Miracle-dz/UniFAR-FTUs huggingface dataset:
Deciphering the targets of retroviral protease inhibitors in Plasmodium berghei

Retroviral protease inhibitors (RPIs) such as lopinavir (LP) and saquinavir (SQ) are active against Plasmodium parasites. However, the exact molecular target(s) for these RPIs in the Plasmodium parasites remains poorly understood. We hypothesised that LP and SQ suppress parasite growth through inhibition of aspartyl proteases. Using reverse genetics approach, we embarked on separately generating knockout (KO) parasite lines lacking Plasmepsin 4 (PM4), PM7, PM8, or DNA damage-inducible protein 1 (Ddi1) in the rodent malaria parasite Plasmodium berghei ANKA. We then tested the suppressive profiles of the LP/Ritonavir (LP/RT) and SQ/RT as well as antimalarials; Amodiaquine (AQ) and Piperaquine (PQ) against the KO parasites in the standard 4-day suppressive test. The Ddi1 gene proved refractory to deletion suggesting that the gene is essential for the growth of the asexual blood stage parasites. Our results revealed that deletion of PM4 significantly reduces normal parasite growth rate phenotype (P = 0.003). Unlike PM4_KO parasites which were less susceptible to LP and SQ (P = 0.036, P = 0.030), the suppressive profiles for PM7_KO and PM8_KO parasites were comparable to those for the WT parasites. This finding suggests a potential role of PM4 in the LP and SQ action. On further analysis, modelling and molecular docking studies revealed that both LP and SQ displayed high binding affinities (-6.3 kcal/mol to -10.3 kcal/mol) towards the Plasmodium aspartyl proteases. We concluded that PM4 plays a vital role in assuring asexual stage parasite fitness and might be mediating LP and SQ action. The essential nature of the Ddi1 gene warrants further studies to evaluate its role in the parasite asexual blood stage growth as well as a possible target for the RPIs. Author summary The antiretroviral drugs (ARVs) such as LP or SQ that inhibit viral proteases reduce the rate of multiplication of the malaria parasites. The mode of action of these drugs against the parasites is however poorly understood. The proteases are among the enzymes that play essential roles in Plasmodium parasites. We sought to investigate the possible mode of action of these drugs by generating mutant parasites lacking specific aspartyl proteases namely PM4, PM7, PM8 or Ddi1 and then evaluate the susceptibility of the mutants to LP and SQ. We successfully generated parasites lacking either PM4, PM7 or PM8 but Ddi1 gene was refractory to deletion. From our data, we demonstrate that, unlike PM7 and PM8, the PM4 and Ddi1 are essential enzymes for asexual blood stage parasite fitness and survival and that the PM4 might be a target for the viral protease inhibitors in reducing parasite growth and multiplication. Further experiments using molecular docking tools show that LP or SQ have a high binding affinity for the Plasmodium aspartyl proteases.
Response of host–bacterial colonization in shrimp to developmental stage, environment and disease

The host‐associated microbiota is increasingly recognized to facilitate host fitness, but the understanding of the underlying ecological processes that govern the host–bacterial colonization over development and, particularly, under disease remains scarce. Here, we tracked the gut microbiota of shrimp over developmental stages and in response to disease. The stage‐specific gut microbiotas contributed parallel changes to the predicted functions, while shrimp disease decoupled this intimate association. After ruling out the age‐discriminatory taxa, we identified key features indicative of shrimp health status. Structural equation modelling revealed that variations in rearing water led to significant changes in bacterioplankton communities, which subsequently affected the shrimp gut microbiota. However, shrimp gut microbiotas are not directly mirrored by the changes in rearing bacterioplankton communities. A neutral model analysis showed that the stochastic processes that govern gut microbiota tended to become more important as healthy shrimp aged, with 37.5% stochasticity in larvae linearly increasing to 60.4% in adults. However, this defined trend was skewed when disease occurred. This departure was attributed to the uncontrolled growth of two candidate pathogens (over‐represented taxa). The co‐occurrence patterns provided novel clues on how the gut commensals interact with candidate pathogens in sustaining shrimp health. Collectively, these findings offer updated insight into the ecological processes that govern the host–bacterial colonization in shrimp and provide a pathological understanding of polymicrobial infections.
Growth patterns of colorectal cancer liver metastases and their impact on prognosis: a systematic review

Background Colorectal cancer liver metastases (CRLM) grow in distinct histological patterns that have been associated with outcome after surgical resection. We conducted a systematic review to evaluate the frequency of different CRLM growth patterns and their impact on prognosis. Methods We searched Embase and MEDLINE databases from inception to 1 December 2017 to identify studies that reported CRLM growth pattern histopathology, their frequencies, and/or data related to outcome. Results We included a total of 23 studies (2432 patients with CRLM) published between 1991 and 2017. There were variations in the terminology used to describe the growth patterns as well as in their histopathological definitions. A ‘desmoplastic’ pattern was most frequently considered, followed by ‘pushing’ and ‘replacement’ patterns. Data supported the presence of both intralesional and interlesional heterogeneity. There were no differences in growth pattern distribution stratified by chemotherapy. While heterogeneity of histopathology assessment precluded formal meta-analysis, the majority of articles found favourable outcomes for desmoplastic and unfavourable outcomes for replacement CRLM, independently of when the study was conducted. Conclusions The results suggest that CRLM growth patterns may have prognostic potential and that they may be considered for standardised routine histopathological reporting. Further understanding of the different growth patterns may provide important insights into the biological mechanisms that underlie metastatic growth in the liver.
Facilitated Event-Related Power Modulations during Transcranial Alternating Current Stimulation (tACS) Revealed by Concurrent tACS-MEG

Visual Abstract Non-invasive approaches to modulate oscillatory activity in the brain are increasingly popular in the scientific community. Transcranial alternating current stimulation (tACS) has been shown to modulate neural oscillations in a frequency-specific manner. However, due to a massive stimulation artifact at the targeted frequency, little is known about effects of tACS during stimulation. It remains unclear how the continuous application of tACS affects event-related oscillations during cognitive tasks. Depending on whether tACS influences pre- or post-stimulus oscillations, or both, the endogenous, event-related oscillatory dynamics could be pushed in various directions or not at all. A better understanding of these effects is crucial to plan, predict, and understand outcomes of solely behavioral tACS experiments. In the present study, a recently proposed procedure to suppress tACS artifacts by projecting MEG data into source-space using spatial filtering was utilized to recover event-related power modulations in the alpha-band during a mental rotation task. MEG data of 25 human subjects was continuously recorded. After 10-minute baseline measurement, participants received either 20 minutes of tACS at their individual alpha frequency or sham stimulation. Another 40 minutes of MEG data were acquired thereafter. Data were projected into source-space and carefully examined for residual artifacts. Results revealed strong facilitation of event-related power modulations in the alpha-band during tACS application. These results provide first direct evidence that tACS does not counteract top-down suppression of intrinsic oscillations, but rather enhances pre-existent power modulations within the range of the individual alpha (= stimulation) frequency.
Quantitative assessment of gait parameters in people with Parkinson’s disease in laboratory and clinical setting: Are the measures interchangeable?

This study aimed to investigate possible differences in spatio-temporal gait parameters of people with Parkinson’s Disease (pwPD) when they are tested either in laboratory using 3D Gait Analysis or in a clinical setting using wearable accelerometers. The main spatio-temporal gait parameters (speed, cadence, stride length, stance, swing and double support duration) of 31 pwPD were acquired: i) using a wearable accelerometer in a clinical setting while wearing shoes (ISS); ii) same as condition 1, but barefoot (ISB); iii) using an optoelectronic system (OES) undressed and barefoot. While no significant differences were found for cadence, stance, swing and double support duration, the experimental setting affected speed and stride length that decreased (by 17% and 12% respectively, P<0.005) when passing from the clinical (ISS) to the laboratory (OES) setting. These results suggest that gait assessment should be always performed in the same conditions to avoid errors, which may lead to inaccurate patient’s evaluations.
Skew t Mixture Latent State-Trait Analysis: A Monte Carlo Simulation Study on Statistical Performance

This simulation study assessed the statistical performance of a skew t mixture latent state-trait (LST) model for the analysis of longitudinal data. The model aims to identify interpretable latent classes with class-specific LST model parameters. A skew t-distribution within classes is allowed to account for non-normal outcomes. This flexible function covers heavy tails and may reduce the risk of identifying spurious classes, e.g., in case of outliers. Sample size, number of occasions and skewness of the trait variable were varied. Generally, parameter estimation accuracy increases with increasing numbers of observations and occasions. Larger bias compared to other parameters occurs for parameters referring to the skew t-distribution and variances of the latent trait variables. Standard error estimation accuracy shows diffuse patterns across conditions and parameters. Overall model performance is acceptable for large conditions, even though none of the models is free from bias. The application of the skew t mixture model in case of large numbers of occasions and observations may be possible, but results should be treated with caution. Moreover, the skew t approach may be useful for other mixture models.
On Being “In Recovery”: A National Study of Prevalence and Correlates of Adopting or Not Adopting a Recovery Identity Among Individuals Resolving Drug and Alcohol Problems

The concept of recovery has become an organizing paradigm in the addiction field globally. Although a convenient label to describe the broad phenomena of change when individuals resolve significant alcohol or other drug (AOD) problems, little is known regarding the prevalence and correlates of adopting such an identity. Greater knowledge would inform clinical, public health, and policy communication efforts. We conducted a cross-sectional nationally representative survey (N = 39,809) of individuals resolving a significant AOD problem (n = 1,995). Weighted analyses estimated prevalence and tested correlates of label adoption. Qualitative analyses summarized reasons for prior recovery identity adoption/nonadoption. The proportion of individuals currently identifying as being in recovery was 45.1%, never in recovery 39.5%, and no longer in recovery 15.4%. Predictors of identifying as being in recovery included formal treatment and mutual-help participation, and history of being diagnosed with AOD or other psychiatric disorders. Qualitative analyses regarding reasons for no/prior recovery identity found themes related to low AOD problem severity, viewing the problem as resolved, or having little difficulty of stopping. Despite increasing use of the recovery label and concept, many resolving AOD problems do not identify in this manner. These appear to be individuals who have not engaged with the formal or informal treatment systems. To attract, engage, and accommodate this large number of individuals who add considerably to the AOD-related global burden of disease, AOD public health communication efforts may need to consider additional concepts and terminology beyond recovery (e.g., “problem resolution”) to meet a broader range of preferences, perspectives and experiences.
Assessment and comparison of the max-ICH score and ICH score by external validation

Objective We tested the hypothesis that the maximally treated intracerebral hemorrhage (max-ICH) score is superior to the ICH score for characterizing mortality and functional outcome prognosis in patients with ICH, particularly those who receive maximal treatment. Methods Patients presenting with spontaneous ICH were enrolled in a prospective observational study that collected demographic and clinical data. Mortality and functional outcomes were measured by using the modified Rankin Scale at 3 months. The ICH score and max-ICH score incorporate measures of symptom severity, age, hematoma volume, hematoma location, and intraventricular hemorrhage, with the max-ICH score also including a term for oral anticoagulation and having 16 score categories vs 11 for the ICH score. We compared the area under the receiver operating characteristic curve (AUC) for the ICH score and max-ICH score for both mortality and poor functional outcome, defined as modified Rankin Scale scores 4–6. Results We analyzed outcomes for 372 patients, including 71 patients (19%) in whom care limitation/withdrawal of life support was instituted. Both the ICH score and max-ICH score showed good prognostic performance for 3-month mortality and poor functional outcomes in the full group as well as the subgroup with maximal treatment (i.e., no care limitations; AUC range 0.80–0.86), with no significant difference in AUC between the scores for either endpoint in either group. Conclusions External validation with direct comparison of the ICH score and max-ICH score shows that their prognostic performance is not meaningfully different. Alternatives to simple scores are likely needed to improve prognostic estimates for patient care decisions.
Men’s Response to Obulamu Campaign Messages about Male Involvement in Maternal Health: Mukono District, Uganda

ABSTRACT Men’s involvement makes a difference in maternal health. Well-informed and supportive men may encourage their wives to get more complete and regular antenatal care. In much of sub-Saharan Africa, however, men’s involvement with their wives’ health during pregnancy is minimal. This study investigated men’s response to Obulamu: How’s Your Pregnancy radio campaign messages about attending antenatal care with their wives, delivering at a health facility, being tested for HIV, maintaining maternal nutrition, and using malaria prevention. We conducted eight focus group discussions ranging from six to ten participants each: two groups of men from a rural area, two groups of men from a peri-urban area, and two groups each of expectant or recent mothers from the same rural and peri-urban areas. We also conducted six key informant interviews of midwives and other healthcare providers. Findings revealed that participants were highly exposed to the Obulamu campaign and knowledgeable about campaign messages. Most men expressed positive attitudes toward behaviors promoted by the campaign and voiced an intention to change their behaviors. Key informant interviews confirmed that since the start of the campaign an increase in male involvement with maternity visits had taken place. However, a sizeable minority of men, mostly rural residents, resisted involvement in their wives’ antenatal visits because of poverty, gender and cultural stereotypes, fear of HIV testing, and incongruity between messages and the realities of antenatal clinical practice. An interaction between individual and institutional-level factors as posited by the social ecological model was clearly evident; there was an incongruity between encouraging Obulamu messages about men’s involvement and the discouraging realities of antenatal clinical practice.
How do facilitators of group programmes for long-term conditions conceptualise self-management support?

Objectives Increasing self-management skills in people with long-term conditions is widely advocated in policies and guidelines. Group programmes are a common format; yet, how self-management support objectives are enacted in their delivery is poorly understood. Our aim is to explore the perspectives of group programme facilitators. Methods We undertook thematic analysis of transcribed data from in-depth semi-structured interviews with health professional facilitators (n = 13) from six diverse self-management support group programmes (of obesity, diabetes and chronic obstructive pulmonary disease). Results Facilitators viewed group programmes as responses to health system pressures, e.g. high patient demand. They focussed on providing in-depth education and instruction on physical health, risks and lifestyle behaviour change and emphasised self-responsibility for behaviour change whilst minimising goal setting and support amongst group participants. There were tensions between facilitators’ professional identity and group leader role. Discussion Group self-management support programmes may not be realising the broader aspirations advocated in long-term condition policy to support medical, emotional and social aspects of long-term conditions by minimising shared learning, problem solving, building of self-efficacy and goal setting. This suggests a disconnect at implementation. Increasing understandings of theoretical and practical self-management support in group programmes across both implementation and health professional (HCP) training will further the professional skills in this format.
Can Dietary and Physical Activity Modifications Reduce Breast Density in Postmenopausal Women? The DAMA Study, a Randomized Intervention Trial in Italy

Background: Few randomized trials have been carried out to evaluate the effect of lifestyle modifications on mammographic breast density (MBD). The randomized 2 × 2 factorial Diet, physical Activity and MAmmography trial aimed to evaluate whether MBD can be reduced in postmenopausal women with high baseline MBD by a 24-month dietary and/or physical activity (PA) interventions. Methods: We randomized healthy postmenopausal women, attending the Florence (Italy) mammographic screening program, ages 50 to 69 years, nonsmokers, with MBD > 50% and no recent hormone therapy, to (i) a dietary intervention focused on plant foods, with a low glycemic load, low in saturated fats and alcohol; (ii) a PA intervention combining daily moderate intensity activities and one weekly supervised session of more strenuous activity; (iii) both interventions; (iv) general recommendations. We evaluated changes in MBD based on Volpara estimates comparing baseline and follow-up digital mammograms by an intention-to-treat-analysis. Results: MBD measures were available for 226 participants. An interaction emerged between treatments and thus we run analyses by arms. A decrease in volumetric percent density emerged for women in the dietary intervention (ratio 0.91; 95% CI, 0.86–0.97; P = 0.002) and in the PA intervention arm (0.93; 95% CI, 0.87–0.98; P = 0.01) in comparison with controls. No clear effect emerged in the double intervention arm. Conclusions: This intervention trial suggests that a 24-month dietary or PA intervention may reduce MBD in postmenopausal women. Impact: A modification of dietary habits or an increase in PA in postmenopausal women may reduce MBD. Further studies are needed to confirm these findings for planning breast cancer preventive strategies.
Native‐born German and immigrant children's development of emotion knowledge: A latent growth curve analysis

Young children in immigrant families tend to face more challenges and can often call upon fewer resources than their native-born peers. This situation adversely affects their social-emotional development. In this study, the development of emotion knowledge of 576 immigrant and native-born German children, aged 3-6 years, was compared at three time points over a 12-month period by means of a latent growth curve analysis. Language abilities and behavioural self-regulation were examined as mediators of the relation between immigration background and emotion knowledge. The immigrant children showed less emotion knowledge than did their native-born peers at each point of measurement. These effects were partially mediated by their behavioural self-regulation and their language abilities. How behavioural self-regulation and language abilities affect the development of emotion knowledge and what this effect means for interventions are discussed. Statement of contribution What is already known on this subject? Emotion knowledge develops rapidly between the ages of three and six. Emotion knowledge develops similarly in different cultures. What does this study adds? This study compares the development of emotion knowledge between immigrant children and native-born children. It includes language skills as mediator on the development of emotion knowledge. It also includes behavioural self-regulation as mediator on the development of emotion knowledge.
Blood Pressure Thresholds and Mortality in Pediatric Traumatic Brain Injury

In this study, through our analysis of the NTDB, we examine early SBP thresholds and mortality after severe pediatric TBI. BACKGROUND: Hypotension after pediatric traumatic brain injury (TBI) is associated with poor outcomes, but definitions of low systolic blood pressure (SBP) vary. Age- and sex-specific, percentile-based definitions of hypotension may help to better identify children at risk for poor outcomes compared with traditional thresholds recommended in pediatric trauma care. METHODS: Using the National Trauma Data Bank between 2007 and 2014, we conducted a retrospective cohort study of children with isolated severe TBI. We classified admission SBP into 5 percentile categories according to population-based values: (1) SBP less than the fifth percentile, (2) SBP in the fifth to 24th percentile, (3) SBP in the 25th to 74th percentile, (4) SBP in the 75th to 94th percentile, and (5) SBP ≥95th percentile. These definitions were compared with the American College of Surgeons (ACS) hypotension definition. The association between SBP percentiles and in-hospital mortality was analyzed by using multivariable Poisson regression models. RESULTS: There were 10 473 children with severe TBI included in this study. There were 2388 (22.8%) patients who died while in the hospital. Compared with SBP in the 75th to 94th percentile, mortality was higher with SBP less than the fifth percentile (relative risk [RR] 3.2; 95% confidence interval [CI] 2.9–3.6), SBP in the fifth to 24th percentile (RR 2.3; 95% CI 2.0–2.7), and SBP in the 25th to 74th percentile (RR 1.4; 95% CI 1.2–1.6). An increased risk of mortality with SBP <75th percentile was present across all age subgroups. SBP targets using the ACS hypotension definition were higher than the fifth percentile hypotension definition, but were lower than the 75th percentile hypotension definition. CONCLUSIONS: Admission SBP <75th percentile was associated with a higher risk of in-hospital mortality after isolated severe TBI in children. SBP targets based on the 75th percentile were higher compared with traditional ACS targets. Percentile-based SBP targets should be considered in defining hypotension in pediatric TBI.