unfamiliar words relying especially on articulatory mapping. In tandem with this dorsal decoding system, anterior inferior frontal gyrus may coordinate control over concrete semantic representations that support mapping of print to sound, which is a novel potential mechanism for semantic influences on reading.
Orienting Attention to Locations in Internal Representations

Three experiments investigated whether it is possible to orient selective spatial attention to internal representations held in working memory in a similar fashion to orienting to perceptual stimuli. In the first experiment, subjects were either cued to orient to a spatial location before a stimulus array was presented (pre-cue), cued to orient to a spatial location in working memory after the array was presented (retro-cue), or given no cueing information (neutral cue). The stimulus array consisted of four differently colored crosses, one in each quadrant. At the end of a trial, a colored cross (probe) was presented centrally, and subjects responded according to whether it had occurred in the array. There were equivalent patterns of behavioral costs and benefits of cueing for both pre-cues and retro-cues. A follow-up experiment used a peripheral probe stimulus requiring a decision about whether its color matched that of the item presented at the same location in the array. Replication of the behavioral costs and benefits of pre-cues and retro-cues in this experiment ruled out changes in response criteria as the only explanation for the effects. The third experiment used event-related potentials (ERPs) to compare the neural processes involved in orienting attention to a spatial location in an external versus an internal spatial representation. In this task, subjects responded according to whether a central probe stimulus occurred at the cued location in the array. There were both similarities and differences between ERPs to spatial cues toward a perception versus an internal spatial representation. Lateralized early posterior and later frontal negativities were observed for both preand retro-cues. Retro-cues also showed additional neural processes to be involved in orienting to an internal representation, including early effects over frontal electrodes.
Influence of Visual Dependence on Inter-Segmental Coordination during Upright Stance in Cerebral Palsy

Abstract The presence of visual dependence as an influential factor on the development of functional stability in ambulatory individuals with cerebral palsy (CP) was studied in 22 adults with spastic bilateral CP, 11 of whom were considered visually dependent, and 18 healthy adults. Participants stood upright during pitch plane disturbances of the visual field and support surface. Intersegmental coordination behaviors were assessed by fitting trajectories of adjacent body segments to an ellipse. Mixed-model repeated measures ANOVAs were performed on ellipse orientation angle and area. Dissimilar stabilizing strategies adopted by the two groups with CP imply that visual dependence impacts postural control. Postural reorganization in response to visual flow in all groups indicates that we cannot ignore perceptual aspects of postural control when designing therapeutic interventions.
Oxidative Stress and Huntington’s Disease: The Good, The Bad, and The Ugly

Redox homeostasis is crucial for proper cellular functions, including receptor tyrosine kinase signaling, protein folding, and xenobiotic detoxification. Under basal conditions, there is a balance between oxidants and antioxidants. This balance facilitates the ability of oxidants, such as reactive oxygen species, to play critical regulatory functions through a direct modification of a small number of amino acids (e.g. cysteine) on signaling proteins. These signaling functions leverage tight spatial, amplitude, and temporal control of oxidant concentrations. However, when oxidants overwhelm the antioxidant capacity, they lead to a harmful condition of oxidative stress. Oxidative stress has long been held to be one of the key players in disease progression for Huntington’s disease (HD). In this review, we will critically review this evidence, drawing some intermediate conclusions, and ultimately provide a framework for thinking about the role of oxidative stress in the pathophysiology of HD.
Financial Hardship and Quality of Life among African American and White Cancer Survivors: The Role of Limiting Care Due to Cost

Background: Financial hardship is common among cancer survivors and is associated with both limiting care due to cost and with poor health-related quality of life (HRQOL). This study estimates the association between limiting care due to cost and HRQOL in a diverse population of cancer survivors and tests whether limiting care mediates the association between financial hardship and HRQOL. Methods: We used data from 988 participants (579 African American, 409 white) in the Detroit Research on Cancer Survivors (ROCS) pilot, a hospital-based cohort of breast, colorectal, lung, and prostate cancer survivors. We assessed associations between financial hardship, limiting care, and HRQOL [measured by the Functional Assessment of Cancer Therapy—General (FACT-G)] using linear regression and mediation analysis controlling for demographic, socioeconomic, and cancer-related variables. Results: FACT-G scores were 4.2 [95% confidence interval (CI), 2.0–6.4] points lower among survivors who reported financial hardship compared with those who did not in adjusted models. Limiting care due to cost was associated with a −7.8 (95% CI, −5.1 to −10.5) point difference in FACT-G scores. Limiting care due to cost explained 40.5% (95% CI, 25.5%–92.7%) of the association between financial hardship and HRQOL overall, and 50.5% (95% CI, 29.1%–188.1%) of the association for African American survivors. Conclusions: Financial hardship and limiting care due to cost are both associated with lower HRQOL among diverse cancer survivors, and this association is partially explained by limiting care due to cost. Impact: Actions to ensure patients with cancer can access appropriate care could lessen the impact of financial hardship on HRQOL.
Acute Respiratory Distress Syndrome Phenotypes

Abstract The acute respiratory distress syndrome (ARDS) phenotype was first described over 50 years ago and since that time significant progress has been made in understanding the biologic processes underlying the syndrome. Despite this improved understanding, no pharmacologic therapies aimed at the underlying biology have been proven effective in ARDS. Increasingly, ARDS has been recognized as a heterogeneous syndrome characterized by subphenotypes with distinct clinical, radiographic, and biologic differences, distinct outcomes, and potentially distinct responses to therapy. The Berlin Definition of ARDS specifies three severity classifications: mild, moderate, and severe based on the PaO2 to FiO2 ratio. Two randomized controlled trials have demonstrated a potential benefit to prone positioning and neuromuscular blockade in moderate to severe phenotypes of ARDS only. Precipitating risk factor, direct versus indirect lung injury, and timing of ARDS onset can determine other clinical phenotypes of ARDS after admission. Radiographic phenotypes of ARDS have been described based on a diffuse versus focal pattern of infiltrates on chest imaging. Finally and most promisingly, biologic subphenotypes or endotypes have increasingly been identified using plasma biomarkers, genetics, and unbiased approaches such as latent class analysis. The potential of precision medicine lies in identifying novel therapeutics aimed at ARDS biology and the subpopulation within ARDS most likely to respond. In this review, we discuss the challenges and approaches to subphenotype ARDS into clinical, radiologic, severity, and biologic phenotypes with an eye toward the future of precision medicine in critical care.
The Determinants of International Migration into the UK: A Panel Based Modelling Approach

Relatively little is known about the factors behind the gross level of international migrant flows into the UK, despite the rapid growth in the number of migrants seen in recent years. This matters because assumptions about the future evolution of migration are an important component of official judgements about the potential trend rate of economic growth. In this paper we develop the first detailed econometric model of the economic and demographic determinants of annual migrant inflows into the UK from a number of different locations. Some of the factors found to be important, such as Ofriends and family' effects from existing migrants, income differentials between the host and source location and the demographic structure of the source location population, have been shown to matter in other host economies as well. But we also show that it is important to allow both for developments in other potential host locations and for heterogeneity in the speed with which migration from different source locations responds to changes in economic circumstances. Neither of these factors have been given much attention to date in the applied literature on international migration. We find that the change in migration over the decade to 1998-2000 is primarily due to population growth in the source locations and the continuing pull effects from the rise in the migrant stock and per capita incomes in the UK relative to the source location.
Revising the structure of a new eicosanoid from human platelets to 8,9–11,12-diepoxy-13-hydroxyeicosadienoic acid

Eicosanoids are critical mediators of fever, pain, and inflammation generated by immune and tissue cells. We recently described a new bioactive eicosanoid generated by cyclooxygenase-1 (COX-1) turnover during platelet activation that can stimulate human neutrophil integrin expression. On the basis of mass spectrometry (MS/MS and MS3), stable isotope labeling, and GC-MS analysis, we previously proposed a structure of 8-hydroxy-9,11-dioxolane eicosatetraenoic acid (DXA3). Here, we achieved enzymatic synthesis and 1H NMR characterization of this compound with results in conflict with the previously proposed structural assignment. Accordingly, by using LC-MS, we screened autoxidation reactions of 11-hydroperoxy-eicosatetraenoic acid (11-HpETE) and thereby identified a candidate sharing the precise reverse-phase chromatographic and MS characteristics of the platelet product. We optimized these methods to increase yield, allowing full structural analysis by 1H NMR. The revised assignment is presented here as 8,9–11,12-diepoxy-13-hydroxyeicosadienoic acid, abbreviated to 8,9–11,12-DiEp-13-HEDE or DiEpHEDE, substituted for the previous name DXA3. We found that in platelets, the lipid likely forms via dioxolane ring opening with rearrangement to the diepoxy moieties followed by oxygen insertion at C13. We present its enzymatic biosynthetic pathway and MS/MS fragmentation pattern and, using the synthetic compound, demonstrate that it has bioactivity. For the platelet lipid, we estimate 16 isomers based on our current knowledge (and four isomers for the synthetic lipid). Determining the exact isomeric structure of the platelet lipid remains to be undertaken.
Design of all-passive higher-order CMOS N-path filters

In this paper, a methodology for designing all-passive higher-order N-path filters is described. The methodology extends known filter synthesis techniques for LC filters to N-path filters through the use of lumped quarter-wave transmission-line (t-line) equivalents that enable series-LC-like N-path structures. The quarter-wave t-line equivalents also isolate N-path filters from each other, allowing N-path sections to be cascaded to realize filters of arbitrary order. A tunable, nominally 6th-order, high-Q N-path bandpass filter based on this methodology has been implemented in 65nm CMOS. The filter has an insertion loss of 4.7-6.2dB, a tuning range of about 35% from 600MHz to 850MHz, and bandwidth that ranges from 9-15MHz, resulting in a Q that ranges from 40-90. The filter achieves an out-of-band (OOB) rejection of 30-50 dB, input-referred in-band (IB) and OOB 1dB compression point of 0dBm and +14dBm, and input-referred IB and OOB IIP3 of +7 and +17.5dBm respectively. The clock path DC power consumption at 700MHz is 75mW from a 1.2V supply.
Clinical and functional characterization of a novel RASopathy‐causing SHOC2 mutation associated with prenatal‐onset hypertrophic cardiomyopathy

SHOC2 is a scaffold protein mediating RAS‐promoted activation of mitogen‐activated protein kinase (MAPK) signaling in response to extracellular stimuli. A recurrent activating mutation in SHOC2 (p.Ser2Gly) causes Mazzanti syndrome, a RASopathy characterized by features resembling Noonan syndrome and distinctive ectodermal abnormalities. A second mutation (p.Met173Ile) supposed to cause loss‐of‐function was more recently identified in two individuals with milder phenotypes. Here, we report on the third RASopathy‐causing SHOC2 mutation (c.807_808delinsTT, p.Gln269_His270delinsHisTyr), which was found associated with prenatal‐onset hypertrophic cardiomyopathy. Structural analyses indicated a possible impact of the mutation on the relative orientation of the two SHOC2's leucine‐rich repeat domains. Functional studies provided evidence of its activating role, revealing enhanced binding of the mutant protein to MRAS and PPP1CB, and increased signaling through the MAPK cascade. Differing from SHOC2 S2G, SHOC2 Q269_H270delinsHY is not constitutively targeted to the plasma membrane. These data document that diverse mechanisms in SHOC2 functional dysregulation converge toward MAPK signaling upregulation.
When is PBL More Effective? A Meta-synthesis of Meta-analyses Comparing PBL to Conventional Classrooms

Problem-based learning (PBL) has been utilized for over 40 years in a variety of diff erent disciplines. Although extensively researched, there is heated debate about the eff ectiveness of PBL. Several meta-analyses have been conducted that provide a synthesis of the eff ects of PBL in comparison to traditional forms of instruction. This study used a qualitative meta-synthesis approach to compare and contrast the assumptions and fi ndings of the meta-analytical research on the eff ectiveness of PBL. Findings indicated that PBL was superior when it comes to long-term retention, skill development and satisfaction of students and teachers, while traditional approaches were more eff ective for short-term retention as measured by standardized board exams. Implications are discussed.