Clinical Testing Research Articles

Biomarkers of glucose-insulin homeostasis and incident type 2 diabetes and cardiovascular disease: results from the Vitamin D and Omega-3 trial

BackgroundDysglycemia and insulin resistance increase type 2 diabetes (T2D) and cardiovascular disease (CVD) risk, yet associations with specific glucose-insulin homeostatic biomarkers have been inconsistent. Vitamin D and marine omega-3 fatty acids (n-3 FA) may improve insulin resistance. We sought to examine the association between baseline levels of insulin, C-peptide, HbA1c, and a novel insulin resistance score (IRS) with incident cardiometabolic diseases, and whether randomized vitamin D or n-3 FA modify these associations.MethodsVITamin D and OmegA-3 TriaL (NCT01169259) was a randomized clinical trial testing vitamin D and n-3 FA for the prevention of CVD and cancer over a median of 5.3 years. Incident cases of T2D and CVD (including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) were matched 1:1 on age, sex, and fasting status to controls. Conditional logistic regressions adjusted for demographic, clinical, and adiposity-related factors were used to assess the adjusted odds ratio (aOR) per-standard deviation (SD) and 95%CI of baseline insulin, C-peptide, HbA1c, and IRS (Insulin×0.0295 + C-peptide×0.00372) with risk of T2D, CVD, and coronary heart disease (CHD).ResultsWe identified 218 T2D case-control pairs and 715 CVD case-control pairs including 423 with incident CHD. Each of the four biomarkers at baseline was separately associated with incident T2D, aOR (95%CI) per SD increment: insulin 1.46 (1.03, 2.06), C-peptide 2.04 (1.35, 3.09), IRS 1.72 (1.28, 2.31) and HbA1c 7.00 (3.76, 13.02), though only HbA1c remained statistically significant with mutual adjustments. For cardiovascular diseases, we only observed significant associations of HbA1c with CVD (1.19 [1.02, 1.39]), and IRS with CHD (1.25 [1.04, 1.50]), which persisted after mutual adjustment. Randomization to vitamin D and/or n-3 FA did not modify the association of these biomarkers with the endpoints.ConclusionsEach of insulin, C-peptide, IRS, and HbA1c were associated with incident T2D with the strongest association noted for HbA1c. While HbA1c was significantly associated with CVD risk, a novel IRS appears to be associated with CHD risk. Neither vitamin D nor n-3 FA modified the associations between these biomarkers and cardiometabolic outcomes.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile X syndrome

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5’ untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. These EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding post-period 1 of the study, participants who received BPN14770 in period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770 measured at the end of period 1. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of a significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Reduced penetrance BRCA1 and BRCA2 pathogenic variants in clinical germline genetic testing

Prior studies have suggested the existence of reduced penetrance pathogenic variants (RPPVs) in BRCA1 and BRCA2 (BRCA) which pose challenges for patient counseling and care. Here, we sought to establish RPPVs as a new category of variants. Candidate BRCA RPPVs provided by two large clinical diagnostic laboratories were compiled to identify those with the highest likelihood of being a RPPV, based on concordant interpretations. Sixteen concordant candidate BRCA RPPVs across both laboratories were systematically assessed. RPPVs included missense, splice site, and frameshift variants. Our study establishes RPPVs as a new class of variants imparting a moderately increased risk of breast cancer, which impacts risk-informed cancer prevention strategies, and provides a framework to standardize interpretation and reporting of BRCA RPPVs. Further work to define clinically meaningful risk thresholds and categories for reporting BRCA RPPVs is needed to personalize cancer risks in conjunction with other risk factors.

The Role of Gender in Turkish Women’s Pregnancy Experiences

Background: Apart from the biological changes women experience throughout pregnancy, their exposure to a gender discrimination stemming from cultural values adopted by the society in which they live can make it difficult for them to adapt to pregnancy and thus lead to negative pregnancy experiences. Aim: This research was conducted using a cross-sectional and relation-seeking approach to evaluate the effects of social gender inequality on pregnancy experiences. Methods: Data for this cross-sectional and relation-seeking study were gathered between 25 November 2019 and 25 January 2020 using face-to face interviews the researcher conducted with childbearing women who visited the outpatient clinic and non-stress test units of a hospital for the pregnancy follow-up. Results:: When using the Pregnancy Experiences Scale to assess childbearing women, higher scores indicated more positive emotions than negative emotions. Independent variables that affect the scores on the Pregnancy Experiences Scale include a willingness to be pregnant, the baby's sex, the woman’s income status, gestational week and the Perception of Gender Scale (p<0.005). A positive but weakly significant relationship was found among the total score on the Perception of Gender Scale, the total score on the Pregnancy Experiences Scale and the average scores of positive emotions intensity and frequency in all sub-dimensions (p<0.005). Conclusion: Based on the data, we conclude that women’s pregnancy experiences are generally positive, and that social gender inequality is a significant determinant affecting pregnancy experiences.

Premature Thelarche: An Updated Review.

Premature thelarche is the most common pubertal disorder in girls. The condition should be differentiated from central precocious puberty which may result in early epiphyseal fusion and reduced adult height, necessitating treatment. The purpose of this article is to familiarize physicians with the clinical manifestations of premature thelarche and laboratory tests that may help distinguish premature thelarche from central precocious puberty. A search was conducted in September 2022 in PubMed Clinical Queries using the key term "Premature thelarche". The search strategy included all clinical trials, observational studies, and reviews published within the past 10 years. Only papers published in the English literature were included in this review. The information retrieved from the above search was used to compile the present article. Premature thelarche denotes isolated breast development before the age of 8 years in girls who do not manifest other signs of pubertal development. The condition is especially prevalent during the first two years of life. The majority of cases of premature thelarche are idiopathic. The condition may result from an unsuppressed hypothalamic-pituitary-gonadal axis in the early years of life, an "overactivation" of the hypothalamic-pituitary axis in early childhood secondary to altered sensitivity to steroids of the hypothalamic receptors controlling sexual maturation, increased circulating free estradiol, increased sensitivity of breast tissue to estrogens, and exposure to exogenous estrogens. The cardinal feature of premature thelarche is breast development which occurs without additional signs of pubertal development in girls under 8 years of age. The enlargement may involve only one breast, both breasts asymmetrically, or both breasts symmetrically. The breast size may fluctuate cyclically. The enlarged breast tissue may be transiently tender. There should be no significant changes in the nipples or areolae and no pubic or axillary hair. The vulva, labia majora, labia minora, and vagina remain prepubertal. Affected girls have a childlike body habitus and do not have mature contours. They are of average height and weight. Growth and osseous maturation, the onset of puberty and menarche, and the pattern of adolescent sexual development remain normal. Most cases of premature thelarche can be diagnosed on clinical grounds. Laboratory tests are seldom indicated. No single test can reliably differentiate premature thelarche from precocious puberty. Premature thelarche is benign, and no therapy is necessary apart from parental reassurance. As enlargement of breasts may be the first sign of central precocious puberty, a prolonged follow- up period every 3 to 6 months with close monitoring of other pubertal events and linear growth is indicated in all instances.

Brief Overview on Pathology of Blood and Urine

Clinical pathology is recognized as an essential component of the preclinical safety evaluation of test articles (new chemical entities, exploratory novel medicines, and xenobiotics), particularly in short- and medium-term toxicity studies. Traditionally, this evaluation includes clinical chemistry, coagulation, hematology, and urinalysis assessments. The findings of these assessments include details on the general state of health of the animals as well as target organs and general metabolic, adaptive, or harmful processes linked to test material exposure. Consequently, in the preclinical safety assessment of a test article, clinical pathology evaluations aid in the establishment of toxicological dose-response correlations. These findings hold significance and relevance for dose selection in long-term research, as well as for risk assessment and management when applied to humans. Guidance on the fundamentals of clinical pathology testing and interpretation in the species utilized in toxicological investigations is the aim of this chapter. In order to increase testing capacity and enhance its ability to identify more sensitive, early signals of drug-induced target organ toxicity or pathophysiology, the application of clinical pathology testing in preclinical safety assessment as well as the areas of development for novel biomarker implementation within the laboratory are discussed. Lastly, the significance of interpreting clinical pathology and combining the results with data from other studies is emphasized when assessing overall safety or risk assessment

Plasmon-Enhanced Photoelectrochemistry of Photosystem II on a Hierarchical Tin Oxide Electrode for Ultrasensitive Detection of 17β-Estradiol.

Despite its excellent efficiency in natural photosynthesis, the utilization of photosystem II (PSII)-based artificial photoelectrochemical (PEC) systems for analytical purposes is hindered due to the low enzyme loading density and ineffective electron transfer (ET) processes. Here, we present a straightforward and effective approach to prepare a PSII-based biohybrid photoanode with remarkable photoresponse, enabled by the use of a hierarchically structured inverse-opal tin oxide (IO-SnO2) electrode combined with gold nanoparticles (Au NPs). The porous, carbon-containing IO-SnO2 structure allows for a high density and photoactivity loading of PSII complexes, while also providing strong electrical coupling between the protein film and the electrode. A new electron transfer pathway mediated by Au NPs was identified at the protein-electrode interface, which efficiently shuttles the photogenerated electrons from the enzyme to the IO-SnO2 electrode. Furthermore, the PEC response of the electrode was significantly enhanced by the surface plasmon resonance (SPR) effect of Au NPs. Upon light irradiation, this PSII-based photoanode exhibited an impressively high and stable photocurrent output, which was utilized to fabricate an aptasensor for 17β-Estradiol (E2) detection. Under optimal conditions, a detection limit of 0.33 pM was obtained, along with a broad detection range from 15 pM to 30 nM. The applicability of the aptasensor was assessed by measuring E2 in water and urine samples, demonstrating its feasibility in environmental monitoring and clinical tests.

A novel approach to detecting microduplication in split hand/foot malformation type 3 at the single-cell level: SHFM as a case study

BackgroundSplit hand/foot malformation (SHFM) is a congenital limb deficiency characterized by missing or shortened central digits. Several gene loci have been associated with SHFM. Identifying microduplications at the single-cell level is challenging in clinical practice, and traditional detection methods may lead to misdiagnoses in embryos and pregnant women.ResultsIn this research, we utilized a low cell count and whole-genome amplification products to employ single nucleotide polymorphism arrays, next-generation sequencing, and third-generation sequencing methods to detect copy number variants of microduplications in a SHFM3 case with limited DNA. Additionally, Karyomapping and combined linkage analysis were conducted to validate the results.ConclusionsThis study establishes a new strategy for identifying microduplications or microdeletions at the single-cell level in clinical preimplantation genetic testing, enhancing the efficiency and accuracy of diagnosing microduplication or microdeletion diseases during IVF-PGT and prenatal diagnosis.

ADVANCEMENTS IN VESTIBULAR PHYSIOTHERAPY: A COMPREHENSIVE REVIEW

Purpose. Vestibular disorders pose significant challenges to individuals' daily functioning and quality of life, necessitating effective management strategies. This comprehensive review explores modern advancements in vestibular physiotherapy, encompassing assessment techniques, intervention modalities, technological innovations, and interdisciplinary collaboration. Material/Methods. Accurate assessment and diagnosis are essential for tailoring treatment plans to individual needs. Traditional clinical tests, such as the Dix-Hallpike maneuver and head impulse test (HIT), remain foundational while emerging technologies like video head impulse testing (vHIT) offer objective measures of vestibular function. Treatment of benign paroxysmal positional vertigo (BPPV) often involves canalith repositioning maneuvers (CRM), with recent modifications and augmented reality applications enhancing efficacy and patient comfort. Results. Vestibular rehabilitation therapy (VRT) plays a pivotal role in promoting central nervous system compensation for vestibular deficits. Incorporating exercises targeting balance, gaze stabilization, habituation, and sensory integration, VRT facilitates symptom reduction and functional improvement. Technological innovations, including virtual reality (VR) systems and smartphone applications, augment traditional VRT approaches, enhancing engagement and accessibility. Moreover, interdisciplinary collaboration among healthcare professionals ensures comprehensive management of vestibular disorders. Physiotherapists, otolaryngologists, neurologists, audiologists, and psychologists collaborate to deliver personalized care and empower patients through education and counseling. Conclusions. Modern vestibular physiotherapy offers a multifaceted approach to address the complex needs of individuals with vestibular disorders. By leveraging evidence-based practices, integrating technological solutions, and fostering interdisciplinary partnerships, healthcare providers can optimize treatment outcomes and enhance patients' overall well-being.

Asymptomatic bacteriuria screening for developing countries using a modified water quality test kit.

Between 2% and 15% of pregnant women unknowingly experience asymptomatic bacteriuria (ASB), defined as ≥105 CFU per milliliter of urine in the absence of symptoms. ASB increases the risk of adverse pregnancy outcomes including pyelonephritis, preterm labor, and low-birth weight infants. While pregnant women in the United States are routinely screened for ASB, those in developing countries with limited resources and funding lack an accurate mechanism for ASB screening. Aquagenx water quality test kits detect Escherichia coli, the most common causative agent of ASB, and total coliform bacteria in drinking water via colorimetric and fluorescent indicators. We found that the Aquagenx system is compatible with human urine and then proceeded to develop an ASB screening protocol using disposable inoculating loops. Our protocol diagnosed artificial ASB- samples (104 CFU/mL E. coli) with a false positive (FP) rate of 33% (n = 18) and ASB+ (105 CFU/mL E. coli) with a false negative (FN) rate of 5.6% (n = 18). Clinical sample testing with our protocol revealed a FP rate of 0% in ASB- samples (n = 28) and a FN rate of 0% in ASB+ samples caused by coliforms (n = 13). Aquagenx did not detect ASB in nine clinical samples with non-coliform etiological agents due to the limitations of the technology. However, with very high accuracy for detection of E. coli and other causative agents that collectively account for 90.1% of ASB cases, these kits could be used as a diagnostic ASB screening tool in developing countries in which there is currently no alternative to urine culture.IMPORTANCEAsymptomatic bacteriuria (ASB) affects 2%-15% of pregnant women and can result in adverse maternal and fetal outcomes if left undetected and untreated. In the United States and other developed nations, pregnant women are regularly screened for ASB via urine culture. However, in low-resource countries where bacterial culture is not available, dipstick testing is used. Although accurate in cases of symptomatic bacteriuria, dipstick detection is ineffective for detecting ASB. Here, we made use of an existing water quality field test for ASB urine screening, which would be readily deployable in low-resource settings. We optimized a dilution protocol for sampling patient urine within the detection limits of the Aquagenx kit technology. Overall, we were able to detect ASB samples with Gram-negative pathogens that collectively account for 90% of all ASB cases. Utilization of this repurposed technology for proactive medical screening may help prevent adverse pregnancy and birth outcomes due to ASB.

The association between dietary quality index- international and metabolic risk factors in RaNCD cohort study

BackgroundNon-communicable diseases (NCDs) are the leading cause of death around the world. The Dietary Quality Index-International (DQI-I) is one of the indicators that shows changes in diet and its association with NCDs. The aim of this study is to measure the association between the DQI-I and major metabolic risk factors.MethodsThis study is a cross-sectional study based on data collected in the first phase of the prospective cohort study on Ravansar non-communicable diseases (RaNCD). To perform clinical and biochemical tests such as lipid profile, blood glucose and liver enzymes, blood samples were collected using standard vacutainer blood collection techniques. Information from the food frequency questionnaire containing 118 food items was used to score each person’s DQI-I. Binary logistic regression was used to determine the association between the DQI-I tertile and the metabolic risk factors. Linear regression was also used for the association between subgroups of DQI-I score and the metabolic risk factors.ResultsThe total number of subjects in this study was 7,115, with a mean age of 47.14 ± 8.29 years. Dietary quality was generally poor, with 37.03% in the lowest tertile. Men had better dietary quality than women. Anthropometric measures, blood pressure, triglycerides and blood glucose were lower in the lowest tertile of dietary quality. A one-unit increase in the total DQI-I resulted in a 0.19 decrease in total cholesterol. Higher dietary quality was associated with a 22% increased risk of high triglycerides, a 19% increased risk of low high-density density lipoprotein, a 5% decreased risk of elevated low-density lipoprotein, a 42% increased risk of high blood pressure, and a 99% increased risk of high fasting blood glucose. Higher dietary quality was also associated with a 33% increased risk of overweight/obesity.ConclusionThe study found that participants had poor dietary quality, with some favorable metabolic outcomes in the lowest tertile, but concerning associations in the highest tertile, including increased risk for high triglycerides, blood pressure, and obesity. The complex associations suggest that balanced, multifaceted interventions are needed.

Targeting ferroptosis: a novel therapeutic strategy for the treatment of retinal diseases

Ferroptosis plays a vital role in the progression of various retinal diseases. The analysis of the mechanism of retinal cell ferroptosis has brought new targeted strategies for treating retinal vascular diseases, retinal degeneration and retinal nerve diseases, and is also a major scientific issue in the field of ferroptosis. In this review, we summarized results from currently available in vivo and in vitro studies of multiple eye disease models, clarified the pathological role and molecular mechanism of ferroptosis in retinal diseases, summed up the existing pharmacological agents targeting ferroptosis in retinal diseases as well as highlighting where future research efforts should be directed for the application of ferroptosis targeting agents. This review indicates that ferroptosis of retinal cells is involved in the progression of age-related/inherited macular degeneration, blue light-induced retinal degeneration, glaucoma, diabetic retinopathy, and retinal damage caused by retinal ischemia-reperfusion via multiple molecular mechanisms. Nearly 20 agents or extracts, including iron chelators and transporters, antioxidants, pharmacodynamic elements from traditional Chinese medicine, ferroptosis-related protein inhibitors, and neuroprotective agents, have a remissioning effect on retinal disease in animal models via ferroptosis inhibition. However, just a limited number of agents have received approval or are undergoing clinical trials for conditions such as iron overload-related diseases. The application of most ferroptosis-targeting agents in retinal diseases is still in the preclinical stage, and there are no clinical trials yet. Future research should focus on the development of more potent ferroptosis inhibitors, improved drug properties, and ideally clinical testing related to retinal diseases.

Smartphone Apps for Pulmonary Hypertension: Systematic Search and Content Evaluation.

Pulmonary hypertension (PH) is a chronic and complex condition, requiring consistent management and education. The widespread use of smartphones has opened possibilities for mobile health apps to support both patients and health care professionals in monitoring and managing PH more effectively. This study aimed to identify and assess the quality of free smartphone apps for PH targeted at either patients or health care professionals. A systematic search was conducted on freely available apps for patients with PH and health care professionals, accessed from a Spanish IP address, on Android (Google Play) and iOS (App Store) platforms. Searches were performed in October 2022 and 2023. Apps were independently analyzed by two reviewers, focusing on general characteristics. Quality assessment was based on the Mobile Application Rating Scale (MARS) framework, and Mann-Whitney U tests compared mean MARS scores against specific variables. In the overall study, 21 apps were identified. In the 2022 search, 19 apps were listed (9 iOS, 7 Android, 3 available on both platforms). In the subsequent 2023 search, 16 apps were identified (6 Android, 7 iOS, 3 available on both platforms). Of those identified in 2022, 14 remained available in 2023, with only 7 updated since 2022. In addition, 12 apps targeted patients or the general population, while 9 targeted health care professionals; none involved patients in the development or design. Conversely, 13 apps involving health care professionals were identified. There were 10 apps that received pharmaceutical industry funding. The primary goal for 81% (17/21) of the apps was to disseminate general information about PH. The overall mean MARS quality was acceptable in 2022 and 2023, with mean ratings of 3.1 (SD 0.6) and 3.3 (SD 0.5), respectively. The functionality category achieved the highest scores in both years, indicating ease of use and intuitive navigation. In contrast, the subjective quality domain consistently received the lowest ratings in the MARS assessment across both years. None of the apps underwent clinical testing themselves; however, 2 incorporated tools or algorithms derived from trials. The overall quality of iOS apps statistically outperformed that of Android apps in both years (P<.05). Furthermore, the involvement of health care professionals in app development was associated with enhanced quality, a trend observed in both years (P=.003 for both years). This review of mobile health apps for PH reveals their emergent development stage, with generally acceptable quality but lacking refinement. It highlights the critical role of health care professionals in app development, as they contribute significantly to quality and reliability. Despite this, a notable stagnation in app quality and functionality improvement over 2 years points to a need for continuous innovation and clinical validation for effective clinical integration. This research advocates for future app developers to actively engage with health care professionals, integrate patient insights, and mandate rigorous clinical validation for PH management.

Nanoplasmonic microarray–based solid-phase amplification for highly sensitive and multiplexed molecular diagnostics: application for detecting SARS-CoV-2

A novel approach is introduced using nanoplasmonic microarray–based solid-phase recombinase polymerase amplification (RPA) that offers high sensitivity and multiplexing capabilities for gene detection. Nanoplasmonic microarrays were developed through one-step immobilization of streptavidin/biotin primers and fine-tuning the amplicon size to achieve high plasmon-enhanced fluorescence (PEF) on the nanoplasmonic substrate, thereby improving sensitivity. The specificity and sensitivity of solid-phase RPA on nanoplasmonic microarrays was evaluated in detecting E, N, and RdRP genes of SARS-CoV-2. High specificity was achieved by minimizing primer-dimer formation and employing a stringent washing process and high sensitivity obtained with a limit of detection of four copies per reaction within 30 min. In clinical testing with nasopharyngeal swab samples (n = 30), the nanoplasmonic microarrays demonstrated a 100% consistency with the PCR results for detecting SARS-CoV-2, including differentiation of Omicron mutations BA.1 and BA.2. This approach overcomes the sensitivity issue of solid-phase amplification, as well as offers rapidity, high multiplexing capabilities, and simplified equipment by using isothermal reaction, making it a valuable tool for on-site molecular diagnostics.Graphical abstract

Efficacy of Nusinersen Treatment in Type 1, 2, and 3 Spinal Muscular Atrophy: Real-World Data from a Single-Center Study

Background: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease characterized by progressive muscle weakness and atrophy due to the absence of the survival motor neuron 1 (SMN1) gene. SMA is classified into types 0 through 4 based on the age of symptom onset and the severity of motor function decline. Recent advances in SMA treatment, including nusinersen, onasemnogene abeparvovec, and risdiplam, have significantly improved the prognosis of SMA patients. This study evaluated the safety and efficacy of nusinersen in pediatric patients with SMA types 1, 2, and 3 in a real-world clinical setting. Methods: This prospective observational single-center study assessed the treatment effects of nusinersen in 23 pediatric patients with genetically confirmed SMA over a 22-month observation period. All the participants received intrathecal loading doses of 12 mg of nusinersen on days 1, 14, 28, and 63, followed by maintenance doses every four months. Functional assessments were conducted using the CHOP-INTEND scale. Data were collected during routine patient visits, including clinical laboratory tests and vital sign parameters, and adverse events were recorded. The inclusion criteria were defined by the national reimbursement program for nusinersen treatment in Poland. Results: Initially, 37 patients ranging from 1 month old to 18 years old were included, but 23 were ultimately observed due to changes in treatment regimens or assessment scales. The patients showed significantly improved CHOP-INTEND scores over the 22-month period. At 6 months, the average increase was 4.2 points, continuing to 17.8 points at 22 months. By the end of the study, 100% of patients showed either stabilization or improvement, with significant clinical improvements observed in several patients. Nusinersen was generally well-tolerated, with post-lumbar puncture headache and lower back pain being the most common adverse events. Conclusions: Nusinersen treatment significantly enhances motor function in pediatric patients with SMA types 1, 2, and 3. This study demonstrates the importance of early and sustained treatment, with most patients showing the continuous improvement or stabilization of motor function. These findings support the use of nusinersen as an effective therapy for SMA; however, further research is needed to understand the long-term outcomes and optimize treatment strategies.

Development and piloting of nurse-led mHealth care for heart failure patients: A feasibility study

Development and piloting of nurse-led mHealth care for heart failure patients: A feasibility study Abstract: Background: Chronic heart failure (cHI) is the most common reason for hospitalization. Telemonitoring (TM) and Heart Failure Nurses (HFN) can detect decompensations and prevent hospitalizations. Aim: The aim was to develop and examine the feasibility of a digitally supported care-guided care model for cHI patients and to evaluate it in terms of adherence, technology usability, satisfaction, self-care and health literacy, disease knowledge, quality of life and health status. Methods: The study was conducted in a user-centered manner using mixed. The 6-month pilot was carried out in the patients' domestics using qualitative (e.g. focus groups) and quantitative methods (validated questionnaires). Results: A total of n = 30 cHI patients (age: M 66, SD 14 years; ♀ n = 10 [31%], ♂ n = 22 [69%]) completed the clinical testing. The intervention consisted of: Training, the TM application, nursing/medical advice and support and a digital library. Adherence to TM was over 80% (relative adherence: M 87, SD 16%; absolute adherence: M 82, SD 19%). Health literacy, disease knowledge and quality of life increased. The state of health improved and those affected felt more confident in dealing with the disease. No changes were recorded for self-care skills. Conclusions: Hybrid care is very well received and demonstrates the potential to promote self-care for those affected.

Evaluation of variation in preclinical electroencephalographic (EEG) spectral power across multiple laboratories and experiments: An EQIPD study

The European Quality In Preclinical Data (EQIPD) consortium was born from the fact that publications report challenges with the robustness, rigor, and/or validity of research data, which may impact decisions about whether to proceed with further preclinical testing or to advance to clinical testing, as well as draw conclusions on the predictability of preclinical models. To address this, a consortium including multiple research laboratories from academia and industry participated in a series of electroencephalography (EEG) experiments in mice aimed to detect sources of variance and to gauge how protocol harmonisation and data analytics impact such variance. Ultimately, the goal of this first ever between-laboratory comparison of EEG recordings and analyses was to validate the principles that supposedly increase data quality, robustness, and comparability. Experiments consisted of a Localisation phase, which aimed to identify the factors that influence between-laboratory variability, a Harmonisation phase to evaluate whether harmonisation of standardized protocols and centralised processing and data analysis reduced variance, and a Ring-Testing phase to verify the ability of the harmonised protocol to generate consistent findings. Indeed, between-laboratory variability reduced from Localisation to Harmonisation and this reduction remained during the Ring-Testing phase. Results obtained in this multicentre preclinical qEEG study also confirmed the complex nature of EEG experiments starting from the surgery and data collection through data pre-processing to data analysis that ultimately influenced the results and contributed to variance in findings across laboratories. Overall, harmonisation of protocols and centralized data analysis were crucial in reducing laboratory-to-laboratory variability. To this end, it is recommended that standardized guidelines be updated and followed for collection and analysis of preclinical EEG data.

When molecular biology transforms clinical oncology: the EGFR journey in colorectal cancer.

The discovery of growth factors and their involvement in cancer represents the foundation of precision oncology. The preclinical and clinical development of agents targeting epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) were accompanied by big hype and hopes, though the clinical testing of such agents clashed with intrinsic and acquired resistance, greatly limiting their therapeutic value. However, a better understanding of the biology of the EGFR signaling pathway in CRC, coupled with the development of liquid biopsy methodologies to study cancer evolution in real time, fostered the clinical refinement of anti-EGFR treatment in CRC. Such a workflow, based on the co-evolution of biology knowledge and clinical development, allowed to couple the discovery of relevant therapy resistance mechanisms to the development of strategies to bypass this resistance. A broader application of this paradigm could prove successful and create an effective shortcut between the bench and the bedside for treatment strategies other than targeted therapy.

SLC4A3 anion exchanger mutations associated to sudden death : short or long QT syndrome?

Abstract Introduction SLC4A3 gene codes for an (Cl-/HCO3-) exchanger present on the surface of cardiomyocytes (AE3 channel) is involved in maintaining the physiological acid-base gradient of the cardiomyocyte at rest. Loss of function of the SLC4A3 gene leading to an increase in intracellular pH has. been reported to be responsible for short QT syndrome (SQT). Methods The aim of our study was to characterize the genotype-phenotype relationships of SLC4A3 mutations identified in the French databases (Paris, Nantes and Lyon) in patients with sudden death. Through systematic exome sequencing we identified 3 new SLC4A3 variants in 3 families with a history of sudden death in two universitary hospitals. Results Family 1. The c.3209G&amp;gt;C variant (p.Gly1070Ala) in the SLC4A3 gene was identified in a 7-yo boy with VF at sleep but admitted in encephalic death. EKG showed short QT (QTc 280ms). Clinical examination, blood tests, TTE and autopsy were normal. There was no family history of sudden death. His mother had EKG evidence of SQT and was carrier the SLC4A3 mutation. She was implanted with an ICD. His two older brothers and the rest of the family had no mutation or pathological ECG and were asymptomatic. Family 2. The c.1027C&amp;gt;T (p.Arg343Cys) mutation in the SLC4A3 gene was identified in a 29-year-old man who presented with sudden death at sleep (VF). Clinical examination, blood tests, TTE and autopsy were normal. A maternal uncle died suddenly while sleeping. His two brothers (30 and 27 yo) are both carriers of the SLC4A3 mutation and exhibit SQT (QTc 320 and 330 ms respectively). TEE, Holter monitoring and stress test were normal in both. Both brothers were treated with hydroquinidine. Over a 2-year follow-up they had no symptom nor AF. Family 3. The c.1022C&amp;gt;G (p.Thr341Arg) mutation was identified in the SLC4A3 gene in a 54-yoman who presented with VF during shower but admitted in encephalic death. There was no family history of sudden death. Clinical examination, blood tests and echocardiography as well as coronary angiogram were normal. The initial ECG showed a prolonged QT interval (QTc 520 ms). QTc decreased to 480 ms in the 48 following hours. His parents and his sister as well as his 18 yo daughter have normal QTc values. We are awaiting the genetic results. Conclusion Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 has been recently reported to cause short QT syndrome but it seems that in rare cases it may also be responsible for LQTS. Further patients are needed to confirm these data. In order to understand the underlying electrophysiological mechanisms, we plan to characterize the cellular impact of these new mutations through IPS.

E-selectin and asymmetric dimethylarginine plasma levels in adult cyanotic congenital heart disease patients: relation to biochemical parameters, vascular function, and clinical status.

Abstract Background and Aim Patients with cyanosis secondary to congenital heart disease (CHD) are characterized by erythrocytosis and increased blood viscosity, which contributes to endothelial dysfunction, increased arterial stiffness, and impaired vascular function, which may affect the final clinical presentation. Asymmetric dimethylarginine (ADMA) and e-selectin (e-sel) are valuable biomarkers for prognosis of endocardial dysfunction and vascular damage. Their concentration levels in blood serum have the potential to be a rapid and easily accessible tool that reflects the severity of the disease. We aimed to assess e-sel and ADMA levels, their relationship with clinical status, as well as endothelial and vascular function. Methods A cross-sectional study including 36 adult CHD cyanotic patients [(17 males)(42.3 +/- 16.3 years)] with arterial blood oxygen saturation less than 92% and 20 healthy controls [(10 males)( 38.2 +/- 8.5 years)] was performed. All patients underwent clinical examination, blood testing, and cardiopulmonary tests. Endothelial function was assessed using intima-media thickness and flow-mediated dilatation (FMD). Vascular function using applanation tonometry methods was completed while considering aortic systolic pressure, aortic pulse pressure (AoPP), augmentation pressure (AP), augmentation index (AI), pulse pressure amplification (PPampl), and pulse wave velocity (PWV). Results Concentrations of e-sel and ADMA were significantly higher in patients with CHD than in controls (56.3 ± 13.6 ng/mL vs. 15.5 +/- 8.6 ng/mL, p&amp;lt;0.001) and (1.48 ± 0.48 ng/mL vs. 0.46 ± 0.1 ng/mL, p&amp;lt;0.001) respectively. E-sel levels correlated with gender, blood oxygen saturation, red blood cell, hemoglobin concentration, hematocrit, augmentation pressure, forced expiratory one second volume, forced vital capacity, and oxygen uptake. ADMA levels were found to correlate with age only. Conclusions E-sel level, unlike ADMA concentration, reflects the degree of severity of erythrocytosis and hypoxia and, thus, the physical status of patients with cyanotic CHD. E-selectin predicts increased augmentation pressure.Figure 1.A) ROC analysis for e-selectin