Combined use of two rapid tests for the conclusive diagnosis of Chagas disease: a systematic scoping review

Objective: The goal of this systematic scoping review is to collect and summarise scientific evidence regarding the validity of two simultaneous immunochromatographic tests for the conclusive diagnosis of Chagas disease. The research was informed by the following review questions: Will the use of two rapid tests be a valid method for the definitive diagnosis of Chagas disease when compared with conventional serological tests? In what type of population has the operation of two rapid tests been tried for the diagnosis of Chagas disease? What are the biomedical and public health advantages of the diagnostic method resulting from the combination of two rapid tests over the conventional serological method? Will it be a cost-benefit strategy for the diagnosis of Chagas with respect to conventional serological tests? Design: Systematic scoping review. Setting: A search of the published and unpublished literature in five databases was carried out, in order to identify, screen and select the studies included in this review. Results: 468 studies were identified, of which 46 were screened with a full-text reading, and finally, three articles were included in the review. All studies were in endemic countries with adult and paediatric populations (n=1133) and, together, they evaluated four different rapid tests. The rapid tests showed good sensitivity (97.4%-100%) and specificity (96.1%-100%) for the diagnosis of Chagas when used in combination and compared with the reference tests. Conclusions: The simultaneous use of at least two immunochromatographic rapid tests is a valid option for the definitive diagnosis of chronic Chagas in endemic rural areas, as long as there are studies that previously evaluate their performance on the areas of implementation. Therefore, this could be an alternative to the current diagnostic standard. However, additional studies are still needed in more countries in order to provide further evidence and to investigate the cost-benefit.S

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Ultra-High-Precision, in-vivo Pharmacokinetic Measurements Highlight the Need for and a Route Toward More Highly Personalized Medicine.

Clinical drug dosing would, ideally, be informed by high-precision, patient-specific data on drug metabolism. The direct determination of patient-specific drug pharmacokinetics ("peaks and troughs"), however, currently relies on cumbersome, laboratory-based approaches that require hours to days to return pharmacokinetic estimates based on only one or two plasma drug measurements. In response clinicians often base dosing on age, body mass, pharmacogenetic markers, or other indirect estimators of pharmacokinetics despite the relatively low accuracy of these approaches. Here, in contrast, we explore the use of indwelling electrochemical aptamer-based (E-AB) sensors as a means of measuring pharmacokinetics rapidly and with high precision using a rat animal model. Specifically, measuring the disposition kinetics of the drug tobramycin in Sprague-Dawley rats we demonstrate the seconds resolved, real-time measurement of plasma drug levels accompanied by measurement validation via HPLC-MS on ex vivo samples. The resultant data illustrate the significant pharmacokinetic variability of this drug even when dosing is adjusted using body weight or body surface area, two widely used pharmacokinetic predictors for this important class of antibiotics, highlighting the need for improved methods of determining its pharmacokinetics

A Trichomonas vaginalis 120 kDa protein with identity to hydrogenosome pyruvate:ferredoxin oxidoreductase is a surface adhesin induced by iron,”

Summary Trichomonas vaginalis , a human sexually transmitted protozoan, relies on adherence to the vaginal epithelium for colonization and maintenance of infection in the host. Thus, adherence molecules play a fundamental role in the trichomonal infection. Here, we show the identification and characterization of a 120 kDa surface glycoprotein (AP120) induced by iron, which participates in cytoadherence. AP120 is synthesized by the parasite when grown in 250 m m m m M iron medium. Antibodies to AP120 and the electroeluted AP120 inhibited parasite adherence in a concentration-dependent manner, demonstrating its participation in cytoadherence. In addition, a protein of 130 kDa was detected on the surface of HeLa cells as the putative receptor for AP120. By peptide matrixassisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), the AP120 adhesin showed homology with a hydrogenosomal enzyme, the pyruvate:ferredoxin oxidoreductase (PFO) encoded by the pfoa gene. This homology was confirmed by immunoblot and indirect immunofluorescence assays with an antibody to the carboxyterminus region of the Entamoeba histolytica PFO. Reverse transcription polymerase chain reaction (RT-PCR) assays showed that a pfoa -like gene was better transcribed in trichomonads grown in iron-rich medium. In conclusion, the homology of AP120 to PFO suggests that this novel adhesin induced by iron could be an example of moonlighting protein in T. vaginalis

A Novel Predictive Machine Learning Model Integrating Cytokines in Cervical-Vaginal Mucus Increases the Prediction Rate for Preterm Birth

Preterm birth (PB) is a leading cause of perinatal morbidity and mortality. PB prediction is performed by measuring cervical length, with a detection rate of around 70%. Although it is known that a cytokine-mediated inflammatory process is involved in the pathophysiology of PB, none screening method implemented in clinical practice includes cytokine levels as a predictor variable. Here, we quantified cytokines in cervical-vaginal mucus of pregnant women (18–23.6 weeks of gestation) with high or low risk for PB determined by cervical length, also collecting relevant obstetric information. IL-2, IL-6, IFN-γ, IL-4, and IL-10 were significantly higher in the high-risk group, while IL-1ra was lower. Two different models for PB prediction were created using the Random Forest machine-learning algorithm: a full model with 12 clinical variables and cytokine values and the adjusted model, including the most relevant variables-maternal age, IL-2, and cervical length- (detection rate 66 vs. 87%, false positive rate 12 vs. 3.33%, false negative rate 28 vs. 6.66%, and area under the curve 0.722 vs. 0.875, respectively). The adjusted model that incorporate cytokines showed a detection rate eight points higher than the gold standard calculator, which may allow us to identify the risk PB risk more accurately and implement strategies for preventive interventions

Mechanism of C3G-Rap1 activation by phosphorylation and CrkL

C3G is a guanine nucleotide exchange factor (GEF) that activates the small GTPase Rap1. C3G promotes the transition from an inactive (GDP-bound) to an active (GTPbound) state of Rap1. C3G (120 kDa) is a modular protein with three distinct segments: an N-terminal region, a flexible central SH3b domain that contains five proline-rich motifs (PRMs, P0 to P4), and a C-terminal region that consists of a REM (Ras Exchange Motif) and a GEF-catalytic Cdc25 homology domain (Cdc25HD). Resting C3G adopts an autoinhibitory conformation stabilized by an intramolecular interaction between the final segment of the SH3b domain (known as Auto-Inhibitory Region or AIR) and the Cdc25HD. Tyrosine phosphorylation of C3G and interaction with Crk adaptor proteins, whose expression is increased in multiple human cancers, participate in C3G activation. CrkL interacts through its SH3N domain with the proline-rich motifs P1 and P2 of inactive C3G in vitro, and these sites are necessary to recruit C3G to the plasma membrane, where Rap1 is located. However, direct stimulation of the GEF activity of C3G requires binding of CrkL to the P3 and P4 sites. P3 is occluded in resting C3G and is essential for activation, while P4 contributes secondarily towards complete stimulation. Tyrosine phosphorylation of C3G alone causes marginal activation. Despite this, phosphorylation reduces the concentration of CrkL required for activation and increases the maximum activity. Unexpectedly, optimal activation needs the interaction of CrkL-SH2 domain with phosphorylated C3G. Phosphorylation and Crk binding form a two-factor mechanism that ensures tight control of C3G activation. The simultaneous SH2 and SH3N interaction of CrkL with C3G, required for the activation, reveals a novel adaptor-independent function of Crk proteins relevant to understanding their role in physiological signaling and their deregulation in diseases

Validation of the Childhood Family Mealtime Questionnaire in Mexican Adolescents with Obesity and Their Caregivers

Background: Childhood obesity is a significant public health concern in Mexico, with far-reaching implications for the nation’s healthcare system and economy. In light of this challenge, our study sought to validate the Childhood Family Mealtime Questionnaire (CFMQ) in Mexican adolescents living with obesity and their primary caregivers. Methods: A sample of 56 adolescents ages 13 to 17 years and their primary caregivers from one pediatric obesity clinic participated in the study. We conducted a comprehensive assessment of the CFMQ’s consistency, reliability, and construct validity among all participants. Internal consistency was determined using Cronbach’s α, and the questionnaire’s reliability was assessed through test–retest and intraclass correlation coefficients. Construct validity was assessed through an exploratory factor analysis. Results: Our findings confirmed strong internal consistency and reliability for both adolescents and caregivers. Construct validity was established through exploratory factor analysis, refining the questionnaire while preserving its original seven dimensions. This validation of the CFMQ highlights its applicability in evaluating family mealtime experiences in this context, providing valuable insights into the dynamics that influence adolescent nutrition and health. Conclusion: The CFMQ proves to be a reliable tool for assessing family mealtime experiences in Mexican adolescents living with obesity and their caregivers who seek care at third-level public hospitals

Mesenchymal Stem Cells From Adipose Tissue Do not Improve Functional Recovery After Ischemic Stroke in Hypertensive Rats

Background and Purpose- Hypertension is the most frequent comorbidity in stroke.The purpose of this study was to evaluate whether hypertension alters the response to treatment with adipose tissue-derived mesenchymal stem cells (ADMSCs) after an ischemic stroke in rats. Methods- Ischemic stroke was induced in male normotensive or hypertensive rats. Either vehicle or 1×106 ADMSC was intravenously administered at 48 hours poststroke. Functional outcome, lesion size and volume, and markers of brain repair (GFAP [glial fibrillary acidic protein], doublecortin, CD-31, α-smooth muscle actin) were evaluated. Results- Hypertensive rats had larger lesions, higher apparent diffusion coefficients (ADC) and worse functional outcomes than normotensive rats. Hypertension increased GFAP and vascular markers (CD-31 and α-smooth muscle actin). The hypertensive rats treated with ADMSC did not show any significant improvement in functional recovery, lesion size, ADC values, or histological markers compared with those which received the vehicle. Conclusions- ADMSC did not reverse the hypertension-induced increase in lesion severity or functional impairment. Gliosis, neurogenesis, or vascular markers were not affected by ADMSC in hypertensive rats. Hypertension has a negative impact on the therapeutic effect of ADMSC after an ischemic stroke