The first case of coronavirus disease 2019 (COVID-19) was diagnosed in December 2019 in Wuhan, China. Since then, this novel infectious disease, caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has grown into a pandemic with over 330 million infected individuals worldwide, many of them with innate or acquired immunosuppression.Liver transplantation (LT) is offered as a curative therapy for end-stage liver disease as well as for acute liver failure cases. Advances in immunosuppressive therapy decreased the rates of acute and chronic graft rejection, significantly improving the quality of life.Liver transplant recipients are considered at particularly high risk for developing critical COVID-19 infection because of their chronic immunosuppressed state. Available data are heterogeneous, and the mortality rate is variably reported in the literature. There is controversy regarding whether their immunosuppressive status is a risk or a protective factor for developing severe respiratory disease. Moreover, the mechanism of action is still unclear.We report the clinical outcome of three liver transplant recipients who had COVID-19 pneumonia at different moments following liver transplantation. All patients received a standard immunosuppression regimen and specific antiviral therapy, requiring no invasive mechanical ventilation. They were discharged from the hospital with no long-term COVID-19 complications. Since the beginning of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, millions of people became victims worldwide -3. ConsiThe presence of a large number of mutations is also a hallmark of the variants of concern, including B.1.1.7 , B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta), which suggests that the viral evolution in immunocompromised patients may be an important factor in the emergence of such variants . Since mMoreover, liver transplant recipients raise obvious concerns worldwide as a consequence of the interaction between their acquired immunosuppression and SARS-COV-2 infection, which makes them particularly vulnerable. They are mostly referred to specialized liver surgery centers ,6. ConveStandard therapy in liver transplantation generally involves a mixture of corticosteroids, calcineurin inhibitors (CNI) (cyclosporine or tacrolimus), and antiproliferative agents (mycophenolate mofetil {MMF}), in accordance with local guidelines . The intA paucity of data is available regarding coronavirus disease 2019 (COVID-19) pneumonia in this particular subpopulation, and only few articles are focusing on the severity of COVID-19 pneumonia correlated with the immune status of a liver-transplanted patient with regard to the time elapsed since the initial surgery . Thus, oCase 1A 64-year-old male patient underwent an orthotopic liver transplant for decompensated liver cirrhosis secondary to hepatitis C virus and grafted hepatocellular carcinoma, in accordance with the Milan criteria for liver transplantation . His medThe patient received 20 mg basiliximab and 500 mg methylprednisolone intraoperatively. Further, the patient was administered a combination of tacrolimus and mycophenolate mofetil, in accordance with the blood count analysis and liver function tests. A second dose of basiliximab was administered on the fourth postoperative day. The patient was discharged after a favorable postoperative evolution, having been prescribed oral immunosuppression therapy with tacrolimus. Four months after the liver transplantation, the patient was transferred to our clinic with acute hypoxemic respiratory failure secondary to COVID-19 infection. The CT findings are illustrated in Figure Despite the moderate-to-severe form of COVID-19 pneumonia, the patient didn’t require management in an intensive care unit (ICU). The patient received supplemental oxygen over a non-rebreather oxygen mask with a maximum flow of 8 l/min. The patient received 10 days of specific antiviral therapy, comprising remdesivir and corticosteroids, while the chronic immunosuppression with oral tacrolimus was continued, with a dosing regimen adjusted in accordance with the plasma concentration. The patient was discharged from the hospital 21 days after the positive SARS-COV-2 test, with no other respiratory features.Case 2A 56-year-old female patient underwent a living donor transplant for decompensated liver cirrhosis secondary to alcoholic hepatitis. Her medical records included grade I-II esophageal varices, atrial and right ventricular dilation, and mixed valvulopathies including moderate mitral, tricuspid, and pulmonary regurgitations. The patient’s preoperative model for end-stage liver disease (MELD) score was 16 points.The patient received 20 mg basiliximab and 500 mg methylprednisolone intraoperatively. Immunosuppression was maintained with tacrolimus and MMF, with dosing guided by the blood count analysis and liver function tests. A second dose of basiliximab was administered on the fourth postoperative day. The patient had a favorable postoperative outcome, and she was discharged from the ICU facility five days later. One week after liver transplantation, the patient showed transitory neurologic impairment consisting of left transitory hemiplegia. The patient was readmitted to the ICU. The MRI-scan identified bilateral parieto-occipito-frontal subacute cortical ischemia  Figure .Specific antiviral therapy with remdesivir and corticosteroids was initiated. Her symptoms subsided after seven days of ICU stay, of which five days with continuous positive airway pressure (CPAP) therapy and two days with supplemental oxygen via a non-rebreather face mask. She was discharged from the hospital after a total stay of 14 days, with no other respiratory features.The functional impact of COVID-19 pneumonia in the patients presented above was minor, regardless of the time since the transplantation. Two patients benefited from supplemental oxygen via a facial non-rebreather mask and one patient required five days of non-invasive mechanical ventilation. Two of them needed management in the ICU. No patient needed invasive mechanical ventilation and none returned with any features of the post-COVID-19 syndrome. Thus, we described the impact of COVID-19 pneumonia on acquired immunosuppression liver-transplanted patients at relevant increasing time points  after surgery, considering variations in immunosuppression intensity after the surgical event, a key issue. At the time of admission, our patients displayed the following symptoms: fever, cough, dyspnea and tachypnea, pale skin, and mucous membranes. Moreover, we identified increased levels of c-reactive protein (CRP), D-dimers, ferritin, and typical blood count changes. Only one patient had shown reversible neurologic impairment, with subacute ischemic changes on MRI scan.Our results are in accordance with those published by Kulkarni et al. . They haMoreover, a meta-analysis revealed that the outcomes of patients infected with SARS-CoV-2 a few days or weeks after liver transplantation was similar to other categories of patients, with no impact on mortality . Our casSome clinical studies suggested changes in immunosuppression regimen for liver-transplanted patients with COVID-19 pneumonia -16. CyclMMF is an antibiotic isolated from Penicillium species that also has immunosuppressive properties . The druCNI and MMF doses were either reduced or discontinued in most of the patients with COVID-19 pneumonia, even though, due to its inhibitory effect on T-cell activation phase, tacrolimus has been associated with an improved survival rate ,16,21. APatient in case 3 received tacrolimus in monotherapy as prophylaxis against host vs. graft reaction in accordance with local protocol. The liver-transplanted patients receive MMF either in perioperative settings or in case of acute rejection. The patients were discharged between the 14th and 26th day after COVID-19 confirmation. Due to the heterogeneity of the data in the literature regarding median hospital stay for immunosuppressed patients, no conclusion could be drawn regarding the severity of the illness based on this criterion. Moreover, prolonged viral shedding in our patients could not be excluded.Basiliximab is a murine/human chimeric monoclonal antibody that binds to the alfa chain of interleukin-2 receptors (CD25 antigen), expressed on the surface of T-lymphocytes in response to antigenic aggression . BasilixBesides various approaches for primary prophylaxis against graft rejection in liver-transplanted patients, specific antiviral therapy against SARS-CoV-2 infection should be added in accordance with the local guidelines . The mosRemdesivir has a short plasma half-life (approx. one hour), however, its analog metabolites have significantly longer half-lives, of up to 35 hours, which enables the administration of remdesivir as a single daily dose - 200 mg loading on the first day of the regimen, followed by 100 mg daily from day two up to five or 10, depending on the patient’s responsiveness to therapy . One of Regarding the neurological impairment observed in the patient of case 2, it could be attributed to COVID-19 infection, as the result of multiple possible mechanisms, including "cytokine storm", virus-induced hypercoagulability, or direct infection of the central nervous system . Viral nAlthough immunosuppressant therapy was inconsistent during hospitalization, our patients had a favorable outcome, requiring no invasive mechanical ventilation. They were quickly diagnosed and treated from the onset of symptoms. While the mortality in COVID-19 immunosuppressed patients is not higher than in the general population, clinicians should be made aware of the potentially severe lung complications associated with this complex pathology.


Material and Methods. The study was divided into two arms. For the first one, we qualified 169 patients with NSTE-ACS treated with PCI who received the drug-eluting stent (DES) coated with a biodegradable polymer Ultimaster . The second arm was composed of 193 patients with ACS who underwent PCI with a magnesium bioresorbable scaffold Magmaris . Both arms were divided into two subsequent groups: the T2DM (59 and 72) and the non-DM . The primary outcomes were cardiovascular death, myocardial infarction, and in-stent thrombosis. The main secondary outcomes included target lesion failure (TLF) and were recorded at a 1-year-follow-up.  Cardiovascular disease (CVD) with significant involvement of coronary artery disease (CAD) remains a major cause of death and disability among the diabetic population. Although percutaneous coronary intervention (PCI) continues to evolve, type 2 diabetes mellitus (T2DM) is a well-established marker of poor clinical prognosis after PCI, which is mainly attributed to the rapid progression of atherosclerosis requiring recurrent revascularizations. Hence, the use of bioresorbable materials could provide some solution to this problem.  There were no significant differences between the diabetic and nondiabetic populations in the primary endpoints or main secondary endpoints  either in the Ultimaster or Magmaris group. At a 1-year follow-up, the primary endpoint in the DM t.2 population was recorded in 2.7% Ultimaster vs. 5.1% Magmaris, respectively.  Both, Ultimaster and Magmaris revealed relative safety and efficiency at a one-year follow-up in the diabetic population in ACS settings. The observed rates of TLF were low, which combined with a lack of in-stent thrombosis suggests that both investigated devices might be an interesting therapeutic option for diabetics with ACS. Nevertheless, further large randomized clinical trials are needed to confirm fully our results. Among patients with acute coronary syndrome, diabetes mellitus in particular is a marker of poor clinical prognosis. Diabetics tend to have rapid progression of atherosclerosis, leading to an increased rate of multivessel disease, which commonly requires recurrent revascularization. According to the current European Society of Cardiology (ESC) guidelines on myocardial revascularization , coronarRecently, the new generation of sirolimus-eluting bioresorbable polymer DES Ultimaster  has demonstrated a favorable 1-year safety and efficacy profile with concomitant rapid vascular wall healing and a high degree of strut coverage . A thin,The aim of this study is to investigate the performance of sirolimus-releasing bioresorbable polymer stents (Ultimaster) compared to bioresorbable magnesium scaffold (Magmaris) and to evaluate the theoretical advantages of this new technology in high-risk population patients with diabetes mellitus in the setting of ACS.Patients with acute coronary syndrome–NSTE-ACS (with exclusion of the STEMI cases) and clinical indication for percutaneous coronary intervention (PCI) were enrolled in this retrospective, observational, study. This study consisted of two major arms . The firMagmaris is a novel metallic (magnesium) sirolimus-eluting scaffold coated with a biodegradable polymer (BIOlute) poly-L-lactide (PLLA). Currently, available scaffold sizes are 3.0 and 3.5 mm in diameter and 15, 20, and 25 mm in lengths. Ultimaster is a cobalt-chromium sirolimus-eluting stent covert abluminal with a biodegradable poly- copolymer (PDLLA-PCL).All patients receive a periprocedural medication regimen according to the routine practice in accordance with current revascularization guidelines . InitialThe primary outcome included death from cardiac causes, myocardial infarction, and stent thrombosis. The main secondary outcome was a target-lesion failure (TLF) composed of cardiac death, target vessel myocardial infarction (TV-MI), or target lesion revascularization (TLR). Also, other secondary outcomes  were reDiabetes (type 1 or type 2) was defined as a previously diagnosed DM treated with pharmacologic or nonpharmacologic, and a new-onset DM was defined according to the American Diabetes Association .p values ≤ 0.05 were accepted as a threshold for statistical significance.The analyses were performed using the R language . Continup = 0.018) and a past history of PCI  as well as was characterized by a significantly lower left ventricular ejection fraction  In contrast, a nondiabetic Magmaris group had more severe initial lipid disorders—total cholesterol  and LDL .The Magmaris group consisted of 72 diabetics and 121 nondiabetic cases. In the diabetic group, the majority of patients received oral antidiabetic treatment rather than insulin (58 (80.5%) vs. 14 (19.5%)). The diabetic group had a significantly higher prevalence of hypertension  and LDL . To the Ultimaster arm, we recruited a total of 59 diabetic subjects and 110 patients to the control group. Among the diabetic participants, the minority was treated with insulin (23.7%). There were no statistically significant differences in comorbidities between the diabetic and nondiabetic Ultimaster populations. The nondiabetics had higher serum level of total cholesterol . All procedural characteristics are shown in The characteristics of the PCI procedures performed in both study arms were heterogeneous. The only statistically significant differences were found in the Ultimaster arm and related to the radiation dose used during the PCI procedure, which was higher in the diabetic group . Noteworthy, the rates of the primary outcome were higher in the diabetic population in the Ultimaster group  at short follow-up (30 days). A similar trend was observed at long-term follow-up (1 year) for principal secondary outcome in the Magmaris arm .All clinical outcomes data are summarized in Tables Despite worldwide public health interventions taken to stop the global growth of diabetes prevalence, it is inexorably increasing. A disproportionate burden of the increase in type 2 diabetes affects the middle-to-high-income countries, particularly Western Europe and the Pacific Ocean island nations . CardiovThe first, also referred to as third-generation DES, involves abluminal coating of a thin metallic backbone with a bioresorbable polymer that degrades uniformly to release the antimitotic drug sirolimus. An example of this technology is the Ultimaster.The second concept pursues complete biosorption of the scaffold. In this scenario, BRS provides short-term performance equivalent to existing drug-eluting stents (DES); however, it avoids permanent caging of the vessel. After the widespread use of first-generation Absorb (Abbott) was discontinued, the second generation of BRS (Magmaris) with a metallic backbone (magnesium) sirolimus-eluting BRS containing an active bioabsorbable coating BIOlute poly-L-lactide (PLLA) entered the market and is currently available for commercial use.in vitro models [Data on the performance of the Ultimaster in the all-comers population are encouraging and demonstrated low late lumen loss, resulting in low rates of in-stent thrombosis, restenosis, and TLR –17. Clino models  and are o models , 20 leado models .It is well known that diabetes mellitus and ongoing ACS are independent risk factors for poor clinical outcomes after PCI. Although there is a lack of convincing data for Ultimaster, few studies conducted so far seem to confirm this paradigm , 23 mainOn the other hand, our favorable results may be related to the detailed lesion selection that we adopted from inclusion criteria of the Magmaris Registry. We avoided high-risk patients with heavy calcification, the STEMI patients with present thrombus, or low-size of the treated vessel. However, the latter factor has been proven to have no effect on clinical outcome after Ultimaster implantation , 23. TheData regarding the performance of Magmaris in the diabetic population are strictly limited , yet encTo the best of our knowledge, this is the first in human study designed to compare the efficacy and safety of fully bioresorbable magnesium scaffold (Magmaris) with a third generation of metallic DES with bioresorbable polymer, in DM t.2 population in ACS settings. We found no differences between the two scaffolds in the diabetic subpopulation. As reported in our study, the 1-year TLF in DM subpopulation for both devices (4.1% vs. 3.3%) is comparable  and evenThis was a nonrandomized study with retrospective data collected in the relatively short observation period (1-year follow-up). The study population was not very large and underpowered for reliable assessment of events, especially in the diabetic subpopulation. Also, the rate of intravascular guidance PCI was comparatively low.In our study both biodegradable polymer DES (Ultimaster) and Magnesium bioresorbable scaffold (Magmaris) revealed relative safety and efficiency features at a one-year follow-up in the diabetic population in ACS settings. The observed rates of TLF were low, which combined with a lack of in-stent thrombosis suggests that both investigated devices might be an interesting therapeutic option for diabetics with ACS. Nevertheless, further large randomized clinical trials are needed in order to confirm fully our results.


Is internet-delivered cognitive behavioral therapy (ICBT) an efficacious and cost-effective treatment for youths with social anxiety disorder (SAD)?In this randomized clinical trial of 103 children and adolescents with a principal diagnosis of SAD and their parents, a 10-week course of ICBT was efficacious and cost-effective compared with an active comparator.Internet-delivered cognitive behavioral therapy has the potential to overcome common treatment barriers and increase the availability of evidence-based psychological treatments for young people with SAD; policy makers could consider ICBT with minimal therapist support a promising, low-intensity treatment for children and adolescents with SAD. Social anxiety disorder (SAD) is a prevalent childhood-onset disorder associated with lifelong adversity and high costs for the individual and society at large. Cognitive behavioral therapy (CBT) is an established evidence-based treatment for SAD, but its availability is limited.To assess the efficacy and cost-effectiveness of therapist-guided internet-delivered cognitive behavioral therapy (ICBT) for SAD in youths vs an active comparator, internet-delivered supportive therapy (ISUPPORT).This single-masked, superiority randomized clinical trial enrolled participants at a clinical research unit integrated within the child and adolescent mental health services in Stockholm, Sweden, from September 1, 2017, to October 31, 2018. The final participant reached the 3-month follow-up (primary end point) in May 2019. Children and adolescents 10 to 17 years of age with a principal diagnosis of SAD and their parents were included in the study.ICBT and ISUPPORT, both including 10 online modules, 5 separate parental modules, and 3 video call sessions with a therapist.The Clinician Severity Rating (CSR), derived from the Anxiety Disorder Interview Schedule, rated by masked assessors 3 months after the end of treatment. The CSR ranges from 0 to 8, with scores of 4 or higher indicating caseness. Secondary outcomes included masked assessor–rated diagnostic status of SAD and global functioning, child- and parent-reported social anxiety and depressive symptoms, and health-related costs.d = 0.67  at the 3-month follow-up. Similarly, all of the secondary outcome measures demonstrated significant differences with small to large effect sizes, except for child-rated quality of life (nonsignificant). The cost-effectiveness analyses indicated cost savings associated with ICBT compared with ISUPPORT, with the main drivers of the savings being lower medication costs  and increased school productivity  in the ICBT group. There was 1 suicide attempt in the ISUPPORT group; no other serious adverse events occurred in either group.Of the 307 youths assessed for eligibility, 103 were randomized to 10 weeks of therapist-guided ICBT (n = 51) or therapist-guided ISUPPORT (n = 52) for SAD. The sample consisted of 103 youths . Internet-delivered cognitive behavioral therapy was significantly more efficacious than ISUPPORT in reducing the severity of SAD symptoms. Mean (SD) CSR scores for ICBT at baseline and at the 3-month follow-up were 5.06 (0.95) and 3.96 (1.46), respectively, compared with 4.94 (0.94) and 4.48 (1.30) for ISUPPORT. There was a significant between-group effect size of In this randomized clinical trial, internet-delivered cognitive behavioral therapy was an efficacious and cost-effective intervention for children and adolescents with SAD. Implementation in clinical practice could markedly increase the availability of effective interventions for SAD.NCT03247075ClinicalTrials.gov Identifier:  This randomized clinical trial assesses the efficacy and cost-effectiveness of therapist-guided internet-delivered cognitive behavioral therapy for social anxiety disorder in youths compared with internet-delivered supportive therapy. Both active treatments were significantly more effective than the waitlist control, but no significant difference was observed between the 2 active treatments.12 To our knowledge, no study evaluating ICBT for SAD has yet used an active comparator, which is essential to distill the true effect of a behavioral intervention beyond the effects of practitioner attention and frequent monitoring and reporting of symptoms.13 Furthermore, no formal health economic evaluations of ICBT for SAD in youths have previously been conducted. Cost-effectiveness analyses are important when evaluating new interventions to guide policy makers on how to best allocate resources.8 This trial aimed to evaluate the efficacy and cost-effectiveness of therapist-guided ICBT for youths with SAD compared with an active comparator. We hypothesized that ICBT would be more efficacious and cost-effective than the active comparator.The digital revolution has brought great opportunities to increase access to evidence-based treatments for mental disorders.This single-masked randomized clinical trial (RCT) compared therapist-guided ICBT with therapist-guided internet-delivered supportive therapy (ISUPPORT) for children and adolescents (10-17 years of age) with a principal diagnosis of SAD. The trial was conducted at a clinical research unit integrated within the Child and Adolescent Mental Health Services in Stockholm, Sweden. Recruitment took place from September 1, 2017, to October 31, 2018. Participants (N = 103) were randomized to 10 weeks of ICBT (n = 51) or ISUPPORT (n = 52). The primary end point was set to 3 months after the treatment period (May 2019) because of a previously observed tendency for participants in ICBT trials to report continued improvement beyond treatment termination.15 Participants randomized to ISUPPORT were offered ICBT after the 3-month follow-up. The trial was approved by the Stockholm Regional Ethical Review Board and publicly registered. Following the Swedish law, younger participants (10-14 years of age) provided verbal assent, whereas older participants (15-17 years of age) and their parents provided written consent. The trial protocol can be found in CONSORT) reporting guideline.DSM-516 criteria; age of 10 to 17 years; ability to read and write Swedish; access to the internet; a parent able to coparticipate in the treatment; and if taking psychotropic medication, having been taking a stable dose for 6 weeks or more before enrollment. Exclusion criteria were as follows: diagnosed autism spectrum disorder, psychosis, bipolar disorder, or severe eating disorder; high risk of suicide; ongoing alcohol or substance abuse; and having received CBT for any anxiety disorder within the last 6 months (defined as ≥5 sessions of CBT including in vivo exposure). Referrals from health care professionals and self-referrals from families living anywhere in Sweden were accepted. The trial was advertised at the Child and Adolescent Mental Health Services clinics in Stockholm, Sweden, in newspapers, and on social media. Inclusion criteria were as follows: a principal diagnosis of SAD according to the 17 jointly with young persons and their parents to ascertain the presence of a diagnosis of SAD or any comorbid disorders according to the DSM-5.16 Verbal and written information was provided to the youths and the parents.The inclusion procedure consisted of 2 steps: an initial telephone screening and a face-to-face assessment at the clinic. The ADIS-C diagnostic interview and child- and parent-report measures were administered before treatment, after treatment (10 weeks), and at 3-month follow-up (22 weeks). Trained psychologists masked to treatment allocation conducted the posttreatment and 3-month follow-up assessments.The random allocation sequence was generated by an independent clinical trials unit, the Karolinska Trial Alliance, in blocks of 4 or 6 and placed in opaque and sealed envelopes. The envelopes were managed by an independent administrator not otherwise involved in the study. An external observer from the Karolinska Trial Alliance also monitored the trial regularly (eMethods in The primary outcome measure was the masked Clinician Severity Rating (CSR) score derived from the ADIS-C interview. The CSR ranges from 0 to 8, with scores of 4 or higher indicating caseness. Secondary outcomes included masked assessor–rated clinical improvement, presence of a SAD diagnosis, global function and treatment adherence, and a range of child- and parent-reported measures of social anxiety, psychopathology, global function, quality of life, treatment credibility, and costs , reduction of safety behaviors and avoidance, replacement of overly negative thinking with adaptive thoughts, and construction of a plan for relapse prevention.The therapist-guided ICBT program is a revised version of the treatment previously developed and piloted by our research group.The active comparator ISUPPORT included psychoeducation about SAD and information about healthy habits  and interpersonal relations (such as the significance friendships may have for one’s well-being). Mimicking supportive therapy, ISUPPORT also included encouragement from the therapists to generate and try strategies for handling challenging social situations and to continue to use strategies that the participant found helpful. Crucially, none of the key components thought to constitute the active elements of CBT for SAD  were included.In both conditions, three 20- to 30-minute video call sessions were provided at weeks 3, 5, and 7, and parents were provided with parallel access to 5 specifically designed modules, which they accessed through a separate login to the secure online platform . A recent trial14 comparing ICBT with an active comparator for mixed anxiety disorders in children found a between-group effect size of d = 0.77. However, SAD may be more challenging to treat than other kinds of anxiety disorders20; thus, we opted for a more conservative estimate of effect size (d = 0.40). A sample size of 101 was calculated to be sufficient using a power of 85%, with a 2-tailed α = .05 and assuming a maximum dropout rate of 10%.The power calculation was made in G*power21 Estimates of population mean effect of time and differential change over time as a function of treatment group were determined with a fixed time and time × group interaction effects (with Satterthwaite approximation for denominator degrees of freedom). As a secondary categorical outcome, we estimated the probability that participants in either group would no longer meet diagnostic criteria for SAD at the 3-month follow-up, using a logistic regression analysis, fitted with maximum likelihood with nonnormality robust SEs.Following the intention-to-treat principle, the primary and secondary outcome analyses included all participants who were randomized. Continuous variables measured at the 3 assessment points  were analyzed with linear mixed models with subject-specific intercepts and slopes (random effects), fitted with full maximum likelihood. Linear mixed models use all available data, account for dependence among repeated observations, and provide unbiased estimates in the presence of missing information under a fairly unrestrictive assumption.d) for continuous variables and odds ratio (OR) for the categorical variable . The α level was set to P < .05 (2-tailed).On the basis of model estimates, we computed effect sizes in the form of standardized mean difference between-group effect size . d = 1.24) for ICBT and moderate (d = 0.52) for ISUPPORT. Mean (SD) CSR scores for ICBT at baseline and at the 3-month follow-up were 5.06 (0.95) and 3.96 (1.46), respectively, compared with 4.94 (0.94) and 4.48 (1.30) for ISUPPORT. We observed a statistically significant time × group interaction effect , with a model-implied between-group effect size of moderate strength for the primary outcome measure (CSR)  at the primary end point, favoring ICBT (P = .26). In all cases, results favored ICBT, and most between-group effect sizes at 3-month follow-up were in the moderate range  (ing ICBT . Statisttioning) . For comP = .09). Treatment completion, adherence, satisfaction, and credibility are reported in the eResults and eTable 5 in The observed proportion of SAD-free participants was larger in the ICBT group than in the ISUPPORT group at the 3-month follow-up (30.6% vs 18.0%). However, the difference was not statistically significant . For more details, see the eResults in The interrater reliability was excellent for the CSR before treatment  and very good for the presence of a SAD diagnosis before treatment (κ = 0.86). Treatment fidelity during the video call sessions was excellent because the external assessors noted no protocol violations. Masking integrity checks found that masked assessors were slightly better than chance at guessing the participants’ group allocation, but no significant difference was found in SAD severity at the 3-month follow-up between participants whose group allocation was guessed correctly compared with those whose allocation was guessed incorrectly . During the period from before treatment to 3-month follow-up, the average societal cost was €2426.2   for the ICBT group and €3502.5   for the ISUPPORT group. The incremental cost-effectiveness ratio regarding total societal cost differences and differences in remitter status was −€17 900.7  , indicating that ICBT was associated with cost savings while generating more participants free of SAD compared with ISUPPORT. The cost-effectiveness plane for societal cost and diagnostic status differences is presented in z = 2.38, P = .02) and decreases of school productivity losses  in the ICBT group  .16 symptom severity,25 frequency of comorbid disorders,27 and duration of SAD symptoms.28 For the ICBT group, a large within-group effect size was observed on the primary outcome measure, which is comparable to the results of a previous ICBT trial.12 Child- and parent-reported symptoms of social anxiety were reduced by more than 25%, corresponding to a large effect. The proportion of SAD-free participants (30.6%) was similar to that of previous ICBT trials of youths12 and adults29 with SAD but lower than in previous face-to-face CBT trials (approximately 50%-60%).30 Guided self-help treatments such as ICBT should not be regarded as a substitute for the criterion standard face-to-face treatment but rather a low-intensity treatment to be deployed as a first step, thus freeing resources for young people who require more intensive treatments.The characteristics of the sample are similar to those in previous face-to-face trials of CBT for SAD regarding age and sex composition,14 of children with mixed anxiety disorders, including SAD, found that ICBT was cost-effective, with the main cost saving being reduced health care costs. In the current trial, the main cost savings originated from reduced medication use and increased school productivity (parent-reported measure of the child’s ability to perform on days when he/she is present in school).A previous ICBT trial31 The optimal amount of therapist support and parental involvement in ICBT, in relation to child age, should be formally investigated. Identifying clinically useful variables associated with ICBT outcome would be valuable to identify and target more specific mechanisms that may be involved in the maintenance of SAD. In addition, dismantling studies are needed to better understand what components of ICBT contribute the most to the observed reduction of social anxiety. Because SAD often occurs with comorbid anxiety disorders (37% of youths in the current sample), it would also be important to compare disorder-specific forms with transdiagnostic forms of ICBT with regard to their efficacy on comorbid conditions. Furthermore, long-term follow-ups are warranted to establish the durability of the results. Participants in the current trial will be followed up 12 months after treatment, but the results will be presented separately.Going forward, some modifications could be considered regarding, for example, treatment length and therapist support. Because young persons with SAD seem to require more time to remit than those with other anxiety disorders, ICBT may require longer periods and/or intensified therapist support. Furthermore, parental involvement in ICBT may be particularly important for preadolescents and younger children to engage in the treatment.This study has several strengths. First, the use of an active comparator effectively controlled for nonspecific aspects of treatment. Second, extensive measures were taken to ensure the reliability of the measurements, integrity of the masked assessments, and adherence to treatment protocols. Third, participant retention was high and data loss minimal (<4% missing on the primary outcome measure). Fourth, the trial was externally monitored.The study also has limitations. One is that most participants were self-referred and could therefore have been more motivated to work with the mostly self-guided treatment compared with typical patients with SAD seen in Child and Adolescent Mental Health Services. Another limitation is that despite best efforts to mimic the format of the active treatment and to make the control treatment as convincing and relevant as possible, the comparator ISUPPORT was seen as somewhat less credible than ICBT. The difference in credibility may have affected treatment expectations, although post hoc analyses (eResults in In this randomized clinical trial of children and adolescents with a principal diagnosis of SAD and their parents, a 10-week course of ICBT was efficacious and cost-effective compared with an active comparator. Internet-delivered cognitive behavioral therapy has the potential to overcome common treatment barriers and increase availability of evidence-based psychological treatments for this patient group.


Patients with severe Coronavirus disease 19 (COVID-19) typically require supplemental oxygen as an essential treatment. We developed a machine learning algorithm, based on deep Reinforcement Learning (RL), for continuous management of oxygen flow rate for critically ill patients under intensive care, which can identify the optimal personalized oxygen flow rate with strong potentials to reduce mortality rate relative to the current clinical practice.We modeled the oxygen flow trajectory of COVID-19 patients and their health outcomes as a Markov decision process. Based on individual patient characteristics and health status, an optimal oxygen control policy is learned by using deep deterministic policy gradient (DDPG) and real-time recommends the oxygen flow rate to reduce the mortality rate. We assessed the performance of proposed methods through cross validation by using a retrospective cohort of 1372 critically ill patients with COVID-19 from New York University Langone Health ambulatory care with electronic health records from April 2020 to January 2021.P < 0.001) from 7.94% under the standard of care to 5.37% under our proposed algorithm. The averaged recommended oxygen flow rate is 1.28 L/min (95% CI: 1.14–1.42) lower than the rate delivered to patients. Thus, the RL algorithm could potentially lead to better intensive care treatment that can reduce the mortality rate, while saving the oxygen scarce resources. It can reduce the oxygen shortage issue and improve public health during the COVID-19 pandemic.The mean mortality rate under the RL algorithm is lower than the standard of care by 2.57% (95% CI: 2.08–3.06) reduction (A personalized reinforcement learning oxygen flow control algorithm for COVID-19 patients under intensive care showed a substantial reduction in 7-day mortality rate as compared to the standard of care. In the overall cross validation cohort independent of the training data, mortality was lowest in patients for whom intensivists’ actual flow rate matched the RL decisions.The online version contains supplementary material available at 10.1186/s12911-021-01712-6. Over the course of the past year, the rapid global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has motivated multidisciplinary investigation efforts to identify effective medical management against coronavirus disease 2019 (COVID-19). Respiratory distress, including mild or moderate respiratory distress, acute respiratory distress syndrome (ARDS) and hypoxia, is a common complication of COVID-19 patients. The therapy of COVID-19 is guided by the knowledge and experience of moderate-to-severe ARDS treatment [A large collection of artificial intelligence (AI) and deep learning (DL) approaches have been proposed to accelerate the drug discovery and the process of diagnosis and treatment of COVID-19 disease , 4. ClinReinforcement learning has been successfully applied in the past to different healthcare problems such as multimorbidity management , HIV theFocusing on RL-based oxygen flow rate control (RL-oxygen), we studied its impact on mortality in COVID-19 patients with respiratory failure. The evolution of patients' ICU histories, including treatments, vitals, and health outcomes, was modeled using a Markov decision process (MDP) , 16. At Our research team used a retrospective cohort of the New York University Langone Health (NYULH) EHR data on COVID-19 patients to derive and validate the RL algorithm. Eligible patients had positive COVID-19 PCR test and had oxygen therapy in hospital between March 1st 2020 and January 19th 2021. We excluded COVID-19 patients aged below 50 and not been hospitalized as the lacked consistent documentation of vital signs, treatments, and laboratory tests. This study was approved by the NYULH IRB and the data were de-identified to ensure anonymity.2), oxygen saturation (SpO2), partial pressure of oxygen (PaO2) and bicarbonate (HCO3), is commonly used biomarkers measuring the severity of ARDS [For each patient, we had access to demographic data, including age, sex, race, ethnicity and smoking status, ICU admits and discharge information, in-hospital living status, comorbidities, treatments, and laboratory test data. The comorbidities, including hyperlipidemia, coronary artery disease, heart failure, hypertension, diabetes, asthma or chronic obstructive pulmonary, dementia and stroke, are defined based on the International Classification of Diseases (ICD)-10 diagnosis codes. To reduce the feature dimensionality, we selected 36 laboratory tests based on two criteria: (1) less than 28% missing values; and (2) COVID-19 related tests and vital signs. In specific, we explore the associations between laboratory tests and COVID-19 based on existing literature and clinical findings. For example, recent studies have shown that a reduced estimated glomerular filtration rate (eGFR), low platelet count, low serum calcium level, increased white blood cell count, Neutrophil-to-lymphocyte ratio (NLR), and red blood cell distribution width-coefficient of variation (RDW-CV) are related to high risk of severity and mortality in patients with COVID-19 –21. Addi of ARDS , 25.In this study, we employed leave-one-hospital-out validation to evaluate the model performance. The whole dataset was divided into 4 batches by the hospital and then we take one batch as validation set and the rest as training set in each simulation.State Action Reward milar to , we usedDiscount factor  0 and 1 . After cWe model patient health trajectory and the clinical decisions during a course of intensive care over a period of ICU stay by a Markov decision process (MDP) with state, action, and reward. The state of a patient includes the observed patient demographics, vital signs, and laboratory tests at each time eatments . The detcritic network, denoted by actor network representing a policy, denoted by The schematic of the proposed scheme with EHR cohort is shown in Fig. mentclass2pt{minimmentclass2pt{minimmentclass2pt{minimWe evaluated the RL-recommended oxygen therapy by comparing its efficacy with the observed one on the cohort from each validation hospital. At each decision time, the RL algorithm recommends an oxygen flow rate for the patient. If the absolute difference of recommended and the observed oxygen flow rate is less than 10 L/min, we say that RL is “consistent” with the critical care physicians.When RL is discrepant with the oxygen flow rate used by physicians, the efficacy of the RL-recommended oxygen therapy is not directly observed. The problem then becomes how to assess the health outcomes in the future after taking RL recommendations. For this reason, we predicted the outcome of the RL-recommended treatment using Cox proportional hazards model, a regression model commonly used for investigating the association between the survival probability of patients during a period and predictor variables of interest in medical observational studies , 27. In p-value < 0.0001) shows no significant difference between true and predicted survival.To assess the performance of the survival models, we compared predicted and observed outcomes (7-day living status) using 4 metrics: similarity, accuracy, Chi-squared test, and concordance index. Overall, the cosine similarity between predicted and actual survival is greater than 99.9%, and the concordance index is 0.83. Both metrics indicate that the predictive model can effectively estimate unobserved health outcomes. Moreover, the paired Chi-squared test . In addition, Table The performance of the RL-oxygen is summarized in Table The efficacy of the RL prescriptive algorithm was consistently observed across age, gender, BMI, and comorbidity subgroups Table . DemograWe further studied 7-days mortality when the actually administered oxygen flow rate differed from the oxygen flow rate suggested by the RL-oxygen in Fig. Last, we observed that the RL-oxygen and physicians recommended consistent flow rates in most times; see Fig. We used a RL approach to learn an optimal policy to continuously control the oxygen device for critically ill patients with COVID-19 who require oxygen therapy. As most people who become seriously unwell with COVID-19 have an acute respiratory illness , 30, ourOur analysis suggests the current practice remains some potential to be improved as actual oxygen flow rate administered by intensivists showed more than fifty percent discrepancy with RL-oxygen recommendations. Importantly, we observe that RL-oxygen tends to prescribe lower oxygen flow rate than physician’s prescribed rates but leads to better outcomes. This finding is especially important in the context of the ongoing and persistent medical oxygen shortages in some developing regions. As COVID-19 patient-care protocols have evolved, medical-grade oxygen is still considered as an essential resource to treatments for critically ill patients. In regions such as Africa, Middle East, and Asia, the surge in demand for medical oxygen to treat COVID-19 exacerbates preexisting gaps in medical-oxygen supplies, leading to substantial supply shortages.Our analysis also identified some clinical patterns that RL-oxygen particularly works well. For example, patients with high risk  observed higher efficacies than patients aged between 50 and 75 by using relatively lower averaged oxygen flow rate than actually administered. RL-oxygen also recommends a higher averaged oxygen flow rate may improve the health outcomes for patients aged from 50 to 65. Moreover, we also notice significant therapeutic discrepancies in patients with stroke and diabetes comorbidities. In both cases, RL-oxygen recommended higher averaged oxygen flow rate than doctors while showing a significant reduction in estimated mortality. In fact, these findings agree with recent studies which reported that “stroke survivors who underwent COVID-19 developed more acute respiratory distress syndrome and received more noninvasive mechanical ventilation”  and “diaAlthough our evaluation methodology controls for several confounding factors and shows high validation accuracy, sample scarcity and a large proportion of missing value may increase estimation uncertainty and affect the treatment recommendations. Larger training data are necessary to cover more of the state space and improve the policy optimization. Moreover, the COVID-19 cohort from NYULH may not be representative of the U.S. COVID-19 population or the oxygen clinical practices in other countries. To ultimately validate the efficacy of the RL algorithm, randomized clinical trials with patients randomly assigned to RL and clinician oxygen therapy would be needed.Through analyzing the EHR data from multiple ambulatory care centers, we demonstrated the feasibility of using reinforcement learning based oxygen therapy to improve the intensive care for COVID-19 patients. The RL-oxygen showed medium concordance (44%) with the current practice of critical care physicians. For all COVID-19 patients requiring oxygen therapy, RL recommendations significantly reduce the mortality rate compared to the current practice. The algorithm has the potential to be integrated into the clinical decision support system and assist physicians to provide timely personalized recommendations of oxygen flow rate for COVID-19 patients in ICU.Additional file 1. Methods and Model Details.


The microvessels area (MVA), derived from microvascular proliferation, is a biomarker useful for high-grade glioma classification. Nevertheless, its measurement is costly, labor-intense, and invasive. Finding radiologic correlations with MVA could provide a complementary non-invasive approach without an extra cost and labor intensity and from the first stage. This study aims to correlate imaging markers, such as relative cerebral blood volume (rCBV), and local MVA in IDH-wildtype glioblastoma, and to propose this imaging marker as useful for astrocytoma grade 4 classification.IDH-wildtype glioblastomas and 7 blocks from 2 IDH-mutant astrocytomas were compiled from the Ivy GAP database. MRI processing and rCBV quantification were carried out using ONCOhabitats methodology. Histologic and MRI co-registration was done manually with experts’ supervision, achieving an accuracy of 88.8% of overlay. Spearman’s correlation was used to analyze the association between rCBV and microvessel area. Mann-Whitney test was used to study differences of rCBV between blocks with presence or absence of microvessels in IDH-wildtype glioblastoma, as well as to find differences with IDH-mutant astrocytoma samples.Data from 73 tissue blocks belonging to 17 IDH-wildtype blocks (p < 0.001), as well as significant differences in rCBV were found between blocks with microvascular proliferation and blocks without it (p < 0.0001). In addition, significant differences in rCBV were found between IDH-wildtype glioblastoma and IDH-mutant astrocytoma samples, being 2–2.5 times higher rCBV values in IDH-wildtype glioblastoma samples.Significant positive correlations were found between rCBV and microvessel area in the IDH-wildtype glioblastoma those regions with microvessels from those without it, and it is significantly correlated with local microvessels area. In addition, the proposed rCBV marker can differentiate the IDH mutation status, providing a complementary non-invasive method for high-grade glioma classification.The proposed rCBV marker, calculated from diagnostic MRIs, can detect in The online version contains supplementary material available at 10.1186/s12885-021-09117-4. IDH-wildtype glioblastoma is the most lethal and common tumor of the central nervous system, resulting in a median prognosis of 12–14 months [4 months –5. Blood4 months –5. One o4 months .IDH-mutation status in high-grade gliomas [IDH-wildtype glioblastomas and IDH-mutant astrocytomas (previously named as IDH-mutated glioblastoma) as different type of gliomas, with different prognosis and vascular characteristics.These pathologic heterogeneity features, including vascular proliferation, robust angiogenesis and extensive microvasculature heterogeneity could vary depending on  gliomas . In fact gliomas  differenMVP is together to necrosis, the first criterion in the last update of 2020 CNS glioma classification and grading , and intConsidering the relevance of this vascular process, the microvessel area (MVA), i.e., the total area covered by the microvessels in the tumor sample, and microvessel density (MVD), i.e., the number of microvessels per volume unit, have been previously investigated –16. DiffA complementary approach to overcomIDH-wildtype glioblastoma and IDH-mutant astrocytoma. Besides, the complementary use of rCBV would involve important advantages since calculations derived from routine presurgical MRIs can be performed through automatic and robust methodologies, such as ONCOhabitats methodology [The integration of advanced and automatic techniques capable of calculating robust imaging markers, including rCBV, could help in high-grade glioma classification, including the diagnosis of hodology –24.IDH-wildtype glioblastoma and this correlation can be measured using a robust MRI processing service. The areal density of microvessels on sections is an unbiased estimator of the volume density of microvessels according to the Delesse principle [In this context, we hypothesize that MVA could be directly associated with the rCBV in rinciple , and we rinciple , the calIDH-wildtype glioblastomas and IDH-mutant astrocytomas [In addition, we hypothesize that rCBV could be useful to find vascular differences between ocytomas , and theIDH- wildtype glioblastoma, and to find differences in vascularity between IDH-wildtype glioblastoma and IDH-mutant astrocytoma. The study’s specific objectives are 1) to analyze the histopathologic and radiologic correlation between the imaging markers (rCBVmean and rCBVmax) with the local MVA in IDH-wildtype glioblastoma; 2) to study whether these imaging markers can differentiate regions of the tumor with presence or absence of microvessels 3) to analyze the capacity of the rCBV to differentiate between IDH-wildtype glioblastoma and IDH-mutant astrocytoma samples.The general purpose of our study is to evaluate the potential use of rCBV, calculated with the ONCOhabitats methodology, to detect the presence or absence of microvessels in different regions of www.glioblastoma.alleninstitute.org) [IDH mutation status. This public database includes 41 verified patients with astrocytoma grade 4, with a total of 42 tumors, with the following information per tumor: 1) images of the resected tumor  database (ute.org)  was usedi) histopathological confirmation of astrocytoma grade 4 (IDH-wildtype glioblastoma or IDH-mutant astrocytoma); ii) access to complete MRI studies, including pre and post-gadolinium T1-weighted , T2-weighted, FLAIR T2-weighted, and DSC T2* perfusion sequences  access to the resected tumor image  approval by an expert radiologist and histopathologist of the correct overlay/registration of the image of the resected tumor and the MRI of each patient  inability to correctly overlay the image of the resected tumor over the MRI; ii) tumor tissue segmentation error during the processing; iii) to present extensive hemorrhage that could affect to a correct quantification of perfusion maps.Exclusion criteria for patients were: IDH-mutant astrocytomas, 1 was not included because of defective T1c image, not allowing a correct process with the ONCOhabitats platform. Finally, 2 IDH-mutant glioblastomas were included in the study.From 3 . More information about MRI data is included in Table Shttps://www.oncohabitats.upv.es. The ONCOhabitats analysis included the following automatic stages ges Fig. :MRI PreThis method is based on Directional Class Adaptive Spatially Varying Finite Mixture Model, or DCA-SVFMM, which consists of a clustering algorithm that combines Gaussian mixture modeling with continuous Markov random fields to take advantage of the self-similarity and local redundancy of the images.https://www.med.upenn.edu/sbia/brats2018/data.html), which currently consist of a corpus with more than 380 glioblastomas manually segmented by several expert radiologists. An evaluation oracle is also available to send the segmentation results over a test set to assess the quality of the network. Currently our results in term of Dice score are: 0.90 in the whole glioblastoma segmentation (necrosis + edema + enhancing tumor), 0.83 in the tumor core (necrosis + enhancing tumor) and 0.86 in enhancing tumor segmentation [3.DSC perfusion quantification .All the information included in this section was collected from the Ivy GAP white paper, available in the Ivy GAP database  or 9 × 7.5 × 9 mm high (tumors W13-W55) tissue blocks. Using custom-fabricated L bars, each block was supported for freezing from the bottom of the L bar assembly (top of tissue block) on a dry ice isopropanol bath. As the block was rapidly frozen, an OCT base was formed with a disposable cryomold, added to the bottom of the tissue block, and frozen with a freeze aerosol  equipped with a 20x objective and Spectrum software. The raw image files of ~ 5 GB per image were archived after converting to JPEG 2000 file format. The preprocessed images were flipped along the horizontal axis, white balanced, and compressed at a rate of 0.8 to ~ 400 MB per image. During post-processing, colorized expression values or heat masks showing ISH signal intensity were generated, and the closest H&E stained image of the same specimen was calculated for each ISH section.During the review of images, the automated bounding box overlay was manually adjusted if necessary, so that each of 8 bounding boxes per slide was placed over the corresponding tissue section, and images of slides with focus or image tile stich misalignments were re-scanned. Images were failed if artifacts compromised data analysis  associated with the corresponding tissue section.a) Localizing the lesion on the MRI images based on the hyperintensity of the T1 contrast and with the help of the segmentation masks, which includes the delineation of the active tumor, the edema and the necrotic tissue.b) Defining the orientation of the resected tumor and its blocks using the photograph provided at the Ivy GAP along with the parameters of orientation, position, and axial slice provided as reference.c) Refining the position by taking into account the necrosis masks and vascularity values in the blocks.) Validation of the proposed overlay by expert radiologist (FAR), oncologist (GR) and histopathologist (JFL).dTo compare the information obtained from the rCBV maps and the MVA obtained from histopathological images, we overlaid the T1c MRI images to the images of tumor resected pieces, including the histopathology blocks’ location Fig. E provideAdditionally, we remove the background and generate a block mask with each block area delimited Fig. G.To evaluate the accuracy of the co-registration technique, we used the Intersection over Union method, i.e. we measured the area proportion overlap between the resected tumor image and the MRI image. We achieved a mean accuracy of 88.8%, and a TRE of 11.2%. In all cases the % was higher than 75.0%, being 76.1% the minimum and 98.1% the maximum.mean and rCBVmax for each independent block , we could obtain the imaging markers rCBVH, we couhttps://zenodo.org/record/4704106#.YJu8GagzY2w) [The ONCOhabitats processing results for the patients with complete pre-surgical MRI  are publicly available in Zenodo (GagzY2w) . For eacFrom each tissue block, several slides with an area of approximately 9 × 7,5 mm were collected with their corresponding hematoxylin and eosin (H&E) images of the IVY Gap database. The areas of different histopathological tissues were delimited in these images Fig. B and quabs is the MVA present in the section s of one particular block b where n sections are available):In order to normalize the MVA according to the area of each section of the tumor, the MVA value was divided by the area of the section. In addition, each block contains information from different sections; therefore, for the statistical analyses, we used the normalized mean value of MVA for each block, calculated with the following formula  blocks with presence of microvessels (MVA > 0) and (2) blocks with absence of microvessels (MVA = 0). An example of the microvessels generated by microvascular proliferation derived from the tumor progression, as opposed to normal vessels, is illustrated in Fig. mean and rCBVmax with the microvascular proliferation area (numeric continuous variable). Spearman coefficients and derived p-values were calculated, and descriptive measures of both rCBVmean and rCBVmax among the whole block samples .Spearman’s correlation test was performed to study the association between the rCBVmean and rCBVmax between the group with presence of microvessels, and the group with absence of microvessels. The descriptive measures of rCBV  for each MVP and non-MVP groups were included.Mann-Whitney tests were conducted to analyze the differences of rCBVmean and rCBVmax between IDH-wildtype and IDH-mutant glioblastoma blocks. The descriptive measures of rCBV  for each IDH population were included.Mann-Whitney tests were conducted to find the differences of rCBVIDH-wildtype glioblastoma and patients with IDH-mutant astrocytoma. In addition, Log rank test was carried out to study the significance of this difference (p < 0.005).Kaplan Meier curves were represented to analyze differences in survival between patients with IDH-mutant glioblastomas ; and the 38 remaining patients presented IDH-wildtype glioblastomas.From the 41 patients included in the Ivy GAP database, 3 of them presented IDH-wildtype glioblastoma, 14 were not included because of incomplete MRI studies ; From the 24 included patients, 3 patients were discarded due to inability to correctly overlay the image of the resected tumor over the MRI . The remaining 21 patients were processed with the ONCOhabitats platform. Of these 21 cases, 3 were excluded due to glioblastoma tissue segmentation errors ; and 1 patient was excluded because of extensive hemorrhage that prevented a correct quantification of perfusion maps in DSC-MRI (W50). Finally, 17 IDH-wildtype glioblastomas were included in the study.From 38 IDH-mutant astrocytomas, 1 was not included because of defective T1c image, not allowing a correct process with the ONCOhabitats platform. Finally, 2 IDH-mutant astrocytoomas were included in the study.From 3 Demographic, clinical and MRI-related data of the total of 19 patients is included in Table SIDH-wildtype glioblastomas were initially considered. To develop the statistical analyses, only those blocks with more than 25 % (> 25%) of tumor, defined by imaging segmentation, were selected. This criterion was based on the existence of blocks that mostly contain necrotic tissue and therefore were not suitable for the study due to their lack of vascularization. Seventy-three (73) tissue blocks formed the final study sample of IDH-wildtype glioblastomas.A total of 124 blocks with complete information from the 17 IDH-mutant glioblastomas. Following the same criterion than for IDH-wildtype tumors, finally 7 blocks formed the final study sample of IDH-mutant glioblastomas.Histopathological and radiologic correlation between MVA and rCBV in IDH-wildtype glioblastomasThirteen blocks were initially considered from 2 mean and rCBVmax for the 73 tissue blocks from 17 IDH-wildtype glioblastomas. The results of the Spearman correlation analyses between the MVA and each imaging marker (rCBVmean and rCBVmax) are also included in Table Table mean and rCBVmax showed a significant positive correlation with MVA. That is, regions of the tumor with higher rCBV present significantly larger microvessel areas.Both rCBV(2)Differences in rCBV according to the presence or absence of microvessels in IDH-wildtype glioblastomasFigure mean and rCBVmax for the blocks corresponding to the groups with presence and absence of microvessels, and the Mann-Whitney test results. All the measures  of rCBVmean and rCBVmax were higher in the group of blocks with presence of microvessels, presenting values two times superior to the group with no evidence of microvessels.Table p < 0.05) between the rCBVmean and the rCBVmax of the groups generated by the presence or absence of microvessels in IDH-wildtype glioblastomas. The rCBVmean and rCBVmax can differentiate those regions of the tumor with microvessels.The Mann-Whitney test yielded significant differences  and the groups with absence of microvessels .(3)Differences in rCBV between IDH-wildtype glioblastomas and IDH-mutant astrocytomaFigure mean and rCBVmax for the tissue blocks corresponding to IDH-wildtype and IDH-mutant astrocytoma. Mean, median and maximum of rCBVmean and rCBVmax were higher in the IDH-wildtype tissue blocks, presenting values more than two times superior to IDH-mutant tissue blocks. In addition, the Mann-Whitney test yielded significant differences (p < 0.05) in rCBVmean and rCBVmax between IDH-wildtype and IDH-mutant glioblastomas.Table mean and rCBVmax between the IDH-wildtype tissue blocks  and the IDH-mutant tissue blocks .Figure IDH-wildtype glioblastoma and IDH-mutant astrocyoma are included in Fig. Sp = 0.099) between groups, estimated survival curves are completely separated, suggesting a substantial difference in survival times between patients with IDH-wildtype glioblastoma and IDH-mutant astrocyoma.The Kaplan Meier curves with the estimated survival functions for patients with Microvascular proliferation is one of the main histopathologic hallmarks of glioblastomas, being key for the current glioma classification , 2. In aBy contrast, imaging markers derived from routinary MRI protocols, such as rCBV, present several advantages since they are fast to calculate, it does not represent any extra cost, and it is non-invasive compared with MVA. However, although rCBV is used for the assessment of brain tumors, it is not widely considered as a biomarker for clinical decision-making yet, probably due to the difficulty to normalize the rCBV values, which can generate confusion about prospective clinical guidelines, but also due to the lack of robust studies using spatially localized histologic correlations .mean and rCBVmax, calculated with the validated method ONCOhabitats [IDH-wildtype glioblastoma samples. Moreover, we analyzed the differences of rCBV between those areas of the tumor with the presence of microvessels from those regions of the tumor without evidence of microvessels.In this sense, here we investigated the association between the imaging markers rCBVhabitats –24, and mean and rCBVmax and MVA when analyzing 73 tissue samples derived from 17 human IDH-wildtype glioblastoma tumors. Also, we found significant results when we evaluated the differences of both rCBVmean and rCBVmax between tissue blocks with presence of microvessels from those blocks defined by the absence of microvessels. Microvascular proliferation is, together to necrosis, the first criterion in the last update of 2020 CNS glioma classification and grading, since it is considered as one of the main hallmarks of high grade-gliomas (including IDH-wildtype glioblastoma and IDH-mutant astrocytoma). Therefore, its correlation with rCBV, makes it also a potential candidate useful in glioma classification. Despite the few similar studies conducted [ρ = 0.42 [ρ = 0.46 [ρ = 0.43 in the present study). However, in previous studies, only 2 and 4 glioblastoma patients were enrrolled, versus the 73 samples derived from 17 patients used in the current study. Increasing the interpatient heterogeneity in our study resulted in not higher correlation coefficients. Nonetheless, the analyses are more robust and p-values more significant. A more detailed comparison with previous studies can be found in Table SWe found significant correlations between rCBVonducted –16, our onducted , 15, simρ = 0.42 ; ρ = 0.4mean and rCBVmax between IDH-wildtype glioblastoma and IDH-mutant astrocytoma samples. We found that blocks from IDH-wildtype glioblastoma present almost 2.5 times higher rCBV values than blocks from IDH-mutant astrocytomas. These represent promising preliminary results to propose the rCBV, calculated with ONCOhabitats, to predict with a non-invasive method the IDH status in these gliomas and a complementary method for diagnosis.Furthermore, in this study we have investigated the differences in rCBVIDH-wildtype and IDH-mutant samples should be considered with caution, since only 7 blocks from 2 patients were included for the IDH-mutant group.This study has some limitations. Firstly, the manual registration between morphologic MRI images and the resected tumor image could be affected by deformations of the tumor tissue morphology when resected and/or the difficulty of finding matchings between both image features. Also, the number of independent analyzed samples is not much higher despite it being higher than in other previous studies. In addition, the results derived from the comparation between The results derived from this work suggest the potential of imaging vascular markers calculated with the ONCOhabitats platform for helping in unmet challenges in high-grade glioma management, including glioma classification and prediction of IDH mutation status, with a non-invasive method and from the initial stage of diagnosis. We consider that the rCBV is a clinically relevant option for decision making in glioblastoma , 29, 30,https://zenodo.org/record/4704106#.YJu8GagzY2w) [In addition, we consider useful to provide the ONCOhabitats results for Ivy GAP dataset with the purpose of enabling researchers investigating other relevant correlations between imaging-based biomarkers and histopathology for prognostic/predictive applications in glioblastoma. These results are publicly available for viewing and downloading in Zenodo (GagzY2w) .IDH-wildtype glioblastoma. The ONCOhabitats method allows a spatial location and detection of different regions of the tumor with presence of microvessels since the first diagnostic stage in a non-invasive way. In addition, significant differences in the rCBV values are found between IDH-wildtype glioblastomas and IDH-mutant astrocytomas, supporting the last update of glioma classification, which consider these gliomas as different tumors [The main conclusion of this study is the demonstration of a significant histopathological and radiologic correlation between the MVA and the rCBV in local regions of t tumors , 2.Additional file 1: Table S1. Information about the Magnetic Resonance Imaging (MRI) acquisition parameters. Table S2. Demographic, clinical and MRI-related data of included patients with IDH-wildtype glioblastoma (n=17) and IDH-mutant astrocytoma (n=2). Table S3. Comparative table with previous studies reported in literature related with the correlation between perfusion MRI and vascular features defined by histopathological analyses. Figure S1. Kaplan Meier curves with the estimated survival functions for IDH-wildtype and IDH-mutant glioblastoma patients from the Ivy GAP database included in the study.


Improving treatment outcomes for multidrug-resistant tuberculosis (MDR-TB) is a leading priority for global TB control. This retrospective cohort study evaluated the factors associated with treatment success among patients treated for MDR-TB in two provinces in Vietnam.Treatment outcomes were evaluated for adult patients treated in Hanoi and Thanh Hoa provinces between 2014 and 2016. The primary outcome was the proportion of patients with treatment success, defined as cure or treatment completion. Logistic regression analysis was used to evaluate the relationship between patient clinical and microbiological characteristics and treatment success.Treatment outcomes were reported in 612 of 662 patients; of these, 401 (65.5)% were successfully treated. The odds of treatment success were lower for male patients , for people living with HIV , and for patients treated for extensive antibiotic resistance (pre-XDR-/XDT-TB) , compared with others. Patients who achieved culture conversion in the first 4 months of treatment had increased odds  of treatment success. In addition, loss to follow-up was less common among patients covered by social health insurance compared to those who paid for treatment out-of-pocket .Among patients with MDR-TB, males, people living with HIV, and those with more extensive antibiotic resistance at diagnosis are at greatest risk of an unsuccessful treatment outcome. Efforts to optimise the management of co-morbidities (such as HIV), ensure rapid bacteriological conversion, and provide financial support for patients promise to improve treatment outcomes.The online version contains supplementary material available at 10.1186/s12879-021-06992-x. M. tuberculosis, and of the 10 million people diagnosed with TB in 2019, 465,000 had rifampicin-resistant (RR-TB) or multidrug-resistant (MDR-TB) forms of the disease [Tuberculosis (TB) is the tenth leading cause of death worldwide. An estimated two billion people have been infected with  disease . VietnamVietnam is a Southeast Asian country with a population of 96 million people and a high annual TB incidence . It is ranked among the high-burden countries for drug-resistant TB, with 8.8 cases of RR-/MDR-TB per 100,000 population. The Vietnamese healthcare system has four levels of care for managing MDR-TB patients (in descending order): Central, Provincial, District, and Commune. This study was conducted in two of Vietnam’s 63 provinces: Hanoi and Thanh Hoa, and included patients with confirmed RR-/MDR-TB who were treated at Provincial and District healthcare facilities within the Vietnamese PMDT program.plus and drug-susceptibility testing (DST). Once diagnosed, patients were treated at a provincial inpatient facility for up to 8 weeks and subsequent outpatient care was administered through district health centres. Standardised treatment for MDR-TB was delivered in accordance with WHO guidelines [At the time of this study, patients with presumptive MDR-TB were identified from among those presenting for the treatment of TB with risk factors for drug-resistance, including a history of prior treatment for TB, HIV infection, and exposure to individuals with known drug-resistant TB. Rifampicin resistance was confirmed using GeneXpert MTB/RIF and additional drug resistance was assessed using Genotype MTBDRidelines , 7. Duriidelines .Participants in this retrospective cohort study included consecutive adult (at least 15 years of age) patients who were diagnosed with either RR-TB or MDR-TB and registered for treatment in the PMDT program between January 01, 2014 and December 31, 2016. MDR-TB was defined as patients shown to be resistant to both isoniazid and rifampicin. This group also included patients with more extensive drug resistance, including extensively drug-resistant tuberculosis (XDR-TB)  and pre-XDR-TB  . AlthougPatient data were extracted from NTP patient registers, individual clinical records, and the Vietnam electronic TB database (eTB Manager). Ten percent of register entries and patient records were selected, at random, for duplicate data transcription in order to verify the accuracy of data entry. Source documents were transcribed into electronic case report forms developed using Epidata 4.4  with a 95% confidence interval were calculated for each variable in the multivariable analysis, and those variables significantly (p ≤ 0.05) associated with treatment success were included in the final model. Multicollinearity between variables was evaluated using the variance inflation factor (VIF). Univariate analyses were also performed for treatment failure, loss to follow-up, and death. However, as the primary outcome of interest was treatment success, multivariable analyses were not performed for the unsuccessful outcomes. Participants for whom a treatment outcome was not evaluated , including patients who were transferred to another treatment unit, were not included in the primary analysis. However, to assess the range of impacts that these missing treatment outcomes may have had on the findings of this study, the upper and lower bounds of the estimated treatment success rate were calculated by assuming individuals without an evaluated outcome all had successful outcomes, or all had unsuccessful outcomes. All analyses and operations were done using IBM SPSS version 26 .Participant characteristics were evaluated using descriptive statistics. Logistic regression analysis was used to determine the associations between independent variables and treatment outcomes. Univariate analyses were first used to calculate crude (unadjusted) odds ratios (cOR) with a 95% confidence interval for each variable, and those variables individually associated with treatment success at a level of Ethical approval for the project was obtained though the Human Research Ethics Committee (HREC) at the University of Sydney in Australia (project no. 2018/746), and the Vietnam National Lung Hospital. Due to the retrospective nature of this study, the need for written informed consent was waived by the HREC at the University of Sydney, and consent to access and analyze the patient treatment data used in this study was obtained through the Vietnam National Lung Hospital. All patient data was stored in a secure database during data collection and de-identified prior to analysis to ensure the confidentiality of study participants. All methods were carried out in accordance with relevant guidelines and regulations.Treatment records for 662 individual patients with RR-/MDR-TB were retrieved and included in the study Table . The 494The median duration of inpatient stay was 28 days (IQR 16–37), and the median total treatment duration was 19 months (IQR 9.7–20.0) (Table Treatment success was reported in 401 (65.5%) of the 612 patients for whom treatment outcome was evaluated Table . Of thesp ≤ 0.20) of an association with a successful treatment outcome (cure or treatment completion). Only 230 of 612 cases were complete  and multiple imputation was thus used to complete the dataset , independently associated with treatment success in the multivariable analysis  of patients did not achieve a successful treatment outcome. This indicates a significant gap between treatment policy and implementation. Unfortunately, the proportion of patients with successful treatment was lower than for the first cohort of patients with MDR-TB treated in Vietnam a decade ago. This may reflect the challenges in scaling-up care for MDR-TB, as well as regional differences in care. Additional interventions are required to retain patients in care, improve reporting of treatment toxicity, and optimize management of co-morbidities. A comprehensive standardized evaluation of co-morbidities at the time of enrolment in treatment may enable clinicians to provide holistic medical care and improve treatment outcomes. In addition, this study provides evidence to expand access to subsidised treatment for all patients, suggesting that further research is required to assess the effects of social health insurance coverage upon loss to follow-up during treatment. Financial support provided through insurance may have an important role in minimizing loss to follow-up, and including as many facets of the treatment process as possible in this scheme may have a beneficial impact on overall treatment adherence.As advanced drug resistance significantly reduces the odd of success treatment outcome, pre-XDR-/XDR-TB patients should be carefully monitored to ensure treatment adherence, particularly during outpatient care. Drug susceptibility testing for second-line antibiotics should be used to individualise treatment in order to ensure optimal treatment outcomes and avoid acquired antibiotic resistance.This study found that among patients with MDR-TB, males, people living with HIV, and those with more extensive antibiotic resistance at diagnosis are at greatest risk of an unsuccessful treatment outcome. Efforts to optimise the management of co-morbidities (such as HIV), ensure rapid bacteriological conversion, and provide financial support for patients promise to improve treatment outcomes and may contribute to a reduction in the risk of community transmission of MDR-TB.Additional file 1. Supplementary figures and tables.Additional file 2. Case report form template used for patient data collection.Additional file 3. Multiple imputation parameters and results.


Case Illustration. We herewith report two patients admitted with confirmed COVID-19 pneumonia with a history of CoronaVac vaccination. The first patient with a relatively milder course of the disease had received two doses of CoronaVac, whereas the second patient with a more progressive course of the disease received only one dose before developing symptoms and being admitted to the hospital. Our observations suggest that vaccination could act in boosting the inflammatory process and reveal the previously asymptomatic COVID-19 illness. Theoretically, vaccines could induce VADE, where only suboptimal, nonprotective titers of neutralizing antibodies were produced or proinflammatory T-helper type 2 response was induced. Secondly, enhanced respiratory disease (ERD) could manifest, where pulmonary symptoms are more severe due to peribronchial monocytic and eosinophilic infiltration. Understanding VADE is important for the decision-making by the public, clinicians, and policymakers and is warranted for successful vaccination uptake.  The COVID-19 pandemic has entered a new phase with the roll-out of several vaccines worldwide at an accelerated phase. The occurrence of a more severe presentation of COVID-19 after vaccination may affect policymakers' decision-making and vaccine uptake by the public. Vaccine-associated disease enhancement (VADE) is the modified presentation of infections in individuals after having received a prior vaccination. Currently, little is known about the potential of vaccine-associated disease enhancement (VADE) following COVID-19 immunization.  We report two cases of patients developing COVID-19 shortly after CoronaVac vaccination in which VADE is likely. We recommend that current vaccination strategies consider the measurement of neutralizing antibody titer as a guide in ensuring the safest strategy for mass immunization. Studies are needed to investigate the true incidence of VADE on vaccinated individuals as well as on how to differentiate between VADE and severe manifestations of COVID-19 that are unrelated to vaccination. The COVID-19 pandemic has affected 109 million people, causing 2.4 million deaths worldwide to date [A goal of manufacturing a safe and efficacious vaccine against SARS-CoV-2 had to be achieved within a 6- to 18-month timeline, generating over 200 vaccine candidates, with 50 in human clinical trials and 18 in efficacy testing . The timOn 13 January 2021, the COVID-19 vaccine roll-out officially began in Indonesia, distributing CoronaVac, a vaccine with chemically inactivated whole-virus vaccine with alum as an adjuvant. Vaccine-associated disease enhancement (VADE) is a modified, often more severe presentation of clinical infection in individuals exposed to a pathogen after having received prior vaccination for the same pathogen. Vaccines for infection by viruses that will cause inflammatory damage are likely to result in VADE, for example, SARS-CoV and RSV . Currentµl, and platelet count of 258.000/µl. The patient had a D-dimer level of 210 µg/l and fibrinogen level of 271 mg/dl, with CRP and procalcitonin levels of 115 mg/l and 0.04 ng/ml, respectively. Laboratory examinations revealed SARS-CoV-2 PCR positive with RdRP Cq of 17.70, E-gene Cq of 17.27, and N-gene Cq of 16.65. Chest X-ray revealed a typical COVID-19 radiological appearance of diffuse infiltrate at the base which extended to the periphery of the lungs.The first patient, a 24-year-old man, presented to the emergency department (ED) of Cipto Mangunkusumo Hospital (RSCM) with the chief complaint of fever which had been present for one day. Notable symptoms upon diagnosis were coughing, rhinorrhea, nasal congestion, and fever. There was no dyspnea, but dysgeusia and anosmia developed on the second day of admission. There were no comorbidities such as obesity or underlying pulmonary disease. The patient was found to have received the first and second doses of CoronaVac 19 days and 5 days prior to the onset of symptoms, respectively. Physical examination revealed normal vital signs, and lung examination demonstrated coarse rales, dominant in the lower left lung. Upon admission, the patient had a hemoglobin level of 14.8 g/dl, leukocyte count of 7.010/µg/l, respectively. Chest X-ray revealed a typical COVID-19 radiological appearance of basal nodular infiltrate at the periphery of the lungs, especially on the left side. Electrocardiography (ECG) revealed a complete right bundle branch block (RBBB). SARS-CoV-2 PCR on the admission day was positive with RdRP Cq of 28.27, E-gene Cq of 27.83, and N-gene Cq of 27.28. The timeline of vaccination and disease manifestation of both patients and chest X-ray are presented in Figures The second patient, a 49-year-old man, came with the chief complaint of fever. The fever was present for 3 days and had started 11 days before admission, ranging from 37.7–38.0°C. The fever started on the same day when the patient received his vaccination. There was unproductive cough, and anosmia and dysgeusia developed on the same day with the fever onset. Diarrhea occurred 1 day before presentation to the hospital. The patient also had longstanding hypertension and diabetes mellitus without regular checkups or medications. At presentation, the patient was hypertensive, with a blood pressure of 190/80 mmHg. There were no rales or other physical abnormalities upon physical examination. Laboratory examination revealed hyperglycemia, hyponatremia hypoosmolar euvolemia, and hypokalemia. Procalcitonin was 0.08 ng/ml and CRP was 79.2 mg/l, while fibrinogen and D-dimer levels were 678.4 mg/dl and 380 We report two hospitalized patients with confirmed COVID-19 pneumonia and a history of CoronaVac vaccinations. The first patient with a relatively milder course of the disease had received two doses of CoronaVac, whereas the second patient with a more progressive course of the disease received only one dose before developing symptoms and being admitted to the hospital. Upon admission of the patients, we were presented with the scientific questions as follows: (1) whether the SARS-COV-2 infection occurred before the production of adequate neutralizing antibody by the vaccine, (2) whether the natural infection that occurred in the patients with prior vaccination did not boost the immune system, but instead trigger a severe manifestation of COVID-19, and (3) does the compatibility between the inactivated virus in the vaccine and the circulating strains of virus matter in determining vaccine efficacy.With regard to exposure, it is highly likely that the patients encountered SARS-CoV-2 prior to either the first or second dose of vaccination in the case of the first patient or prior to the first dose in the second patient. It is therefore intriguing to speculate on the interaction between vaccination and the presence of active SARS-CoV-2 in an asymptomatic individual with low-level, high-level, or without preexisting neutralizing antibody. Both patients in this report did not have high levels of the RDP antibody.Our observations suggest that vaccinations could act in boosting the inflammatory process and reveal the previously asymptomatic COVID-19 illness . COVID-1In vitro experiments demonstrated the enhancement of SARS-CoV-2 entry into cells mediated with spike protein-specific antibodies in plasma from recovered elderly patients [Theoretically, vaccines could induce vaccine-associated disease enhancement (VADE), where only suboptimal, nonprotective titers of neutralizing antibodies were produced or proinflammatory T-helper type 2 response was induced. Secondly, enhanced respiratory disease (ERD) could manifest, where pulmonary symptoms are more severe due to peribronchial monocytic and eosinophilic infiltration –10. Precpatients . CoronaVpatients ; howeverOur two cases suggest that determining whether vaccine recipients are SARS-CoV-2 infected albeit being asymptomatic could be important as vaccine administration could theoretically enhance inflammation and disease progression. VADE adds to the complexities of the sociodemographic and health factors as well as the extreme heterogeneity of individuals and populations . VADE coWhen an individual is found to be PCR positive for SARS-CoV-2, we recommend checking antibody levels prior to vaccination for assessing whether the neutralizing antibody had been sufficiently produced as it is suggested that neutralizing antibodies only mediate ADE at the suboptimal neutralizing concentration . AlternaIn conclusion, we report two cases of patients developing COVID-19 shortly after vaccination with CoronaVac in which VADE is highly likely. We are currently investigating the relationship between inactivated virus strains in the vaccine and the circulating strains of virus in determining vaccine efficacy. As an increasing number of individuals are being vaccinated, more data are needed on VADE. To date, no clinical markers are in use to distinguish between naturally progressive, severe COVID-19 and VADE in clinical practice. We recommend that current vaccination strategies consider the measurement of neutralizing antibody titers as a guide in ensuring the safest strategy for mass immunization. Fully determining the risk, burden, and mitigation of VADE is warranted in order to increase the success of vaccine uptake. Further studies are needed to investigate the true incidence of VADE on vaccinated individuals as well as on how to differentiate between VADE and severe manifestations of COVID-19 that are unrelated to vaccination.