Lung cancer (LC) stands as the foremost cause of cancer-related fatality rates worldwide. Early diagnosis significantly enhances patient survival rate. Nowadays, low-dose computed tomography (LDCT) is widely employed on the chest as a tool for large-scale lung cancer screening. Nonetheless, a large amount of chest radiographs creates an onerous burden for radiologists. Some computer-aided diagnostic (CAD) tools can provide insight to the use of medical images for diagnosis and can augment diagnostic speed. However, due to the variation in the parameter settings across different patients, substantial discrepancies in image voxels persist. We found that different voxel sizes can create a compromise between model generalization and diagnostic efficacy. This study investigates the performance disparities of diagnostic models trained on original images and LDCT images reconstructed to different voxel sizes while making isotropic. We examined the ability of our method to differentiate between benign and malignant nodules. Using 11 features, a support vector machine (SVM) was trained on LDCT images using an isotropic voxel with a side length of 1.5 mm for 225 patients in-house. The result yields a favorable model performance with an accuracy of 0.9596 and an area under the receiver operating characteristic curve (ROC/AUC) of 0.9855. In addition, to furnish CAD tools for clinical application, future research including LDCT images from multi-centers is encouraged.

Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1–5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.

Home environments of infants exposed to poverty exhibit fewer affordances for child development. This study aimed to investigate the association between contextual factors and affordances in the home environments of infants facing poverty. Term infants (n = 128) were divided into two groups: (1) exposed group (EG), comprising term infants exposed to poverty, and (2) comparison group (CG), consisting of term infants classified with medium and high socio-economic status. The main dependent variables were physical space, variety of stimulation, gross and fine motor toys, and the total score; measured using the Brazilian version of the Affordances in the Home Environment for Motor Development-Infant Scale (AHEMD-IS) questionnaire, named Affordances no Ambiente Domiciliar para o Desenvolvimento Motor-Escala Bebê. Statistical analysis employed independent sample t-tests or Mann–Whitney tests, chi-square tests, and stepwise multiple linear regression models to evaluate predictors of less adequate home environments. The EG presented significantly fewer affordances in gross motor toys (Cohen’s r = 0.353; p < 0.01); fine motor toys (Cohen’s r = 0.327; p < 0.01); and total score (Cohen’s r = 0.377; p < 0.01). Binary logistic regression analysis showed a significant association (r2 = 0.828, p < 0.01) between the less than adequate home environment category and maternal age (p = 0.043, OR: 0.829 (0.692–0.994)), revealing that maternal age was associated with better quantity and quality of affordances for child development.

This study aims to establish precise quality indicators for evaluating and enhancing ultrasound performance, employing a methodology based on a comprehensive review of the literature, expert insights, and practical application experiences. We conducted a thorough review of both the domestic and international literature on ultrasound quality control to identify potential indicators. A dedicated team was formed to oversee the complete indicator development process. Utilizing a three-round modified Delphi method, we sought expert opinions through personalized email correspondence. Subsequently, data from diverse hospital indicators were collected to validate and assess feasibility. A novel set of seven indicators was compiled initially, followed by the convening of a 36-member nationally representative expert panel. After three rounds of meticulous revisions, consensus was reached on 13 indicators across three domains. These finalized indicators underwent application in various hospital settings, demonstrating their initial validity and feasibility. The development of thirteen ultrasound quality indicators represents a significant milestone in evaluating ultrasound performance. These indicators empower hospitals to monitor changes in quality effectively, fostering efficient quality management practices.

Background and Objectives: An interventional diagnostic procedure (IDP), including intracoronary acetylcholine (ACh) provocation and coronary physiological testing, is recommended as an invasive diagnostic standard for patients suspected of ischemia with no obstructive coronary arteries (INOCA). Recent guidelines suggest Thrombolysis In Myocardial Infarction frame count (TFC) as an alternative to wire-based coronary physiological indices for diagnosing coronary microvascular dysfunction. We evaluated trajectories of TFC during IDP and the impact of ACh provocation on TFC. Materials and Methods: This was a single-center, retrospective study. Patients who underwent IDP to diagnose INOCA were included and divided into two groups according to the positive or negative ACh provocation test. Wire-based invasive physiological assessment was preceded by ACh provocation tests and intracoronary isosorbide dinitrate (ISDN). We evaluated TFC at three different time points during IDP; pre-ACh, post-ISDN, and post-hyperemia. Results: Of 104 patients, 58 (55.8%) had positive ACh provocation test. In the positive ACh group, resting mean transit time (Tmn) and baseline resistance index were significantly higher than in the negative ACh group. Post-ISDN TFC was significantly correlated with resting Tmn (r = 0.31, p = 0.002). Absolute TFC values were highest at pre-ACh, followed by post-ISDN and post-hyperemia in both groups. All between-time point differences in TFC were statistically significant in both groups, except for the change from pre-ACh to post-ISDN in the positive ACh group. Conclusions: In patients suspected of INOCA, TFC was modestly correlated with Tmn, a surrogate of coronary blood flow. The positive ACh provocation test influenced coronary blood flow assessment during IDP.

Background: The Italian National Institute of Health (Istituto Superiore di Sanità) funded a 30-month project (July 2021–January 2024) to conduct a twin study of the relationships between Positive Mental Health (PMH) and cellular longevity. Only a few previous studies have focused on the biomarkers of aging in relation to psychological well-being, and none of them exploited the potential of the twin design. Method: In this project, following the standard procedures of the Italian Twin Registry (ITR), we aim to recruit 200 adult twin pairs enrolled in the ITR. They are requested to complete a self-report questionnaire battery on PMH and to undergo a blood withdrawal for the assessment of aging biomarkers, i.e., telomere length and mitochondrial DNA functionality. The association between psychological and aging biomarker measures will be assessed, controlling for genetic and familial confounding effects using the twin study design. Results and conclusions: Biomarker assays are underway. Once data are available for the total study sample, statistical analyses will be performed. The project’s results may shed light on new mechanisms underlying the mind–body connection and may prove helpful to promote psychological well-being in conjunction with biological functioning.

Background and Objectives: The purpose of this retrospective population-based cohort study was to analyse the association between attendance of physiotherapy with mortality in the Spanish general population and describe the profile of people who do not visit a physiotherapist in Spain. Material and Methods: The data sources were the 2011/2012 National Health Survey (ENSE11) and the national database of death in Spain, and the participants were all adult respondents in the ENSE11. Results: Of 20,397 people, 1101 (5.4%) visited the physiotherapist the previous year, and the cumulative incidence of total mortality was 5.4% (n = 1107) at a mean follow-up of 6.2 years. Visiting the physiotherapist was associated with lower all-cause mortality in the population residing in Spain, quantified at 30.1% [RR = 0.699; 95% CI (0.528–0.927); p = 0.013]. The factors associated with not visiting a physiotherapist were the following: rating one’s health as good (9.8%; n = 1017; p < 0.001), not having any hospital admission in the previous year (9.6%; n = 1788; p < 0.001), not having visited the general practitioner in the previous month (9.6%; n = 1408; p < 0.001), and not having attended a day hospital in the previous year (9.7%; n = 1836; p < 0.001). Conclusions: Visiting a physiotherapist was associated with a lower mortality from all causes in the population living in Spain.

Despite the advances in the treatment of pre-B-ALL leukemia in children, adult pre-B-ALL continues to represent a major challenge. This work focuses on the use of differential responses to fasting conditions between normal and cancer cells to achieve cancer-free survival. We show that a fasting-mimicking diet in combination with vincristine causes a synergistic increase in the toxicity to pre-B-ALL cells resulting in high cancer cell death. While fasting is not sufficient to promote cancer-free survival, the combination of fasting/FMD and vincristine promotes autophagy inhibition, which is at the center of the high toxicity phenotype specific to leukemia cells, possibly through a mechanism involving immune cells.

Type 1 diabetes (T1DM) is a public health issue for children, young people, and families (CYPF) and requires innovative interventions. The DigiBete app is a self-management and educational app to help CYPF and healthcare professionals (HCPs) manage T1DM, featuring educational advice and resources such as guidance, quizzes, and educational and instructional videos on how to manage T1DM. To assess the impact and implementation of the app, the service-level evaluation deployed a mixed-methods design. App data were captured via the DigiBete platform and an online survey with a non-probability sample of HCPs (N = 178) and CYPF (N = 1165) = 1343. Overall, 55.7% (n = 512/919) of app users were female, and 4855 videos were viewed across the participating areas, with an average of 1213 videos per site (range 776–1679) and 4.4 videos per app user. The most popular videos were how to give a glucagon injection and “My Sick Day Rules”, which showed what to do when CYPF were unwell due to T1DM. Interviews (n = 63) were undertaken with 38 CYPF and 25 HCPs. The findings indicate that CYPF and HCPs found the app an essential tool in the management of T1DM. CYPF and HCPs felt the app provided a valuable educational resource in a central location that was invaluable in an emergency or unknown situation. The app was a trusted and bona-fide source of information that could be accessed at any time. HCPs validated DigiBete in helping CYPF to manage their T1DM. At the same time, the app saved HCPs’ service time and money and helped CYPF take back some of the control in managing their diabetes.

Clinical prediction models for spine surgery applications are on the rise, with an increasing reliance on machine learning (ML) and deep learning (DL). Many of the predicted outcomes are uncommon; therefore, to ensure the models’ effectiveness in clinical practice it is crucial to properly evaluate them. This systematic review aims to identify and evaluate current research-based ML and DL models applied for spine surgery, specifically those predicting binary outcomes with a focus on their evaluation metrics. Overall, 60 papers were included, and the findings were reported according to the PRISMA guidelines. A total of 13 papers focused on lengths of stay (LOS), 12 on readmissions, 12 on non-home discharge, 6 on mortality, and 5 on reoperations. The target outcomes exhibited data imbalances ranging from 0.44% to 42.4%. A total of 59 papers reported the model’s area under the receiver operating characteristic (AUROC), 28 mentioned accuracies, 33 provided sensitivity, 29 discussed specificity, 28 addressed positive predictive value (PPV), 24 included the negative predictive value (NPV), 25 indicated the Brier score with 10 providing a null model Brier, and 8 detailed the F1 score. Additionally, data visualization varied among the included papers. This review discusses the use of appropriate evaluation schemes in ML and identifies several common errors and potential bias sources in the literature. Embracing these recommendations as the field advances may facilitate the integration of reliable and effective ML models in clinical settings.

Background and Objectives: In case of the ineffectiveness of pharmacological and non-pharmacological treatments in managing chronic neuropathic pain, spinal cord stimulation (SCS) with BurstDR™ stimulation may reduce pain and increase the quality of life. The term “burst” refers to a series of stimulation impulses that are compressed into small packets and separated by intervals of latency. Materials and Methods: A group of 30 consecutive patients who received the BurstDR™ stimulator using the minimally invasive percutaneous method was selected. Patients selected for our study underwent numerous spinal surgeries before SCS implantation. In the study, analgesics and co-analgesics and their doses used by patients before and 6 months after SCS implantation were examined and compared. Using the visual analogue scale (VAS), pain was compared before and after the procedure. Patients` quality of life was assessed using the Oswestry Disability Index (ODI). Results: We observed a significant reduction in opioid daily doses by an average of 32.4% (±36.1%) and a reduction in paracetamol daily doses by an average of 40% (±33.4%). There was a reduction in pregabalin doses as well. Ketoprofen daily dose reduction was 85.4 mg. The mean VAS difference before and after procedure was 3.9 (±2.3), and the mean difference in ODI was 12.9 (±9), which benefits operative treatment. The VAS and ODI results were statistically significant as well. Conclusions: According to our research, BurstDR™ stimulation improves the quality of life by reducing doses of analgesics and the level of pain.

Background: Postural changes are considered a public health problem, especially those that affect the spine, as they may predispose to degenerative conditions of the spine in adulthood. Musculoskeletal disorders are the main cause of chronic pain, illness, reduced educational performance, productivity, and quality of life, and are responsible for increased absenteeism, which could compromise the future career of students. The purpose of this study was to identify the prevalence of postural changes and the occurrence of musculoskeletal disorders in different anatomical regions in the 12 months prior and 7 days prior to the application of the questionnaire and the number of affected anatomical regions. Methods: This is an observational, descriptive, cross-sectional study. It included 508 students selected by a stratified random sample. Our outcomes were the Portuguese version of the Standardized Nordic Musculoskeletal Questionnaire, the Adam’s test, a scoliometer, and the visual analog pain scale associated with the Nordic Musculoskeletal Questionnaire. Results: In total, 79.3% of the students tested positive with the Adam’s test. The neck, shoulder, lumbar region, and knee stood out in all of the temporal references, the 12 months prior (44.3%; 35.2%, 50.2%, 34.1%) and the 7 days prior (16.5%, 16.9%; 28.9%, 17.5%), and even in the restriction of activity due to painful symptoms in the 12 months prior (4.3%, 5.3%, 10.6%, 8.5%). Conclusions: Out of 497 students, 403 were identified with postural changes. The high prevalence rate of identified musculoskeletal symptoms in the anatomical regions of the neck, lumbar region, and shoulder raises the need for intervention in students. Gender appears to generate differences between men and women. Pain from multiple body sites is frequent among young adults.

Background: Veno-arterial extracorporeal membrane oxygenation (va-ECMO) can provide circulatory and respiratory support in patients with cardiogenic shock. The main aim of this work was to investigate the association of blood biomarkers with mortality in patients with myocardial infarction needing va-ECMO support. Methods: We retrospectively analyzed electronic medical charts from patients receiving va-ECMO support in the period from 2008 to 2021 at the Medical University Innsbruck, Department of Anesthesiology and Intensive Care Medicine. Results: Of 188 patients, 57% (108/188) survived to discharge, with hemorrhage (46%) and thrombosis (27%) as the most frequent adverse events. Procalcitonin levels were markedly higher in non-survivors compared with survivors during the observation period. The multivariable model identified higher blood levels of procalcitonin (HR 1.01, p = 0.002) as a laboratory parameter associated with a higher risk of mortality. Conclusions: In our study population of patients with myocardial infarction-associated cardiogenic shock, deceased patients had increased levels of inflammatory blood biomarkers throughout the whole study period. Increased procalcitonin levels have been associated with a higher risk of mortality. Future studies are needed to show the role of procalcitonin in patients receiving ECMO support.

Cancer-related fatigue (CRF) is the most common and distressing symptom in cancer survivors, severely affecting their quality of life. However, clinicians and patients are not well recognized for its importance and lack timely screening and assessment. With the rapid development of artificial intelligence and personalized care, early screening and assessment of CRF using machine learning to construct risk prediction models may contribute to this. Therefore, we redefined the predictors of CRF based on the predisposing, precipitating, and perpetuating (3P) model to develop a valid basis for the feature selection of future prediction models, intending to provide a more accurate and personalized plan for the clinical diagnosis and management of CRF.

Osteoarthritis (OA) most frequently affects the knee joint and is associated with an elevated expression of cytokines and extracellular cartilage matrix (ECM), degrading enzymes such as matrix metalloproteinases (MMPs). Differences in gene expression of the intra-articularly located infrapatellar fat pad (IPFP) and other fatty tissue suggest its autonomous function, yet its role in OA pathogenesis remains unknown. Human IPFPs and articular cartilage were collected from OA patients undergoing total knee arthroplasty, and biopsies from the IPFP of healthy patients harvested during knee arthroscopy served as controls (CO). Isolated chondrocytes were co-cultured with either osteoarthritic (OA) or CO-IPFPs in a transwell system. Chondrocyte expression of MMP1, -3, -13, type 1 and 2 collagens, interleukin IL1β, IL6, IL10, and tumor necrosis factor TNFα was analyzed by RTD-PCR at day 0 and day 2, and TNFα secretion was analyzed by ELISA. The cytokine release in IPFPs was assessed by an array. Results: Both IPFPs (CO, OA) significantly reduced the expression of type 2 collagen and TNFα in chondrocytes. On the other hand, only CO-IPFP suppressed the expression of type 1 collagen and significantly induced the MMP13 expression. On the contrary, IL1β and IL6 were significantly induced when exposed to OA-IPFP. Conclusions: The partial loss of the suppressive effect on type 1 collagen gene expression found for OA-IPFP shows the pathological remodeling and dedifferentiation potential of the OA-IPFP on the chondrocytes. However, the significant suppression of TNFα implies that the OA- and CO-IPFP could also exhibit a protective role in the knee joint, preventing the progress of inflammation.

Bacteria are engaged in a constant battle against preying viruses, called bacteriophages (or phages). These remarkable nano-machines pack and store their genomes in a capsid and inject it into the cytoplasm of their bacterial prey following specific adhesion to the host cell surface. Tailed phages possessing dsDNA genomes are the most abundant phages in the bacterial virosphere, particularly those with long, non-contractile tails. All tailed phages possess a nano-device at their tail tip that specifically recognizes and adheres to a suitable host cell surface receptor, being proteinaceous and/or saccharidic. Adhesion devices of tailed phages infecting Gram-positive bacteria are highly diverse and, for the majority, remain poorly understood. Their long, flexible, multi-domain-encompassing tail limits experimental approaches to determine their complete structure. We have previously shown that the recently developed protein structure prediction program AlphaFold2 can overcome this limitation by predicting the structures of phage adhesion devices with confidence. Here, we extend this approach and employ AlphaFold2 to determine the structure of a complete phage, the lactococcal P335 phage TP901-1. Herein we report the structures of its capsid and neck, its extended tail, and the complete adhesion device, the baseplate, which was previously partially determined using X-ray crystallography.

Angiotensin–converting enzyme (ACE) inhibitors are the primarily chosen drugs to treat various cardiovascular diseases, such as hypertension. Although the most recent guidelines do not differentiate among the various ACE inhibitory drugs, there are substantial pharmacological differences. Goal: Here, we tested if lipophilicity affects the efficacy of ACE inhibitory drugs when used as the first therapy in newly identified hypertensives in a prospective study. Methods: We tested the differences in the cardiovascular efficacy of the hydrophilic lisinopril (8.3 ± 3.0 mg/day) and the lipophilic enalapril (5.5 ± 2.3 mg/day) (n = 59 patients). The cardiovascular parameters were determined using sonography (flow-mediated dilation (FMD) in the brachial artery, intima-media thickness of the carotid artery), 24 h ambulatory blood pressure monitoring (peripheral arterial blood pressure), and arteriography (aortic blood pressure, augmentation index, and pulse wave velocity) before and after the initiation of ACE inhibitor therapy. Results: Both enalapril and lisinopril decreased blood pressure. However, lisinopril failed to improve arterial endothelial function (lack of effects on FMD) when compared to enalapril. Enalapril-mediated improved arterial endothelial function (FMD) positively correlated with its blood–pressure–lowering effect. In contrast, there was no correlation between the decrease in systolic blood pressure and FMD in the case of lisinopril treatment. Conclusion: The blood–pressure–lowering effects of ACE inhibitor drugs are independent of their lipophilicity. In contrast, the effects of ACE inhibition on arterial endothelial function are associated with lipophilicity: the hydrophilic lisinopril was unable to improve, while the lipophilic enalapril significantly improved endothelial function. Moreover, the effects on blood pressure and endothelial function did not correlate in lisinopril-treated patients, suggesting divergent mechanisms in the regulation of blood pressure and endothelial function upon ACE inhib

Bacteriophage λ’s CI repressor protein controls a genetic switch between the virus’s lysogenic and lytic lifecycles, in part, by selectively binding to six different DNA sequences within the phage genome—collectively referred to as operator sites. However, the minimal level of information needed for CI to recognize and specifically bind these six unique-but-related sequences is unclear. In a previous study, we introduced an algorithm that extracts the minimal direct readout information needed for λ-CI to recognize and bind its six binding sites. We further revealed direct readout information shared among three evolutionarily related lambdoid phages: λ-phage, Enterobacteria phage VT2-Sakai, and Stx2 converting phage I, suggesting that the λ-CI protein could bind to the operator sites of these other phages. In this study, we show that λ-CI can indeed bind the other two phages’ cognate binding sites as predicted using our algorithm, validating the hypotheses from that paper. We go on to demonstrate the importance of specific hydrogen bond donors and acceptors that are maintained despite changes to the nucleobase itself, and another that has an important role in recognition and binding. This in vitro validation of our algorithm supports its use as a tool to predict alternative binding sites for DNA-binding proteins.

Apart from being preventable and treatable, tuberculosis is the deadliest bacterial disease afflicting humankind owing to its ability to evade host defence responses, many of which are controlled by epigenetic mechanisms. Here, we report the temporal dynamics of the proteome of macrophage-like host cells after infecting them for 6, 18, 30, and 42 h with two laboratory strains (H37Ra and H37Rv) and two clinical strains (BND433 and JAL2287) of Mycobacterium tuberculosis (MTB). Using SWATH-MS, the proteins characterized at the onset of infection broadly represented oxidative stress and cell cytoskeleton processes. Intermediary and later stages of infection are accompanied by a reshaping of the combination of proteins implicated in histone stability, gene expression, and protein trafficking. This study provides strain-specific and time-specific variations in the proteome of the host, which might further the development of host-directed therapeutics and diagnostic tools against the pathogen. Also, our findings accentuate the importance of proteomic tools in delineating the complex recalibration of the host defence enabled as an effect of MTB infection. To the best of our knowledge, this is the first comprehensive proteomic account of the host response to avirulent and virulent strains of MTB at different time periods of the life span of macrophage-like cells. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE repository with the dataset identifier PXD022352.

Hypoxia-inducible factor (HIF)-1α represents an oxygen-sensitive subunit of HIF transcriptional factor, which is usually degraded in normoxia and stabilized in hypoxia to regulate several target gene expressions. Nevertheless, in the skeletal muscle satellite stem cells (SCs), an oxygen level-independent regulation of HIF-1α has been observed. Although HIF-1α has been highlighted as a SC function regulator, its spatio-temporal expression and role during myogenic progression remain controversial. Herein, using biomolecular, biochemical, morphological and electrophysiological analyses, we analyzed HIF-1α expression, localization and role in differentiating murine C2C12 myoblasts and SCs under normoxia. In addition, we evaluated the role of matrix metalloproteinase (MMP)-9 as an HIF-1α effector, considering that MMP-9 is involved in myogenesis and is an HIF-1α target in different cell types. HIF-1α expression increased after 24/48 h of differentiating culture and tended to decline after 72 h/5 days. Committed and proliferating mononuclear myoblasts exhibited nuclear HIF-1α expression. Differently, the more differentiated elongated and parallel-aligned cells, which are likely ready to fuse with each other, show a mainly cytoplasmic localization of the factor. Multinucleated myotubes displayed both nuclear and cytoplasmic HIF-1α expression. The MMP-9 and MyoD (myogenic activation marker) expression synchronized with that of HIF-1α, increasing after 24 h of differentiation. By means of silencing HIF-1α and MMP-9 by short-interfering RNA and MMP-9 pharmacological inhibition, this study unraveled MMP-9’s role as an HIF-1α downstream effector and the fact that the HIF-1α/MMP-9 axis is essential in morpho-functional cell myogenic commitment.