Using corticosteroids together with antiemetics showed reduced and lower grade vomiting (p = 0.01). LP-irinotecan TACE was tolerated well and had a high proportion of completed treatment plans. This minimally invasive locoregional treatment can be used together with concomitant systemic therapy or ablation.CIREL, a prospective, Europe-wide, observational study aimed to assess the real-world feasibility and tolerability of irinotecan-based transarterial chemoembolization (LP-irinotecan TACE) for unresectable colorectal cancer liver metastases with regard to the treatment plan and adverse events (AEs). CIREL enrolled 152 eligible patients (≥18 years) with liver-only or dominant metastases treated with LP-irinotecan TACE following a multidisciplinary tumor board decision. Data were prospectively collected for baseline, the number of planned and performed sessions, and technical information and safety according to CTCAE 4.03/5.0. Results from 351 analyzed treatment sessions showed technical success for 99% of sessions, and 121 patients (79%) completed all planned sessions. Further, 60% of sessions were performed using opioids, 4% intra-arterial anesthetics, and 25% both. Additionally, 60% of patients experienced at least one peri-interventional AE of any grade; 8% of grade 3–4. Occurrence of AEs was related to larger liver-involvement ( A majority, 80%, of patients with metastatic colorectal cancer (mCRC) confined to liver metastases (CRLM) are not eligible for surgery or local thermal ablation. In these patients, disease control via anti-cancer medical treatment represents the main treatment goal . CombinaHowever, for most patients, those strategies result in either a continuous administration of systemic treatment , or pFor patients with liver-only or liver-dominant lesions, irinotecan-based transarterial chemoembolization (irinotecan-TACE) has to be considered as part of the toolbox of loco-regional treatment strategies . It can The prospective, observational study CIrse REgistry for LifePearl microspheres (CIREL) was designed and conducted by multidisciplinary teams, including interventional radiologist and oncologists, and captured real-life data of 152 CRLM patients treated with irinotecan-TACE using irinotecan-eluting microspheres (LP-irinotecan TACE). This analysis was performed as a part of the CIREL study protocol in order to provide a full-cohort summary of the use at different stages of the CRLM cancer continuum care and evaluate the feasibility and safety of the procedure, in terms of completed treatment plans and occurrences of AEs. Further, the aim of our analysis was to identify the potential association between more frequent or more severe AEs and characteristics, such as disease severity or treatment characteristics.The CIREL rationale and methodology was published by Pereira et al., 2020 . Hence, Eligible patients were  ≥18 years with histologically confirmed colorectal adenocarcinoma with liver-only or liver-dominant metastases, and scheduled for treatment with LP-irinotecan TACE  as decided in a multi-disciplinary tumor (MDT) board. Patients were enrolled between February 2018 and August 2020. Technical aspects regarding the treatments were performed at the treating physician’s discretion and patients may have received prior intra-arterial treatment.first line or consolidation treatment after response to first line systemic therapy,use of LP-irinotecan TACE in combination with ablation in a curative intent,as an intensification of treatment with/without concomitant therapy for chemo-refractory patients still eligible for further systemic treatment,as salvage treatment in progressive patients for chemo-refractory patients non-eligible for further systemic treatment.The primary objective was analyzing the real-life use of LP-irinotecan TACE via the treatment intention defined as follows: Patient were defined as non-eligible for further treatment, i.e., salvage therapy patients, in case of progressive disease after treatment with irinotecan, oxaliplatin, anti-angiogenics and anti-EGFR-antibodies (in case of RAS and BRAF wt) or were defined as salvage therapy patients by the treating physicians. In contrast to a previously published methodology , observeAs a secondary objective feasibility, procedural data and safety were analyzed. Feasibility was evaluated in terms of analysis of treatment plans. In detail, the number of procedures planned to be performed, as well as whether unilobar (treatment sessions only in the right or only in the left liver lobe) or bilobar (treatment sessions in both liver lobes) was planned, were collected and analyzed with respect to the actually performed number of treatment sessions and actually performed unilobar or bilobar treatment of the patients.Procedural data—regarding bead size, the total dose infused –, peri-procedural management, as well as technical success  were collected and analyzed. For the analysis of safety, the occurrence of AEs was registered and evaluated. AEs were classified according to CTCAE 4.03 and 5.0 (Cancer Institute’s Common Terminology Criteria for Adverse Events) and were collected continuously. AEs reported on the day as any LP-irinotecan treatment session were defined as peri-interventional and AEs reported within 2–30 days of any treatment session or reported on the same day as any LP-irinotecan treatment session but lasted longer than 24 h were defined as acute AEs. Pain, nausea, vomiting, and fever were counted as PES when they occurred on the same day as any LP-irinotecan treatment session.Biologic AEs were defined using laboratory values that were collected periodically during the treatment cycle  and were analyzed when the CTCAE grade increased compared to baseline. For this, abnormal laboratory values were identified using the reference ranges in Clinical and technical data were collected via e-CRFs using OpenClinica 3. Automated data checks and verifications were employed via a separate data management system and remote monitoring was conducted quarterly to discuss internal data logic.p values ≤ 0.05 were considered significant). A multivariable analysis was performed using a binary logistic regression model whereby the predictor variables were determined following the univariable Chi-squared test and a stepwise variable selection procedure with a significance level of 0.1 for entering the predictor into the stepwise model. Additionally, the total number of sessions performed was added to adjust for the connection between bilobar/unilobar treatment and the total number of sessions performed.To describe and compare safety and toxicity, the proportion of patients or sessions with at least 1 AE (≥1 AE), as well as the AE burden score (AE-BS) were used. The AE-BS was employed to analyze the cumulative burden to a patient and was calculated according to Le-Rademacher et al., 2020 . BrieflyData were analyzed and plotted using RStudio version 1.2.1335 under R4.1.1. The Chi-squared test, Kruskal-Wallis test and the multivariable binary logistic regression were performed using IBM SPSS Statistics 25.Briefly, 152 CRLM patients with a median age of 66 years (range 37–90) were enrolled, of which 93 (61%) were male and 66 (43%) also had extra-hepatic disease. Further, 71 (47%) had 1–3, 52 (34%) had 4–10, and 29 (19%) had >10 liver lesions. Liver involvement was <25% in 82 (54%), 25–50% in 59 (39%), and >50% in 11 (7%) patients. Moreover, 87 patients (57%) had liver lesions located in both liver lobes, 54 (36%) only in the right lobe, and 11 (7%) only in the left lobe. Baseline characteristics are summarized in LP-irinotecan TACE was most frequently used in patients that had not responded to prior systemic treatment: in 41 (27%) as “intensification treatment with/without concomitant therapy” for patients that were still eligible for further systemic treatment, and in 46 (30%), and as “salvage therapy in progressive patients” for chemo-refractory patients that were non-eligible for further systemic treatment. However, for 41 (27%) and 19 (13%) patients, LP-irinotecan TACE was either used as “first line treatment or consolidation treatment” after response to first line systemic therapy or as “combination treatment with ablation with curative intent”, respectively.Briefly, 73 (48%) patients were planned to receive unilobar treatment, most frequently with one or two sessions , whereas 3 sessions were planned for two patients and four sessions for three patients. Further, 79 (52%) patients were planned to receive bilobar treatment, most frequently with two or four sessions  and only one and five patients were planned to receive one and three sessions, correspondingly . Addition = 270; 77%), small beads (100 µm) were used and the most common loading dose was 100 mg  treatment sessions as defined by either completely delivering the dose , complete stasis , or both .Briefly, 91 (60%) patients experienced at least one AE occurring on the day of the treatment session , and 49 (32%) patients at least one acute AE between 2 and 30 days after a treatment session . The mosThe AE-BS as a cumulative burden of AEs experienced per patient after each session is summarized in p = 0.001), bilobar treatment (p = 0.01), larger bead sizes (p < 0.001), and receiving LP-irinotecan TACE as the first session (p = 0.01) were significantly associated with ≥1 AE. More treatment sessions per patients and higher doses of irinotecan were not found to increase peri-interventional AEs. Neither were prior intra-arterial treatment of the liver nor prior use of irinotecan as systemic chemotherapy. To identify which baseline- and treatment-specific factors could be related to a higher occurrence of AEs, the proportion of patients and treatment sessions with ≥1 AE was used . For perp < 0.001) and bilobar treatment (p = 0.03) were significantly related to the presence of AEs.For acute AEs, higher ECOG score (p = 0.002), >25% liver involvement , >100 µm bead size  with an increase in sessions with ≥1 peri-interventional AEs. Neither increase in dose nor the number of performed sessions were associated with increased ≥1 peri-interventional AEs  was associated with more AEs and confirmed that dose and the total number of sessions performed were not associated with more AEs . Taking into account the heterogeneous data set and observational nature of the data collection, no post-hoc pair-wise comparison was performed. However, the groups were further analyzed to assess bias due to association with the factors that were previously identified to be connected with ≥1 PES AEs  and had a median PES AE-BS of 1. Sessions where intra-arterial anesthetic together with opioids was used had the lowest occurrence of ≥1 PES AEs  and had a median PES AE-BS of 0. Opioids alone, opioids together with antiemetics, or all four groups combined were associated with similar frequencies of ≥1 PES AEs, 49/125 (39%), 36/85 (42%), and 26/55 (47%) and median AE-BS of 0. While we could not find significant differences in the proportion of ≥1 PES AEs between the groups, there were significant differences between median PES AE-BS across all groups ( PES AEs . While sp = 0.01) and reduced reports of grade 1 pain (p = 0.01), but increased reports of grade 2 pain (p = 0.009) when corticosteroids were used.Next, we compared the number of PES AEs reported after treatment sessions performed without corticosteroids or with corticosteroids and antiemetics , findingCIREL was designed to capture the real-life use of LP-irinotecan TACE for CRLM across Europe to improve the evidence-base and support the real-world practice of CRLM treatment. Historically, irinotecan-TACE was associated with salvage therapy for patients who had failed first, second, and third-line systemic chemotherapy. However, due to its favorable toxicity profile and high local efficacy, irinotecan-TACE can be an attractive loco-regional treatment for earlier stages of the continuum care for CRLM cancer, such as in combination with systemic therapy or to obtain a sustained disease control, allowing halt of treatment  and/or to alleviate the toxicity-burden of maintenance systemic treatment ,30. The The favorable toxicity profile of drug eluting microspheres is supported by other studies reporting low incidence of serious AEs (0–10%) ,16,21,22Despite the low occurrences of grade 3 and 4 AEs, increasing the awareness of what factors are related to more frequent AEs, how to apply preventive methods using peri-procedural medications and the appropriate pre-procedural consultation, as well as post-procedural monitoring are important to ensure the completion of the treatment plan and maintain the patients’ quality of life. Our results show that 60% of patients had at least 1 peri-interventional AE, the vast majority PES-related. Indeed, most studies report PES as the most frequent AE. However, the occurrence rates vary between 10% and 60%  and someMoreover, the need to differentiate TACE protocols for hepatocellular carcinoma (HCC) from TACE protocols for CRLM has been highlighted ,34. FirsWe found that patients with a higher percentage of liver involvement or with a disease extended to both lobes (and therefore were planned for bilobar treatment), also experienced peri-interventional AEs more frequently. Additionally, the first session was associated with significantly more occurrences of ≥1 peri-interventional AEs and the effect of decreased odds for the occurrence of AEs when more sessions were performed was further confirmed by our multivariable analysis. This could be partially attributed to the high number of patients with plans for bilobar treatment that aborted the treatment plan after the first session  and to tAssessing the effectiveness of one or two sessions for uni- and bilobar treatments, respectively, will give crucial insight to help optimize treatment planning. With that information, the possibility to reduce the number of sessions or adapt to on-demand treatment planning could be explored more safely.Another differentiation to HCC protocols should be the recommendations for bead sizes. According to the most recent evidence and since CRLM are less hypervascular compared to HCC, smaller bead sizes should be used as they have the potential to deliver the dose deeper into the tissue ,36,37,38Regarding the association between AEs and dose, one study found a relationship between the injection of more than 100 mg irinotecan and increased toxicity . HoweverOne other major factor that should be considered when discussing AEs is the type of procedural medications used. We aimed to shed light on what procedural medications should be used to limit the most commonly experienced PES AEs and found that using intra-arterial anesthetic without opioids resulted in a higher median PES AE-BS score. Further, the use of corticosteroids together with antiemetics was connected to significantly lower incidence of vomiting but higher incidence of pain. Steroids are suggested by some but not all TACE recommendations for CRLM ,26. SincWhile multi-center, non-interventional data provide a very suitable reflection of the real-world scenario, limitations due to potential bias resulting from uncontrolled confounding factors have to be acknowledged. Especially when trying to identify causal associations between AEs and patient- and treatment-related factors or procedural medications, we have to be apprehensive of potential bias introduced due to unequal groups, as well as center-specific under- or overreporting of AEs. Being feasible, safe, with a high technical success rate, and proposed beyond salvage indications, our analysis confirmed that LP-irinotecan TACE represents an adequate treatment option for patients with CRLM. However, it is used in different settings with different protocols in terms of procedural medications. The low occurrence of AEs likely contributes to the high proportion of completed treatment plans. The main factor for aborted treatment plans was bilobar disease. Understanding the correct procedural medications and identifying patients who are more vulnerable to AEs could allow us to offer an effective and safer procedure to patients with CRLM.


Laboratory TB testing among patients with COVID-19 at repurposed departments of TB hospitals is feasible in Belarus and may improve TB case-finding.A significant drop in tuberculosis (TB) case-finding has been widely reported during the period of the COVID-19 pandemic. To address a decrease in TB notification, Belarus introduced laboratory TB testing in patients with the laboratory-confirmed coronavirus disease 2019 (COVID-19). We conducted a secondary analysis of health records among 844 patients with laboratory-confirmed COVID-19 diagnosis who were admitted to repurposed departments at TB hospitals and who were tested by Xpert MTB/RIF  in five Belarus regions between April and October 2021. Quantitative analysis followed by 13 individual interviews with health managers, physicians, and nurses participating in the intervention. Most patients were male (64%) and mean age was 43.5 ± 16 years. One in twenty  patients were co-infected with active pulmonary TB, and over one-third of them (n = 18) had rifampicin resistance. In-hospital mortality was comparable in patients with and without TB co-infection (2.1% and 2.3% respectively,  Tuberculosis (TB) was a major cause of death from a single infectious agent before the escalation of coronavirus disease 2019 (COVID-19), a novel disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . Both diIn addition, there are indirect effects of COVID-19 pandemic on the diagnosis of TB. Reduced attendance at TB diagnostic services and reassignment of TB personnel have been widely reported . Many coBelarus is one of 18 priority countries in the World Health Organization (WHO) European Region to combat TB, and one of the 30 countries with the highest burdens of rifampicin-resistant and multidrug-resistant TB (MDR/RR-TB) in the world  is just another test. “Doctor, do what you have to do, I feel so bad”. Some people are concerned. They consider COVID-19 as a relatively “good disease” while TB is a “bad disease”. They say: “Why? I have never had TB. I’m not homeless. I’m not an alcoholic. Why should I do it?”. In this case, we explain that Belarus is endemic for TB”.“Participants described sputum collection procedures in line with the national standards. All facilities had special rooms and trained staff to assist with sputum collection. However, sputum collection rooms were not always a part of the ‘red zone’, a pathway designed for patients with COVID-19. As a result, sputum could be collected in a treatment unit shared by several patients. Sputum collection in the treatment unit was common among patients with severe COVID-19, who were oxygen-dependent and had low mobility capacity.In TB hospitals, it is a well-established algorithm. We have a sputum collection room with an engineering level of infection control, such as mechanical ventilation, and personal protection equipment for staff. We use respirators and protective suits. The laboratory is in the same building. Usually, we receive results within a day”.“If the patient is oxygen dependent, and 99% of our patients [with COVID-19] are oxygen dependent…if we transport them to the sputum collection room, which is located in another building block, and back, we could make them worse”.“(TB Doctor)Sputum induction by inhalation of an aerosol of hypertonic saline helps patients cough up secretions from the lungs. Considering the high risk of airborne transmission of respiratory pathogens, an isolation room is recommended for the procedure. During interviews, health workers shared that sputum induction could be conducted in the treatment unit. In some repurposed departments, particularly intensive care units, up to 50% of the patients with severe COVID-19 could not produce sputum without induction. Transportation of these patients to an airborne infection isolation room was not always possible.All TB hospitals were equipped with laboratories and physicians received test results within a day. Participants described logistics of sputum transportation to the laboratory according to local safety protocols. Health workers participating in the interviews did not report any side effects during TB testing among patients with COVID-19.Most patients with laboratory-confirmed COVID-19 and TB co-infection were transferred to the TB department within the same hospital—a special unit for patients with COVID-19 and TB co-infection or individual rooms. Respondents pointed out that it was easier to find an individual room in the TB department rather than in the repurposed department for COVID-19, considering the reduction in TB notifications. In some hospitals, patients remained in the treatment unit the end of their COVID-19 treatment if it was an individual room. Practices of co-infection treatment management varied between different regional hospitals. In hospitals, where TB physicians and nurses worked in both COVID-19 and TB departments, patients could continue to be managed by the physician appointed for COVID-19 treatment even after their transfer to the TB department. If there was no overlap in the staff across departments, TB physicians from the TB department managed the co-infection treatment on their own or with a guidance of a Pulmonologist/Infectious Diseases Physician from the COVID-19 department.According to the infection control measures, we transfer a patient with the diagnosis [of COVID-19 and TB co-infection] to the department for drug-sensitive or drug-resistant TB. We have these separated. Patients remain in an isolation ward, with their own bathroom. In 2020, all TB physicians in our hospital were remotely trained on coronavirus infection. Therefore, they can treat the co-infection together with Pulmonologists, and on their own.”“(TB Nurse)Study participants believed that TB testing at TB hospitals is a ‘debugged system’, and repurposed departments do not experience any barriers related to staff, equipment, or logistics. Health workers who worked at the facilities where sputum collection rooms were not a part of ‘a red zone’ reported this as a single barrier. When asked about testing worries and fears among patients, physicians and nurses believed that it is not a barrier. From their experience, additional counseling fully resolves the issue, and all patients with testing anxiety were tested after the additional counseling was done. Staff at repurposed departments of TB hospitals were motivated to continue laboratory TB testing among patients with COVID-19. Representatives of the National TB Programme stressed that implementation of the intervention was feasible because it did not require additional human or financial resources.We expected to diagnose and treat more patients than we have now. TB resources are underused. Xpert MTB/RIF cartridges and anti-TB drugs have limited shelf-life. We can waste resources if a decrease in TB detection will continue. TB hospitals do not need additional training to implement Xpert MTB/RIF testing among patients with COVID-19. There is no need for additional funding. With this intervention, we will use resources more efficiently.”“Integration of TB screening in repurposed departments of other facilities might be challenging. Respondents suggested the scale up of Xpert MTB/RIF  among patients with COVID-19 admitted to Infectious Diseases Hospitals at facilities where staff have been trained in sputum collection. When asked about obstacles for the TB screening in patients with COVID-19 in other health facilities, respondents named the limited number of nurses trained in sputum collection, lack of motivation among health workers, shortage of GeneXpert Systems and longer turnaround time to obtain test results. Physicians emphasized that it is critical to have an Order of the Ministry of Health recommending laboratory TB testing among hospitalized patients with COVID-19 in other facilities, similar to the one developed for repurposed departments of TB hospitals.Of course, we have to scale up [Xpert MTB/RIF testing among patients with COVID-19] in other hospitals. However, there is one problem, they don’t have enough trained staff. Sputum collection is not a routine procedure there. Secondly, they often don’t have enough sputum collection rooms. Plus, logistics. Not all hospitals have GeneXpert. Transportation of a dangerous biological sample, considering COVID-19 and TB, is another issue.”“The COVID-19 pandemic decreased TB detection through a shift in the healthcare priorities and diversion of resources. Our study addressed the question of whether TB screening among patients with COVID-19 is feasible and can help identify missed TB cases. The Belarus National TB Programme, together with the WHO Regional Office for Europe, explored outcomes of Xpert MTB/RIF  testing among patients admitted to repurposed departments of TB hospitals for COVID-19 treatment.In our study, one in twenty patients (5.6%) with COVID-19 requiring hospitalization were found to be co-infected with active pulmonary TB. This result was higher than the findings of a recent meta-analysis from 43 countries (mostly from Africa and Asia), where pooled prevalence of active pulmonary tuberculosis was about 1.1% among all patients with COVID-19 and 3.9% among patients with severe COVID-19 who received inpatient treatment .About one in five patients with COVID-19, who tested positive for TB, had a history of prior TB treatment or were co-infected with HIV. HIV infection is a well-known risk factor for TB due to immunosuppression . MultiplAs compared to other study sites, Vicebsk’s TB hospital had a considerably higher proportion of patients with COVID-19 and TB co-infection, controlling for other patient characteristics. About one-third of admitted patients with COVID-19 tested positive for active TB there. This finding is unexpected considering that Vicebsk is not a region with high TB burden compared to other study sites. The National TB Programme conducted an investigation in Vicebsk and came to a conclusion that the region experienced a TB outbreak at the time of data collection, which was related to partial interruption of TB screening services in a few months preceding the intervention. Contrary to the national trend, TB notifications started to increase in the region since August 2021, a month before the intervention was implemented. There was no evidence of preferential testing, i.e., only among patients with a high level of TB suspicion.We did not find a higher risk of in-hospital mortality in patients with TB and COVID-19 co-infection as compared to patients without TB co-infection. It is inconsistent with the findings of systematic reviews, which showed that patients with concurrent TB and SARS-CoV-2 infection are prone to poor outcomes ,18. OverThe qualitative component of our study examined attitudes on laboratory TB screening among patients with COVID-19 among health workers involved in the intervention. A general theme emerged that TB screening should be differential, targeting certain groups of patients with COVID-19. While recommendations of respondents were in line with the WHO guideline on TB screening among people with shared symptoms, exposures and risk factors for two diseases, there was a demand for more specific criteria considering constrained resources. The quantitative study suggests that COVID-19 and TB co-infection was more common among unemployed and patients with comorbidities. Belarus may prioritize these groups for joint COVID-19 and TB screening. In this regard, bi-directional algorithm of COVID-19 and TB screening in India is of interest . India sIndividual interviews highlighted several challenges of infection control during TB testing among patients with COVID-19, such as a lack of sputum collection room in-hospital zones repurposed for treatment of COVID-19 or inability to transport patients with severe illness to these rooms. While aerosol-generating procedures are generally not recommended due to their potential infection risk to healthcare providers and other people , our finOur study was restricted to TB hospitals, which are better equipped for TB testing compared to other health facilities. Several barriers of scaling up Xpert MTB/RIF  among patients receiving COVID-19 treatment in other hospitals were mentioned in the interviews, such as limited human and financial resources, lack of legislation regulating service implementation, and training needs. Implementation barriers were consistent with those reported in the literature .There are several important limitations to the study. The study population represented patients admitted for inpatient treatment for COVID-19 in TB hospitals, which may limit the generalizability and transportability of findings across Belarus and other countries. In Belarus, patients with COVID-19 requiring hospitalization were admitted to TB hospitals based on proximity criteria  or when other hospitals experienced shortage of beds. The study did not include asymptomatic COVID-19 patients and symptomatic COVID-19 patients receiving outpatient treatment. Therefore, we might have overestimated the true prevalence of COVID-19 and TB co-infection. Our study was restricted to pulmonary TB diagnosis, and we did not assess the co-infection of COVID-19 and extrapulmonary TB. A general weakness of the in-depth interviews is that the quality of results depends highly on the interviewee’s willingness to provide truthful information. Sampling bias could occur for the selection of the participants for the individual interviews. The limitations of remote interviews include digital literacy, reduction of social cues, and challenges in maintaining connection, amid a lack of control over the participant’s physical environment, its security, and privacy.This is the first study assessing the proportion of pulmonary TB among patients with COVID-19 in Europe to the best of our knowledge. Interventions on TB screening among patients with COVID-19 remain rare in TB-endemic countries. The strengths of our study include a relatively large cohort of patients and a combination of quantitative and qualitative methods. While the study objectives did not include the follow-up of patients after receiving Xpert MTB/RIF result, we conducted a sensitivity analysis to retrospectively examine whether positive results were further confirmed by sputum culture or other examinations.Our study has several implications. TB screening of patients with COVID-19 at repurposed departments of TB hospitals identified many new TB cases. Most patients who tested positive for TB did not have a history of prior TB and were not co-infected with HIV. Thus, they were not subjected to the routine periodic TB screening implemented in Belarus. It is likely that their TB disease would be diagnosed at later stages. The early detection of TB and COVID-19 co-infection is very important for the prevention of contact transmission, and proper management of both diseases. As an implication of the operational research, a Ministry of Health Order was approved that regulates TB testing among patients with COVID-19 admitted to repurposed departments of TB hospitals. When the National TB Programme initiated TB testing among patients with COVID-19, the intervention was recommended to TB hospitals and implementation was optional. With a new order, all TB hospitals accepting patients with COVID-19 were engaged in the intervention. This study identified gaps and barriers in TB testing among patients with COVID-19 that will inform further implementation of the intervention and a potential scale-up in other hospitals. More efficient use of TB resources is another implication. With a reduction in TB notifications, Xpert MTB/RIF  cartridges are underused. Furthermore, fewer TB diagnoses led to a decrease in uptake of anti-TB drugs. TB screening among patients with COVID-19 at TB hospitals did not impose additional financial burden and allowed to utilize resources that could be unexploited otherwise. Considering implications for future research, the promise of laboratory TB testing among patients with COVID-19 should be evaluated, such as the number needed to screen and cost-effectiveness of the screening algorithm.Nearly one in twenty patients with COVID-19 who had lung changes and required hospitalization in Belarus were co-infected with active pulmonary TB, and over one-third of them had rifampicin resistance. The qualitative study has demonstrated that it is feasible to deliver laboratory TB testing among patients with COVID-19 at repurposed departments of TB hospitals considering available human, material, and financial resources. The intervention may help to improve TB case-finding during the COVID-19 pandemic and can be recommended for the routine practice in Belarus and similar settings with high TB burden.


There were no differences between groups regarding postoperative complications, conversion, drain removal time, total drainage output, and length of hospital stay. Conclusions: COVID-19 infection did not affect the outcomes of thoracoscopic lobectomy for lung cancer. The treatment of these patients should not be delayed in case of recent COVID-19 infection and should not differ from that of the general population.Background: The COVID-19 outbreak had a massive impact on lung cancer patients with the rise in the incidence and mortality of lung cancer. Methods: We evaluated whether a recent COVID-19 infection affected the outcome of patients undergoing thoracoscopic lobectomy for lung cancer using a retrospective observational mono-centric study conducted between January 2020 and August 2022. Postoperative complications and 90-day mortality were reported. We compared lung cancer patients with a recent history of COVID-19 infection prior to thoracoscopic lobectomy to those without recent COVID-19 infection. Univariable and multivariable analyses were performed. Results: One hundred and fifty-three consecutive lung cancer patients were enrolled. Of these 30 (19%), had a history of recent COVID-19 infection prior to surgery. COVID-19 was not associated with a higher complication rate or 90-day mortality. Patients with recent COVID-19 infection had more frequent pleural adhesions ( The COVID-19 outbreak had a massive impact on healthcare worldwide. COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first detected in December 2019 in Wuhan, (China) and declared a pandemic in March 2020 [Oncological patients suffered many consequences of the COVID-19 pandemic. In the initial phases of the pandemic, the accessibility to diagnostic and therapeutic pathways was impaired due to the conversion of several departments into COVID-19 units, causing disruptions to oncological screening, treatment, and surveillance ,11,12,13Lung cancer is nowadays one of the most common and fatal cancer and lobectomy is the treatment of choice for its curative intent ,39,40,41It is fair to ask if COVID-19 is a risk factor for complications after VATS lobectomy, given that some patients, after the infection, present alterations in the pulmonary tissue, such as fibrosis and mediastinal lymphadenopathy, that may complicate the surgical dissection. In addition to that, long-term effects of COVID-19 infection, known as Long COVID ,50,51,52The aim of this study was to evaluate the outcomes of thoracoscopic lobectomy for lung cancer in patients with recent COVID-19 infection, and whether previous COVID-19 infection was associated with a higher rate of complications and mortality compared to the control group.This was a retrospective mono-centric study including all consecutive patients undergoing VATS lobectomy for lung cancer between January 2020 and August 2022.The clinical data of (i) patients undergoing VATS lobectomy for lung cancer and (ii) patients with complete data and a follow-up for at least 9 months were included in the analysis. We excluded the data of (i) patients undergoing lung resection different from lobectomy ; (ii) patients undergoing lobectomy via upfront thoracotomy; and (iii) patients with incomplete data and follow-up.The endpoint of the study was to evaluate whether recent COVID-19 infection prior to surgery negatively affected the outcome of VATS lobectomy. The patients were divided into two groups based on whether they had a history of COVID-19 infection in the 3 months prior to surgery (the COVID group) or not (the no-COVID group).Diagnosis of COVID-19 infection was documented in all patients of the COVID group with positive RT-PCR molecular swab test for SARS-CoV-2. Postoperative complications, mortality, and general surgical outcomes were evaluated and compared between the two groups. Furthermore, univariable, and multivariable analyses were performed to evaluate whether COVID-19 infection was an independent predictive risk factor for complications.All procedures performed were in accordance with the international guidelines, with the Helsinki Declaration of 1975, revised in 1983, and the rules of the Italian laws of privacy. Each patient signed an anonymous informed consent letter for the use of their data for anonymous clinical investigations and scientific publications. The local research ethics committee approved the study design. Due to the retrospective nature of the study, no specific approval code was required because there was no modification in the standard of patient care.Anamnestic data: demographic data ), comorbidities, smoking status, symptoms, laboratory data, respiratory function data, and tumor characteristics , history of recent COVID-19 infection (in the 3 months preceding the surgery), and vaccination history against COVID-19.Peri and postoperative data: operative time (minutes), blood loss (mL), presence of pleural adhesions, conversion, need for transfusion, chest tube drainage output (mL), length of chest drainage (days), length of hospital stay (LHOS) (days), postoperative complications , and 90-day mortality.Pleural adhesions were classified according to the topography  and according to the severity (loose or firm and vascular), as proposed by Kobayashi et al. .The complications were classified into 2 groups according to the Systematic Classification of Morbidity and Mortality After Thoracic Surgery . Minor cFor patients in the COVID group, the severity of COVID-19 symptoms was recorded along with the volume of lung tissue impaired after COVID infection assessed on preoperative HRCT using the Simple Chest CT Severity Score . The volFor each patient, the following data were recorded:In all cases, the tumor was staged with a whole-body PET/CT scan. Preoperative histological diagnosis was obtained in the majority of patients with CT-guided lung biopsy, or alternatively with a trans-bronchial needle aspiration biopsy or broncho-alveolar lavage during bronchoscopy. Neoadjuvant chemotherapy was administered when indicated following oncological consultation.When the preoperative diagnosis was not possible or in case of undetermined results, the diagnosis was made through intra-operative pathological examination. Patients with lung function impairment (predicted postoperative FEV1 or DLCO < 30%) were evaluated with cardiopulmonary exercise testing (CPET) and if not functionally fit for surgery, redirected to alternative treatments through a multidisciplinary discussion.For this reason, 10 patients were excluded from surgical treatment due to respiratory impairment: 2 patients for post-COVID-19 respiratory impairment and 8 for severe chronic obstructive pulmonary disease.Twenty-four hours before admission, all patients routinely performed an RT-PCR molecular swab test for SARS-CoV-2, mandatory for hospital admission during the study period to exclude asymptomatic infections.All the patients underwent pulmonary lobectomy with systematic ilo-mediastinal lymphadenectomy using an anterior thoracoscopic triportal approach. The procedure was performed under general anesthesia with selective intubation. At the end of the procedure, a single 28Fr drainage tube was placed in the pleural cavity through the camera incision and connected to an underwater seal chest drain system. The chest drainage was removed when re-expansion of the lung was achieved, when the amount of fluid drained was less than 250 mL in 24 h, and in absence of air leaks. After the surgery, the patients were directed either to follow-up or oncological treatment based on the pathological stage and histology.The patients in the COVID group were scheduled for surgery after at least four weeks from reverse transcription polymerase chain reaction (RT-PCR) negativity, and in all cases performed an additional high-resolution CT scan of the thorax after COVID-19 infection. Patients with severe symptoms or that required hospitalization were carefully evaluated by the thoracic surgeon and anesthesiologist to schedule the surgery.t-test for continuous variables. Univariable and multivariable logistic regression was performed to identify predictive risk factors for postoperative complications (dependent variables).Data were expressed as mean ± standard deviation (SD) for continuous variables and as absolute numbers and percentages for categorical variables. Intergroup differences were compared using chi-square for categorical variables and with a p-value less than 0.05 was considered statistically significant. MedCalc statistical software  was used for this analysis.A n = 21); upfront thoracotomy (n = 6); and incomplete data (n = 2).In the study period, 182 patients underwent lung resections for cancer. The data of 29 patients were excluded from the analysis due to resections different from lobectomy  in the COVID group and 123 (80%) in the no-COVID group.In the COVID group, sixteen (53%) patients had an asymptomatic COVID-19 infection, fourteen (47%) had symptomatic COVID-19, and two of them (7%) required hospitalization .The lung volume tissue involvement after COVID-19 was none (score 0) in five (17%) patients, minimal (score 1) in seven (23%) patients, mild (score 2) in eight (27%) patients, moderate (score 3) in seven (23%) patients, severe (score 4) in three (10%) patients, and extensive in none.p = 0.0003).As summarized in p = 0.03).The patients in the COVID group experienced more frequently thoracic pain as presenting symptoms compared to the no-COVID group .There was no difference in the rate of vaccination against COVID-19 between groups (The data regarding perioperative outcomes and complications were summarized in p = 0.57), blood loss (p = 0.41), conversion (p = 0.82), and transfusion rate (p = 0.65) between the two groups. The chest drainage output (p = 0.16), length of chest drainage (p = 0.23), LHOS (p = 0.23), and ICU stay (p = 0.13) were also similar between groups.No significant differences were found regarding operative time . The adhesions were more frequently firm and vascular and localized in the portion of the pleural cavity in both groups.The COVID group patients had a higher incidence of pleural adhesions compared with the no-COVID group  had complications following the surgery. Of these, 49 patients had minor complications (32%) while 10 had major complications (6%).Major complications consisted of respiratory failure (n = 2), myocardial infarction (n = 2), a pneumothorax that needed re-drainage (n = 2), pneumonia that requested ICU management (n = 2), empyema (n = 1), and bowel infarction (n = 1).p = 0.51). Mortality at 90 days was 2%, without significant differences between groups (p = 0.38).No significant difference was found regarding the incidence of postoperative complications between groups (The most common complications were respiratory (21%), mainly hypoxemia (20%), prolonged air leaks (18%), and atelectasis (18%).The most common non-respiratory complication was postoperative anemia (16%). No patient needed reoperation, while two patients needed re-drainage due to persistent air leaks and atelectasis.p = 0.015), coronary artery (p = 0.007), and FEV1 < 70% (p = 0.03).On univariable analysis  capturinp = 0.006) and coronary artery disease (p = 0.016) were the only two independent significant prognostic factors for complications.However, in multivariable analysis, COPD (The management of oncological patients during the COVID-19 pandemic has been challenging, and while it is suspected that COVID-19 infection during the perioperative period is a risk factor for morbidity and mortality ,57,58, tFirst, there was no difference in the incidence of complications and 90-day mortality between patients with a history of recent COVID-19 infection and patients without a history of recent COVID-19 infection, and we found that COVID-19 infection was not an independent predictive risk factor for complications. In our study population, we found that the patients with recent COVID-19 infection had more frequent pleural adhesions compared with the control group. Since pleural adhesions are often a result of previous inflammatory processes , this diWe reported two cases of extensive pleural adhesions in patients with a history of COVID-19 in We also found that the patients with a history of COVID-19 had a higher rate of preoperative thoracic pain, which has been described as part of post-COVID pain syndromes  and shouSecond, our results highlighted that coronary artery disease and COPD were risk factors for complications.In the literature, COPD has been already associated with an increased risk for pulmonary complications ,68, whilThird, we observed that many patients were referred to our department exhibiting post-COVID chest X-ray or CT scans recommended by general practitioners as a follow-up after the infection. In these cases, COVID-19 infection has incidentally influenced the course of the patient’s treatment since small nodules could have otherwise gone unnoticed until a more advanced stage.Post-COVID-19 HRCT often showed pulmonary changes, even in asymptomatic or mildly symptomatic patients, such as generally newly found GGO opacities, subpleural interstitial involvement, bronchial dilation, and subpleural bands. We performed a thorough examination of preoperative CT, and when needed we used 3D reconstruction of the lung to predict possible difficulties in the resection and to assist the nodule localization in case of lung tissue alterations.The appropriate timing of surgery after COVID-19 is still debated; some authors suggest waiting 4–6 weeks to schedule elective surgery after COVID-19 infection , while oThe main limitations of our study is its retrospective nature and the relatively small sample size. Additionally, it is possible that some cases of COVID-19 were undetected, asymptomatic patients, but we accounted that this number would not be significant in our analysis since the patients were strictly monitored in the period before admission during the preoperative examination performed at our institution. Furthermore, the patients undergoing lung resection were highly selected and it could affect the surgical results. In the COVID group, we did not compare the complication rate between asymptomatic and symptomatic patients due to the small sample size and since the complication rate did not differ from that of the no-COVID group.Our results point toward the safety of performing thoracoscopic lobectomy in patients with recent COVID-19 infection without lung function impairment and after at least four weeks from the infection. The treatment of patients with recent infection of COVID-19 should not be delayed, but it is mandatory to carefully evaluate the patient’s respiratory and cardiac conditions, in case of ICU admission for COVID-19 or severe respiratory/cardiac comorbidities. Performing a preoperative HRCT is useful to plan the surgery and predict difficulties in nodule localization and the dissection in case of lung tissue post-COVID alterations.COVID-19 infection did not affect the outcomes of thoracoscopic lobectomy for lung cancer in patients without lung function impairment, including post-COVID consequences, and was scheduled after at least four weeks from the infection. The treatment of these patients should not be delayed in case of recent COVID-19 infection and should not differ from that of the general population. An appropriate cardiorespiratory and radiological post-COVID evaluation is mandatory to prevent complications.


TM or GoBackTM re-entry catheter in combination with a balloon as a target to accomplish wire passage, when conventional antegrade and retrograde recanalization attempts had been unsuccessful. Procedural outcomes included technical success , safety , and clinical outcome . Results: Thirty-six consecutive patients underwent target balloon-assisted recanalization attempts. Fourteen (39 %) patients had a history of open vascular surgery in the index limb. Fifteen patients were claudications . The locations of the occlusive lesions were as follows: iliac arteries in 3 cases, femoropopliteal artery in 39 cases, and in below-the-knee arteries in 12 cases. In 15 cases, recanalization was attempted in multilevel occlusions. Retrograde access was attempted in 1 case in the common femoral artery, in the femoropopliteal segment in 10 cases, in below-the-knee arteries in 23 cases, and finally in 2 patients via the brachial artery. In 10 cases, the re-entry devices were inserted via the retrograde access site. Technical success was achieved in 34 (94 %) patients. There were 3 periprocedural complications, none directly related to the target balloon-assisted re-entry maneuver. Amputation-free survival was 87.8 % and freedom from clinically driven target lesion revascularization was 86.6 % after 12-months follow-up. Conclusion: Target balloon-assisted use of re-entry devices in chronic total occlusions provides an effective and safe endovascular adjunct, when conventional antegrade and retrograde recanalization attempts have failed. Purpose, Retrograde recanalizations have gained increasing recognition in complex arterial occlusive disease. Re-entry devices are a well described adjunct for antegrade recanalizations. We present our experience with target balloon-assisted antegrade and retrograde recanalizations using re-entry devices in challenging chronic total occlusions. Materials and Methods: We report data from a retrospective multicenter registry. Eligibility criteria included either antegrade or retrograde use of the Outback Over the past decade, there has been a paradigm shift in the treatment of infrainguinal arterial chronic total occlusions (CTOs). As endovascular technology, techniques and experience have developed, outcomes in amputation free survival and mortality have become equivalent to those of open surgery in the context of critical limb threatening ischemia .TM re-entry catheter  and the GoBackTM device  are well described examples to aid recanalizations, helping in crossing back into the true lumen when conventional wire and catheter techniques have failed [Advances in endovascular techniques, operator’s skills as well as innovations in dedicated medical devices have helped to facilitate technical success rates and outcomes even in complex lesions. The Outbacke failed ,3.TM re-entry catheter and retrograde vessel access, with the device deployed in a retrograde manner may be utilized in particularly complex chronic total occlusions [TM and the GoBackTM re-entry catheters in complex peripheral arterial revascularizations. Successful wire passage through challenging occlusions was also improved through the introduction of retrograde recanalization techniques ,5,6,7,8.clusions . In seleclusions ,12,13, tTM or the GoBackTM re-entry catheter in procedures, where both antegrade and conventional retrograde recanalization were unsuccessful. The study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the Institutional Review Boards. Due to the retrospective, non-interventional nature of the study based solely on data generated and documented during clinical practice, informed and written consent was not required in accordance with the statement of the Institutional Review Boards. A total of 36 consecutive patients were treated in 4 different institutions between October 2014 and February 2021. All cases were discussed by a multidisciplinary team prior to the intervention. Patients with claudication symptoms were offered endovascular therapy after failure of conservative and medical treatment and persisting lifestyle-limiting symptoms. Eligibility included all endovascular cases involving balloon-targeted use of the OutbackData were collated from the picture archiving and communication systems (PACS), radiology information systems (RIS) and electronic patient records in each institution. Patient and procedural characteristics were collected for gender, age, Rutherford clinical stage, history of previous vascular surgery in the treated limb, degree of calcification (PACCS score) , lesion Technical success was defined as target balloon-assisted wire passage through the occlusion, delivery of adjunctive therapy and <30% residual stenosis at final angiogram. The procedural outcome measures included complications , amputation-free survival as well as freedom from clinically driven target lesion revascularization (cd-TLR) at 12-months follow-up.The decision to target the re-entry catheter to a balloon, entered either via the antegrade or retrograde route, was made at the primary operator’s discretion after failure of conventional recanalization attempts. Antegrade access was either from the ipsilateral common femoral artery, the brachial artery or the contralateral common femoral artery using a crossover technique. Five-thousand IU of heparine was administered after sheath placement. In longer procedure, ACT was measured with a target of >200 s.Distal retrograde access was accomplished with a 21-gauge micro-puncture access needle under either ultrasound or, in the majority of cases, using fluoroscopic guidance with an 0.018″ support wire,  introduced. To prevent spasm, nitroglycerine was administered according to the discretion of the interventionalist. In cases of failed retrograde wire passage through the occlusion, the re-entry catheter was inserted either through a sheath as per Instructions for Use (IFU) or, in the interest of a low-profile approach, sheath-less, again at the primary operator’s discretion. In cases of retrogradely advanced target balloons, they were introduced either sheath-less or via a 4 F sheath. Target balloons  were inflated with low pressure (2–4 atm). Re-entry into the target balloon was aimed at the most distal part of the balloon to allow maximal length of wire insertion  into the punctured balloon . In combCompletion angiography at the treated segment as well as below-the-knee run-off was performed to assess treatment outcome and procedural complications. Postinterventional medical treatment varied between the centers. In general, in the absence of an indication for oral anticoagulant therapy, dual antiplatelet therapy for at least 4 weeks was most often recommended post-procedural, or more recently, low dose rivaroxaban in combination with single antiplatelet therapy.The number of observations represents patients. Continuous variables are reported as mean ± standard deviation (SD), median and inter-quartile range. Categorical data are presented as number and percentage. Freedom from clinically driven target lesion revascularization and amputation-free survival are reported with Kaplan–Meier methods. Statistical analysis was performed with SPSS software (version 25).In 36 patients , recanalization was attempted with target balloon-assisted re-entry using the Outback™ device  in 33 caFourteen patients (39%) had a prior history of open vascular surgery of the target limb, including common femoral endarterectomy, femoro-popliteal bypass, femoro-femoral bypass, and aorto-bifemoral bypass. In 10 patients (28%), the re-entry catheter was introduced via the retrograde route, in 20 cases (56%) retrograde access was established without the use of a sheath. Retrograde access arteries and balloon re-entry sites are shown in Successful target balloon-assisted lesion recanalization could be achieved in 34 out of 36 patients (94%). In one patient with an occluded femoropopliteal bypass, despite additional retrograde access, the Outback™ re-entry catheter could not be positioned close enough to the target-balloon to allow the needle to reach the inflated balloon, most likely due to severe fibrosis at the area of the distal bypass anastomosis. The patient then underwent revascularization with a bypass and was discharged 10 days thereafter. In a second case, the Outback™ re-entry needle did not reach the balloon in an occluded common iliac artery. However, after wire escalation and alternative strategies (CART etc.), wire passage and adjunctive therapy could be accomplished. Since the initial strategy  failed, we consider that case as not successful in respect to our registry.In all remaining patients, wire passage via balloon-puncture and adjunctive therapy could be performed successfully with a documented patency and <30% residual stenosis at final angiogram. Recanalized segments and adjunctive therapy can be found in Four patients were lost to follow-up and 4 died within the first year. There were no major amputations. The survival rate was 87.8% and freedom from cd-TLR was 86.6% at 12 months .One patient with known coronary artery disease died 2 days after the intervention due to cardiac arrest. In one patient, perforation after aggressive lesion preparation in a severely calcified superficial femoral artery (PACCS score: 4) required implantation of a Viabahn™ endoprothesis. In another patient, 10 mg rt-PA were administered due to semi occlusive thrombus formation at the level of the tibioperoneal trunk. Although no bleeding was seen on the final angiogram, the patient experienced late bleeding complication 6 h after the procedure at the retrograde access site in the proximal anterior tibial artery. The patient developed compartment syndrome, requiring fasciotomy, with subsequent full recovery. According to SVS reporting standards , the carOur multicenter retrospective analysis demonstrated that target balloon-assisted use of re-entry devices is safe and effective and might help to further improve the technical success rates in challenging occlusions.TM catheter incorporates intravascular ultrasound imaging to potentially further enhance the precision and safety of the re-entry but also adding costs to the procedure. In another report, target balloon-assisted use of the Outback™ enabled recanalization of a thrombosed femoropopliteal bypass graft [Subintimal recanalizations of occluded peripheral arteries were first described by Bolia et al. Technical success was achieved in 76% of cases in femoropopliteal occlusion with moderate lesion length . After pss graft . In all This study is limited by its retrospective design and data acquisition. Therefore, we cannot report on the important clinical outcome parameters  in our cohort. It has been performed across four international centers with multiple operators with different decision making processes, non-standardized post-interventional treatment protocol, etc. There was also no comparator group in this study, but as described, this intervention was only reserved as a “bail-out“-option after conventional revascularization attempts had failed. Of note, there is a certain learning curve regarding the use of re-entry devices, and they add a significant cost to the procedure. A significant number of patients were treated despite presenting with claudication instead of critical limb threatening ischemia. Our approach could be considered rather aggressive and is not necessarily in accordance with current guidelines. However, we strongly believe that, where conventional revascularization methods have failed, the low complication rate demonstrated by our multicenter operators, justifies endovascular treatment, including target balloon-assisted retrograde recanalizations in patients presenting with lifestyle-limiting claudication as well as critical limb threatening ischaemia.In summary, target balloon-assisted retrograde application of the Outback™ and GoBack™ re-entry catheter is feasible and safe as demonstrated in our retrospective multi-center cohort study. It provides a valuable option in CTOs, where both antegrade and conventional retrograde subintimal recanalization attempts have failed.


To quantify the impact of a home-based cardiac rehabilitation intervention (Rehabilitation Enablement in Chronic Heart Failure (REACH-HF)) on objectively assessed physical activity (PA) of patients with heart failure (HF) and explore the extent by which patient characteristics are associated with a change in PA.Secondary analysis of randomised controlled trial data.Five centres in the UK.247 patients with HF .REACH-HF versus usual care (control).PA was assessed over 7 days via GENEActiv triaxial accelerometer at baseline (pre-randomisation), post-intervention (4 months) and final follow-up (6–12 months). Using HF-specific intensity thresholds, intervention effects (REACH-HF vs control) on average min/day PA ) over all days, week days and weekend days were examined using linear regression analysis. Multivariable regression was used to explore associations between baseline patient characteristics and change in PA.Although there was no difference between REACH-HF and control groups in 7-day PA levels post-intervention or at final follow-up, there was evidence of an increase in weekday MVPA , light PA  and decreased inactivity  in favour of REACH-HF. Baseline factors associated with an increase in PA from baseline to final follow-up were reduced MVPA, increased incremental shuttle walk test distance, increased Hospital Anxiety and Depression Scale anxiety score and living with a child >18 years (p<0.05).While participation in the REACH-HF home-based cardiac rehabilitation intervention did not increase overall weekly activity, patient’s behaviour patterns appeared to change with increased weekday PA levels and reduced inactivity. Baseline PA levels were highly predictive of PA change. Future focus should be on robust behavioural changes, improving overall levels of objectively assessed PA of people with HF.ISRCTN78539530 and ISRCTN86234930. The use of population-specific intensity thresholds to derive physical activity (PA) intensity provides a more reliable and robust estimate of PA levels of patients with heart failure.The use of rigorous data processing and analysis methods to look beyond a single PA metric  revealed interesting patterns in the data, however this increase in granularity causes a reduction in statistical power and future studies should consider this in sample size calculations.As this was an exploratory study, there may be an increased risk of type 1 errors with multiple repeated tests, and some frequency counts of variables included in multivariable models were low.Physical activity (PA) has numerous health benefits for patients with heart failure (HF) including reduced HF mortality and HF hospitalisation, and improved quality of life.Traditionally, cardiac rehabilitation (CR) interventions have prioritised increasing exercise capacity rather than PA behaviour, and evidence that CR increases PA toward recommended levels is lacking.Furthermore, although some studies have shown that PA levels are associated with a number of factors including age, body mass index, exercise capacity and disease severity in patients with HF, these have been limited by cross-sectional design that do not measure within-person PA change.Due to the wide range of health benefits associated with increased PA in patients with HF, further studies, using improved, objective and population-specific PA assessment techniques are needed to understand and clarify the impact of CR on PA levels and the relationships between PA and patient level characteristics. Therefore the primary aim of this study was to assess the impact of a home-based CR programme (Rehabilitation Enablement in Chronic Heart Failure (REACH-HF)et alA key element of the REACH-HF intervention development process was the involvement of a local patient and public involvement (PPI) group consisting of nine patients with HF and caregivers of people with HF. The PPI group co-created the REACH-HF intervention, and were involved in the recruitment process, and associated research questions and topic guides  that randomised patients with HF 1:1 to a home-based CR intervention plus usual care (REACH-HF group) or to usual care alone (control group), stratified by site and N-terminal Brain Natriuretic Peptide (NT-proBNP). The first was a pilot RCT of the REACH-HF intervention for patients with HF with preserved ejection fraction  >45%), and the second was a multicentre RCT of the REACH-HF intervention for patients with HF with reduced ejection fraction . Accelerometry-measured PA was a secondary outcome of the original studies, and full details of these trials are presented elsewhere.In summary, REACH-HF is a theory-based, comprehensive self-management programme consisting of four core elements; (1) an HF self-help manual with a choice of two structured exercise programmes; a chair-based exercise DVD, and a progressive walking training programme ; (2) a patient ‘progress tracker’ booklet designed to facilitate learning and record symptoms and other actions related to healthcare; (3) a ‘family and friends resource’ manual for caregivers to increase their understanding of HF and their own physical and mental well-being; and (4) facilitation by specially trained cardiac nurses, physiotherapists or exercise therapists to individually tailor the intervention. Participating patients and caregivers worked through the REACH-HF manual for 12 weeks. Participants in both the pilot RCT and full RCT received the same programme.This study complies with the Declaration of Helsinki.A total of 247 adults (aged ≥18 years) with a confirmed diagnosis of HF , and complete baseline accelerometer data sets (participants were required to have ≥16 hours per day and ≥7 days of wear) were included in this analysis. Participants were recruited and completed the baseline visit between January 2015 and February 2016, from primary and secondary care settings in five UK centres . All participants provided written informed consent.PA data were collected via accelerometry on three occasions: at baseline (pre-randomisation), post-intervention (4 months) and final follow-up (6–12 months). Given the final accelerometry data follow-up for the two trials was at 6 months for patients with HFpEF, and 12 months for patients with HFrEF we have therefore combined data at these two ‘final follow-up’ time points for this study.The following patient level data were collected at baseline: medical history  class, concomitant medication), socio-demographic information , NT-proBNP measurement via blood sample, exercise tolerance via incremental shuttle walk test (ISWT) and health outcome questionnaires, that is, disease-specific health-related quality of life (HRQoL) using the Minnesota Living with Heart Failure Questionnaire, and the Health-Related Quality of Life (HeartQoL) questionnaire; psychological well-being using the Hospital Anxiety and Depression Scale (HADS) questionnaire; generic HRQoL using the EuroQol-5 Dimension-5 level (EQ-5D-5L) questionnaire; and Self-Care of HF Index questionnaire (SCHFI).http://cran.r-project.org). Initial processing included autocalibration, and detection of abnormally high values and non-wear.At the clinical visits, participants were provided with and instructed to wear a GENEActiv triaxial accelerometer  for 24-consecutive hours for 7 days. Accelerometers were returned to the clinical trials unit using postage-paid envelopes. Data were downloaded using GENEActiv PC software  and processed in R  using the GGIR software package : 16.7 mg (left wrist), 18.6 mg (right wrist), MVPA : 43.6 mg (left wrist), 45.5 mg (right wrist)) were applied to calculate the average minutes per day spent inactive, in light PA and MVPA, over all days, weekend days and weekdays. These thresholds were established by a recent accelerometer calibration study in 21 patients with HF.Descriptive statistics were calculated as means and SDs or counts and percentages unless otherwise stated.Data from final follow-up were used for primary analysis in line with the primary endpoints of the two original trials.Univariate linear regression was used to investigate the baseline socio-demographic , medical history , ISWT and health status variables  associated with change in MVPA, adjusting for baseline MVPA, treatment group and trial stratification variables .2 values were used to inform model comparison and selection.In addition to univariate regression, we undertook multivariable regression to explore the association between selected patient characteristics and change in MVPA. Variables with statistical evidence of univariate association with change in MVPA (p<0.15) were selected for entry into a series of multivariable regression models to establish which variables were independently and most strongly associated with change in PA at final follow-up and post-intervention, mutually adjusting for trial stratification variables, baseline MVPA and treatment group. Model 1—socio-demographic and medical history variables only, model 2—exercise capacity and health status variables only and model 3—socio-demographic, medical history, exercise capacity and health status variables identified as significant (p<0.05) predictors in models 1 and 2. Checks and diagnostics were performed for model assumptions, residuals, multicollinearity (variance inflation factor) and influential observations (Cook’s distance). Akaike information criterion (AIC) and RStatistical analyses were performed using Stata .Two hundred and forty-seven patients had accelerometer data at baseline which met the criteria for inclusion in analysis. Post-intervention, 198 patients were included and at final follow-up 173 patients were included in the analysis . Patient10.1136/bmjopen-2022-063284.supp1Supplementary dataThe effects of REACH-HF intervention versus control at final follow-up on PA  over all days, weekdays and weekend days are presented in At post-intervention follow-up, there were no significant differences between REACH-HF group and control for all bouted PA intensities or days  .At final follow-up, using unbouted PA data, there was a small increase in weekday MVPA and decrease in weekday inactivity in the REACH-HF group, with the reverse found in control group, (between group differences showing a trend in favour of REACH-HF (MVPA: 15.18 (95% CI: −0.32 to 30.67), p=0.06; inactivity: −21.25 (95% CI: −43.24 to 0.75), p=0.06; In terms of prevalence of meeting PA guidelines, no differences were found between REACH-HF and control group at either follow-up time point .Post-intervention, presence of diabetes and SCHFI maintenance scores at baseline were associated with a decrease in MVPA (p<0.05), whereas individuals with greater ISWT distance at baseline were more likely to increase their MVPA p<0.05; .Multivariable models to predict change in MVPA post-intervention are presented in Variance inflation factor (VIF) ranged from 1.06 to 1.18 across the six models indicating a low level of multicollinearity.We undertook an in-depth analysis of RCT data of a CR intervention (REACH-HF) objectively assessing PA levels of patients with HF using intensity thresholds specifically developed for this population group. When PA levels were averaged over all 7 days of the week, there was no evidence that participation in REACH-HF impacted daily PA levels compared with control. As some 48% of patients in the REACH-HF trials were already meeting UK PA guidelines at baseline (based on bouted data), it may be that there was a ceiling effect, where those already physically active would have difficulty further improving on MVPA levels, making small changes in PA difficult to pick up statistically. This has often been the case in other CR trials.However, separating weekend and weekdays revealed important patterns in the PA response. Average weekday PA levels showed a consistent trend where MVPA and light PA increased , and inactivity decreased (−38 min/day) in the REACH-HF group compared with the control group. Over weekend days, the reverse appeared to be true, with an increase in inactivity and decrease in PA. This pattern was not evident in either group at baseline, therefore these findings suggest that the REACH-HF participants may have compensated for increased PA during the week by being less active at the weekend, which could account for the lack of overall PA increase found. Compensation for increased exercise with increased inactivity in the subsequent days has been demonstrated in other populations such as older adults,Traditionally, CR programmes have been developed with a focus on increasing exercise capacity rather than PA promotion. In its current format we have shown modest positive influences of a home-based CR programme on weekday PA levels of patients with HF. In order to achieve greater PA benefits to patients, CR programmes may need to adapt, placing stronger emphasis on increasing unstructured daily PA behaviour or targeting both PA and sedentary behaviour. This could be facilitated by simplified PA messaging such as sit less, move more, every day, which might be easier for patients to understand and sustain in the longer-term, leading to higher levels of total PA and reduced sedentary time and is likely to have significant health benefits to patients with HF.Given the large variation in PA differences from baseline up to final follow-up in MVPA, we were interested to investigate potential factors associated with a change in MVPA. To our knowledge, this is the first study to explore this. Our results showed that particular living situations of the patient were associated with PA change (living with a parent or child >18 years), which may indicate involvement of family members is associated with PA behaviour change and self-care of patients with HF.This study has a number of strengths. First, the objective measurement of PA, and robust and rigorous accelerometer data processing and analysis. Literature reporting accelerometer measured PA in patients with HF with CR intervention is limited, especially in large, representative samples. The use of population-specific intensity thresholds provides a more reliable estimate of PA levels of patients with HF, compared with application of commonly used thresholds based on healthy adults.This study highlights the benefit of extracting more detailed PA data, looking beyond a single PA metric  and considering within-week differences in PA patterns. In line with updated PA guidelines that acknowledge bouts less than 10 min can also be beneficial for health,As this was an exploratory study, multiple repeated independent tests were conducted comparing treatment groups and between baseline characteristics and change in MVPA. Given the dangers of multiple testing, which may have led to increased risk of type 1 errors, our results must be treated with caution. In addition, variables associated with MVPA change were inconsistent across the two follow-up points and explained only a small proportion (10–15%) of the variance in MVPA change and combining the final follow-up data sets from 6 and 12 months may have introduced variation to the data. While the sample size was sufficient for this exploratory study, some of the frequency counts of variables included in the multivariable models were low. Further studies using objective PA assessment are needed to clarify the impact of exercise-based CR interventions in patients with HF and the patient factors associated with change in PA.This pooled analysis of RCTs shows that participation in a home-based CR intervention did not impact 7-day PA compared with control. However, participating in CR did appear to increase weekday PA levels and participants may have compensated for this by becoming more inactive during the weekend. Understanding of the behavioural effects of a home-based CR intervention could provide key targets for clinicians and researchers to adapt CR focus and PA messaging, in order to encourage patients to increase overall weekly PA and reduce inactivity. Understanding the factors associated with change in PA with CR intervention could potentially enhance development of more intense interventions specifically tailored or targeted at those with lower baseline PA or exercise capacity levels, as these patients will have the most to gain from increasing their PA.


Palliative care is an essential intervention to improve the quality of life for patients with cancer, whereas the ongoing COVID-19 pandemic poses a challenge to supportive and palliative care providers. This survey aims to explore the current status of palliative care practice for cancer and the influence of COVID-19, from the perspective of oncologists.The semi-structure electronic questionnaire was designed. Mixed-mode surveys including electronic questionnaires, face-to-face interactions, and telephone interviews were adopted according to the willingness of respondents. Face-to-face and telephone interviews were based on same questions in the online questionnaire. Participants working in cancer-related departments with frontline palliative care experience during the COVID-19 outbreak were included. Surveys covered experiences and perspectives regarding the impact of COVID-19 on clinical work, personal lives, and palliative care practice. Suggestions on coping strategies were further proposed and qualitatively analyzed.Thirty-seven oncologists participated in this study from September 2021 to January 2022. The majority of them believed COVID-19 significantly and negatively affected their clinical work routines (75.7%), personal daily lives (67.6%), and palliative care practice (64.9%). Most specialists considered that currently the palliative care system remained underdeveloped (73.0%), and other factors besides COVID-19 were associated with this situation (78.4%). Seventeen participants further made suggestions on how to promote palliative care during COVID-19, and three themes emerged through the qualitative analysis: (1) Remote or online service (88.2%); (2) Publicity, education, or shared decision-making for patients (29.4%); (3) Guidelines, training, or programs for care providers (23.6%).Oncologists consider that COVID-19 has an adverse impact on their palliative care practice and daily routine. In addition to COVID-19, other factors affecting palliative care should not be neglected. Corresponding measures are warranted to encourage palliative care practice during COVID-19. In December 2019, coronavirus diseases 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Subsequently, COVID-19 has rapidly become a severe pandemic and significantly impacted various clinical practices . The outThe two-sides of practice indicates that one side is the recipient of care and the other side is for the care providers. Thus, both care practitioners and patients play an important role in the practice of palliative care. With early studies suggesting that cancer patients are particularly susceptible to COVID-19, the current pandemic is forcing oncology professionals to explore and practice more , 7, 8. MWith the increasing difficulty to provide palliative care during the COVID-19 pandemic, the wide emphasis on the experiences and viewpoints of palliative care providers, as well as the urgent need for useful coping strategies to better tackle the influence of COVID-19 on palliative care practice, this survey was conducted in order to shed light on these issues. We not only explored the impact of the COVID-19 pandemic on the clinical practice of supportive and palliative care for patients with cancer, from the perspective of oncologists, but also proposed some useful countermeasures to promote and encourage the clinical practice of palliative care during COVID-19.via email, if they were willing to provide their email addresses and some other personal information only for this purpose.We designed a semi-structured electronic questionnaire to elicit the perspectives of clinical oncologists through both quantitative and open-ended qualitative questions. Mixed-mode surveys including online electronic questionnaires, face-to-face interactions, and telephone interviews were adopted based on the willingness of respondents. If they agreed to receive face-to-face or telephone surveys, they would be individually asked the same questions in the online electronic questionnaire in person, and the information was collected. After obtaining permission from respondents in face-to-face and telephone surveys, all interviews were digitally recorded and transcribed verbatim to assure accuracy. If participants chose to answer the electronic questionnaire, they would complete a self-administered anonymous web-based questionnaire in both Chinese and English. The Independent Ethics Committee of National Cancer Center approved this research. Informed consent was obtained from all individual participants included in the study. They can access the online Participant Information Consent Form via a secure web link and complete it using mobile phones or computers. After the completion of survey, participants could receive an e-card gift and a thank-you note The study was conducted from September 2021 to January 2022 in China. In the approximately two-year pandemic background, this survey was primarily in the setting where palliative care was provided for cancer patients during the COVID-19 period, including medical centers, hospitals, nursing homes, palliative care institutions, community healthcare centers, etc.Eligible participants were those over 18 years of age currently working in cancer-related departments, such as the department of medical oncology, radiation oncology and surgical oncology, etc, in medical establishments or other sites that provide palliative care practice. Among them, oncologists who had clinical front-line working experiences during the COVID-19 pandemic (from December 2019 to the date participating in the survey), possessed and were able to use online electronic mobile devices autonomously, and proficiently mastered Chinese or English language, were finally included.The questionnaire survey or interview outline covered: (1) Demographic characteristics: Age, gender, country, educational attainment, workplace and currently working department, supportive and palliative care training experience, the primary place of palliative care practice.(2) Subjective perceptions regarding the influence of the COVID-19 pandemic: Do you think the COVID-19 pandemic has a significant impact on your clinical work in oncology? Yes, mainly negative impacts. / Yes, mainly positive impacts. / No. / Other. Do you think the COVID-19 pandemic has a significant impact on your personal life or daily routine? Yes, mainly negative impacts. / Yes, mainly positive impacts. / No. / Other. Do you think the COVID-19 pandemic has a significant impact on clinical practice of palliative care for cancer patients? Yes, mainly negative impacts. / Yes, mainly positive impacts. / No. / Other.(3) Subjective perspectives regarding the status quo of palliative care: Do you agree that the current supportive and palliative care system in your working environment is adequate or fully developed? Yes. / No. / I am not sure. / Other. Do you agree that other factors, except for the influence of COVID-19, are associated with the current status of palliative care practice system? Yes. / No. / I am not sure. / Other.(4) Suggestions and advice: Do you have any suggestions to improve the clinical practice of palliative care during the COVID-19 pandemic? If yes, please give your precious and specific advice.Data was collected from the electronic questionnaire surveys and interviews on oncologists in China from September 2021 to January 2022. Demographics and subjective perspectives of respondents were quantitatively summarized mainly using descriptive statistics. Personal suggestions of free-text narrative responses were qualitatively analyzed through inductive thematic analyses. All data were translated into English before analysis. All face-to-face and telephone interview surveys were digitally recorded and transcribed verbatim by two researchers (W.Y. and X.M.) together to assure maximum accuracy. Two investigators (W.Y. and D.W.), without previous knowledge of the participants and not involved in the distribution of questionnaires, independently collected and analyzed the questionnaire content, and they further compared and verified their research results. Any discrepancies between two researchers (W.Y. and D.W.), especially in summarizing countermeasures proposed by participants, were solved by consulting senior investigators (X.Z. and N.B.).Thirty-seven eligible clinical oncologists participated in this study. Among them, 32 (86.5%) were surveyed by online questionnaires, 4 (10.8%) by face-to-face interviews, and 1 (2.7%) by a telephone interview. The baseline demographic characteristics were presented in In terms of subjective perceptions and opinions with respect to the impact of COVID-19, the majority of participants agreed that the COVID-19 pandemic had a significantly negative effect on their clinical work in the cancer field 75.7%, , as wellFurthermore, a total of 17 specialized physicians proposed their suggestions on how to tackle the adverse influence of COVID-19 on palliative care practice. The qualitative analysis resulted in the following three themes:  PublicitBox 1Theme 1. Offering remote or online service”“Offering more online guidance on palliative care for cancer patients and their familiesBefore the COVID-19 epidemic, there were more cancer patients from other provinces in our hospital, but due to the restrictions of the epidemic, the access and follow-up of these patients were very limited. Adding more online consultations may help them” #P25“Promoting remote multidisciplinary cooperationMultidisciplinary cooperation members cannot meet on-site due to epidemic restrictions, but the mechanism of online MDT (multidisciplinary treatment) is not mature enough and needs to be improved urgently” #P34“Invite the professional palliative medicine team to join the multidisciplinary consultation” #P9“Strengthening home-based palliative care…palliative care at home for cancer patients should be given a higher priority, and access to remote medical guidance is less clear for physicians as well as patients” #P20“The trend of shifting palliative care settings from hospital to home has been accelerated by COVID-19” #P37“Using more modern technology in palliative care…mobile phones and WeChat could become important tools to provide remote palliative care guidance during this COVID-19 period. It would be better to have some platforms like WeChat public account for telemedicine that do not involve doctors' personal privacy” #P32“Theme 2. Increasing the publicity, education, or shared decision-making for patientsEncouraging shared decision-makingThe situation of patients who need palliative care is often complex, especially end-of-life patients, and it could be more helpful and effective if patients and doctors share the decision-making process” #P35“Increasing the publicity and education of palliative medicineIncrease palliative care education, positive publicity, and concept shaping, the actual potential demand in China is huge” #P19“Theme 3. More guidelines, training, or programs for care providersStandardizing palliative medicine training for medical workersPalliative care providers working in different sites, different regions, and different fields will need more specialized training” #P11“Most care providers actually do not specialize in this. They might lack relevant professional experience. More professional training in palliative medicine might be helpful” # P36“Enhancing personalized palliative care programsDuring COVID-19, government support may be more helpful, such as more palliative care programs and financial investments” #P5“…promoting projects about personalized palliative care practices could be of great benefit, given that each doctor's situation (under the COVID-19 pandemic) is different” #P37“Updating more information on COVID-19 in palliative care guidelinesThe prevention and control of the COVID-19 in China is becoming more and more regular. Information and guidelines on palliative care also should be updated accordingly” #P35“A total of 17 participants  answered the free-text questions and gave their narrative suggestions on coping strategies. Among them, P32, P33, P34, P36, and P37 were interviewed face to face or by telephone. These suggestions were also summarized in It is known that the integration of team-based, timely and targeted supportive and palliative care into standard oncology care for all patients with cancer is of great significance . The chaAlthough it is universally accepted that palliative care should be adopted by specialists in all oncology settings to benefit cancer patients and their families . The lacMore importantly, 67.6% oncologists in our study considered that their personal lives and daily routines also had been significantly and negatively affected by the COVID-19 outbreak. In a study from Italy during COVID-19, frontline health care workers were reported severe posttraumatic stress symptoms, which could seriously affect their lives and careers . Previouvia telehealth services, digital consultations, and intelligent devices (Furthermore, when it comes to the current status of the palliative care system in China, most specialists deemed that it remained underdeveloped. They also agreed that many other factors besides COVID-19 were associated with it, presumably on account of the unbalanced medical resources, conflicts of traditional values, and reluctance from patients –35. Thus devices , 37. ThePalliative care providers and hospice sectors play an essential role in the response to COVID-19 . OncologThere are several limitations. First, the sample size was moderate, but we have adopted some design strategies to improve response rates, including small financial incentives, mixed-mode survey, and brief questionnaire . In the The COVID-19 pandemic has a significant adverse impact on palliative care practice, daily clinical routine, and personal lives, from the perspective of oncologists. Most of them consider the current palliative care system underdeveloped in China, and other factors besides COVID-19 may be associated with this situation. The corresponding measures should be taken to improve the clinical practice of palliative care during COVID-19, such as incorporating more online guidance and remote assistive technology in palliative care, encouraging home-based and personalized palliative care treatment according to the condition of patients, and promoting up-to-date information and practical training for palliative care practitioners.m13992895327@163.com.The datasets presented in this article are not readily available because questionnaire data and interview transcripts are available upon reasonable request. Requests to access the datasets should be directed to YW, This study was approved by the Ethics Committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Informed consent was obtained from all individual participants included in this survey.YW, DW, and XM acquired, analyzed, and interpreted all data. YW and YH drafted and revised the manuscript. XZ and NB reviewed and edited this manuscript critically. All authors contributed to the concept and design of this work and approved the final version to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.