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Physiotherapy is a critical area of healthcare that involves the assessment and treatment of physical disabilities and injuries. The use of Artificial Intelligence (AI) in physiotherapy has gained significant attention due to its potential to enhance the accuracy and effectiveness of clinical decision-making and treatment outcomes. Nevertheless, it is still a rather innovative field of application of these techniques and there is a need to find what aspects are highly developed and what possible job niches can be exploited. This systematic review aims to evaluate the current state of research on the use of a particular AI called deep learning models in physiotherapy and identify the key trends, challenges, and opportunities in this field. The findings of this review, conducted following the PRISMA guidelines, provide valuable insights for researchers and clinicians. The most relevant databases included were PubMed, Web of Science, Scopus, Astrophysics Data System, and Central Citation Export. Inclusion and exclusion criteria were established to determine which items would be considered for further review. These criteria were used to screen the items during the first and second peer review processes. A set of quality criteria was developed to select the papers obtained after the second screening. Finally, of the 214 initial papers, 23 studies were selected. From our analysis of the selected articles, we can draw the following conclusions: Concerning deep learning models, innovation is primarily seen in the adoption of hybrid models, with convolutional models being extensively utilized. In terms of data, it's unsurprising that body signals and images are predominantly used. However, texts and structured data present promising avenues for groundbreaking work in the field. Additionally, medical tests that involve the collection of 3D images, Functional Movement Screening, or thermographies emerge as novel areas to explore applications within the scope of physiotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Abstract: This article reviews the main ethical issues that arise from the use of artificial intelligence (AI) technologies in medicine. Issues around trust, responsibility, risks of discrimination, privacy, autonomy, and potential benefits and harms are assessed. For better or worse, AI is a promising technology that can revolutionise healthcare delivery. It is up to us to make AI a tool for the good by ensuring that ethical oversight accompanies the design, development and implementation of AI technology in clinical practice., (Copyright © 2024 Copyright: © 2024 Singapore Medical Journal.)

Oral and maxillofacial pathology, the branch of dentistry concerning clinical and histopathological diagnosis of pathologies of the oral and maxillofacial region, started to develop in Colombia in the mid- 19 th century. Since 1950s, dedicated dental clinicians from different dental schools played an important role in its inception and subsequent development. The first significant wave of progress occurred in the 1970s with the appearance of the first formally trained oral pathologists. It was sometime in the late 1980s and early 1990s that dentists Ines Velez and Benjamin Herazo had separate initiatives and created the first oral pathology postgraduate programs in Bogotá. It was in the late 80's and early 90's that dentists Ines Velez and Benjamin Herazo had their own initiatives and created the first oral pathology postgraduate programs in the city of Bogotá. A concomitant of their achievements was the establishment of the first on-site oral pathology biopsies units and registers at Colegio Odontãlogico Colombiano, Pontificia Universidad Javeriana and Escuela Colombiana de Medicina dental schools. The programs have trained many dentists in the field over the years and two of them remain active and fully accredited. The past and present contributions and leaderships of some academic figures and graduates have allowed a steady evolution of the specialty nationwide. Currently, the ability to manage and overcome educational and professional challenges is necessary to advance the growth of this specialty in this country., (Copyright 2023 © American Academy of the History of Dentistry.)

Objectives: Advances in endocrinology and nutrition (E&N) and the importance of its associated disorders require that its teaching within the medical degree meets adequate standards of quality and homogeneity Our objective was to expand the data on E&N undergraduate teaching in Spain., Methods: We designed an observational, cross-sectional web-based study addressed to the coordinators of E&N teaching at the 42 faculties of medicine that had taught the subject during the 2020-2021 academic year., Results: One in three faculties had a professor who was an E&N specialist, but less than half had a full professor of E&N. There is great variability in teaching programmes, although most of them dedicate 6 ECTS credits to the subject. Over two-thirds of the faculties maintain theoretical lessons with over 50 students per class. Most programmes dedicate between four and six hours to hypothalamic pituitary disorders, thyroid diseases and adrenal gland disorders. However, there is great variability in the time dedicated to diabetes and nutrition. In one-third of the faculties, students are not required to do a rotation in the E&N department. Teachers at the universities widely participate in undergraduate/master's students' final projects and master's degree studies., Conclusions: The E&N specialty maintains a good position within universities, but there is still great heterogeneity in the teaching structure of the subject., (Copyright © 2022 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Comorbidities are expected to impact the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, comorbidity profiles are usually reduced to a few comorbid disorders. Systems medicine approaches can model phenome-wide comorbidity profiles to improve our understanding of HFpEF and infer associated genetic profiles., Methods: We retrospectively explored 569 comorbidities in 29,047 HF patients, including 8062 HFpEF and 6585 HF with reduced ejection fraction (HFrEF) patients from a German university hospital. We assessed differences in comorbidity profiles between HF subtypes via multiple correspondence analysis. Then, we used machine learning classifiers to identify distinctive comorbidity profiles of HFpEF and HFrEF patients. Moreover, we built a comorbidity network (HFnet) to identify the main disease clusters that summarized the phenome-wide comorbidity. Lastly, we predicted novel gene candidates for HFpEF by linking the HFnet to a multilayer gene network, integrating multiple databases. To corroborate HFpEF candidate genes, we collected transcriptomic data in a murine HFpEF model. We compared predicted genes with the murine disease signature as well as with the literature., Results: We found a high degree of variance between the comorbidity profiles of HFpEF and HFrEF, while each was more similar to HFmrEF. The comorbidities present in HFpEF patients were more diverse than those in HFrEF and included neoplastic, osteologic and rheumatoid disorders. Disease communities in the HFnet captured important comorbidity concepts of HF patients which could be assigned to HF subtypes, age groups, and sex. Based on the HFpEF comorbidity profile, we predicted and recovered gene candidates, including genes involved in fibrosis (COL3A1, LOX, SMAD9, PTHL), hypertrophy (GATA5, MYH7), oxidative stress (NOS1, GSST1, XDH), and endoplasmic reticulum stress (ATF6). Finally, predicted genes were significantly overrepresented in the murine transcriptomic disease signature providing additional plausibility for their relevance., Conclusions: We applied systems medicine concepts to analyze comorbidity profiles in a HF patient cohort. We were able to identify disease clusters that helped to characterize HF patients. We derived a distinct comorbidity profile for HFpEF, which was leveraged to suggest novel candidate genes via network propagation. The identification of distinctive comorbidity profiles and candidate genes from routine clinical data provides insights that may be leveraged to improve diagnosis and identify treatment targets for HFpEF patients., (© 2023. The Author(s).)

Our goal in this paper is to reassess the relationship between norms and life by drawing on the philosophy of Georges Canguilhem, particularly some of his unpublished lectures about teratology and sexual determination. First, we discuss the difficulties Canguilhem identified in the introduction of life and sexuality as objects of philosophical reflection. Second, we reassess Canguilhem's understanding of normativity as rooted in life and the axiological activity of the living. Third, we analyze how Canguilhem drew from past and contemporary teratology to conceive of the notions of anomaly and abnormality. Finally, we reconstruct Canguilhem's analysis of a case of hermaphroditism, highlighting how he presented it as evidence that sexual determination is the result of a normative choice. One of the key contributions of the paper to scholarly literature on Canguilhem is a better understanding of his notion of choice, which was considered not the conscious and intentional act of a subject but rather an axiological activity of the living. We conclude by positioning Canguilhem's concept of normativity and his belief that norms are produced by the living in relation to the naturalist/normativist divide in medicine., (© 2022. Springer Nature Switzerland AG.)

Background: Medical specialists are an essential resource for the functioning of the health system and in Chile there is a growing deficit of these specialists. To address this shortage, the government has strategies for training health professionals, such as a national public contest for medical scholarships, named CONISS, which stands out for its high capacity to produce medical specialists. The scoring system of this contest is used for the allocation of training resources to the best candidates., Aim: To describe the results of the CONISS scoring system between 2016 and 2020., Material and Methods: Analysis of public registries of physicians participating in the CONISS contest between 2016 and 2020., Results: During the study period 7,373 physicians participated in this contest (49% females). Annual participation increased progressively. The participants graduated from 21 Chilean universities and a variable number from foreign universities. The scores obtained by participants improved by 1.47 points between the first and last year of the study period., Conclusions: Interpretation of these results is complicated by the characteristics and limitations of the measurements of the CONISS scoring system. This precludes establishing whether this system effectively filters out the best candidates for medical specialization programs.

Due to sanitary restrictions secondary to the COVID-19 pandemic, various interactions between the pharmaceutical industry and physicians have changed. One of them has been the method for promoting medicinal products through academic meetings around diseases of financial interest. A recent modality has been unilateral promotion by the pharmaceutical industry through academic events with the invitation of so-called "experts" for the promotion of a specific drug. These meetings are often biased not towards optimal care of a disease, but rather towards commercial promotion of a specific drug, which may or may not be the best option, without considering associated therapeutic alternatives. The Committee of Ethics and Transparency in the Physician-Industry Relationship, of the National Academy of Medicine, analyzes this new circumstance and proposes some considerations to the medical community., (Copyright: © 2022 Permanyer.)

Gender equality is a social issue that affects various disciplines. Within the field of medicine, inequality regarding the role of women in surgical specialties has been clearly identified. Limited female representation in leadership positions regarding surgical or academic societies, salary differences when compared to their male colleagues, and lack of mentoring programs for a balanced career are some of the difficulties faced by women who pursue a surgical career. This article explores the status of women who pursue surgical careers in Peru and the specific limitations they face; it also highlights the importance of female participation in surgery and proposes some suggestions to improve the role of women in the surgical field.

Background: The Program of Combined Studies in Medicine (PECEM, by its acronym in Spanish) is a program for simultaneous bachelor and doctorate studies (MD/PhD) that enrolls students who show academic excellence and interest in scientific research. The initial doctoral training comprises seven six-month research stays in different laboratories or clinical or computer areas with different high-quality scientific advisors who provide students with a unique experience for their scientific training. Therefore, satisfaction in this stage is decisive for students' performance and physical and psychological health. The aim of the present study was to administer a questionnaire to measure students' satisfaction with their research experience as a service-product bundle., Methods: Students answered an online questionnaire that evaluated three dimensions: perceived quality of the advisor, skills development, and infrastructure and support. Several satisfiers were also evaluated: recommendation of the advisor to peers, fulfillment of student expectations and satisfaction with the program. Correlations were calculated using Fisher's exact test. The significance was set at p < 0.05., Results: The high quality of the advisor, skills development and guidance during the stay were satisfiers correlated to the students' recommendation of their advisors to their peers and to the fulfillment of the students' scientific expectations. Conversely, skills development and infrastructure and support were satisfiers for a good to excellent experience as a PECEM student. A lack of direct interaction with the advisor's workgroup was related to dissatisfaction., Conclusions: The nontangible products of the service, such as a positive interaction between the student, the advisor and the advisor's workgroup as well as support obtained during the research stay, were satisfiers. These data indicate that promoting a fruitful bond between the student and advisor is a priority to ensure the quality of our innovative MD/PhD program.

Introduction: The objective of this study was to evaluate the impact of an intervention based on unsolicited consultations by an infectious diseases specialist (IDS) on the adequacy of antimicrobial treatment and mortality in patients with BSI., Methods: A prospective cohort study was performed in a 410-bed hospital. An intervention based on unsolicited consultation by an IDS for patients with BSI was performed only on days when an IDS was available. Outcomes were the percentage of days on optimal antimicrobial treatment (PDOAT) and mortality. Analyses were performed by linear regression and multivariate logistic regression., Results: Of 400 episodes of BSI included, 292 received the intervention. The median (interquartile range) PDOAT among those with and without the intervention was 93 (6-100) and 0 (0-53), respectively. The intervention was independently associated with a higher PDOAT (r = 0.5; p < 0.001) but not with mortality. The IDS recommendations were followed in full in 183 episodes, and not in 109. Mortality was 10.4% and 27.6%, respectively. Adherence to recommendations was associated with lower mortality (adjusted OR = 0.3; 95% CI: 0.1-0.5)., Conclusions: An intervention based on unsolicited IDS consultation for BSI episodes was associated with improved use of antibiotics and, when the recommendations were fully followed, with lower mortality., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Medicine subspecialty consultation is becoming increasingly important in inpatient medicine., Objective: We conducted a survey study in which we examined hospitalist practices and attitudes regarding medicine subspecialty consultation., Design and Setting: The survey instrument was developed by the authors based on prior literature and administered online anonymously to hospitalists at 4 academic medical centers in the United States., Measurements: The survey evaluated 4 domains: (1) current consultation practices, (2) preferences regarding consultation, (3) barriers to and facilitating factors of effective consultation, and (4) a comparison between hospitalist-fellow and hospitalist-subspecialty attending interactions., Results: One hundred twenty-two of 261 hospitalists (46.7%) responded. The majority of hospitalists interacted with fellows during consultation. Of those, 90.9% reported that in-person communication occurred during less than half of consultations, and 64.4% perceived pushback at least "sometimes " in their consult interactions. Participants viewed consultation as an important learning experience, preferred direct communication with the consulting service, and were interested in more teaching during consultation. The survey identified a number of barriers to and facilitating factors of an effective hospitalist-consultant interaction, which impacted both hospitalist learning and patient care. Hospitalists reported more positive experiences when interacting with subspecialty attendings compared to fellows with regard to multiple aspects of the consultation., Conclusion: The hospitalist-consultant interaction is viewed as important for both hospitalist learning and patient care. Multiple barriers and facilitating factors impact the interaction, many of which are amenable to intervention.

In this paper, we analyse the medical specialty training system in Spain (the so-called "residency system"). In order to do so, we a) summarize its historical evolution; b) describe the five major architectural pillars on which the system is currently based; c) analyse the special contract of the specialist-in-training; d) discuss the three major challenges for the medical specialist training future: the evolution and expansion of the residency system to other health professions, the issue of grouping specialties with a common core trunk and the continuity of the learning process; and e) draw four conclusions that may be relevant for those who are in the process of developing or revising their own medical specialization systems.

Only recently has the critical importance of electromagnetic (EM) field interactions in biology and medicine been recognized. We review the phenomenon of resonance signaling, discussing how specific frequencies modulate cellular function to restore or maintain health. The application of EM-tuned signals represents more than merely a new tool in information medicine. It can also be viewed in the larger context of EM medicine, the all-encompassing view that elevates the EM over the biochemical. The discovery by Zhadin that ultrasmall magnetic intensities are biologically significant suggests that EM signaling is endogenous to cell regulation, and consequently that the remarkable effectiveness of EM resonance treatments reflects a fundamental aspect of biological systems. The concept that organisms contain mechanisms for generating biologically useful electric signals is not new, dating back to the nineteenth century discovery of currents of injury by Matteucci. The corresponding modern-day version is that ion cyclotron resonance magnetic field combinations help regulate biological information. The next advance in medicine will be to discern and apply those EM signaling parameters acting to promote wellness, with decreasing reliance on marginal biochemical remediation and pharmaceuticals.

Chemoprevention is effective in inhibiting the onset of cancer in experimental animal models, but the transferability of similar results to humans is questionable. Therefore, reliable intermediate molecular biomarkers are needed to evaluate the efficacy of chemopreventive agents before the onset of cancer. The use of genomic biomarkers is limited by their poor predictive value. Although post-genomic biomarkers (i.e., gene-expression analyses) are useful for evaluating the safety, efficacy, and mechanistic basis of chemopreventive agents, the biomarkers are often poorly related to the phenotype, due to posttranscriptional regulation. Proteome analyses can evaluate preclinical phenotype alterations, but only at low protein counts. MicroRNA alterations, which are essential for the development of cancer, may be modulated by chemopreventive agents. Furthermore, microRNA delivery may be used to counteract carcinogenesis. Exposure to cigarette smoke induces microRNA let-7 downregulation and cell proliferation that can be converted to cell growth arrest and apoptosis upon let-7a transfection. Therefore, microRNAs are reliable biomarkers for evaluating chemoprevention efficacy and may be used to counteract carcinogenesis., (© 2012 New York Academy of Sciences.)

Coronary heart disease (CHD) patients are currently attended by many different medical specialities. CHD patients must achieve the highest grade of treatment implementation and risk factors control. The aims were to describe differences in medical treatment of CHD according to the medical specialities. For this purpose we conducted an observational, cross-sectional, and multicenter study of CHD patients attended by internal medicine (IM), outpatient clinic cardiologist (OCC), hospital cardiologist (HC), and general practitioners (PC). Burden of noncardiac diseases was evaluated by the Charlson index. Joint prescription of antiplatelets, statins, beta-blockade agents and blockade of the renin-angiotensin system by angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptors blockers (ARB) was considered optimal medical treatment (OMT). A total of 2987 patients, mean age 67.4 (11.5) years and 71.5% males, were analyzed. Patients visited by IM physicians had slightly higher mean age and higher prevalence of hypertension, diabetes, and noncardiac diseases (median Charlson index 3.0, 1.0-5.0, vs. 2.0, 1.0-4.0, of total sample). OMT was prescribed in 25.9% (95% CI 25.6-26.2) of the patients and was statistically more frequently carried out by HC (32.1%) and OCC (29.0%) compared to IM (22.0%) and PC practitioners (21.5%). Multivariate analysis showed an independent association between OMT prescription and HC (OR 1.42; 95% CI 1.08-1.87) or OCC (OR 1.31; 95% CI 1.04-1.67); this association remained after including the Charlson index. Noncardiac diseases are the main clinical differences in CHD patients visited by different medical specialist although it does not explain the higher prescription of OMT by cardiologist.

Objective: There is a lack of standard methods for determining the clinical priority of patients referred by general practitioners (GPs) for specialist outpatient consultations. We introduced a system of progressive involvement by general practitioners and specialists with 80 diagnostic procedures. The aim of this study was to evaluate this new method of prioritization of patients suffering from significant gastroenterological disorders needing rapid access to diagnostic procedures., Methods: The study included 438 outpatients who were referred for and underwent a gastroscopy or colonoscopy. GPs used a ranking of waiting times for different levels of clinical priority, called 'homogeneous waiting groups'. Specialists also assigned a priority level for each patient as well as evaluating the appropriateness of the referral and the presence of significant endoscopic disorders. Agreement between GPs' and specialists' priority assessments was evaluated by the kappa statistic., Results: Most referrals (74.4%) were deemed low priority by GPs, with no maximum waiting time assigned. The level of agreement between GPs and specialists as regards patients' priorities was poor or moderate: for gastroscopy the kappa was 0.31 (weighted kappa 0.47) and for colonoscopy 0.44 (weighted kappa 0.46). There was an association between the proportion of significant disorders identified with endoscopy and the priority assigned to the referral (chi2 = 18.9, 1 df, p < 0.001). The overall proportion of referrals deemed inappropriate by specialists was 22.1%., Conclusions: There is value in liaison between GPs and specialists for achieving timely referrals and avoiding delayed diagnosis though higher levels of agreement need to be achieved.

This paper describes preliminary experience in shared clinical management of patients located in Pointe Noire, Africa, and a referral center, Sacco University Hospital, located in Milan, Italy. The employed infrastructure INteractive TeleConsultation Network for Worldwide HealthcAre Services (INCAS) jointly developed by CEFRIEL (Center of Excellence For Research, Innovation, Education & Industrial Labs partnership) and ENI (Ente Nazionale Idrocarburi) is based on commercial off-the-shelf technology. This minimizes maintenance problems, while permitting a simple and friendly sharing of data using the telephone and e-mail for store-and-forward applications. The critical aspect of the flow of events comprising the exchange of information is discussed. In 60% of cases, only one telemedicine consultation was required. In the remainder 40%, a number of telemedicine consultations were required for appropriate management of clinical cases. The project demonstrated flexibility as documented by the wide range of pathologies that can be dealt with it. Finally the possibility of using shared clinical management as a learning tool is highlighted by the steep and rising learning curve. We conclude, however, that the patient, although handled in a "virtual" manner, should be viewed as very "real," as some of them elected to close the gap physically between Pointe Noire and Milan, and chose to be treated at the referral site.

Abstract Background The thymus, responsible for T cell-mediated adaptive immune system, has a structural and functional complexity that is not yet fully understood. Until now, thymic anatomy has been studied using histological thin sections or confocal microscopy 3D reconstruction, necessarily for limited volumes. Methods We used Phase Contrast X-Ray Computed Tomography to address the lack of whole-organ volumetric information on the microarchitecture of its structural components. We scanned 15 human thymi (9 foetal and 6 postnatal) with synchrotron radiation, and repeated scans using a conventional laboratory x-ray system. We used histology, immunofluorescence and flow cytometry to validate the x-ray findings. Results Application to human thymi at pre- and post-natal stages allowed reliable tracking and quantification of the evolution of parameters such as size and distribution of Hassall’s Bodies and medulla-to-cortex ratio, whose changes reflect adaptation of thymic activity. We show that Hassall’s bodies can occupy 25% of the medulla volume, indicating they should be considered a third thymic compartment with possible implications on their role. Moreover, we demonstrate compatible results can be obtained with standard laboratory-based x-ray equipment, making this research tool accessible to a wider community. Conclusions Our study allows overcoming the resolution and/or volumetric limitations of existing approaches for the study of thymic disfunction in congenital and acquired disorders affecting the adaptive immune system.

Abstract Fibromyalgia is a musculoskeletal syndrome characterized by chronic widespread pain that is often associated with systemic manifestations. Since mitochondria are the main source of cellular energy, we hypothesized that fibromyalgia syndrome (FMS) could be linked to mitochondrial impairment. Aim was to study mitochondrial dysfunction in peripheral blood mononuclear cells isolated from 50 patients with primary FMS and 20 apparently healthy controls. Although no differences in mitochondrial basal respiration were observed between patients with primary FMS and healthy controls, a lower median bioenergetic health index (BHI; − 22.1%, p = 0.03), a proxy of mitochondrial function, was found in patients. According to fibromyalgia severity score (FSS), a composite of widespread pain index and symptom severity scale, a lower median BHI (− 18.7%) was found in patients with a FSS ≥ 20 compared to those with a FSS

Abstract Patients with carotid stenosis can receive indication for either carotid endarterectomy (CEA) or carotid artery stenting (CAS), with both techniques having an impact on the autonomic function and baroreflex control. Seventy carotid stenosis patients randomly assigned to CEA or CAS were enrolled. After exclusion of some recordings, 33 CEA (age 67.79 ± 5.32 yrs, 26 males) and 25 CAS (age 70.32 ± 3.63 yrs, 14 males) were admitted to analysis. Autonomic and baroreflex sensitivity markers were derived from the analysis of heart period and systolic arterial pressure spontaneous variability derived in supine position and during active standing (STAND), before (PRE) the intervention and after a 6 and 12-month follow-up (FU6, FU12). CEA had a preserved response of autonomic and baroreflex control to STAND in PRE and FU6, suggesting an early improvement. CAS had a similar response at PRE but a blunted one at the follow-ups. When directly compared, the two groups had a similar autonomic function, with CAS having a reduced baroreflex control in PRE and lower autonomic function at FU6. All the differences disappeared at the long-term follow-up, showing a similar long term effect of the surgical procedures, suggesting that CEA and CAS induced a similar long-term impairment of autonomic and baroreflex controls.

Abstract An interconnected system employing Kinect Azure and Fitbit Sense for continuous and non-intrusive data collection was used in the PRO-HOME protected discharge program, aiming at monitoring functional and clinical parameters in hospitalized older patients at different risks of frailty. The present study shows the findings on 30 older patients included in the PRO-HOME project. The Fitbit Sense recorded the mean daily and hourly number of steps, mean daily walked distance, and time spent inactive. Moreover, Kinect infrared camera captured gait speed and daily mean latero-lateral (body sway) and antero-posterior oscillations (lean-in). Patients underwent a standard Comprehensive Geriatric Assessment (CGA) to compute the Multidimensional Prognostic Index (MPI), including basic and instrumental activities of daily living (ADL, IADL), cognition (Short Portable Mental Status Questionnaire, SPMSQ) and nutrition, risk of pressure sores (Exton-Smith Scale, ESS), comorbidity, number of drugs and cohabitation status. Significant correlations between the mean hourly number of steps and MPI (p = 0.022), IADL (p = 0.013), SPMSQ (p = 0.006), ESS (p = 0.009), and both mean and maximum automated gait speed (p = 0.046 and p = 0.048) were found. Automated gait speed was also correlated with mean walked distance per day (p = 0.007) and lean-in (p = 0.047). Domotic technological monitoring through Fitbit Sense and Kinect Azure provides information on multidimensional frailty, including mobility and cognitive and functional status, in older people.

Abstract Connexins (Cxs) are fundamental in cell–cell communication, functioning as gap junction channels (GJCs) that facilitate solute exchange between adjacent cells and as hemichannels (HCs) that mediate solute exchange between the cytoplasm and the extracellular environment. Mutations in the GJB1 gene, which encodes Cx32, lead to X-linked Charcot-Marie-Tooth type 1 (CMTX1), a rare hereditary demyelinating disorder of the peripheral nervous system (PNS) without an effective cure or treatment. In Schwann cells, Cx32 HCs are thought to play a role in myelination by enhancing intracellular and intercellular Ca2+ signaling, which is crucial for proper PNS myelination. Single-point mutations (p.S85C, p.D178Y, p.F235C) generate pathological Cx32 HCs characterized by increased permeability (“leaky”) or excessive activity (“hyperactive”). We investigated the effects of abEC1.1-hIgG1, a fully human immunoglobulin G1 (hIgG1) monoclonal antibody, on wild-type (WT) and mutant Cx32D178Y HCs. Using HeLa DH cells conditionally co-expressing Cx and a genetically encoded Ca2+ biosensor (GCaMP6s), we demonstrated that mutant HCs facilitated 58% greater Ca2+ uptake in response to elevated extracellular Ca2+ concentrations ([Ca2+]ex) compared to WT HCs. abEC1.1-hIgG1 dose-dependently inhibited Ca2+ uptake, achieving a 50% inhibitory concentration (EC50) of ~ 10 nM for WT HCs and ~ 80 nM for mutant HCs. Additionally, the antibody suppressed DAPI uptake and ATP release. An atomistic computational model revealed that serine 56 (S56) of the antibody interacts with aspartate 178 (D178) of WT Cx32 HCs, contributing to binding affinity. Despite the p.D178Y mutation weakening this interaction, the antibody maintained binding to the mutant HC epitope at sub-micromolar concentrations. In conclusion, our study shows that abEC1.1-hIgG1 effectively inhibits both WT and mutant Cx32 HCs, highlighting its potential as a therapeutic approach for CMTX1. These findings expand the antibody’s applicability for treating diseases associated with Cx HCs and inform the rational design of next-generation antibodies with enhanced affinity and efficacy against mutant HCs.

We report a patient with lobomycosis caused by Paracoccidioides loboi fungi in the Andes-Amazon region of Bolivia. We examined clinical, epidemiologic, and phylogenetic data and describe potential transmission/environmental aspects of infection. Continued surveillance and identification of lobomycosis cases in South America are crucial to prevent the spread of this disease.

Abstract Human milk proteins, a mixture of whey proteins including caseins, milk fat globule membrane (MFGM) proteins, various peptides, and their amino acids, play a crucial role in infant growth and development, as do non-nutritional bioactive components. The extracellular nicotinamide phosphoribosyltransferase (eNAMPT) or visfatin is a conserved cytokine/enzyme released by many mammalian cells, related to multiple metabolic and immune processes. Few investigations have been reported about detecting visfatin in skimmed milk and the hypothesis of its potential role in regulating infant adiposity through breast milk. Milk samples from a donated human milk bank were analyzed. After milk fractionation by centrifugation, skimmed milk and MFGM were analyzed by SDS-PAGE, MALDI-TOF mass spectrometry ELISA and/or Western blot. The ELISA assay showed a higher visfatin content in raw skimmed milk than in pasteurized samples. Meanwhile, MFGMs revealed higher visfatin levels in pasteurized samples. This is the first time visfatin has been identified associated with MFGM, and these results could suggest an affinity of this molecule for a lipidic environment.

Abstract Hemoglobin (Hb) performs its physiological function within the erythrocyte. Extracellular Hb has prooxidative and proinflammatory properties and is therefore sequestered by haptoglobin and bound by the CD163 receptor on macrophages. In the present study, we demonstrate a novel process of Hb uptake by macrophages independent of haptoglobin and CD163. Unexpectedly, macrophages do not degrade the entire Hb, but instead transfer it to neighboring cells. We have shown that the phenomenon of Hb transfer from macrophages to other cells is mainly mediated by extracellular vesicles. In contrast to the canonical Hb degradation pathway by macrophages, Hb transfer has not been reported before. In addition, we have used the process of Hb transfer in anticancer therapy, where macrophages are loaded with a Hb-anticancer drug conjugate and act as cellular drug carriers. Both mouse and human macrophages loaded with Hb-monomethyl auristatin E (MMAE) effectively killed cancer cells when co-cultured in vitro.

Abstract This study aimed to analyze Optical Coherence Tomography (OCT) parameters and Macular Pigment Optical Density (MPOD) changes in patients affected by Retinitis pigmentosa (RP). Eighteen eyes of 18 patients suffering from early-stage RP were enrolled in our observational study. 18 eyes of 18 patients age and gender matched were enrolled as controls. Patients were analyzed at baseline by undergoing complete baseline ophthalmologic examination, Spectral-domain Optical Coherence Tomography (OCT), Electroretinogram (ERG) and Heterochromatic Flicker Photometry (HFP). Main outcome measures were Macular Pigment Optical Density (MPOD), Central macular thickness (CMT), Central Choroidal Thickness (CCT) and Choroidal Vascularity Index (CVI). Lower CCT (p = 0.006), CVI (p

Abstract This study presents a comprehensive multimodal analytical study of an Egyptian ritual Bes-vase, of the 2nd century BCE employing cutting-edge proteomics, metabolomics, genetics techniques, and synchrotron radiation-based Fourier Transformed Infrared microSpectroscopy (SR µ-FTIR) to characterize organic residues of its content. We successfully identified the presence of various functional, bioactive, psychotropic, and medicinal substances, shedding light on the diverse components of a liquid concoction used for ritual practices in Ptolemaic Egypt. Using LC-MS/MS with a new methodological approach, we identified key proteins and metabolites, enabling the identification of botanical sources, confirmed by genetic sequences. Our analyses revealed traces of Peganum harmala, Nimphaea nouchali var. caerulea, and a plant of the Cleome genus, all of which are traditionally proven to have psychotropic and medicinal properties. Additionally, the identification of human fluids suggests their direct involvement in these rituals. Furthermore, metabolomics and SR µ-FTIR analyses also revealed the presence of fermented fruit-based liquid and other ingredients such as honey or royal jelly. The identification of specific chemical compounds, such as alkaloids and flavonoids, provides insight into the psychoactive and therapeutic uses of these in ancient ritual practices. This multidisciplinary study highlights the complexity of ancient cultures and their interactions with psychoactive, medicinal, and bioactive substances. These findings contribute to our understanding of ancient belief systems, cultural practices, and the utilization of natural resources, ultimately enhancing our knowledge of past societies and their connection to the natural world.

ABSTRACT Introduction and objectives: The optimal treatment of nonculprit angiographic intermediate lesions (diameter stenosis 40%-69%) in patients with ST-segment elevation myocardial infarction (STEMI) is still unknown. Lesions with fractional flow reserve (FFR) ≤ 0.80 are indicative of ischemia and benefit from revascularization. However, lesions with FFR > 0.80 and optical coherence tomography (OCT) findings of vulnerability have been hypothesized to cause adverse events during follow-up. The study aims to compare the efficacy of a preventive treatment with stent implantation plus optimal medical therapy vs optimal medical therapy alone for nonculprit intermediate lesions with FFR > 0.80 and OCT findings of plaque vulnerability in STEMI patients at 4 years of follow-up. Methods: This parallel-group, multicenter, controlled, single-blind, and 1:1 randomized trial will enroll a total of 600 STEMI patients with ≥ 1 intermediate nonculprit lesions with FFR > 0.80 and OCT findings of plaque vulnerability. The primary endpoint is target vessel failure, defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization. The study will include a parallel registry of patients with FFR > 0.80 but without OCT findings of vulnerability. Vulnerable plaques are defined as lipid-rich fibroathermas with plaque burden ≥ 70% and a thin fibrous cap (≤ 80 μm). Results: The VULNERABLE trial will reveal the role of preventive treatment with stent implantation for nonculprit and functionally nonsignificant vulnerable plaques in STEMI patients. Conclusions: This is the first randomized trial of OCT-guided treatment of vulnerables plaques. Registered at ClinicalTrials.gov (NCT05599061).

ABSTRACT Severe aortic stenosis is the most frequent valve condition requiring surgery, and its incidence is increasing yearly. Transcatheter aortic valve implantation (TAVI) is the first-line treatment for patients at all levels of surgical risk. Nevertheless, modifications to the procedure often appear to improve clinical outcomes. A major concern after TAVI is the higher rate of permanent pacemaker implantation (PPMI) compared with surgical valve replacement. Optimal implantation depth is crucial to reduce the burden of PPMI without causing serious complications such as valve embolization. The classic implantation technique, where the 3 cusps are aligned in the same plane, has been modified to a cusp overlap projection by isolating the noncoronary cusp and superimposing the left and right cusps. This simple modification provides optimal visualization during deployment and helps to achieve the desired implant depth to reduce conduction disturbances and PPMI. Another limitation after TAVI is coronary reaccess due to the frame of the transcatheter valve obstructing the coronary ostia. Commissural alignment of the prostheses with the native valve may facilitate selective cannulation of the coronary arteries after this procedure. This review will discuss the techniques and supporting evidence for these modifications to the deployment and implant projection methods, and how they can improve TAVI outcomes.

Abstract Background Only a few cases of bilateral traumatic sternoclavicular dislocations have been reported in the literature. This injury is considered one of the rarest injuries of the human musculoskeletal system. Therefore, we present the first documented case of a cyclist with a third-degree open thoracic trauma (Gustilo–Anderson 3a) associated with a dislocated manubrium sterni fracture in the upper thoracic aperture, bilateral anterior dislocations of the sternoclavicular joints, rib fractures, and pleural ruptures. Case presentation The patient, a 27-year-old Caucasian male, incurred this injury while participating in a professional cycling race at Nürburgring, Germany and received immediate interdisciplinary surgical treatment and has encountered no complications. We conducted a 1-year follow-up and present the clinical findings of this follow up. Additionally, we conducted a comprehensive review of the existing literature on this injury. Conclusions Immediate interdisciplinary intervention, including surgical repair and meticulous postoperative care, facilitated successful patient recovery. This underscores the critical role of comprehensive trauma management in complex polytrauma cases. In conclusion, this case report highlights the rarity and complexity of a traumatic injury involving bilateral sternoclavicular dislocation, with this case being the first case reported with concomitant open thorax trauma. Our patient benefited greatly from immediate air-bound transportation to an interdisciplinary care provider, which houses both thoracic and trauma surgery departments.

Abstract The ultrastructure of human oocytes has been described only qualitatively. To offer a precise organelle spatial distribution and organelle volume during the main maturation stages, we previously conducted stereological studies on prophase-I (GV) and metaphase-I (MI) oocytes, and here we present results on metaphase-II (MII) oocytes. Five donor oocytes from different donors were processed for transmission electron microscopy, and quantification of organelle distribution was performed using point-counting stereology. Statistical tests compared the means of the relative volumes occupied by organelles among oocyte regions. The most abundant organelles were elements of the smooth endoplasmic reticulum (SER), such as SER small vesicles, SER medium vesicles, SER large vesicles and SER isolated tubules, along with mitochondria, followed by SER tubular aggregates, cortical vesicles and lysosomes. Significant differences between oocyte regions were found for lysosomes, cortical vesicles and SER large vesicles. Comparisons of MII oocytes to previous findings in GV and MI oocytes evidenced specific patterns of organelle distribution and relative volumes. This final evaluation thus enables to track organelle spatial reorganization across oocyte stages, which, in addition to gathered knowledge, may be useful to assist in improvements of stimulation protocols, in-vitro maturation media and cryopreservation techniques.

Abstract Aquatic species living in productive coastal habitats with abundant primary producers have evolved in highly dynamic diel and seasonally fluctuating environments in terms of, for example, water temperature and dissolved oxygen. However, how environmental fluctuations shape the thermal tolerance of marine species is still poorly understood. Here we hypothesize that the degree of predictability of the diel environmental fluctuations in the coastal area can explain the thermal response of marine species. To test this hypothesis, we measured the thermal tolerance of 17 species of marine ectotherm from tropical, warm temperate and cold temperate latitudes under two levels of oxygen (around saturation and at supersaturation), and relate the results to their site-specific temperature and oxygen fluctuation and their environmental predictability. We demonstrate that oxygen and temperature fluctuations at tropical latitudes have a higher predictability than those at warm and cold temperate latitudes. Further, we show that marine species that are adapted to high predictability have the potential to tune their thermal performance when exposed to oxygen supersaturation, despite being constrained within a narrow safety margin. We advocate that the predictability of the environmental fluctuation needs to be considered when measuring and forecasting the response of marine animals to global warming.

Abstract Background and aim Migraine is a common disabling conditions which, globally, affects 15.2% of the population. It is the second cause of health loss in terms of years lived with disability, the first among women. Despite being so common, it is poorly recognised and too often undertreated. Specialty centres and neurologists with specific expertise on headache disorders have the knowledge to provide specific care: however, those who do not regularly treat patients with migraine will benefit from a synopsis on the most relevant and updated information about this condition. This paper presents a comprehensive view on the hallmarks of migraine, from genetics and diagnostic markers, up to treatments and societal impact, and reports the elements that identify migraine specific features. Main results The most relevant hallmark of migraine is that it has common and individual features together. Besides the known clinical manifestations, migraine presentation is heterogeneous with regard to frequency of attacks, presence of aura, response to therapy, associated comorbidities or other symptoms, which likely reflect migraine heterogeneous genetic and molecular basis. The amount of therapies for acute and for prophylactic treatment is really wide, and one of the difficulties is with finding the best treatment for the single patient. In addition to this, patients carry out different daily life activities, and might show lifestyle habits which are not entirely adequate to manage migraine day by day. Education will be more and more important as a strategy of brain health promotion, because this will enable reducing the amount of subjects needing specialty care, thus leaving it to those who require it in reason of refractory condition or presence of comorbidities. Conclusions Recognizing the hallmarks of migraine and the features of single patients enables prescribing specific pharmacological and non-pharmacological treatments. Medical research on headaches today particularly suffers from the syndrome of single-disease approach, but it is important to have a cross-sectional and joint vision with other close specialties, in order to treat our patients with a comprehensive approach that a heterogeneous condition like migraine requires.

Abstract Background The Brazilian Policy for Comprehensive Care for People with Rare Diseases was implemented in 2014; however, national epidemiological data on rare diseases (RDs) are scarce and mainly focused on specific disorders. To address this gap, University Hospitals, Reference Services for Neonatal Screening, and Reference Services for Rare Diseases, all of which are public health institutions, established the Brazilian Rare Diseases Network (RARAS) in 2020. The objective of this study was to perform a comprehensive nationwide epidemiological investigation of individuals with RDs in Brazil. This retrospective survey collected data from patients receiving care in 34 healthcare facilities affiliated with RARAS in 2018 and 2019. Results The survey included 12,530 participants with a median age of 15.0 years, with women representing 50.5% of the cohort. Classification according to skin color demonstrated that 5044 (47.4%) participants were admixed. Most had a confirmed diagnosis (63.2%), with a predominance of phenylketonuria (PKU), cystic fibrosis (CF), and acromegaly. Common clinical manifestations included global developmental delay and seizures. The average duration of the diagnostic odyssey was 5.4 years (± 7.9 years). Among the confirmed diagnoses, 52.2% were etiological (biochemical: 42.5%; molecular: 30.9%), while 47.8% were clinical. Prenatal diagnoses accounted for 1.2%. Familial recurrence and consanguinity rates were 21.6% and 6.4%, respectively. Mainstay treatments included drug therapy (55.0%) and rehabilitation (15.6%). The Public Health System funded most diagnoses (84.2%) and treatments (86.7%). Hospitalizations were reported in 44.5% of cases, and the mortality rate was 1.5%, primarily due to motor neuron disease and CF. Conclusion This study marks a pioneering national-level data collection effort for rare diseases in Brazil, offering novel insights to advance the understanding, management, and resource allocation for RDs. It unveils an average diagnostic odyssey of 5.4 years and a higher prevalence of PKU and CF, possibly associated with the specialized services network, which included newborn screening services.

Abstract Following up the previously published systematic review on the same topic and realizing that new studies and evidence had emerged on the matter, we conducted an update on the same research terms. With the objective of updating the information relating environmental risk factors on neurodegenerative diseases and the geographic approaches used to address them, we searched PubMed, Web of Science and Scopus for all scientific studies considering the following three domains: neurodegenerative disease, environmental atmospheric factor and geographical analysis, using the same keywords as in the previously published systematic review. From February 2020 to February 2023, 35 papers were included versus 34 in the previous period, with dementia (including Alzheimer’s disease) being the most focused disease (60.0%) in this update, opposed to multiple sclerosis on the last review (55.9%). Also, environmental pollutants such as PM2.5 and NO2 have gained prominence, being represented in 65.7% and 42.9% of the new studies, opposed to 9.8% and 12.2% in the previous review, compared to environmental factors such as sun exposure (5.7% in the update vs 15.9% in the original). The mostly used geographic approach remained the patient’s residence (82.9% in the update vs 21.2% in the original and 62.3% in total), and remote sensing was used in 45.7% of the new studies versus 19.7% in the original review, with 42.0% of studies using it globally, being the second most common approach, usually to compute the environmental variable. This review has been registered in PROSPERO with the number CRD42020196188.

Abstract Classifying individuals based on metabotypes and lifestyle phenotypes using exploratory factor analyses, cluster definition, and machine-learning algorithms is promising for precision chronic disease prevention and management. This study analyzed data from the NUTRiMDEA online cohort (baseline: n = 17332 and 62 questions) to develop a clustering tool based on 32 accessible questions using machine-learning strategies. Participants ranged from 18 to over 70 years old, with 64.1% female and 35.5% male. Five clusters were identified, combining metabolic, lifestyle, and personal data: Cluster 1 (“Westernized Millennial”, n = 967) included healthy young individuals with fair lifestyle habits; Cluster 2 (“Healthy”, n = 10616) consisted of healthy adults; Cluster 3 (“Mediterranean Young Adult”, n = 2013) represented healthy young adults with a healthy lifestyle and showed the highest adherence to the Mediterranean diet; Cluster 4 (“Pre-morbid”, n = 600) was characterized by healthy adults with declined mood; Cluster 5 (“Pro-morbid”, n = 312) comprised older individuals (47% >55 years) with poorer lifestyle habits, worse health, and a lower health-related quality of life. A computational algorithm was elicited, which allowed quick cluster assignment based on responses (“lifemetabotypes”). This machine-learning approach facilitates personalized interventions and precision lifestyle recommendations, supporting online methods for targeted health maintenance and chronic disease prevention.

Abstract A Right Ear Advantage (REA) is well-established in perceptual tasks but it has been found also during imagery. It is ascribed to the left temporoparietal activity for language, and it can be absent/reversed in some clinical conditions including auditory hallucinations. We applied 1-Hz repetitive TMS over TP3/TP4 (left/right language areas) identified through neuronavigation in 18 healthy participants, before administering a modified white noise (WN) speech illusion paradigm: a voice was presented at one ear, at the same or lower intensities with respect to binaural WN. In some trials the voice was not presented, but participants were anyway instructed to report in which ear they believed perceiving it in all trials. Results confirmed the REA both when the voice was present (perceptual REA) and when it was absent (imaginative REA). Interestingly, results suggested that the correct localization of the voice when the stimulus was ambiguous (presented at low intensity and “masked” by WN) was better when TMS was applied over the right/left hemisphere, in male participants with a low/high proneness to unusual experiences (e.g., auditory hallucinations), respectively. This interaction must be further explored to shed light on the relationship between hemispheric asymmetries and auditory hallucinations, in healthy and clinical samples.

Abstract Elastic fibers are crucial for aortic valve (AoV) function and are generated and maintained by valvular interstitial cells (VICs). VICs exhibit diverse phenotypes, yet the specific subpopulation responsible for producing and regulating elastic fibers remains unclear. This gap in knowledge is significant, given that elastin (Eln) abnormalities lead to congenital AoV defects and initiate AoV diseases. This study characterizes the timing of Eln expression in murine AoV, revealing it peaks during late embryogenesis and early postnatal stages, decreasing in adulthood. Spatial transcriptomics and RT-qPCR indicate that Eln expression correlates with genes associated to elastogenesis, including Acta2, a smooth muscle cell marker. While Eln expression is not exclusive to a single VIC subpopulation, RNAscope and immunofluorescence demonstrate a population of Eln-expressing VICs that co-express alpha smooth muscle actin and melanocytic markers. As previously reported in adult mice, we show a relationship between AoV pigment and elastic fiber patterning during early postnatal stages and further show that melanocytes may play a critical role in elastogenesis. In summary, Eln is expressed in the AoV during early postnatal stages by cells co-expressing markers of various types, highlighting the complexity of VICs phenotypes and their role in elastic fiber regulation.

Abstract In 2014, the World Health Organisation (WHO) published target product profiles (TPP) for development of novel tuberculosis (TB) diagnostics. One of the key highlights is the need for point-of-care non-sputum-based tests capable of detecting all forms of TB through identification of characteristic biomarkers or biosignatures. Compared to the limitations associated with sputum-based TB tests, non-sputum samples are easy to collect, non-invasive, with potential to improve TB diagnosis among children and among people living with HIV/AIDS (PLHIV). This review gives an overview of the existing evidence on TB diagnostic studies of non-sputum-based samples collected non-invasively from or through the oral–gastrointestinal tract (GI) and nasal pharynx regions of humans and the biomarkers detected. We further summarized evidence of these biomarkers and sample types from research done in paediatric and PLHIV. The review identified; saliva, cough aerosols, oral swabs, oral wash, dental plaque, tongue swabs, face mask sampling, exhaled breath, and stool, as the non-sputum samples investigated. These biomarkers can be categorized into Deoxyribose Nucleic Acid (DNA), Ribonucleic Acid (RNA), inflammatory, antigen–antibody, volatile and non-volatile compounds, microbiome and microbiota. The biomarkers identified were derived both from the host and pathogen. Similar biomarkers were identified in the general population, children and among PLHIV. These biomarkers have been detected by either already approved simple point of care or sophisticated devices. Differences in methodology and sample types investigated, small sample size of children and PLHIV populations, bias due to confounding factors, were some of the identified challenges in these studies. There is need to conduct larger and standardized multi centre studies to evaluate non-sputum-based biomarker-based tests in children and PLHIV.

Abstract The field of photonic integrated circuits has witnessed significant progress in recent years, with a growing demand for devices that offer high-performance reconfigurability. Due to the inability of conventional tunable directional couplers (TDCs) to maintain a fixed phase while tuning the reflectivity, Mach-Zehnder interferometers (MZIs) are employed as the primary building blocks for reflectivity tuning in constructing large-scale circuits. However, MZIs are prone to fabrication errors due to the need for perfect balanced directional couplers to achieve 0-1 reflectivity, which hinders their scalability. In this study, we introduce a design of a TDC based on coupling constant tuning in the thin film Lithium Niobate platform and present an optimized design. Our optimized TDC design enables arbitrary reflectivity tuning while ensuring a consistent phase across a wide range of operating wavelengths. Furthermore, it exhibits fewer bending sections than MZIs and is inherently resilient to fabrication errors in waveguide geometry and coupling length compared to both MZIs and conventional TDCs. Our work contributes to developing high-performance photonic integrated circuits with implications for various fields, including optical communication systems and quantum information processing.

Abstract Students play a key role in university social responsibility (USR), as they are the protagonists of change and the fundamental axis in the teaching-learning process. This study aims to assess the factors associated with the perception of university social responsibility among dental students from two universities in the Peruvian capital. This analytical cross-sectional study assessed 754 students from two Peruvian universities between May and July 2023. The study utilized a validated 51-item questionnaire to assess sociodemographic factors and dental students’ perception of USR. A Poisson regression model with robust variance and prevalence ratio (PR) was used to assess the influence of variables such as age, sex, marital status, type of university, academic year, and awareness of taking subjects related to USR. The significance was set at p

Abstract Background Liquid biopsy based on cell-free DNA (cfDNA) analysis holds significant promise as a minimally invasive approach for the diagnosis, genotyping, and monitoring of solid malignancies. Human tumors release cfDNA in the bloodstream through a combination of events, including cell death, active and passive release. However, the precise mechanisms leading to cfDNA shedding remain to be characterized. Addressing this question in patients is confounded by several factors, such as tumor burden extent, anatomical and vasculature barriers, and release of nucleic acids from normal cells. In this work, we exploited cancer models to dissect basic mechanisms of DNA release. Methods We measured cell loss ratio, doubling time, and cfDNA release in the supernatant of a colorectal cancer (CRC) cell line collection (N = 76) representative of the molecular subtypes previously identified in cancer patients. Association analyses between quantitative parameters of cfDNA release, cell proliferation, and molecular features were evaluated. Functional experiments were performed to test the impact of modulating DNA methylation on cfDNA release. Results Higher levels of supernatant cfDNA were significantly associated with slower cell cycling and increased cell death. In addition, a higher cfDNA shedding was found in non-CpG Island Methylator Phenotype (CIMP) models. These results indicate a positive correlation between lower methylation and increased cfDNA levels. To explore this further, we exploited methylation microarrays to identify a subset of probes significantly associated with cfDNA shedding and derive a methylation signature capable of discriminating high from low cfDNA releasers. We applied this signature to an independent set of 176 CRC cell lines and patient derived organoids to select 14 models predicted to be low or high releasers. The methylation profile successfully predicted the amount of cfDNA released in the supernatant. At the functional level, genetic ablation of DNA methyl-transferases increased chromatin accessibility and DNA fragmentation, leading to increased cfDNA release in isogenic CRC cell lines. Furthermore, in vitro treatment of five low releaser CRC cells with a demethylating agent was able to induce a significant increase in cfDNA shedding. Conclusions Methylation status of cancer cell lines contributes to the variability of cfDNA shedding in vitro. Changes in methylation pattern are associated with cfDNA release levels and might be exploited to increase sensitivity of liquid biopsy assays.

Abstract Background The potential efficacy of early combination therapy, based on an antiviral plus a monoclonal antibody, for COVID-19 in severely immunocompromised patients is matter of debate. Objectives Our aim was to describe the impact on clinical outcomes of COVID-19 treatments in severely immunocompromised individuals, evaluating differences between a combination and a monotherapy. Methods We included severely immunocompromised outpatients with mild-to-moderate COVID-19 who received an early treatment (either monotherapy with nirmatrelvir/ritonavir or remdesivir or the combination of an antiviral plus sotrovimab). We then assessed differences between the two treatment strategies on three main outcomes (30-day mortality, access to emergency department, hospitalization), separately and as a composite by using a propensity score weighted (PSW) approach. Results Eighty one severely immunocompromised patients were included, 39 receiving early combination therapy and 42 receiving monotherapy. No significant difference was observed in the 30-day mortality rate and hospitalization rate between subjects in the two groups, while access to the emergency department following treatment administration was significantly higher in people who received a combination therapy. After applying the PSW, it was observed that combination therapy impacted favourably on the composite outcome, in a statistically significant fashion. In addition, PSW approach for mortality showed that age was the only significant factor influencing the death as stand-alone outcome. Conclusions Early combination therapy showed a favourable impact on a composite outcome (including mortality, hospitalizations and access to emergency department) in severely immunocompromised hosts who were all vaccinated. However, further studies are needed to support our results.