Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparison between lab variability and in silico prediction errors for the unbound fraction of drugs in human plasma

Abstract Variability of the unbound fraction in plasma (fu) between labs, methods and conditions is known to exist. Variability and uncertainty of this parameter influence predictions of the overall pharmacokinetics of drug candidates and might jeopardise safety in early clinical trials. Objectives of this study were to evaluate the variability of human in vitro fu-estimates between labs for a range of different drugs, and to develop and validate an in silico fu-prediction method and compare the results to the lab variability. A new in silico method with prediction accuracy (Q2) of 0.69 for log fu was developed. The median and maximum prediction errors were 1.9- and 92-fold, respectively. Corresponding estimates for lab variability (ratio between max and min fu for each compound) were 2.0- and 185-fold, respectively. Greater than 10-fold lab variability was found for 14 of 117 selected compounds. Comparisons demonstrate that in silico predictions were about as reliable as lab estimates when these have been generated during different conditions. Results propose that the new validated in silico prediction method is valuable not only for predictions at the drug design stage, but also for reducing uncertainties of fu-estimations and improving safety of drug candidates entering the clinical phase.
Identifying the Most Important Confounders When Assessing the Association Between Low-Grade Systemic Inflammation and Musculoskeletal Pain: A Modified Delphi Study

Abstract Objective The association between low-grade systemic inflammation and musculoskeletal pain may be influenced by multiple factors. However, little is known about the relative importance of these factors, and few studies account for them. This Delphi study aimed to reach consensus on the most important confounders which influence the association between low-grade systemic inflammation and musculoskeletal pain. Methods The panel consisted of 48 experts. In Round 1, the experts proposed what they believed were important confounders. In Round 2, the experts indicated for each confounder whether they believed it was important (yes/no). At least 50% of experts had to indicate the confounder was important to be considered in the final round. In Round 3, the experts rated the importance of each confounder on a 7-point Likert scale. Consensus was reached if ≥75% of the experts considered the factor either extremely or moderately important. Results In Round 1, 120 confounders were proposed, which were synthesized into 38 distinct factors. In Round 2, 33 confounders met the criterion to be considered important. In Round 3, consensus was reached for 14 confounders: acute illness/trauma, immune disease, medication use, endocrine, nutritional, or metabolic disease, other musculoskeletal conditions, age, handling of blood samples, sex, cancer, body composition, pregnancy, cardiovascular disease, physical activity, and pain characteristics. Conclusions These findings provide insight in the complexity of the association between low-grade systemic inflammation and musculoskeletal pain. Some factors currently listed as confounders may be re-classified as moderators or mediators as insights progress.
Treponema pallidum Macrolide Resistance and Molecular Epidemiology in Southern Africa, 2008 to 2018

Treponema pallidum macrolide resistance and clinical treatment failure have emerged rapidly within communities where macrolides have been used as convenient, oral therapeutic alternatives to benzathine penicillin G for syphilis or for other clinical indications. Macrolides are not included in the South African syndromic management guidelines for genital ulcer disease; however, in 2015, a 1-g dose of azithromycin was incorporated into treatment algorithms for genital discharge. ABSTRACT Treponema pallidum macrolide resistance and clinical treatment failure have emerged rapidly within communities where macrolides have been used as convenient, oral therapeutic alternatives to benzathine penicillin G for syphilis or for other clinical indications. Macrolides are not included in the South African syndromic management guidelines for genital ulcer disease; however, in 2015, a 1-g dose of azithromycin was incorporated into treatment algorithms for genital discharge. We determined the prevalence of 23S rRNA macrolide resistance-associated point mutations in 135 T. pallidum-positive surveillance specimens from Botswana, Zimbabwe, and South Africa between 2008 and 2018. Additionally, we investigated the association between macrolide resistance, T. pallidum strain type, and HIV coinfection. A significant increase in the prevalence of the A2058G macrolide resistance-associated point mutation was observed in specimens collected after 2015. There was a high level of molecular heterogeneity among T. pallidum strains circulating in the study communities, with strain type 14d/f being the most predominant in South Africa. Fourteen novel strain types, derived from three new tpr gene restriction fragment length polymorphism patterns and seven new tp0548 gene sequence types, were identified. There was an association between A2058G-associated macrolide resistance and T. pallidum strain types 14d/f and 14d/g but no association between T. pallidum macrolide resistance and HIV coinfection. The majority of T. pallidum strains, as well as strains containing the A2058G mutation, belonged to the SS14-like clade. This is the first study to extensively detail the molecular epidemiology and emergence of macrolide resistance in T. pallidum in southern Africa.
Effect of feed efficiency on growth performance, body composition, and fat deposition in growing Hu lambs

Abstract The present study aimed to investigate the relationship between growth performance, body composition, and fat deposition factors, and feed efficiency in growing lambs. We measured average daily feed intake (ADFI) and body weight (BW) from 653 Hu sheep that were fed a pellet diet. The residual feed intake (RFI) not significantly genetic and phenotypic correlated with the metabolic body weight (MBW) and average daily gain (ADG), but it was significantly genetic and phenotypic correlated with ADFI and the feed conversion ratio (FCR) (p < 0.01). However, the FCR was significantly associated with growth traits (p < 0.01). With the same ADG, body fat deposition was greater in animals with low feed efficiency compared with high feed efficiency. Therefore, excessive fat deposition can affect the feed efficiency of the body, and organ weight and gut-weight have a greater impact on the feed efficiency of lambs. The reticulum stomach and jejunum of lambs with a low RFI were smaller compared with that in the high RFI, indicating that lambs with a low RFI have less intake and a higher absorption rate. Small organs, such as the liver, of lambs with high FE might be associated with low energy expenditure and slow metabolism. This study provides a new perspective to study the biological processes responsible for feed efficiency variation in lambs.
Connectedness, Self-Esteem, and Prosocial Behaviors Protect Adolescent Mental Health Following Social Isolation: A Systematic Review

ABSTRACT Societal trends and COVID-19 quarantines have increased the number of adolescents experiencing social isolation, placing them at heightened risk for mental health issues. The aim of this review is to explore protective factors that might mitigate psychological harm in the presence of social isolation. A systematic literature review was conducted using Fink’s step-by-step process. Four library databases were searched, and results were reported using PRISMA. Of the 246 studies reviewed, 12 studies were retained following the quality assessment. The sample includes 14,064 participants from USA, Australia, and Europe, ranging from 10-19 years old. Social connectedness (ie., family connectedness, school connectedness, social support), self-esteem, and prosocial behaviors were the most common protective factors to social isolation. Additional factors such as self-efficacy, optimism, and ethnic identity are discussed. Implications for future research are recommended, including the need to explore spiritual, biological, and sociocultural factors influencing social connectedness and mental health in adolescents.
UL25 Capsid Binding Facilitates Mechanical Maturation of the Herpesvirus Capsid and Allows Retention of Pressurized DNA

Most viruses undergo a maturation process from a weakly assembled particle to a stable virion. Herpesvirus capsid undergoes mechanical maturation to withstand tens of atmospheres of DNA pressure. ABSTRACT The maturation process that occurs in most viruses is evolutionarily driven, as it resolves several conflicting virion assembly requirements. During herpesvirus assembly in a host cell nucleus, micron-long double-stranded herpes DNA is packaged into a nanometer-sized procapsid. This leads to strong confinement of the viral genome, resulting in tens of atmospheres of intracapsid DNA pressure. Yet, the procapsid is unstable due to weak reversible interactions between its protein subunits, which ensures free energy minimization and reduces assembly errors. In this work, we show that herpesviruses resolve these contradictory capsid requirements through a mechanical capsid maturation process facilitated by multifunctional auxiliary protein UL25. Through mechanical interrogation of herpes simplex virus 1 (HSV-1) capsid with atomic force microscopy nano-indentation, we show that UL25 binding at capsid vertices post-assembly provides the critical capsid reinforcement required for stable DNA encapsidation; the absence of UL25 binding leads to capsid rupture. Furthermore, we demonstrate that gradual capsid reinforcement is a feasible maturation mechanism facilitated by progressive UL25 capsid binding, which is likely correlated with DNA packaging progression. This work provides insight into elegantly programmed viral assembly machinery, where targeting of capsid assembly mechanics presents a new antiviral strategy that is resilient to the development of drug resistance. IMPORTANCE Most viruses undergo a maturation process from a weakly assembled particle to a stable virion. Herpesvirus capsid undergoes mechanical maturation to withstand tens of atmospheres of DNA pressure. We demonstrate that this mechanical capsid maturation is mainly facilitated through binding of auxiliary protein UL25 in herpes simplex virus 1 (HSV-1) capsid vertices. We show that UL25 binding provides the critical capsid reinforcement required for stable DNA encapsidation. Our data also suggest that gradual capsid reinforcement by progressive UL25 binding is a feasible capsid maturation mechanism, correlated with DNA packaging progression.
Providing Treatment in a Prison-Based Therapeutic Community for Those Who Have Committed Sexual Offences

This article explores some of the difficulties inherent in managing risk in those who have committed sexual or other violent offences and how this may impact on their ability to re-integrate into the community. It discusses the work undertaken at HMP Grendon, a prison-based therapeutic community (TC), to address these difficulties and help residents develop a pro-social lifestyle starting in custody and continuing on release. The article aims to describe how the TC model offers a containing and adaptive environment, and how this can provide opportunities to address offence-related behaviour, which is not always possible in other prison settings. Furthermore, it describes some of the difficulties inherent in undertaking work of this nature, in the need for an accurate understanding of the relevant areas of risk, and the tensions developing a therapeutic relationship with individuals with complex needs. Methods of assessment of risk and need are discussed, and how they are used in a collaborative manner to have the most accurate picture of what will help residents to maintain their pro-social lifestyle on release.
Adverse Childhood Experiences and Intimate Partner Violence; Findings From a Community Sample of Hispanic Young Adults

In the United States, a substantial proportion of the adult population (36% of women and 34% of men) from all socioeconomic and ethnic backgrounds report experiencing intimate partner violence (IPV) over the life course. Family risk factors have been linked to adolescent and young adult IPV involvement, yet few studies have examined the effect of multiple, co-occurring adverse childhood experiences (ACEs) in the stability and change of IPV behaviors over young adulthood—the period of highest risk for IPV. We investigated the relationship between the degree of ACE exposure and IPV victimization and perpetration at age 22 and two years later at age 24 among a sample of Hispanic young adults (N= 1,273) in Southern California. Negative binomial regression models compared the incident rate ratio (IRR) of past-year verbal and physical IPV victimization and perpetration of respondents with 1–3 ACE and with ≥4 ACE to their peers who reported no history of ACE cross-sectionally (age 22) and longitudinally (age 24). At age 22, participants with 1–3 and ≥4 ACE were overrepresented in all IPV behaviors and had higher IRRs of verbal and physical victimization and perpetration compared to their peers with no ACE. By age 24, respondents with a history of ≥4 ACE were at significantly greater risk for escalating IPV behaviors over this time period than their peers with 1–3 ACE and no ACE. These findings highlight the importance of investing in coordinated efforts to develop strategies that help young people cope with the downstream effects of early life adversity. Research should continue to identify what individual, community, and cultural assets that promote resilience and are promising foci of IPV prevention approaches among vulnerable populations.
A Necessary Pain: A Literature Review of Young People’s Experiences of Self-Harm

Abstract Background: Self-harm is defined as intentional self-injury without the wish to die. People who self-harm report feeling poorly treated by healthcare professionals, and nurses wish to know how best to respond to and care for them. Increased understanding of the meaning of self-harm can help nurses collaborate with young people who self-harm to achieve positive healthcare outcomes for them. Aim: This review aimed to synthesise qualitative research on young peoples’ experiences of living with self-harm. Method: A literature search in CINAHL, PubMed, and PsycINFO resulted in the inclusion of 10 qualitative articles that were subjected to metasynthesis. Results: The results show that young people’s experiences of living with self-harm are multifaceted and felt to be a necessary pain. They used self-harm to make life manageable, reporting it provided relief, security, and a way to control overwhelming feelings. They suffered from feeling addicted to self-harm and from shame, guilt, and self-punishment. They felt alienated, lonely, and judged by people around them, from whom they tried to hide their real feelings. Instead of words, they used their wounds and scars as a cry for help. Conclusion: Young people who harm themselves view self-harm as a necessary pain; they suffer, but rarely get the help they need. Further research is necessary to learn how to offer these people the help they need.
Prenatal androgen exposure alters KNDy neurons and their afferent network in a model of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS), the most common endocrinopathy affecting women worldwide, is characterized by elevated luteinizing hormone (LH) pulse frequency due to the impaired suppression of gonadotrophin-releasing hormone (GnRH) release by steroid hormone negative feedback. Although neurons that co-express kisspeptin, neurokinin B and dynorphin (KNDy cells) were recently defined as the GnRH/LH pulse generator, little is understood about their role in the pathogenesis of PCOS. We used a prenatal androgen-treated (PNA) mouse model of PCOS to determine whether changes in KNDy neurons or their afferent network underlie altered negative feedback. First, we identified elevated androgen receptor gene expression in KNDy cells of PNA mice, whereas progesterone receptor and dynorphin gene expression was significantly reduced, suggesting elevated androgens in PCOS disrupt progesterone negative feedback via direct actions upon KNDy cells. Second, we discovered GABAergic and glutamatergic synaptic input to KNDy neurons was reduced in PNA mice. Retrograde monosynaptic tract-tracing revealed a dramatic reduction in input originates from sexually dimorphic afferents in the preoptic area, anteroventral periventricular nucleus, anterior hypothalamic area and lateral hypothalamus. These results reveal two sites of neuronal alterations potentially responsible for defects in negative feedback in PCOS: changes in gene expression within KNDy neurons, and changes in synaptic inputs from steroid hormone-responsive hypothalamic regions. How each of these changes contribute to the neuroendocrine phenotype seen in in PCOS, and the role of specific sets of upstream KNDy afferents in the process, remains to be determined.
Comparison of seven heterophile antibody assays for laboratory diagnosis of infectious mononucleosis in pediatric patients

Heterophile antibody assays have been used to aid the diagnosis of infectious mononucleosis caused by the Epstein‐Barr virus. Seven commercially available assays currently widely utilized in clinical laboratories were compared in this study. Variable performance characteristics and assay times are observed, and these pieces of data may assist clinical laboratories in assay selection and result interpretation.
Relationships between subendocardial perfusion impairment, arterial stiffness and orthostatic hypotension in hospitalized elderly individuals

Background: Orthostatic hypotension is an independent risk factor for cardiovascular morbidity and mortality. Arterial stiffness has been shown to be a pathophysiological mechanism linking orthostatic hypotension and increased cardiovascular risk. This study aims to evaluate the relationship between arterial stiffness, orthostatic hypotension and subendocardial viability ratio (SEVR) and moreover to identify the main predictors of orthostatic hypotension, carotid-femoral pulse wave velocity (PWV-cf) and SEVR. Methods: Seventy-five patients were enrolled (mean age 82.95 ± 6.45) in Verona's AOUI Geriatric ward. They underwent blood pressure, heart rate, body weight measurements and also comorbidity, arterial stiffness (PWV-cf measured by applanation tonometry), SEVR and biochemical indexes. Results: Prevalence of orthostatic hypotension was 46.6%. Even after adjustment for age, sex, glomerular filtration rate and mean arterial pressure, SEVR values corrected for arterial oxygen and haemoglobin content were statistically lower in orthostatic hypotension patients (P = 0.05) and PWV-cf values were statistically higher in orthostatic hypotension individuals (P = 0.042). In a binary logistic regression, PWV-cf was the only significant predictor of orthostatic hypotension (odds ratio 1.123; P = 0.039; confidence interval = 1.006--1.17). In a backward logistic regression model sex, creatinine clearance and orthostatic hypotension were significant predictors of SEVR corrected for O2 content. Mean arterial pressure, creatinine clearance and orthostatic hypotension were significant predictors of PWV-cf. Conclusion: This study shows that orthostatic hypotension is related to increased arterial stiffness, confirming its higher prevalence in elderly patients. Orthostatic hypotension was also associated with reduced values of corrected SEVR, showing a relevant consequence of orthostatic hypotension on subendocardial perfusion impairment.
Development of Biomimetic Hydrogels as Cell-Laden Devices for Muscle Regeneration

The aim of this thesis was to develop a novel cross-linking strategy to prepare defined collagen-based hydrogel networks to investigate stiffness-induced cell differentiation for skeletal muscle tissue engineering. Volumetric muscle loss (VML) occurs with traumatic injury or aggressive tumour ablation and results in a diminished natural capacity for repair. Whilst autologous muscle transfer offers the gold standard treatment option, the level of success is limited by surgical expertise, availability of healthy tissue, donor site morbidity and a loss of muscle strength and function due to scar tissue formation. As a result, a clear need exists for therapeutic strategies that can enhance the innate ability of skeletal muscle to regenerate following VML. Thiol-ene photo-click collagen hybrid hydrogels were systematically developed and prepared via step-growth reaction using thiol-functionalised type-I collagen and 8-arm poly(ethylene glycol) norbornene terminated (PEG8NB). Collagen was thiol-functionalised by a ring opening reaction with 2-iminothiolane (2IT), whereby up to 80% functionalisation and 90% triple helical preservation were recorded in addition to improved solubility of the material. Type, i.e. Irgacure 2959 (I2959) or lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), and concentration of photoinitiator were varied to ensure minimal photoinitiator- induced cytotoxicity in line with the in vitro study. Gelation kinetics proved to be largely affected by the specific photoinitiator and the concentration, with LAP- containing thiol-ene mixtures leading to 8 times faster gelation times compared to I2959-containing mixtures. Photo-click hydrogels with tunable storage moduli (G’: 0.54- 6.4 kPa), elastic modulus (Ec: 1.2- 12.5 kPa), gelation time (ԏ: 73- 331 s) and swelling ratio (SR: 1500- 3000 wt.%) were prepared. Three of these hydrogels (Ec: 7, 10, 13 kPa) were taken forward for in vitro tests with a myoblast cell line due to their similarity to the elasticity of natural muscle. These three hydrogels were shown to support cell attachment, spreading, proliferation and maturation/ differentiation of myoblasts into myotubes. A subcutaneous model was used to analyse the immune response of these new materials at 1, 4 and 7 days after implantation using Mucograft® as the control. Mucograft® was shown to present a lower immune response and reduced inflammation, whereas, the immune response from the hydrogel, promoted angiogenesis, which can be more beneficial for muscle regeneration.
HCV eradication in recurrent hepatitis C after liver transplantation normalizes enhanced endothelial activation

The increased risk of cardiovascular disease (CVD) conferred by hepatitis C virus (HCV) is especially relevant after liver transplantation (LT), but its mechanism is still not well defined. This study aimed to evaluate the influence of HCV eradication in inflammatory and endothelial activation markers after LT. We evaluated inflammatory (TNF‐alfa, IL‐6, IL‐8, and MCP‐1) and endothelial activation (E‐selectin, ICAM‐1, VCAM‐1, and MMP‐9) markers before and after eradication in 45 LT recipients with HCV infection (LT+/HCV+) and 44 non‐transplanted HCV‐infected patients (LT‐/HCV+). We also considered an additional group of 40 LT recipients without HCV infection (LT+/HCV‐). LT+/HCV+ patients presented a higher endothelial activation status before eradication compared with LT+/HCV‐ patients. However, levels of E‐selectin, ICAM‐1, VCAM‐1, and MMP‐9 were comparable between LT+/HCV+ and LT‐/HCV+ patients before eradication. HCV eradication decreased ICAM‐1 (5466.55 pg/ml vs. 3354.88 pg/ml, P < 0.001) and VCAM‐1 (10456.52 pg/ml vs. 6658.85 pg/ml, P < 0.001) levels in LT+/HCV+ and LT‐/HCV+ patients. Remarkably, HCV eradication restored levels of endothelial activation markers of LT+/HCV+ patients compared with that of LT+/HCV‐ patients. HCV plays a major role in endothelial dysfunction after LT. Furthermore, HCV eradication restores endothelial activation despite the exposure to immunosuppressive therapy.