Search Results (2,251)

Background: Chronically non-healing thoracic wounds after cardiac and non-cardiac thoracotomy, including cases when coronary artery bypass grafting (CABG) is performed, represent a great clinical challenge. It is often that a conservative treatment of the wounds does not provide effective regeneration of the damaged tissues. It is especially critical in patients with infected wounds, in patients owning a systemic infection, and in elderly people. Methods: The article presents a case report of successful treatment of a 63-year-old man with refractory chronic osteomyelitis of the sternum and mediastinitis four years after CABG, complicated by COVID-19 at the time of reconstructive surgery. Due to the low effectiveness of conservative treatment methods, a two-stage approach was applied: radical surgical wound debridement followed by infiltration of the wound with allogenic mesenchymal stromal cells (MSCs) of Wharton’s jelly (WJ-MSCs). Results: This double-stage therapy successfully modulated the inflammatory environment and stimulated granulation, facilitating final thoracoplasty and osteosynthesis. The patient achieved complete healing of the sternum, demonstrating benefits of WJ-MSCs in treating conservative treatment-resistant infections in the surgical wound. Conclusions: The advantages of using perinatal mesenchymal stem cells, with WJ-MSCs as a type of this class of MSCs, were demonstrated in treating chronically infected sternal surgical wounds. We also compared their regenerative properties to other stem cell types like bone marrow MSCs. Full article

Background: Although the main target of SARS-CoV-2 is the respiratory system, in some patients, it may affect multiple organ systems, leading to multi-organ failure. Acute kidney injury (AKI) remains one of the most frequent and clinically significant complications of severe COVID-19, with clinical importance extending beyond the acute phase due to its association with long-term renal outcomes and persistent morbidity. The incidence of AKI is particularly high among patients admitted to the intensive care unit (ICU), where its development has been consistently associated with prolonged hospitalization and increased mortality. The primary aim of this study was to determine the incidence of COVID-19-associated AKI, identify factors related to its development and severity, and evaluate mortality as a clinical outcome. Methods: Data from 238 COVID-19 patients monitored in the Intensive Care Unit of Ankara University Ibni Sina Hospital (ISH-ICU) between 1 January 2021 and 1 January 2022 were retrospectively reviewed. Patients were divided into two groups according to the presence of AKI. Those with AKI were staged according to KDIGO criteria (stages 1–2–3). Demographic characteristics, comorbidities, disease severity scores, laboratory parameters, and mortality outcomes were analyzed and compared between groups. Results: AKI was identified in 54.6% of patients. Of the patients with AKI, 32 (13.4%) had stage 1, 25 (10.5%) had stage 2, and 73 (30.7%) had stage 3 AKI. Thirteen patients (5.5%) had already developed AKI at ICU admission. AKI developed at a median of 11 days after symptom onset and 3 days after ICU admission. Advanced age, hypertension, cardiovascular disease, and chronic kidney disease were more frequent in patients with AKI (p < 0.001). Higher Charlson Comorbidity Index (CCI) and Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) scores were observed in patients with stage 3 AKI. Lymphopenia and elevated levels of D-dimer, ferritin, IL-6, CRP, and procalcitonin were significantly higher in patients with stage 3 AKI than in patients with other AKI stages and the non-AKI group. Mortality rates were higher in patients with AKI and increased with advancing AKI stage (p < 0.001). ICU length of stay was significantly longer in the AKI group (p < 0.001). Conclusions: AKI is a common complication among critically ill patients with COVID-19 and is associated with prolonged ICU stay and higher mortality rates, particularly in advanced stages. Early identification of clinical and laboratory factors associated with AKI may support timely risk stratification and targeted management in this high-risk population. Full article

Background: The COVID-19 virus is a source of both acute and chronic stress for many people. This stress could uniquely impact children and their mental health. Research has shown that children with neurodevelopmental disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD) are at an increased risk of negative mental health symptoms due to stress, but high-quality sleep may be associated with a protective role against these symptoms. We, therefore, aimed to investigate whether the impacts of COVID-19 and sleep problems were independently linked with children’s mental health and to examine whether sleep could mediate the relationship between COVID-19 impact and child mental health. Finally, we sought to compare the degree to which sleep problems could mediate this relationship in children without ADHD and in children with ADHD. Methods: In this cross-sectional study, a total of 304 parents of children were sampled from a larger study investigating the impact of the COVID-19 pandemic on Canadian families and children in the spring of 2021. Parents reported on their children’s mental health, sleep, and the impacts of COVID-19 on their child. Of the total sample, 234 children were reported as having an ADHD diagnosis, and 70 children were reported to not have ADHD. Results: We found that both the impact of COVID-19 and sleep problems independently and positively contributed to the mental health symptoms (p < 0.001) experienced by children with ADHD and without ADHD. Children with ADHD were found to have higher scores for COVID-19 child impact, sleep problems, and negative mental health. However, sleep problems had a greater impact on the mental health of children without ADHD compared to ADHD children. Additionally, the results suggest that sleep problems mediated ~20% of the relationship between COVID-19 impact and child mental health in children with ADHD and ~51% of this relationship in children without ADHD. Conclusions: The findings emphasize the significant role of sleep in mediating child mental health symptoms during periods of stress in children without ADHD and in children with ADHD. We highlight the importance of considering sleep quality and supporting healthy sleep in times of stress to improve child mental health symptoms. Full article

Background: Acute kidney injury (AKI) is increasingly recognised in children with acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C), yet the long-term renal consequences in younger paediatric populations remain unclear. Most studies focus on acute illness or mixed-age cohorts, with limited data specific to children aged 0–12 years. Objectives: This study aimed to systematically identify, evaluate, and synthesise evidence on post-acute (≥30 days) and long-term (≥90 days) kidney outcomes following SARS-CoV-2 infection or MIS-C in children aged 0–12 years, including chronic kidney disease (CKD), eGFR decline, proteinuria, haematuria, hypertension, and need for kidney replacement therapy. Methods: We searched MEDLINE, Embase, CINAHL, and PubMed (December 2019–30 November 2025), following PRISMA 2020 guidelines and a registered PROSPERO protocol (CRD420251241949). Observational studies reporting kidney outcomes ≥30 days post-infection in children aged 0–12 years were included. Risk of bias was assessed using the Newcastle–Ottawa Scale or ROBINS-I. Owing to heterogeneity and absence of ≥3 comparable datasets, a narrative synthesis was performed. Results: Seven studies met inclusion criteria (five MIS-C cohorts, two acute COVID-19 cohorts). Only a subset provided extractable data specific to children aged 0–12 years. Follow-up ranged from 30 days to 12 months; four studies reported outcomes ≥ 180 days. Across all studies, no incident CKD, sustained eGFR decline, or kidney replacement therapy were reported among children completing long-term follow-up; however, most long-term outcome data were derived from MIS-C cohorts with median ages around 8–11 years that included some adolescents, rather than exclusively children aged 0–12 years. One MIS-C study reported long-term hypertension in 14% of children. A cross-sectional Italian cohort of mild COVID-19 demonstrated hyperfiltration, proteinuria, and microhaematuria at ~3 months, though chronicity could not be assessed due to absence of baseline values. A large US EHR-based cohort identified increased CKD risk after COVID-19 in the broader < 21-year population; however, 0–12-year-specific event counts were not reported, preventing quantitative synthesis for young children. Conclusions: Evidence on long-term kidney outcomes after SARS-CoV-2 infection in children aged 0–12 years remains limited, and only a small subset of studies provided extractable, age-specific data. On the other hand, MIS-C cohorts generally show favourable renal recovery, small sample sizes, lack of control groups, and short follow-up restrict confidence in these findings. Large paediatric EHR studies suggest potential long-term renal risk in broader paediatric populations, highlighting the need for age-stratified, prospective cohorts with serial eGFR, urine studies, and blood pressure assessments. Until definitive evidence emerges, structured renal follow-up may be warranted for children with AKI or MIS-C during COVID-19. Full article

ROS derived from NADPH oxidase, particularly NOX2, are central to antimicrobial defense, coupling direct pathogen killing with redox signaling that shapes inflammation. This narrative review integrates recent advances on NOX2 structure, assembly, and spatiotemporal control in phagocytes, and outlines how ROS interact with NF-κB, MAPK, and Nrf2 networks to coordinate microbicidal activity and immune modulation. We summarize evidence that both ROS deficiency, as in chronic granulomatous disease, and uncontrolled excess, as in sepsis and severe COVID-19, drive clinically significant pathology, emphasizing the need for precise redox balance. Emerging therapeutic strategies include selective NOX2 inhibitors that limit pathological oxidative bursts, redox-modulating peptides that disrupt upstream activation cues, and Nrf2 activators that enhance endogenous antioxidant capacity, with attention to dosing challenges that preserve host defense while mitigating tissue injury. Key gaps remain in biomarker standardization, real-time in vivo ROS monitoring, and translation from animal models to patients, motivating personalized, combination approaches to redox medicine in infectious diseases. Full article

Background: The integration of artificial intelligence (AI) into mobile health (mHealth) applications has been accelerated by the widespread adoption of smartphones and recent technological advances, particularly in the wake of the COVID-19 pandemic. This experience has expanded the role of AI-powered apps in real-time health monitoring, early detection, and personalized treatment pathways. Aim: This review aims to summarize recent evidence on the use of AI in healthcare-related mobile applications, with a focus on clinical trends, practical implications, and future directions. Methods: Studies were prioritized based on methodological rigor, with systematic reviews forming the core of the analysis. Additional literature was considered to capture emerging trends and applications where a relevant rigorous screening and scoring procedure was applied to ensure methodological quality and relevance. Only studies addressing healthcare applications, rather than computational or computer science frameworks, were included to reflect the journal’s clinical scope. Results and Discussion: Fifty-six secondary studies were analyzed in detail. Thematic synthesis revealed a post-pandemic shift toward applications targeting mental health, chronic care management, and preventive services. Additional screening showed that, despite their increasing use in clinical contexts, few AI-based apps were formally classified as medical devices. This highlights a gap between technological innovation and regulatory oversight. Ethical concerns—including algorithm transparency, clinical responsibility, and data protection—were frequently reported across studies. Conclusions: This review underscores the growing impact of AI in mobile health, while drawing attention to unresolved challenges related to regulation, safety, and clinical accountability. A more robust integration into health systems will require clearer governance frameworks, validation standards, and interdisciplinary dialogue between developers, clinicians, and regulators. Full article

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated not only with respiratory illness but also with profound vascular and coagulation disturbances. Long COVID (LC) is characterized by persistent symptoms such as fatigue, dyspnea, cognitive impairment, and palpitations. Mechanistically, SARS-CoV-2 induces direct endothelial injury, promotes a pro-inflammatory cytokine milieu, and activates platelets, leading to immunothrombosis and impaired fibrinolysis. Consequently, patients exhibit microthrombosis, elevated plasma D-dimer, fibrinogen dysregulation, and persistent hypercoagulability. Clinically, this translates into an increased risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, as well as arterial thrombotic events such as myocardial infarction and stroke, which may persist months after acute infection. Understanding the interplay between endothelial injury, inflammation, and coagulation is crucial for risk stratification and the development of preventive and therapeutic strategies. We conducted a systematic narrative review of the literature, including human clinical and mechanistic studies identified through PubMed, Scopus and Web of Science up to 30 September 2025. This review synthesizes current evidence on vascular complications in LC, highlighting endothelial dysfunction as a central pathophysiological nexus linking the acute phase of SARS-CoV-2 infection with chronic LC manifestations. Full article

Background: Persistent low-grade inflammation has been proposed as part of the biological mechanisms underlying post-COVID condition (PCC), which can result in laboratory tests abnormalities. However, the accuracy of routine laboratory tests for the diagnosis and follow-up of PCC is still under discussion. Methods: Patients with SARS-CoV-2 infection enrolled in the prospective, multinational ORCHESTRA cohort study, which included both European and non-European countries, were followed up for 18 months after acute infection. Blood test results were collected at acute infection and at 6, 12, and 18 months. A multivariable analysis was performed to estimate the relationship between the alterations of biochemical markers and the presence of four distinct PCC phenotypes, identified previously through a principal component analysis—respiratory (RESc), chronic pain (CPc), chronic fatigue (CFc), and neurosensorial (NSc)—during follow-up. Furthermore, this study investigated the correlation between biochemical parameters measured during the acute phase and the subsequent development of PCC. Finally, the relationship between the severity of the acute infection and biochemical abnormalities observed during follow-up was assessed. Results: The cohort included 4587 patients, 58% male, with a mean age of 58.7 (±15.5) years. A robust multivariable analysis demonstrated that, compared to controls, patients with PCC, and in particular those in the RESc cluster, presented higher mean C-reactive protein (CRP) levels at the 12- and 18-month follow-up (p-value = 0.01). In each follow-up, CRP values in patients with PCC and RESc were above 3 mg/L, corresponding to those observed in low-grade inflammation (3–10 mg/L). The severity of COVID-19 acute infection was associated with increased levels of CRP, ferritin and LDH during follow-up (p < 0.001). Biochemistry abnormalities detected during the early stages of acute COVID-19 did not correlate with an increased risk of developing PCC and its phenotypes. Conclusions: In patients with the RESc PCC phenotype, identified through a principal component analysis, blood test abnormalities consistent with prolonged and sustained low-grade inflammation can be detected up to 18 months after acute infection, supporting its role in the pathogenesis of PCC. Based on these results, trials on anti-inflammatory drugs, together with symptom-tailored interventions for patients with RESc, should be planned to prove their effectiveness in managing PCC and improving patient outcomes. Full article

VD (VD), a hormone-like, fat-soluble molecule, is essential for several biological processes, such as gene regulation, calcium balance, bone health, immune function, antiviral defense, and neuromuscular activity. Its deficiency is associated with various disorders, including chronic hypocalcemia and increased risk of severe diseases, such as COVID-19. Monitoring 25-hydroxyVD (25-OH-D) levels is vital, with serum 25-OH-VD being the standard marker. While chromatography and immunometric assays are well-established, innovative point-of-care (POC) platforms like AFIAS-1^® (Boditech & Menarini, Gangwon, Republic of Korea) are emerging as rapid and automated alternatives, particularly advantageous for decentralized settings such as pharmacies, general practitioners’ offices, and specialized hospital centers like intensive care units. This study compared AFIAS-1^® using whole blood with the gold standard UHPLC-MS/MS using plasma in 50 samples, showing a strong correlation and confirming AFIAS-1^® as a reliable method for measuring 25-OH-D levels. Full article

Teacher occupational health is a critical issue worldwide that COVID-19 has worsened. While previous research has highlighted the impact of chronic work-related stress and limited personal resources on burnout, much of this research relies on cross-sectional data that do not capture how these effects develop over time. Additionally, the role of positive organizational factors remains underexplored. Our study examined burnout trajectories among 101 Portuguese elementary teachers (94.1% women, M = 46.03 years, 85.6% enrollment rate) over five data collection points spanning the 1st and 2nd COVID-19 waves (2019–2021) and investigated the impact of organizational climate on teacher burnout indicators. Main work-related stressors were identified through an open-ended question. Trajectories of occupational stress and burnout were analyzed using independent ANOVAs, and moderation analyses tested the relationship between organizational climate, occupational stress, and burnout indicators. Results showed a significant drop in perceived personal accomplishment during the first lockdown. Key stressors included greater job demands and more strained interpersonal relationships. Organizational climate significantly moderated the effect of work-related stress on emotional exhaustion, while having a positive main effect on personal accomplishment. This research contributes to a strengthened theoretical understanding of burnout as a dynamic, context-sensitive process, offering new empirical evidence, especially in underrepresented educational systems like Portugal. It emphasizes the importance of addressing contextual factors when working to reduce teacher burnout. Rethinking professional development and workplace relationships is essential for supporting teachers’ occupational health in today’s uncertain educational environments. Full article

This review article attempts to provide a unifying hypothesis to explain the myriad of symptoms and predispositions underlying the development of PASC (Postacute Sequelae of COVID), often referred to as Long COVID. The hypothesis described here proposes that Long COVID is best understood as a disorder of persistent immune dysregulation, with chronic macrophage activation representing the fundamental underlying pathophysiology. Unlike transient post-viral syndromes, Long COVID involves a sustained innate immune response, particularly within monocyte-derived macrophages, driven by persistent spike protein (peripherally in MAIT cells and centrally in Microglial cells), epigenetic imprinting, and gut-related viral reservoirs. These macrophages are not merely activated temporarily but also become epigenetically “trained” into a prolonged inflammatory state, as demonstrated by enduring histone acetylation markers such as H3K27acDNA Reprogramming. It is proposed that recognizing macrophage activation as the central axis of Long COVID pathology offers a framework for personalized risk assessment, targeted intervention, and therapeutic recalibration. Full article

Background: Heart failure (HF) remains a major global health challenge, with orthotopic heart transplantation (OHT) serving as the gold-standard therapy for end-stage disease. Chronic immunosuppression required to prevent graft rejection increases the risk of infections and malignancies. The COVID-19 pandemic underscored the particular vulnerability of transplant recipients to severe SARS-CoV-2 infection. Specific immunosuppressive agents used in OHT patients may differentially affect SARS-CoV-2 infection. In particular, mTOR inhibitors may modulate viral replication and immune responses, potentially influencing disease severity. Objectives: This study evaluated the impact of immunosuppressive regimens—particularly mTOR inhibitors—on COVID-19 outcomes in heart transplant recipients, comparing mTOR-based therapy (with or without calcineurin inhibitors, CNIs) to non-mTOR-based regimens. Methods: This single-center retrospective observational study included 556 orthotopic heart transplant recipients (76.3% male; median age, 58 years) followed from March 2020 to March 2024. To compare patients receiving mTOR inhibitors with similar non-mTOR recipients, 3:1 propensity score matching was performed based on age, sex, and body mass index. Among the study population, 88 patients (15.8%) received mTOR inhibitors (everolimus or sirolimus), of whom 66 were concomitantly treated with calcineurin inhibitors and 22 without. Data were obtained from the National Health Fund database and clinical follow-ups. Results: Overall mortality was 13.5%, and COVID-19-related mortality 3.2%. COVID-19 incidence was 33% in the mTOR group versus 36.7% in the non-mTOR group (p = 0.52). Hospitalization rates were 3.4% and 6.4% (p = 0.29), respectively. All-cause mortality was higher among mTOR users (21.6% vs. 11.7%, p = 0.02), especially in the mTOR+CNI subgroup. Notably, no COVID-19-related deaths occurred in the mTOR CNI-free group. Conclusions: mTOR-based immunosuppression was non-inferior to standard therapy for COVID-19 outcomes. The absence of COVID-19-related deaths in patients on mTOR CNI-free regimens suggests potential protective effects that merit further investigation. Full article

Background: Prehospital emergency professionals are exposed to high psychosocial demands that may impact their mental health, but pre-COVID-19 baseline data from Spanish services are scarce. This study aimed to assess the general health and psychosocial risk factors in a regional prehospital emergency service before the COVID-19 pandemic. Methods: We conducted a cross-sectional descriptive study (September–December 2019) including 51 physicians, nurses, and emergency medical technicians working at the 061 Health Emergency Center in Granada (Andalusia, Spain). General health and chronic problems were assessed with the Goldberg General Health Questionnaire (GHQ-28/CGHQ-28), and work-related psychosocial risks were evaluated using the COPSOQ-ISTAS21 questionnaire. Descriptive statistics, group comparisons, and exploratory Spearman correlations between health indicators and psychosocial dimensions were performed. Results: Most participants reported good self-perceived general health, but the chronic coding of the GHQ (CGHQ-28) indicated long-term difficulties mainly related to social dysfunction, somatic symptoms, and anxiety/insomnia. Exposure to unfavorable psychosocial risk was frequent, particularly in psychological demands, double presence (work–family conflict), and low esteem, with intermediate–unfavorable patterns in active job/development, insecurity, and social support/leadership. Exploratory correlations suggested that double presence was the psychosocial factor most consistently associated with chronic distress. Conclusions: In this pre-COVID-19 cohort of prehospital emergency professionals, good perceived general health coexisted with chronic psychological strain and high exposure to adverse psychosocial work factors. These findings support the need for organizational measures to reduce psychological demands and work–family conflict and to strengthen social support and leadership in prehospital emergency teams. Full article

Vector-borne parasites might be transmitted through transfusion, notably Plasmodium spp. and Trypanosoma cruzi. Prevention strategies include blood donor screening, deferral, and blood unit treatment by pathogen inactivation methods. At the end of 2015, in line with European guidelines, Italian legislation introduced a questionnaire to identify donors at risk and their screening by serological methods. In early 2016, the Laboratory of Parasitology at Pisa University Hospital started the serological analysis of donors at risk, referring to Transfusion Services located in northwestern Tuscany. The aim of the present study was to describe the prevalence of seropositive donors observed during 8 years of screening. Donors at risk of transmitting malaria were screened by ELISA (Enzyme Linked Immunosorbent Assay). The DRG ELISA kit was employed until 2020, when it was substituted by the Euroimmun ELISA kit based on the results of a comparative evaluation of available commercial kits. Seropositive donors were offered the possibility of Plasmodium DNA testing by Loop-Mediated AMPlification (LAMP) to exclude current infection. Donors at risk of transmitting Chagas disease were screened by ICT employing recombinant antigen until 2021, when it was substituted by ELISA employing lysate antigen because of its higher accuracy. Seropositive donors were further tested by CLIA, and WB was performed in case of discordant results, according to WHO guidelines for diagnosis of chronic Chagas disease. A total of 3754 donors were tested for anti-Plasmodium antibodies, revealing a 6.8% (95% CI = 6.1–7.7%) seroprevalence. Seropositivity was higher among donors from Sub-Saharan Africa (42.9%; 95% CI = 36.1–49.9%) and Southeast Asia (10.6%; 95% CI = 6.7–16.4%). A lower seropositivity was observed when employing Euroimmun ELISA (4.8; 95% CI = 3.8–5.9%) than DRG ELISA (8.2%; 95% CI = 7.1–9.3%). Seropositivity dropped to 3.6% (95% CI = 2.4–5.6) in 2020, likely because of travel restrictions during the COVID-19 pandemic. None of the tested seropositive donors (n = 20) tested positive for Plasmodium DNA LAMP testing. A high proportion of seroreversion was observed after one year of testing. Among 4285 donors tested for anti-T. cruzi antibodies seroprevalence was 0.7% (95% CI = 0.5–1.1%), a higher value than what was observed in a recent national survey. All seropositive donors were born in Europe or Latin America. Seropositivity was apparently lower with ELISA (0.5%, 95% CI = 0.2–1.2%) than ICT (0.8%, 95% CI = 0.6–1.2%), possibly due to ELISA’s higher specificity, although the difference is not significant. No confirmed cases of chronic Chagas disease were identified. The study emphasizes the importance of defining the serological test employed for screening and the need to confirm seropositive results with further testing. The high seroreversion observed in the study suggests repeating seropositive donor screening after a year to minimize deferral and blood unit loss. Full article

Background and Objectives: COVID-19 is an infection caused by the SARS-CoV-2 coronavirus that may develop several complications. Interstitial lung disease (ILD) is the major long-term complication of COVID-19 disease leading to progressive lung fibrosis and reduced respiratory function. The aim of this narrative review is to provide an updated overview of post-COVID-19 ILD by examining research publications and clinical guidelines selected from PubMed, Web of Science, and major respiratory medicine journals from 2020 to 2025. Methods: ILDs are diagnosed by medical history, physiological examination, pulmonary function tests, and chest X-ray or high-resolution computed tomography (HRCT) scan. Lung biopsy, especially cryobiopsy or video-assisted thoracoscopic (VATS) biopsy, can be performed to define histological patterns and confirm the diagnosis. Results: Post-COVID-19 ILD is a chronic condition characterized by long-term respiratory symptoms, radiological findings, and reduced lung function. Fibrotic injury is a consequence of the initial infection and could be influenced by persistent inflammation and dysregulated tissue repair. Risk factors include severe acute illness, advanced age, male sex, and smoking. Clinical course and prognosis of post-COVID-19 ILD is uncertain, as most patients experience gradual improvement or stability, whereas others develop progressive lung function decline. Treatment of post-COVID-19 ILD is not presently defined by guidelines but comprises corticosteroids, antifibrotics (including new drugs such as nerandomilast), supportive oxygen, pulmonary physiotherapy rehabilitation, smoking cessation, and vaccination. Conclusions: ILD represents a significant long-term complication of COVID-19 infection. Further investigations are required to better understand its pathophysiology and clinical management. As research progresses, more effective diagnostic and therapeutic strategies are expected to emerge. Full article