Orthorexia nervosa (ON) is a relatively new potential eating disorder characterized by an intense fixation on one’s eating habits and the imposition of rigid and inflexible rules on oneself. Psychological factors such as obsessive–compulsive tendencies, perfectionism and self-esteem may interact in complex ways and contribute to the development and maintenance of ON.This cross-sectional study included 977 participants from Italy, Lebanon, and Poland. Participants completed a questionnaire consisting of socio-demographic information, the Eating Habits Questionnaire, Obsessive–Compulsive Inventory, Obsessive Beliefs Questionnaire-44, Multidimensional Perfectionism Scale, and Rosenberg Self-Esteem Scale. Cluster analysis was used to identify subgroups of individuals with common psychological characteristics associated with ON.Three distinct clusters were identified based on their levels of obsession-compulsive beliefs, perfectionism, and self-esteem. The first group, labeled “High Self-Mastery,” consisted of 37.0% of participants and exhibited low levels of obsession-compulsion, obsessive beliefs, and perfectionism, but high self-esteem. The second group, “Moderate Self-Mastery,” comprised 39.5% of participants and had moderate levels of these traits. The third group, “Low Self-Mastery,” consisted of 23.6% of participants and exhibited the highest levels of obsession-compulsion, obsessive beliefs, and perfectionism, but the lowest self-esteem. Additionally, a multivariable analysis revealed that being Lebanese (Beta = 3.39) and belonging to the last cluster (Beta = 4.53) were significantly associated with higher ON tendencies.Our findings show that individuals with low self-mastery, characterized by low self-esteem and high levels of obsessive perfectionism, are more likely to exhibit ON tendencies. This study emphasizes the need to have a comprehensive understanding of how cultural and psychological factors interact in the development of eating disorders. Orthorexia nervosa (ON) is a relatively new eating disorder that involves an intense focus on eating habits and strict rules about food. This study aimed to identify factors that may predict the development of ON. A questionnaire was given to 977 participants from Italy, Lebanon, and Poland to assess their psychological characteristics such as obsessive–compulsive tendencies, perfectionism, and self-esteem. Cluster analysis was performed to identify subgroups of individuals with common psychological characteristics associated with ON. The study found that participants from Lebanon, and individuals with low self-mastery, characterized by low self-esteem and high levels of obsessive perfectionism, are more likely to exhibit ON tendencies and were particularly vulnerable to the disorder. Over time, the psychopathology of eating disorders has undergone alterations possibly as a result of various environmental factors, giving rise to novel presentations within this domain. In recent years, there has been a surge of interest in orthorexia nervosa (ON), a relatively new condition characterized by an intense fixation on one's eating habits and the imposition of rigid and inflexible rules on oneself. These rules are strictly enforced and may involve spending excessive amounts of time planning, acquiring, preparing, and/or consuming one’s food . This caOverall, ON can have a significant impact on an individual's physical, emotional, and social well-being, highlighting the importance of seeking professional help when necessary. The prevalence of this condition is variable across countries and populations due to the lack of established diagnostic criteria, making it difficult to fully understand trends in its occurrence within the general population. Notably, rates range from 6.9% among Italians to 88.7% among nutrition Brazilian students  characterized with low obsession-compulsion, obsessive beliefs and perfectionism as well as high self-esteem; this cluster was labeled “High Self-Mastery (H-SM)” The second group  had moderate obsession-compulsion, obsessive beliefs and perfectionism and self-esteem; this cluster was called “Moderate Self-Mastery (M-SM)” A third group  was characterized with the highest obsession-compulsion, obsessive beliefs and perfectionism and lowest self-esteem; this group was labelled “Low Self-Mastery (L-SM)” , Poland and Lebanon (p < .001) and between Lebanon and Italy (p < .001). Moreover, participants who drank alcohol compared to those who didn’t and those belonging to Cluster 3 had the highest mean EHQ scores. Finally, higher BMI , but not age , was significantly associated with higher EHQ scores.The results of the bivariate analysis are summarized in Table The results of the linear regression showed that participants from Lebanon (Beta = 3.39) compared to those from Poland, and belonging to Cluster 3 compared to Cluster 1 Beta = 4.53) were significantly associated with higher EHQ scores  consisted of low obsessive perfectionism and high self-esteem. Individuals in cluster 2  were characterized as having moderate obsessive perfectionism and moderate self-esteem. The last group, cluster 3 , contained individuals having high obsessive perfectionism and low self-esteem.Our findings showed that individuals in the low self-mastery cluster (cluster 3) were more likely to exhibit ON tendencies than those in the high self-mastery cluster (Cluster 1), indicating that obsessive behaviors, perfectionism, and low self-esteem may predict the risk of developing ON. These findings align with previous studies that have suggested a link between obsessive–compulsive symptoms and ON , 13, 44.Low self-esteem has been identified as a significant risk factor for the development of eating disorders , a findiOn another note, the study suggests that geography or country of residence may affect ON tendencies, consistent with a previous study that also found a higher prevalence of ON in the Lebanese sample compared to the Polish sample . HoweverWhile this study provides valuable insights into the associations of various psychological variables with ON and the cross-cultural difference in its emergence, several limitations need to be considered. No individuals of non-binary gender individual were recruited in our study. One area for improvement is the cross-sectional design of the study, which may compromise its internal validity and prevent drawing causal inferences. Additionally, the self-administered questionnaire may introduce self-reporting bias, as participants may have either under or overestimated their responses. The cross-cultural nature of the study also introduces a potential source of bias, as participants from different cultures may interpret questionnaire items differently. Furthermore, the study did not account for all potential psychological and cultural factors that may influence the manifestation of ON, such as religion or social norms and traditions. Finally, the use of convenience sampling may introduce selection bias and reduce the generalizability of the results to the broader population. To address these limitations, future studies could utilize alternative methods of sampling and data collection, such as random sampling and face-to-face interviews, to minimize selection and self-reporting biases. Additionally, longitudinal designs could be used to investigate the causal relationship between psychological variables and ON, allowing for more robust causal inferences. Furthermore, future studies could aim to account for additional confounding variables related to ON and culture to reduce residual confounding bias. By addressing these limitations, future studies can improve the validity and generalizability of their findings and provide a more comprehensive understanding of the complex interplay between psychological variables and ON across different cultures.The study highlights the importance of assessing self-esteem, obsessive–compulsive symptoms, and perfectionism in individuals with ON tendencies. These factors seem closely associated with the development and severity of ON. Therefore, interventions aimed at building self-esteem and reducing obsessive–compulsive and perfectionism symptoms may benefit those in the Low Self-Mastery cluster. Therefore, enhancing self-mastery can be an important target for treatment interventions in individuals with ON, predicting higher self-ratings of health and a greater sense of control , 59. FurIn conclusion, this study offers valuable insights into the complex relationship between ON, self-esteem, and obsessive perfectionism. It emphasizes that individuals with low self-mastery, characterized by low self-esteem and high levels of obsessive perfectionism, are more prone to ON tendencies. Additionally, cultural factors may contribute to the development of this condition. These findings highlight the need for interventions promoting self-mastery and preventing the emergence of ON across diverse cultural contexts. Ultimately, this research underscores the importance of understanding the complex interplay between psychological and cultural factors in the development of eating disorders.


Kaposi Sarcoma Inflammatory Cytokine Syndrome (KICS) is a serious, uncommon disease that occurs in patients who are positive for HIV and human herpesvirus-8 (HHV-8). It is characterized by a constellation of clinical findings, including fever, weight loss, and fluid retention, as well as a lack of multicentric Castleman disease (MCD) features on histopathology and an elevated serum HHV-8 viral load. Diagnosis is often delayed, and treatment options are limited, culminating in high mortality rates.We hereby present a 32-year-old male patient with HIV who was untreated for a few years and came with fever, night sweats, pancytopenia, and widespread adenopathy. A thorough evaluation of opportunistic infections was unremarkable. Clinically MCD was suspected, but lymph node biopsy only showed Kaposi sarcoma (KS) with no characteristic features of MCD. However, with clinical deterioration, KICS was strongly suspected. Kaposi sarcoma immune reconstitution syndrome (KS-IRIS) was also a possibility as the patient was restarted on antiretroviral therapy. Rituximab was commenced, but the patient suffered a cardiac arrest and could not be revived.Alternative diagnosis must be explored in patients with HIV presenting with constitutional symptoms, cytopenia, and adenopathy after opportunistic infections and malignancies are ruled out. If they have KS with HHV-8 positivity and there is a lack of characteristic features of MCD in lymph node biopsy, prompt suspicion of KICS should be made, and treatment with rituximab and/or chemotherapy should be instituted rapidly. KS-IRIS is also possible if patients have recently received antiretroviral therapy and have a rapid decline in viral load and increase in CD4 counts . HHV8 viral load levels may help to distinguish between these two inflammatory conditions. Kaposi sarcoma inflammatory cytokine syndrome (KICS) is a rare disease that occurs exclusively in patients with a co-infection of human herpesvirus-8 (HHV-8) and HIV . Its cliWe present the case of a 32-year-old male with a past medical history of HIV who presented with fever and night sweats for over one month. He had exertional shortness of breath and a mild non-productive cough. He had not taken antiretroviral medications for approximately the last three years and had not had any laboratory tests performed for the past two years. He had been prescribed bictegravir, emtricitabine, and tenofovir regimen for HIV. Initial workup revealed significant pancytopenia with leukocytes - 3.28 Th/ul, hemoglobin - 7.1 g/dl, and platelets - 80 Th/ul. CT scan of the abdomen/pelvis revealed marked hepatosplenomegaly and lymphadenopathy predominantly within the iliac chains and periaortic/paracaval lymph nodes. CT angiogram of the chest noted prominent axillary, supraclavicular, and mediastinal lymph nodes and cardiac enlargement with small pericardial effusion. These findings were suggestive of lymphoproliferative disorder versus opportunistic infection. He was started on empiric doxycycline, given his exposure to birds and the possibility of psittacosis. It was initially decided to hold ART until a definitive diagnosis was reached to avoid IRIS.Further, the workup revealed a CD4 count of 90 cells/uL and an HIV-1 RNA quantitative log of 6.37 copies/ml. The urinalysis was unremarkable, and the urine toxicology screen was negative. COVID-19 polymerase chain reaction (PCR) testing also came back negative. Tests for various antibodies, including Antinuclear (ANA), anti-mitochondrial (AMA), anti-smooth muscle actin (SMA), and celiac antibodies, all returned negative results. Similarly, antigen tests for Histoplasma in the urine, strep pneumonia in the urine, and legionella in the urine were negative.We conducted a hepatitis panel and a pneumonia panel, both of which were unrevealing. Respiratory panel PCR testing for various organisms such as chlamydia, mycoplasma, bordetella, metapneumovirus, and parainfluenza virus all returned negative results. We performed a bone marrow biopsy which revealed hypercellularity but no evidence of leukemia or lymphoma. Tests for cytomegalovirus (CMV) and Epstein Barr virus (EBV) using PCR were negative. Blood and urine cultures showed no bacterial growth. Finally, we restarted the patient on his ART. The pneumocystis PCR test came back negative. We performed a right inguinal lymph node biopsy, and both the Acid-fast bacilli (AFB) and Gram stain on the lymph node tissue were negative. Later, we conducted an esophagogastroduodenoscopy (EGD) and colonoscopy to evaluate the patient for probable iron deficiency anemia and to rule out intestinal lymphoma. The results were unremarkable, except for the presence of esophageal candidiasis. For this, we started the patient on fluconazole. The patient had intermittent fevers, so we started him on an anti-Mycobacterium avium complex (MAC) regimen, which included azithromycin and ethambutol. Despite these interventions, the patient continued to have pancytopenia.Clinically, there was also concern for HHV-8-associated MCD. Lymph node biopsy results arrived more than a week later and showed that nodal tissue was largely replaced by KS Figure . The resThere was also a potential concern about KICS accounting for the patient's presentation. With further worsening of liver and kidney function and persistent pancytopenia, it was finally decided to start rituximab and dexamethasone immediately and commence liposomal doxorubicin (lipo-dox) in addition as well. The patient was explained the risk of toxicity (including death) in the setting of organ dysfunction, and the patient consented. The patient was administered 40 mg of IV dexamethasones. Rituximab infusion was commenced concomitantly, and if he tolerated it well, then lipo-dox was to be administered. During rituximab infusion, the patient developed a severe hypersensitivity reaction. Hypersensitivity protocol was initiated, and once the vitals were stabilized, rituximab was restarted at half the rate. Soon after, the patient went into cardiac arrest with pulseless electrical activity (PEA). Resuscitation measures were initiated and performed for almost an hour, but the patient could not be brought back. Labs revealed severe hyperkalemia. However, anaphylaxis-induced cardiac arrest was also a possibility.KICS is a newly recognized rare disease entity that occurs in patients co-infected with HIV and HHV-8 and is characterized by systemic inflammation and signs and symptoms resembling MCD without the characteristic pathology on lymph node biopsy . The diaTally T et al. described an HIV-positive patient initially suspected of sepsis . FurtherKICS is a rare under-recognized severe disease with high mortality. It usually occurs in HIV-infected patients who are co-infected with HHV-8. Symptoms and clinical presentation often mimic opportunistic infection/sepsis. In patients who are rapidly deteriorating clinically, have no infectious cause identified, and show a lack of response to antibiotics, KICS should be considered one of the differentials. The only way to differentiate it from clinically similar MCD is lymph node biopsy showing a lack of characteristic MCD features. KICS and KS-IRIS have very overlapping findings. KS-IRIS is associated with the initiation of ART and occurs when CD4 counts have improved, and HIV loads have been suppressed. One way to distinguish is by measuring HHV-8 viral load. It is very high in patients with KICS but low in patients with KS-IRIS. Treatment with rituximab and lipo-dox may help in the treatment of KICS. However, despite treatment, mortality rates are high. More insight into the pathophysiology of KICS may help us to form better treatments. More prospective studies evaluating currently used drugs like rituximab and new drugs like IL-6 antagonists should be conducted for KICS.


Changes in H+ concentration, expressed as pH, are thought to be associated with various biological processes, such as gene expression, in the brain. Accumulating evidence suggests that decreased brain pH is a common feature of several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and Alzheimer's disease. However, it remains unclear whether gene expression patterns can be used as surrogates for pH changes in the brain. In this study, we performed meta-analyses using publicly available gene expression datasets to profile the expression patterns of pH-associated genes, whose expression levels were correlated with brain pH, in human patients and mouse models of major central nervous system (CNS) diseases, as well as in mouse cell-type datasets. Comprehensive analysis of 281 human datasets from 11 CNS disorders revealed that gene expression associated with decreased pH was over-represented in disorders including schizophrenia, bipolar disorder, autism spectrum disorders, Alzheimer's disease, Huntington's disease, Parkinson's disease, and brain tumors. Expression patterns of pH-associated genes in mouse models of neurodegenerative disease showed a common time course trend toward lower pH over time. Furthermore, cell type analysis identified astrocytes as the cell type with the most acidity-related gene expression, consistent with previous experimental measurements showing a lower intracellular pH in astrocytes than in neurons. These results suggest that the expression pattern of pH-associated genes may be a surrogate for the state- and trait-related changes in pH in brain cells. Altered expression of pH-associated genes may serve as a novel molecular mechanism for a more complete understanding of the transdiagnostic pathophysiology of neuropsychiatric and neurodegenerative disorders.Hydrogen ion (H Thease (AD) –17.Tissue pH has been considered as an indicator of the quality of preserved tissues and a variable that is confounded by some antemortem and postmortem conditions, especially agonal experiences –21. TherIt is technically difficult to exclude the potential effects of such variables on brain pH in human studies, especially those using postmortem brain samples. Therefore, animal models that are exempt from such confounding factors may help to confirm whether changes in brain pH are involved in the pathophysiology of neuropsychiatric and neurodegenerative disorders. Our recent large-scale analysis showed that decreased brain pH, which correlates with increased levels of metabolic acid lactate, is a common feature in various animal models of neuropsychiatric and neurodegenerative disorders, supporting the idea that the phenomenon reflects an underlying pathophysiology of the disorders rather than a mere artifact . Given t2 . The meta-analysis identified genes whose expression levels were robustly correlated with tissue pH from four studies  was imported into the bioinformatics tool BaseSpace  and six datasets from the Gene Expression Omnibus (GEO) repository at the National Center for Biotechnology Information (NCBI) archives (https://www.ncbi.nlm.nih.gov/geo/), where raw microarray data and tissue pH of individual subjects were publicly available: Stanley Kato   , StanleyBD = 32) , GSE1151BD = 32) , GSE5392BD = 32) , GSE1619BD = 32) , GSE2193BD = 32) , and GSEBD = 32) . The incBD = 32)  to obtaiHomo sapiens) RNA expression datasets from the BaseSpace database using disease names as keywords . Datasets with an extremely small number of DEGs were excluded. Datasets from in vitro culture studies were also excluded for direct comparison with tissue pH-associated genes. In addition, we obtained the recent hippocampal expression data of schizophrenia, bipolar disorder, and major depressive disorder (MDD) from http://research.libd.org/dg_hippo_paper/data.html (P < 0.05 (patients vs. controls) into BaseSpace, and used them for subsequent analyses.All gene expression datasets used in this study have been previously published and are publicly available and have been included in the BaseSpace database . The datata.html , importeWe searched the time-course expression datasets of neurodegenerative animal models in the BaseSpace database. The time-course expression datasets consisted of the microarray data analyzed between mutant and wild-type mice at different ages from young to older adult. We used the following datasets in this study: transgenic mice with heterozygous and homozygous human amyloid precursor protein (APP) and presenilin1 (PSEN1) mutations, transgenic mice with heterozygous microtubule-associated protein tau (MAPT) mutation  as AD models; transgenic mice with human superoxide dismutase (SOD1) mutation  as an ALS model; and transgenic mice expressing mutant huntingtin (HTT)  as a Huntington's disease (HD) model.The hiI/hiM genes were obtained from our previous study . To examP-value Acid-gene index = –log10 Alkaline-gene index = –logIn the analysis of individual human subject datasets, the resulting index values were used to examine the correlations with tissue pH . In the Pathway enrichment analysis using BaseSpace revealed that the pH-upregulated genes were highly associated with terms related to the synapse  and channel activity  . The pH-P < 0.0001, effect of batch: P < 0.0001, interaction: P = 0.046, two-way ANOVA), BD , and AD , but not patients with ALC , compared with normal controls. The acid-gene index and the alkaline-gene index were significantly negatively  and positively  correlated, respectively, with the tissue pH on an individual basis , and 89 of BT .The acid- and alkaline-gene indices of each dataset are shown in P-value of 8.5 × 10−5, the shared genes were apparently inconsistent in the direction of change between pH-up/downregulated genes and hiI/hiM genes.We have previously shown that expression changes of genes related to neuronal hyperexcitation-induced pseudoimmaturity in the brain, which were denoted by hiI/hiM genes, are commonly overrepresented in several neuropsychiatric disorders including SZ, ASD, and AD . To inver = 0.61, P = 1.65 × 10−5) and a significant negative correlation between time points and alkaline-gene index , confirming that the acid-gene index increased and the alkaline-gene index decreased with time.We then determined whether or when pH-associated genes were expressed in CNS tissues of established animal models of neurodegenerative disease. The availability of the time-course data from disease models in public resources allowed us to examine the short- and long-term effects of risk events on the expression of pH-associated genes. We analyzed the time-course expression data from the cortex and hippocampus of three AD models, striatum of one HD model, and the spinal cord of one ALS model. In this analysis, we found a common trend in the time-course pattern: over time, the acid-gene index increased and the alkaline-gene index decreased –J. FurthMultiple types of neuronal and glial lineage cells comprise CNS tissues, and the intracellular pH has been suggested to be maintained at different levels in certain types of neurons and astrocytes , 80. We The results showed that glial cell types tended to have a higher acid-gene index and a lower alkaline-gene index than neuronal cell types. Specifically, astrocytes exhibited the highest acid-gene index and lowest alkaline-gene index among the cell types examined . BergmanIn this study, we provide transcriptomic evidence that the expression of pH-associated genes is overrepresented among the DEGs involved in multiple CNS disorders, supporting the idea of decreased brain pH in these disorders. Furthermore, our results suggest that pH-associated genes are differentially expressed in different cell types. As the pH-associated genes used in this study were identified in neurologically healthy individuals, our results suggest that altered expression associated with pH changes in CNS disorders is an extension of physiologically relevant pH changes.+-gated channels  were highly associated with gene ontology terms related to synapse. It has been reported that in mouse hippocampal slice cultures, chronic experimental acidosis reduces spine density and length without affecting dendritic architectures mediated by acid-sensing ion channel 1a (ASIC1a), voltage-independent, Hchannels . This efc spines . Furtherc spines . TherefoIn our previous study, we demonstrated that expression changes of genes related to pseudoimmaturity inducible by neuronal hyperexcitation in the brain, which were denoted by hiI/hiM genes, were commonly overrepresented in several neuropsychiatric disorders . One migOur analysis of mouse models of neurodegenerative disease showed that the degree of overrepresentation of pH-associated genes increased with age. The severity of symptoms in these mouse models is known to be related to age. In the AD mouse lines studied, both APP/PSEN1 mice and TAU mice showed no apparent amyloid plaques in the hippocampus and cortex at 8 weeks of age and then progressively developed plaques from 4 to 18 months of age . Similar+/H+ exchangers (NHEs), Na+-driven Cl−/+-−/in vitro study  were analyzed for human pH-associated genes. Although there is minimal variation in pH across brain regions , 24, 25,In conclusion, pH changes could be represented by specific gene expression signatures in the context of CNS disorders and different cell types in the brain. Gene expression signatures associated with pH changes may be a common endophenotype in several neuropsychiatric and neurodegenerative disorders, potentially providing new insights into the transdiagnostic molecular mechanism of these disorders.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Ethical review and approval was not required for the animal study because the publicly available gene expression datasets of humans and mice analyzed in this study were obtained from previous studies conducted elsewhere with the approval of human or animal study ethics committees.HH planned the study and performed the analysis of the datasets. TMu helped draft the manuscript. HH and TMi wrote the manuscript. TMi supervised the present study. All authors have read and approved the final manuscript.


Cognitive models of depression highlight the role of inhibitory control - the cognitive control ability which supports our goal directed behavior – as key and even causal feature of the disorder. According to these models, deficits in inhibitory control prevent the exclusion of irrelevant negative information, leading to rumination and sustained negative mood which result in depressive episodes. However, the scientific evidence linking deficits in inhibitory control to depression is thus far mixed. Moreover, although one’s inhibitory control ability may fluctuate, it is often assessed using a single-time measurement in the lab.Here we aimed to assess the association between intra-individual fluctuations in inhibitory control measured in ecological settings, daily mood states, and depressive symptoms.st step, and depressive symptoms post-EMA and their interaction with inhibition were included in the 2nd step.N=106 participants  reported their depressive symptoms  and completed a mobile version of the Go-NoGo inhibition task at baseline. They then completed a 5-day ecological-momentary-assessment (EMA) protocol, in which they reported their current mood  and performed a shortened version of the Go-NoGo task twice/day using a mobile application. Depressive symptoms were assessed again following the 5-day EMA. Hierarchical-linear-modeling (HLM) was applied to examine the association between momentary IC and mood, with post-EMA depressive symptoms as a moderator. Inhibitory control was included as a time-varying predictor for mood in the 1pr = .035, n.s). However, individuals with elevated depressive symptoms demonstrated worse and more variable inhibition performance over time , as captured in the EMA measures. In addition, participants with more variable inhibitory control performance over time also reported more depressive symptoms at the end of the 5-day period . Finally, post-EMA depressive symptoms moderated the association between momentary inhibitory control and daily mood, such that reduced inhibition was associated with more negative mood only for those with lower, but not with higher, depressive symptoms .At baseline, there were no correlations between depressive symptoms and inhibitory control (Image:Variable, rather than mere reduced inhibitory control is related to depressive symptoms. Moreover, the role of inhibition in modulating mood differs in non-depressed vs. depressed individuals. These findings contribute to our understanding of inhibition and mood in real life and help account for some of the discrepant findings related to cognitive control models of depression. Future investigations should examine the validity of these outcomes in other, clinical samples.None Declared


N = 2611), 60 were seen to via hybrid delivery. The outcomes evaluated pre and post-rehabilitation included PROMIS® global physical health (GPH), global mental health (GMH), physical function (PF), and the ability to participate in social roles and activities (SRA). The patient experience outcomes included the Net Promoter Survey (NPS®) and the Select Medical Patient-Reported Experience Measure (SM-PREM). A linear and logistic regression was used to examine the between-group differences in the PROMIS and SM-PREM scores while controlling for covariates. The hybrid and in-clinic-only cases improved similarly in all PROMIS outcomes . The association between the delivery mode and the likelihood of achieving the minimal important change in the PROMIS outcomes was non-significant . No between-group differences were observed in the NPS or SM-PREM scores . Although more research is needed, this real-world evidence suggests that hybrid rehabilitation care may be equally beneficial for and acceptable to cancer survivors and supports calls to expand access to and reimbursement for telerehabilitation.Diminished health-related quality of life (HRQOL) is common among cancer survivors but often amendable to rehabilitation. However, few access real-world rehabilitation services. Hybrid delivery modes  became popular during the COVID-19 pandemic and offer a promising solution to improve access beyond the pandemic. However, it is unclear if hybrid delivery has the same impact on patient-reported outcomes and experiences as standard, in-clinic-only delivery. To fill this gap, we performed a retrospective, observational, comparative outcomes study of real-world electronic medical record (EMR) data collected by a national outpatient rehabilitation provider in 2020–2021. Of the cases meeting the inclusion criteria ( Ignited by the COVID-19 pandemic, the use of telerehabilitation or rehabilitation services delivered using synchronous communication technology ,3. Of thTelerehabilitation could decrease barriers to access by delivering services to patients when and where they need them. Research trials performed prior to the COVID pandemic suggest telerehabilitation is safe and feasible ,18,19,20Hybrid delivery methods could be used to maximize access to and the impact of cancer rehabilitation care beyond the COVID-19 pandemic. The existing research supports that offering a mix of in-clinic and at-home telerehabilitation based on the patient’s needs may minimize a patient’s barriers to attending in-clinic appointments  while maintaining the rigor of high-specialized therapeutic interventions and hands-on care ,28,29. YThis is a retrospective, observational study of real-world EMR data collected by a national outpatient rehabilitation provider from 1 January 2020 to 31 December 2021. We report the study methods following the Professional Society for Health Economics and Outcomes Research (ISPOR) checklist for retrospective database studies .Cancer survivors attended outpatient PT or OT appointments provided by a single-institution provider of outpatient cancer-specialized rehabilitation services in the United States . PT or OT services were delivered in a community-based outpatient rehabilitation clinic  or via a combination of in-clinic and synchronous telerehabilitation appointments . Within the institution, telerehabilitation was offered during the COVID pandemic as a new mode of service delivery for patients to continue treatment while keeping them and employees safe. Telerehabilitation sessions were offered based on patient preferences, state-based COVID restrictions and practice acts, and therapist clinical judgment and discretion as standard of practice. Telerehabilitation sessions were conducted using the Doxy.me platform. Rehabilitation interventions were provided by cancer-specialized therapists following typical practice. Therapists providing telerehabilitation received additional training on telerehabilitation best practices, including patient consent and safety, technical skills, remote assessment, and the collection of outcome measures. The content and frequency of rehabilitation interventions were determined by ir therapists based on the individual patient’s needs and goals. All services were billed through insurance for skilled therapy needs per typical practice. Cases that met the following criteria were included in the study: (1) seen for an initial PT or OT evaluation within the study period (January 2020–December 2021), (2) reported cancer diagnosis (identified via ICD10 code[s] applied by the treating therapist), and (3) had patient-reported outcome measures (PROM) at an initial evaluation (pre) and at discharge (post). An honest broker used these criteria to identify eligible cases in the electronic medical record (EMR) to create de-identified dataset for the analysis. The available rehabilitation characteristics included delivery mode (hybrid or in-clinic-only), the number of sessions attended, duration , discipline (PT or OT), and clinic location via United States region. The available patient characteristics included age at the start of rehabilitation, sex, cancer type via ICD 10 code, and payer type . For the between-groups analysis and regression modeling, we categorized cancer type into the following four groups based on similarities in cancer biology, treatment, and baseline PROM scores: (1) breast, (2) gastrointestinal, genitourinary, colorectal, or gynecologic; (3) heme or lymphoid; and (4) other . Outcome measures included three PROMs and two PREMs.® instruments are validated with state-of-the-science methods to be psychometrically sound and are freely available for research and clinical use [Developed by the National Institutes of Health (NIH), PROMISical use . The folical use ,33. In aical use ,35. PROMical use . Patient experience measures include the Net Promoter Survey   and the The SM-PREM© was developed and validated by the institution, demonstrating strong internal consistency to measure patient experience in a study of over 89,000 patients attending orthopedic outpatient PT and OT . The SM-t-tests or Mann–Whitney U tests for continuous variables and Pearson chi-squared (Χ2) or Fisher’s exact test tests for categorical variables. For each PROMIS outcome, we used a paired samples t-test to examine the within-group change from initial evaluation to discharge, then used a multiple linear regression to model to evaluate the effect of the delivery mode (hybrid vs. in-clinic only) on the T-score change while controlling for covariates . In each regression model, we evaluated the change in scores instead of the post-score value to account for differences in the baseline scores. We used a binary logistic regression to model the impact of the delivery mode on the likelihood of achieving the MIC on each PROMIS outcome while controlling for the same covariates. The level of significance was set to α = 0.05 for all hypothesis tests. All analyses were performed using IBM SPSS Statistics (Version 27).To examine the between-group differences in patient and rehabilitation treatment characteristics, we used independent samples p < 0.001) over a longer period  and were more likely to be in the Northeastern region of the United States (48.3%) than other regions (p < 0.001). There were no other between-group differences in the patient or rehabilitation characteristics (The cancer rehabilitation cases (N = 2611) were 60.80 ± 12.9 years old (range: 19–95), mostly female (80.3%), and most had a diagnosis of breast cancer (64.5%). Most cases participated in PT (87.0%) and had private (50.2%) health insurance. Sixty cases were seen using a hybrid delivery mode. Hybrid cases attended approximately 29% of their appointments using telerehabilitation (IQR: 7% to 64%) rather than in-clinic appointments. Descriptively, when compared to those who attended in-clinic-only rehabilitation, the hybrid cases attended more PT/OT visits . From the initial evaluation to discharge, the hybrid cases (N = 60) improved significantly in each PROMIS measure: GPH , GMH , PF , and SRA . The in-clinic-only cases (N = 2551) also improved significantly in each PROMIS measure: GPH , GMH , PF , and SRA . The average T-scores at each time point are plotted in At the initial evaluation, the PROMIS T-scores were similar between the hybrid and in-clinic-only cases , GMH (p = 0.415), PF (p = 0.118), and SRA (p = 0.287). However, the hybrid cases exceeded the MIC in each PROMIS measure, whereas the in-clinic-only cases achieved the MIC on three of four PROMIS measures . When controlling for covariates, the delivery mode (hybrid vs. in-clinic-only) was not associated with a superior improvement on any PROMIS measure , the proportion of NPS promoters , the SM-PREM item scores , or the SM-PREM overall scores (p = 0.642).The NPS response rate was 65% among the hybrid cases (n = 39) and 47% among the in-clinic-only cases (n = 1186). The SM-PREM response rate was 53% among the hybrid cases (n = 20) and 16% among the in-clinic-only cases (n = 384). The overall NPS score was 87.2  for the hybrid cases compared to 92.3 for in-the clinic-only cases . The median SM-PREM score was 5.00 (IQR: 4.32 to 5.00) for the hybrid cases compared to 5.00 (IQR: 4.57 to 5.00) for the in-clinic-only group. When compared between the hybrid and in-clinic care cases, there was no difference in the NPS rating , suggesting that patient experience was poorer for telehealth patients [This study, to our knowledge, is the first to examine validated patient experience measures captured during routine hybrid cancer rehabilitation care. Previous studies have relied on retrospective surveys  and intepatients . The autpatients . Previous authors have suggested that hybrid models may enhance a cancer survivor’s ability to maintain appointments by reducing barriers to rehabilitation, including transportation restrictions, inclement weather, illness, anxiety, and depression, and time constrictions due to work or other responsibilities ,45,46. IAs with any retrospective study of real-world data, there are inherent limitations such as the reliance on existing data collected for purposes other than research and limited access to confounding variables that could potentially impact outcomes . In addition, the hybrid group was relatively small compared to the in-clinic-only group, potentially limiting the detection of any between-group differences, especially in the categorical patient experience outcomes. Furthermore, because the participants and therapists selected the care delivery modes (as opposed to being randomized), bias may also influence the findings of this study. That being said, the hybrid group was powered above 80% to detect a significant within-group difference in the primary outcome (GPH).The limited ability to control for all the potential confounding variables is another important limitation of this study. We included the available covariates in the main effects analyses, although additional variables could be investigated in future studies, including diagnosis stage and treatment type and status , patientOur findings demonstrating significant improvements of similar magnitude for both modes of delivery can help support the case to preserve reimbursement for telerehabilitation long beyond the COVID-19 pandemic. By making specialized, skilled PT and OT services accessible when and where survivors need them, hybrid delivery could meet the unmet health and well-being needs of cancer survivors. As the technology used in healthcare rapidly changes, understanding the impact of technology on clinical workflow, processes, and institutions will be critical to ensuring sustainable delivery modes and promoting equitable access to new modes of care . For exaIn this study, the survivors who attended hybrid-delivered outpatient cancer PT and OT rehabilitation services improved significantly in terms of HRQOL outcomes and reported a highly positive patient experience. Furthermore, there were no differences in HRQOL improvement or patient experience for those who attended hybrid versus in-clinic-only care after controlling for covariates. Although more research is needed, these findings suggest that hybrid rehabilitation may be equally as beneficial and acceptable to patients as traditional in-clinic-only care and support calls to expand the access to and reimbursement for telerehabilitation services beyond the COVID-19 pandemic.


Furthermore, analysis comparing our collective findings against a larger global sample of e’athletes (n = 993) was conducted. Results demonstrated that CS:GO players who displayed higher levels of self-regulation tended to perceive stressful situations as challenges, consequently showcasing superior accuracy and time trial performance. In contrast, individuals with lower self-regulation tended to perceive such situations as threats, which correlated with less favorable performance outcomes. On a broader scale, the study observed that CS:GO competitors generally exhibited lower levels of self-regulation when compared to the larger global sample. Furthermore, self-regulation was identified as a mediating variable in the relationship between stress appraisal and performance, suggesting that improved self-regulation skills can lead to enhanced accuracy and quicker time trial performance. This may imply that competitors with greater self-regulatory abilities perceive themselves as having more personal resources, enabling them to effectively assess challenging situations and employ problem-focused coping strategies. Overall, this research underscores the significance of self-regulation in optimizing esports performance, while providing valuable insights for player development, action performance, and overall outcomes in the field.Electronic sport has seen substantial growth in market value and popularity in the last 10 years. With this growth has come the pursuit of elite esports performance, especially from a psychological perspective. This study aimed to investigate potential variations in self-regulation levels among athletes of different levels , compare the self-regulation profiles of CS:GO players in the current study to an international sample of e’athletes and to assess the predictive capacity of self-regulation on performance outcomes. A total of 53 esports athletes (student competitors,  Sporting success requires constant cognitive, behavioral and emotional regulation, over a long period of time both during practice and in competitive settings . To exceAchieving high performance is perceived as being paramount in the realm of professional sports culture . This hoSpecifically, esports psychology research has shown significant interest in stress and coping  psycholoSelf-regulation can be defined as the cyclical “capacity to plan, guide, and monitor one’s behavior” , p. 62. The In highly competitive environments such as sport, research suggests that an athlete’s capacity for self-regulation positively influences both their development  and perfResearchers acknowledge the potential benefits of investigating self-regulation in esports for players and their social networks . A studyThe cognitive-motivational-relational theory (CMRT), proposed by In recent years, there has been attention given to the study of stress and coping mechanisms in esports. Though, stress appraisal in esports athletes has remained relatively understudied. The primary aim of this study was to investigate potential variations in self-regulation levels among athletes of different levels  and subsequently compare the self-regulation profiles of CS:GO players in the current study to an international sample of e’athletes, utilizing data acquired from previous research . FurtherM age = 21.89, SD = 3.52) consisting of 13.2% females (n = 7) and 86.8% males (n = 46). Participants were separated based on two criteria: student competitors (SC) who were actively competing in local or University-based competitions and aiming to become national competitors (n = 27), consisting of 3 females and 24 males, and national competitors (NC) who were actively aiming to become professional international competitors (n = 26) consisting of 4 females and 22 males. The SC participants had in-game ranks which ranged from Distinguished Master Guardian to Global Elite. These participants represented the top 13.99% of all CS:GO players. All NC participants were actively preparing with their teams for ESL Premiership Spring 2022. The ESL premiership is the highest national division of CS:GO in the United Kingdom and Republic of Ireland. The participants, termed national competitors, comprised of four full teams (n = 20), including the teams back-up players (n = 6). These individuals were salaried only during the competitive season during the time of data collection. The NC participants had in-game ranks which ranged from Supreme Master First Class to Global Elite. These participants represented the top 3.39% of players (96%). However, all but one of the NC participants were in the top 0.75% of all CS:GO players. All individuals held normal or corrected vision and had no known psychiatric or neurological disorders. The study protocol received ethical approval from the United Kingdom-based institution.A total of 53 participants were used as part of the study  to complete the CS:GO time-trial and the shooting accuracy percentage in hitting targets. In the context of esports, action performance pertains to attributes such as accuracy that can influence the outcome, such as winning or losing a match . Each par = 0.94, p < 0.01) and has been previously employed to measure self-regulation within diverse sporting populations , data was gathered by the last-named author , and the participants were instructed to abstain from consuming any beverages containing caffeine for a 24-h period prior to the testing (see The present study involved the extraction of performance data from a subset of the work conducted by t-tests were performed using the rstatix package (0.7.0) to investigate the relationships between challenge and threat appraisals, self-regulation, and performance (see t-test was then run to compare the self-regulation mean scores from prior literature (p) was set at 0.05 and Cohen’s d  were used as effect size estimates  with the R statistical package (v 4.2.1). Assumptions were assessed using the ggplot2 function of the ggpubr package (0.4.0), including evaluations of normality  and the ance see , and exaterature  with SRQterature  to exploterature . The alpstimates .t-tests were performed , novice to elite –7. When b = 0.312, 95% CI ]. Direct effects  and indirect effects were found to be statistically significant . See Two simple mediation analyses, following b = −0.296, 95% CI ]. Direct effects  and indirect effects were found to be statistically significant . See Second, self-regulation significantly mediated the relationship between DRES and time trial performance. The total effect of the model was significant [This study aimed to explore the variations in self-regulation among NC and SC CS:GO players, compared their self-regulation results with an international sample, and investigated self-regulation’s predictive role in performance. It also explored self-regulation as a potential mediator between stress appraisal and performance. The findings indicated that the examined group of e’athletes demonstrated compromised or borderline compromised levels of self-regulation. However, the NC group exhibited significantly higher self-regulation than the SC group. When comparing the self-regulation of CS:GO players to a global sample of e’athletes, it was observed that the CS:GO players exhibited significantly weaker self-regulatory skills than the international population . FurtherInitial data suggested that the NC group exhibited self-regulation skills at the lower end of the moderate range, with only borderline scores  between impaired and moderate self-regulation being reported. Nonetheless, this finding corroborated earlier research, which found that e’athletes reported borderline moderate/impaired-level self-regulation skills . On the When examining self-regulation in comparison to a global population sample, the SC group demonstrated significantly lower levels of self-regulation across all subscales, in contrast to all comparison skill groups. The NC group exhibited significantly lower scores in informational input, search, and implementation when compared to the top 10% skill group in the global sample . NotablyRegarding the appraisal process, it was observed that the NC group demonstrated a greater tendency to appraise situations as challenges, while the SC group tended to perceive situations as threats. This discrepancy may be attributed to several factors. Firstly, the NC group reported significantly higher levels of in-game skills, such as accuracy and time trial performance, as well as self-regulation than the SC group. Additionally, the NC group had access to additional resources, such as coaches and organizational support. These internal and external personal and perceived resources may have resulted in the CS:GO players appraisal of stressful situations as challenges. According to the Mediation analysis revealed that self-regulation played a significant mediating role in the relationship between stress appraisal and performance outcomes . The results indicated a direct effect of stress appraisal on both performance factors, with appraising a stressful situation as a challenge being associated with higher accuracy and faster time trial performance. Moreover, the indirect effects demonstrated that self-regulation mediated the relationship between stress appraisal and performance outcomes, whereby higher self-regulation explained the performance outcomes when e’athletes appraised the stressful situation as a challenge. To the authors’ knowledge, this study represents the first examination of the mediating effect of self-regulation between stress appraisal and performance factors. One possible explanation for this mediating effect is that e’athletes who perceive a stressful situation as a challenge possess better self-regulatory skills, allowing them to adopt problem-focused coping strategies to directly deal with the problems which are causing their stress. The current study tentatively suggests that enhancing self-regulatory skills may contribute to better performance in terms of accuracy and time trial results in esports. This would imply that interventions targeting self-regulation could positively impact the overall performance of e’athletes.The incorporation of psychological skills, such as goal setting and imagery, into the training regimen of e’athletes is worthy of consideration for the purpose of fostering self-regulation. Particularly for novice e’athletes, who demonstrated impaired self-regulatory abilities, these psychological skills hold potential for substantial benefits. While further investigation specific to e’athletes is warranted, existing research has recognized an associated link between self-regulatory skills and academic as well as sports performance . IdeallyThis study presents certain limitations that warrant acknowledgment. Foremostly the sample size utilized in this research is relatively small, comprising solely one esports discipline within a specific geographical region. Consequently, the generalizability of these findings to other esports or larger cohorts of e’athletes remains uncertain. Cultural, socioeconomic, and environmental factors inherent to the geographical region (UK and the Republic of Ireland) where participants were recruited could have influenced the results in ways that may not be applicable to e’athletes from diverse backgrounds or alternative gaming ecosystems. Therefore, caution should be exercised when attempting to extrapolate these findings to a broader population of e’athletes or when comparing them across different regions or cultural contexts.Additionally, the study’s focus on one esports discipline limits its applicability to variations in self-regulatory processes across different games. Previous research has suggested that different genres of video games may promote development of different cognitive skills . HoweverFurthermore, it has been posited that primary and secondary appraisal constitute integral components of the preparatory phase of self-regulation . HoweverAnother limitation is that the present study did not differentiate between different types of self-regulation . As a result, we have not explored the effectiveness of other interventions which could be used to target the development of specific forms of self-regulation. For example, although PST is known to foster behavioral self-regulation , other iFinally, current research exploring regulation in esports has focused on the individual athlete. However, as many esports games occur in teams future research should explore how cognitive and behavioral regulation occurs in teams in esports. Previous research has reported that teammates represent a large proportion of stressors for e’athletes . How teaThis study reveals that CS:GO players exhibited impaired self-regulation compared to a global sample of e’athletes. However, CS:GO players with better self-regulatory skills outperformed their peers in shooting accuracy and time trial performance. Better self-regulation was also associated with the appraisal of stressful situations as challenges, while lower self-regulation was associated with threat appraisal. These findings align with previous research in sports, emphasizing the importance of psychological skills development to enhance self-regulation and improve esports performance. It is recommended that athletes, coaches, and organizations in esports prioritize the cultivation of psychological skills that contribute to improved self-regulation. It may be beneficial to have to have a sport psychologist support the introduction or augmentation of psychological skills into the performance environment, especially if e’athletes are at risk of, or suffer from mental ill health. Additionally, this study highlights the need for interventions targeting information input skills, essential for effective coping and initiating self-regulation. Furthermore, self-regulation was found to mediate the relationship between stress appraisal and performance, indicating that better self-regulation leads to improved shooting accuracy and faster time trial performance. This suggests that e’athletes with higher self-regulatory skills perceive themselves as having more personal resources, enabling them to appraise challenging situations and utilize problem-focused coping strategies. Overall, this research underscores the significance of self-regulation in esports performance and provides valuable insights for player development, action performance, and outcomes in the field.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by the University of Chichester Research Ethics Committee. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.MT: Conceptualization, Data curation, Methodology, Project administration, Writing—original draft, Writing—review and editing. EO: Data curation, Formal analysis, Methodology, Writing—review and editing. BS: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing—original draft, Writing—review and editing.


Introduction: Exploring the potential efficacy of a drug is a valid approach for drug development with shorter development times and lower costs. Recently, several computational drug repositioning methods have been introduced to learn multi-features for potential association prediction. However, fully leveraging the vast amount of information in the scientific literature to enhance drug-disease association prediction is a great challenge.Methods: We constructed a drug-disease association prediction method called Literature Based Multi-Feature Fusion (LBMFF), which effectively integrated known drugs, diseases, side effects and target associations from public databases as well as literature semantic features. Specifically, a pre-training and fine-tuning BERT model was introduced to extract literature semantic information for similarity assessment. Then, we revealed drug and disease embeddings from the constructed fusion similarity matrix by a graph convolutional network with an attention mechanism.Results: LBMFF achieved superior performance in drug-disease association prediction with an AUC value of 0.8818 and an AUPR value of 0.5916.Discussion: LBMFF achieved relative improvements of 31.67% and 16.09%, respectively, over the second-best results, compared to single feature methods and seven existing state-of-the-art prediction methods on the same test datasets. Meanwhile, case studies have verified that LBMFF can discover new associations to accelerate drug development. The proposed benchmark dataset and source code are available at: https://github.com/kang-hongyu/LBMFF. In recent decades, drug discovery techniques and biological systems have been intensively studied by multidisciplinary researchers. However, drug development remains a time-consuming, costly and labor-intensive process. It normally requires more than one to two billion dollars and an average of about 10–15 years to discover a new drug . ApproxiIn recent years, computational drug repositioning methods  have attComplex network methods refer to linking drugs to diseases through heterogeneous networks construction  with higMachine learning methods have been established techniques in drug repositioning in recent years, which can be divided into two steps: first extracting biological features of drugs and diseases and then predicting novel drug-disease associations. etc. With the rapid accumulation of biological network data, GNN has become an effective tool in bioinformatics tasks . LBMFF not only integrated multiple heterogeneous biological interactions , but also extracted semantic embeddings and contextual information from large-scale of scientific literature. Specifically, we constructed drug-drug similarities and disease-disease similarities based on multi-feature and associations from public databases and PubMed literature. Then, a GCN with an attention mechanism was employed to capture structural information from a comprehensive similarity matrix and known drug-disease associations. LBMFF achieved optimal results compared to single-feature methods, which demonstrated the significance of literature information and feature fusion. It also showed superior performance in drug-disease association prediction compared to 7 state-of-the-art methods.In our study, the benchmark dataset downloaded from More importantly, we searched and selected 673,665 full-text scientific literature, which titles or abstracts contained the drugs or diseases from the benchmark dataset. This vast literature serves as a corpus for the semantic similarity computation section based on a pre-training and fine-tuning BERT model.Furthermore, we introduced a dataset from • Association and Semantic Feature Extraction. We integrated several measurements for drug and disease similarities computing, including drug SMILES sequences, disease MeSH tree numbers, drug-side effect associations, drug-target associations, and literature semantic information. A Pre-training and fine-tuning BERT model was introduced for semantic information recognition and understanding.• Similarity Calculation and Feature Representation. For feature fusion and similarity computing, an adjusted weight for each measurement was applied to achieve optimal performance by a step of 0.01. We then constructed a feature matrix based on the drug fusion similarity, disease fusion similarity and known drug-disease associations.• Association Prediction. We applied two GCN layers to learn the embeddings of drugs and diseases with an attention mechanism. An inner product decoder was used to discover unknown drug-disease associations.The LBMFF combined embeddings in drug-disease-target-side effect networks from public databases including CTD, Drugbank, SIDER and MeSH. What’s more, semantic features from a vast amount of scientific literature were added to LBMFF as an improved approach. The workflow of LBMFF was briefly shown in Drugs can usually be characterized by biological or chemical descriptors, that is, molecular fingerprints. Molecular fingerprints are ways of encoding the structure of a molecule. The most common type of fingerprint is a series of binary digits (bits) that represent the presence or absence of particular substructures in the molecule . In thisn is the number of all substructures. If there is a substructure in the drug, Based on this principle, we convert a drug into an n-dimensional fingerprint vector From the view of “if a drug has the same side effects, it may have the same indication”, in 2008, Similarly, drug-target interactions are also a valid approach for drug similarity calculations. We extract this information from Drugbank and adopt the Jaccard index to measure drug-drug similarity d, we denote its DAG as d and its ancestor nodes, d as The Medical Subject Headings (MeSH) thesaurus is a controlled and hierarchically-organized vocabulary produced by the National Library of Medicine. Based on this definition, disease semantic similarity can be presented as follow:The model architecture was shown in The BERT model is firstly pre-trained on the dataset containing 673,665 full-text scientific literature downloaded from PubMed, which includes drugs and diseases mentioned in the benchmark dataset. We implement parameters during the pre-training step, with training epochs of 10,000, vector dimension of 128, learning rate of 0.01and dropout of 0.1.After pre-training the BERT model, we used fine-tuning to train a binary classification model via five-fold cross validation. Fine-tuning is a method of making small adjustments to a pre-trained model for a specific task. In the binary classification task, our objective was to minimize the cross-entropy loss function, which can be represented as following:The training procedure uses only drug-disease associations from the training set and no associations from the test set. Specifically, we use this fine-tuning process to improve the accuracy of semantic comprehension and ability of similarity calculation for drugs and diseases. When we feed drug-drug or disease-disease pairs into the BERT-model, it can compute the corresponding drug-drug similarities and disease-disease similarities  based on the previous mentioned fine-tuning BETT-model.Based on the above four characteristics  of drugs, drug similarity Similarly, disease similarity m is the number of drugs and n is the number of diseases. When drug In this paper, we construct the association feature representation between drug and diseases based on drug comprehensive similarity matrix, disease comprehensive similarity matrix and known drug-disease associations. Binary matrix The adjacency matrix of drug-disease association features can be expressed as:GCN is a multilayer connected neural network architecture used to learn low-dimensional representations of nodes from graph-structured data .The adjacency matrix Furthermore, we introduce a layer attention mechanism  in LBMFFThe final embedding of drugs and diseases is denoted as follows:To reconstruct the adjacency matrix for drug-disease associations, we introduce sigmoid as the activation function into the GCN decoder, and the predicted association matrix can be expressed as:Due to the fast training speed of the GCN model, it can be retrained when new drug/disease nodes were added.We constructed five-fold cross validation to evaluate the performance of LBMFF in our study. All known drug-disease associations were randomly divided into five mutually exclusive subsets of the same size, that is, four subsets were selected as the training set each time, while the remaining one was used as the test set. Each round of training started from the initial state and the association prediction was performed on the test set after training. At last, we adopted the average of the five training performances as the final results.Area Under Curve (AUC) and Area Under Precision/Recall Curve (AUPR) were used as the primary metrics to evaluate the prediction performances. In addition, we also take several binary classification metrics into consideration, including accuracy (Acc), recall (Rec), specificity (Spe), precision (Pre) and F1-score (F1).In this study, we considered multi-features of drugs and diseases, which were chemical structure, drug-side effect association, drug-target association, disease similarity from MeSH, and especially semantic similarity supported by a large scale of literature. The weights of each feature were optimized at a step of 0.01 during the process of feature fusion. The optimal prediction results appeared with the fusion coefficients of To demonstrate the significance of the vast amount of literature texting mining for association prediction, we did ablation studies that compared LBMFF with single-feature methods and Multi-Feature Fusion (MFF) method in Firstly, it should be noted the significance of literature-based semantic feature on the prediction of unknown relations compared to other single-feature methods, with the most relative improvements of 2.4% on AUPR. Secondly, the results also indicated that MFF outperforms the single-feature methods in terms of AUPR, AUC and Acc. Thirdly, LBMFF reached the best performance: AUC = 0.8818, which achieved relative improvements of 1.23%, 1.28%, 0.49%, 0.56% higher than single-feature methods and 0.56% higher than MFF; AUPR = 0.5961, achieving relative improvements of 2.79%, 1.87%, 3.02%, 0.44% higher than single-feature methods and 1.09% higher than MFF. We reached the best performance in both F1 and Rec.According to the aforementioned performance metrics, MFF first achieved better performance than single-feature methods due to the adjusted weights for each measurement. It demonstrated that feature fusion played an essential role in drug-disease association prediction due to the integrated information from different dimensions. LBMFF further extracted semantic information from large-scale literature, which then led to improved performance of MFF-based model.In this section, we compared LBMFF with seven state-of-the-art association prediction methods by using the same dataset, Bdataset:• BNNR  was a bo• DRHGCN  and DRWB• LAGCN  predicte• NIMCGCN  was a no• DDA-SKF  construc• REDDA  proposedSpecifically, we listed these methods as follows.According to To further verify the effectiveness of LBMFF, we denoted another public benchmark, TL-HGBI with 963 drugs, 1,263 diseases and 54,921 drug-disease associations, into LBMFF and the seven baseline methods mentioned above. The results in To demonstrate the capability of LBMFF to discover new indications and new therapies, all known drug-disease associations have been used to predict unknown drug-disease associations with this model. We conducted case studies with verification from clinical indications that were already in use, ClinicalTrials, CTD and public literature. ClinicalTrials is the largest clinical trials database run by the United States National Library of Medicine (NLM), holding registrations from over 329,000 trials from 209 countries. CTD is a publicly available research resource that curates scientific data describing relationships between chemicals, genes and human diseases by professional curators. In our study, we constructed three kinds of case studies to verify the predictive capability: 1) the top 10 drug-disease associations predicted by LBMFF in We listed the top 10 drug-disease associations predicted by LBMFF in We selected dexamethasone (MeSH ID: D003907) and doxorubicin (MeSH ID: D004317) as two drug cases to validate the ability to discover new indications. For each drug, the top 10 candidate diseases are ranked according to the prediction scores as shown in Dexamethasone is a corticosteroid that prevents the release of substances in the body that cause inflammation, such as allergic disorders and skin conditions. It is also used to treat ulcerative colitis, arthritis, lupus, psoriasis, and respiratory disorders. Seven of the top 10 predicted associations have been confirmed by databases, literature and clinical use of dexamethasone. According to literature, dexamethasone works against paclitaxel drug allergy (PMID: 28704328), chest syndrome in patients with sickle cell disease (PMID: 21799397) and dyspnea in cancer patients (PMID: 27330023). What’s more, Doxorubicin is an anthracycline type of chemotherapy that is used to treat several different types of cancer. Six of the top ten predicted associations have been confirmed in this section. It is approved for the treatment of non-small cell lung cancer, glioma, hematologic tumors and acute lymphoblastic leukemia, either alone or in combination with other drugs. Additionally, a combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has also been used as a treatment for idiopathic pulmonary fibrosis .The remaining associations predicted by the LBMFF model have not received much attention so far, providing an avenue for new indications to be discovered.Furthermore, we conducted two detailed case studies to further verify the capability of new therapies discovery, and the chosen diseases were seizures (MeSH ID: D012640) and hypertension (MeSH ID: D006973). The top 10 related drugs for both diseases were listed in in vivo. The Drug combinations of bumetanide plus phenobarbital and vitamin B12 plus carbamazepine have been proven effective in treating seizures (PMID: 29563977). Moreover, animal models in mice presented with prednisolone or sirolimus had less severe seizures than the negative control group.In the section on seizures, we confirmed eight of the top 10 results through database and literature evidence. Specifically, quinidine significantly reduced the seizure burden (by about 90%). Tetracycline-class antibiotics were protective against partial seizures In the section on hypertension, we found evidence for eight drug candidates in the top ten through databases and literature. For example, pioglitazone modulated the vascular contractility in hypertension by interference with the ET-1 pathway (PMID: 31712626), and acetazolamide leads to more effective control of increased intracranial pressure (PMID: 26154918). Furthermore, ClinicalTrials and CTD proved the possibility of the other six new drug-disease associations.In this study, we proposed a method called LBMFF for drug-disease association prediction. Due to the huge amount of information contained in both biomedical public databases and scientific literature, we computed drug-drug and disease-disease similarities by multi-feature fusion and utilized two GCN layers to capture structural embeddings from the association feature matrix. Concretely, the association feature matrix consisted a drug comprehensive similarity matrix, a disease comprehensive similarity matrix and a known drug-disease association. Moreover, an attention mechanism was denoted into the GCN model to extract information more effectively. The proposed method achieved excellent performance compared to seven state-of-the-art methods on the same test datasets, and we demonstrated its potential for identifying new drug-disease associations for practical use.However, there are still some limitations in our work that require an in-depth investigation. First, more association features should be further considered in our work. We can collect more prior biological knowledge from literature, such as drug-protein, drug-gene, disease-gene and drug-pathway, to improve similarity accuracy. Second, the two-layer GCN is a basic model for learning on graph-structured data, while some other graph neural network models are worth investigating in the future.Above all, LBMFF is able to learn scattered information from both public databases and scientific literature to identify the latent drug-disease associations. It gives researchers, pharmacologists, and pharmaceutical companies a tremendous opportunity to study and validate predictive associations that are more likely to exist. We expect LBMFF to be an efficient approach that can further improve drug repositioning and shorten its cost and time.


The aim of these clinical standards is to provide guidance on ‘best practice’ care for the diagnosis, treatment and prevention of post-COVID-19 lung disease.A panel of international experts representing scientific societies, associations and groups active in post-COVID-19 lung disease was identified; 45 completed a Delphi process. A 5-point Likert scale indicated level of agreement with the draft standards. The final version was approved by consensus (with 100% agreement).Four clinical standards were agreed for patients with a previous history of COVID-19: Standard 1, Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease; Standard 2, Patients with lung function impairment, reduced exercise tolerance, reduced quality of life (QoL) or other relevant signs or ongoing symptoms ≥4 weeks after the onset of first symptoms should be evaluated for treatment and pulmonary rehabilitation (PR); Standard 3, The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to an individual patient’s needs; and Standard 4, Each patient undergoing and completing PR should be evaluated to determine its effectiveness and have access to a counselling/health education session.This is the first consensus-based set of clinical standards for the diagnosis, treatment and prevention of post-COVID-19 lung disease. Our aim is to improve patient care and QoL by guiding clinicians, programme managers and public health officers in planning and implementing a PR programme to manage post-COVID-19 lung disease. Generally, sequelae that include persistent but reversible symptoms with no need for treatment are classified as mild. Sequelae that need action in terms of further investigation and treatment, even if usually treatable and reversible, are defined as moderate. Severe sequelae include deep vein thrombosis, strokes or pulmonary embolism.25 Furthermore, rare severe sequelae are those presenting with chronic organ failure, such as cardiovascular events, including myocarditis, postural orthostatic tachycardia syndrome, renal failure or pulmonary fibrosis. Pathophysiological processes impacting long COVID include organ damage, resulting from acute phase infection, complications from a dysregulated inflammatory state and inadequate antibody response against SARS-CoV-2.26 Although it is acknowledged that long COVID affects several organs and/or body systems, here we primarily focus on lung damage. In summary, the term post-COVID-19 lung disease as used here includes signs and symptoms from sequelae, which continue or develop after the acute phase, and feature all the relevant conditions described above.14Here, we discuss how these health consequences can be addressed by implementing clinical standards for the diagnosis, treatment and prevention of post-COVID-19 lung disease. These standards build on a statement by the European Respiratory Society (ERS) describing follow-up strategies for long COVID (which acknowledged that the evidence for follow-up care was limited at the time of publication in 2023).31 We have therefore extrapolated from data on other respiratory conditions and previously published clinical standards to inform our approach.35 Evidence on post-COVID lung disease is still lacking in areas such as benefits/risks evaluations, and costs and cost-analysis. We present an ‘optimal’ set of standards (recommendations for the best possible approach), but acknowledge that implementing this approach may be difficult in some settings. We therefore include adaptations for special settings and situations to indicate how the approach can be modified as needed.Our aim is to provide expert guidance on ‘best practice’ for diagnosis, treatment and prevention of post-COVID-19 lung disease. Developing standards for a new, incompletely characterised disease is challenging, as we have only limited long- to medium-term experience of the condition. However, the type of lung damage and their symptoms are similar to the sequelae or complications observed in other respiratory diseases, including post-TB lung disease (PTLD).Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease (Standard 1).Patients with lung function impairment, reduced exercise tolerance, reduced quality of life (or other relevant signs or ongoing symptoms) ≥4 weeks after the onset of the first symptoms should be evaluated for treatment and pulmonary rehabilitation (PR) (Standard 2).The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to the patient’s needs (Standard 3).Each patient undergoing and completing PR should be evaluated to determine its effectiveness and have access to a counselling/health education session (Standard 4).This consensus-based document describes the following process for patients with a previous history of COVID-19:In addition, consensus-based research priorities were identified.n = 47) were asked to comment on an initial set of six draft standards developed by a core team (n = 7) of researchers via a Delphi process. Of these, 45 researchers provided valid answers; following the Delphi process, the six draft standards were reduced to four. The final writing panel included the following 40 experts: COVID/infectious diseases and respiratory clinicians (n = 32), public health specialists, including respiratory epidemiologists (n = 4), a physiotherapist, an occupational physician, a paediatrician and a methodologist. A 5-point Likert scale  was used to indicate agreement with the standards. At the first Delphi round, agreement was high, with a median value of >4 . Based on substantial initial agreement, the expert panel developed an initial draft, which underwent five rounds of revisions. The final version was approved by consensus (100% agreement). As evidence in this field is rapidly accumulating, this document will be updated once significant new evidence emerges.A panel of 63 global experts were invited to represent the main scientific societies, associations and groups active in post-COVID-19 lung disease. Of the 63 experts, 4 declined, and 12 did not respond after one invitation reminder. All respondents  ression) .36–39 In41 Thoracic imaging of pulmonary sequelae of COVID-19 from 10 to 12 months after the acute event has revealed fibrotic changes, including parenchymal bands, irregular interfaces and reticular opacities, with or without honeycomb-like changes.43 Where available, CT/HRCT can be used to identify post-COVID pulmonary abnormalities,44 considering that the type of abnormality may vary according to the severity of the acute phase, duration of hospitalisation and need for mechanical ventilation.47 For patients who may require imaging based on clinical findings, symptom management and a rehabilitation plan can often be initiated simultaneously with the imaging workup. However, it is important to point out that CT imaging is not available in many countries, and be aware that patients could present with clinical symptoms and radiological signs evoking post-COVID-19 without a previous diagnosis of COVID-19.The relationship between thoracic images and persisting abnormalities in lung function requires further study. In patients with normal chest radiography and oxygen saturation, computed tomography  imaging of the chest might have some role for assessing pulmonary disease.48 Assessment and treatment with anti-platelet therapies and or anticoagulants are outside the scope of this document and is fully addressed in guidelines for antithrombotic treatment for COVID‐19.49 Antibody tests, when available, could help to confirm diagnosis, especially when reverse transcription polymerase chain reaction or rapid antigen test was not done for the initial diagnosis of COVID-19, although many individuals will since have been vaccinated.23Patients, especially those with severe COVID-19, may develop micro-clots that persist months after the initial infection.51 involving nurses, physiotherapists and psychologists. The presence of respiratory signs and symptoms will aid the identification of patients with respiratory sequelae at risk of deterioration and most likely to benefit from PR as discussed below.A comprehensive assessment should be done in individuals experiencing new or ongoing symptoms at least 4–12 weeks or more after the acute phase see  to identPatients with lung function impairment, reduced exercise tolerance, reduced QoL or other relevant signs or ongoing symptoms ≥4 weeks after the onset of the first symptoms, should be evaluated for treatment and PR.52 Treatment of post-COVID-19 lung disease should focus on managing the patient’s symptoms, improving function and health-related QoL. Recent evidence supports the need for prompt referral to rehabilitation in patients hospitalised for COVID-19 disease, while for non-hospitalised patients, referral should follow an assessment by healthcare workers or a watch and wait/self-management approach for at least 6 weeks. An overall evaluation of functional impact and physical performance in post-COVID-19 patients should focus on symptoms limiting daily activities, pulmonary function tests (PFT), diffusion capacity of the lung for carbon monoxide (DLCO), blood gas analysis (BGA), pulse oximetry at rest and on exertion, QoL, anxiety and depression (77 Patients presenting with lung function impairment (airflow obstruction or restriction or mixed and/or impaired DLCO and/or gas exchange), reduced exercise tolerance and related impairment in QoL and other relevant signs or symptoms  should be evaluated for PR.PR is described as a ‘comprehensive intervention based on a thorough patient assessment, followed by patient-tailored therapies that include, but are not limited to, exercise training, education and behaviour change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviours’.pression .9,17,23,68 Patients in need of early and effective PR are those who had suffered from the severe acute forms of COVID-19 and those with persistent abnormal chest X-ray or CT or reduced DLCO.17A pilot study from 2021 evaluated COVID-19 patients 6 months after discharge from hospital and showed that persistent dyspnoea was associated with reduced physical fitness.53 Such patients are likely to benefit from PR. Finally, patients experiencing severe lung impairment during COVID-19 acute illness, prone to altered PFT and 6-min walk test (6MWT) results, are a subgroup of patients that could also benefit from PR.69Patients with COVID-19 admitted to intensive care unit (ICU) may develop a post-intensive care syndrome (PICS), with impaired physical, exercise-induced oxygen desaturation, muscle weakness and reduced mobility.The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to the patient’s needs.52 There is strong evidence that PR is also successful when multiple comorbidities are present.78 PR should be completed within the framework of a multidisciplinary programme. Based on the experience with other respiratory conditions, this programme consists of physical and exercise therapy, along with psychology, nursing and medical interventions, as needed. Symptoms reported by post-COVID-19 patients include breathlessness, anxiety, depression, fatigue, reduced lung and muscle capacity and comorbidities, highlighting the emerging role of PR as an effective intervention in post-COVID-19 lung disease.86 A dysfunctional or abnormal breathing pattern has also been reported by patients with long COVID, both at rest and during exercise testing. In patients with post-COVID-19 dysautonomia, such as postural orthostatic tachycardia syndrome, breathing exercises in an upright position can be challenging and a supine position during exercise should instead be recommended.89PR is a multidisciplinary, non-pharmacological intervention aiming to improve symptoms, health status, and exercise capacity and reduce disability in post-acute and chronic respiratory diseases.90 Such programmes should be tailored to the patient’s needs and include some minimum and essential requirements.91 These include areas of rehabilitation and interventions focused on the baseline assessment, exercise training, education to support self-management, psychological counselling as required, and recommendations for home-based exercise and physical activity,92 with a programme length ranging from 1–12 weeks.77 A follow-up plan is recommended to maintain benefits from PR and evaluate additional clinical problems arising at a later stage. PR programmes cannot be planned without considering the local organisation of health services, such as hospital settings, community, one-stop-shop clinics, out-patient clinics, or integrated into primary care.100 They should also be organised according to feasibility, effectiveness and cost-effectiveness criteria,101 and adapted to the context and resources available in different settings to ensure that they are as accessible as possible for patients, including children and adolescents.103 PR programmes can also be delivered in person, through tele-rehabilitation, depending on each patient’s individual context.PR programmes for long COVID have been proposed in different settings according to the local organisation of health services, ranging from in- and out-patients, home and tele-rehabilitation.104 Yoga, incorporating breathing exercises, stretching and gentle chair and standing exercises, is offered by patient advocacy organisations such as the Irish Lung Fibrosis Association (https://ilfa.ie/blog/online-yoga-class/) as an adjunct to PR and warrants further evaluation. The benefits of structured singing programmes for lung health, which are offered outside the traditional health service model, are also emerging.105Both during and after the COVID-19 pandemic, there has been an accelerated interest in alternative forms of exercise training, such as yoga and dance, integrated with or as an adjunct to PR programmes. Dance improves motor function  in older patients in other disease contexts and is being evaluated as an adjunct to PR in respiratory conditions.106 PR could accelerate recovery in post-COVID-19 patients, but further studies are needed to identify effective and cost-effective strategies to deliver PR in the different settings. The core components of a PR programme are summarised in 113Our understanding of the benefits of PR is mostly derived from the experience of people affected by chronic respiratory diseases, especially chronic obstructive pulmonary disease (COPD), where it has proven to be cost-effective in preventing hospital readmission.Each patient undergoing and completing pulmonary rehabilitation should be evaluated to determine its effectiveness and have access to a counselling/health education session.115 and respiratory symptoms. In this context, the strongest independent predictors of persistent respiratory impairment with need for follow-up115 are patients with COVID-19 presenting with dyspnoea 3 weeks after hospital discharge and those with impaired gas exchange on admission to hospital. Data show that functional capacity and QoL should not be neglected,117 and a multidisciplinary rehabilitation strategy is essential to address this.Studies with strong evidence on the efficacy of interventions, in particular, PR and long-term monitoring for post-COVID-19 lung disease are lacking. No guidelines for post-COVID-19 interventions exist, and standardised methods for evaluating their efficacy have not been developed. Standard 4 includes a short description on how to evaluate the effectiveness of PR, comparing core variables pre- and post-rehabilitation. The standard also suggests how to organise the patient’s follow-up to maintain or improve the results achieved, organised according to feasibility and cost-effectiveness criteria, based on the local organisation of health services and tailored to an individual patient’s needs. For patients with long COVID, the objective of PR is to increase functional independence. This can be evaluated  by a significant improvement in PFT results114 Community health workers can contribute to the COVID-19 response by providing screening, facilitating referrals, arranging support for home care, staffing community-based isolation centres, and being involved in surveillance, contact tracing, service delivery to people with disabilities, home visits, outreach activities and advocacy campaigns.114Community-based PR interventions and monitoring may also be beneficial during pandemics.123 The secondary area of prevention includes intervening during acute disease to prevent sequelae: pharmacological treatment with antivirals and corticosteroids, selective prophylactic anticoagulants, critical care and early rehabilitation in acute care.124 Tertiary prevention interventions, including disability limitation and rehabilitation, are post-acute disease. Quaternary interventions include activities that help in preventing treatment and vaccine side effects.There are points in the sequence of events spanning SARS-COV-2 infection to reporting prolonged and persistent suffering due to post-COVID sequelae, at which there is the possibility of a preventive intervention/strategy. Primary prevention is based on avoiding SARS-COV-2 infection; the basic interventions that can be implemented are well acknowledged: face-masks, hand sanitisation, personal distancing, appropriate ventilation of indoor settings and vaccination.125 are summarised below.Examples of future research prioritiesIdentification of predictors of post-COVID lung disease: patient characteristics , biomarkers, extrinsic factors , radiological patterns during acute disease, manifestations and severity of COVID disease;Development and evaluation of diagnostic tools and algorithms for post-COVID lung disease;Evaluation of the effectiveness of multidisciplinary, post-COVID-19 clinics vs. traditional GPs’ assessment with referral to organ specialists;Definition of criteria for severity of post-COVID disorders;Assessment of knowledge on post-COVID lung disease of health workers in primary care centres and public hospital clinics;Development and validation of tools for auditing activities on post-COVID lung disease;Evaluation of long-term consequences of post-COVID lung disease, with special focus on bronchiectasis and pulmonary fibrosis;Impact of post-COVID in developing countries.Exploration of role  of the different drugs for the various manifestations of post-COVID lung disease: antibiotics, corticosteroids, anti-fibrotic drugs , anti-histamines, combination therapy of anti-platelet therapies and anti-coagulants in the later variants of SARS‐CoV‐2;Evaluation of the long-term impact of PR on disability and QoL;Assessment of rehabilitation knowledge and needs, aimed at elaborating training programmes;Exploration of optimal treatments and their outcomes in patients with immunodeficiencies;Exploration of role  of non-conventional, non-pharmacological interventions ;Efficacy of anti-COVID-19 vaccines as treatment of post-COVID lung disease;Identification of cost-effective strategies to deliver PR;Establishing standards for assessing fitness to work and return to normal duties.Efficacy of anti-COVID-19 vaccines on the prevention of post-COVID lung disease;Efficacy of other preventive measures on the prevention of post-COVID lung disease: daily facial masks, hand washing/disinfection, limitations on re-occurrence of disease;Identification of factors that can be potential targets for interventions to prevent post-COVID disease;Evaluation of the impact of early and personalised PR in the acute phase of COVID-19 to prevent post-COVID sequelae;Exploring strategies and developing guidelines to prevent venous thromboembolism (VTE) occurrence and post-COVID VTE recurrence;Evaluation of the role of antifibrotic therapy for the prevention of pulmonary fibrosis in patients with reduced DLCO 12 weeks after SARS-CoV-2 infection;Strategies and approaches for the prevention of exacerbations and bronchiectasis;Identification of pharmaceutical, physical and psychological interventions in those with infection to prevent progress to post-COVID-19 disease;Telemedicine for video-observed PR;Inclusion of educational modules on the effect of air pollution and the benefits of smoking cessation.91 There is preliminary, but increasing evidence that PR interventions are useful for post-COVID-19 lung disease; however, implementation of these programmes remains slow. Beyond adopting what is already acknowledged as effective, there is a strong need to accumulate and evaluate the increasing evidence on the use of PR for post-COVID-19 lung disease and investigate innovative PR interventions. There is also a need for research on the underlying mechanisms of post-COVID-19 pulmonary sequelae. As the currently available evidence is only modest, we need periodical evaluations of PR to guide evidence-based implementation of adequate measures to assess and manage post-COVID-19 lung disease.A significant number of people continue to require care after recovering from acute COVID-19.126Within the ‘optimal’ approach to the management of post-COVID-19 lung disease these Clinical Standards promote, digital services may help to reduce costs and the time lost to travel in some settings. Digital services supporting both treatment, management and PR of patients include asynchronous clinical communications, real-time virtual care, messaging, telephony or video conferencing, virtual health assessments and medication review.


Fub-1 has an important role in gene regulation during development in Drosophila.An unexpected interaction between a long non-coding RNA locus and a genetic insulator called  Related research article Ibragimov A, Bing XY, Shidlovskii Y, Levine M, Georgiev P, Schedl P. 2023. lncRNA read-through regulates the BX-C insulator Fub-1. eLife12:e84711. doi: 10.7554/eLife.84711.Genes that code for proteins account for less than 2% of the human genome: what does the rest of the genome do? Some of it is given over to genes for RNA molecules that have vital roles in cellular processes, such as ribosomal RNAs, transfer RNAs and small regulatory RNAs. However, the roles of other RNA molecules – notably molecules called long non-coding RNAs (lncRNAs) – are not fully understood, although many lncRNAs are known to be involved in the regulation of gene transcription .The non-coding part of the genome also contains regions called cis-regulatory DNA elements that orchestrate the precise timing, location and extent of gene expression . These eDrosophila which reveal an unexpected role for lncRNAs in the regulation of hox genes (Gene regulation means that the different cell types in a multi-cellular organism decode the same genetic information (the genome) in a cell-type-specific manner. One widely studied example of this is the regulation of hox genes, which have an important role during animal development . Howeverox genes .Ubx (which is short for Ultrabithorax), the researchers studied the function of Fub-1, an insulator that is positioned between the regulatory domains that determine how Ubx is expressed in two distinct body segments in Drosophila embryos . This was unusual because depleting a classic insulator element typically results in abnormal segmental identity , and the complexity of their function. Moreover, although it was carried out in