In the current context of tailoring interventions to maximize impact, it is important that current data of clinical epidemiology guide public health programmes and health workers in the management of severe disease. This study aimed at describing the burden of severe malaria at hospital level in two areas with distinct malaria transmission intensity.A hospital-based surveillance was established in two regional hospitals located in two areas exposed to different malaria transmission. Data on paediatric severe malaria admissions were recorded using standardized methods from August 2017 to August 2018 with an interruption during the dry season from April to June 2018.P. falciparum density was significantly higher in the LMT area compared to the HMT area: 22,861 trophozoites/µL  vs 11,291.9 trophozoites/µL . Among enrolled cases, coma was present in 70 (9.2%) participants. 196 patients (21.8%) presented with two or more convulsions episodes prior to admission. Severe anaemia was present in 448 children (49.2%). Other clinical features recorded included 184 (19.9%) cases of lethargy, 99 (10.7%) children with incoercible vomiting, 80 (8.9%) patients with haemoglobinuria, 43 (4.8%) children with severe hypoglycaemia, 37 (4.0%) cases where child was unable to drink/suck, 11 (1.2%) cases of patients with circulatory collapse/shock, and 8 cases (0.9%) of abnormal bleeding (epistaxis). The adjusted odds of presenting with coma, respiratory distress, haemoglobinuria, circulatory collapse/shock and hypoglycaemia were significantly higher (respectively 6.5 (95%CI 3.4–12.1); 1.8 (95%CI 1.0–3.2); 2.7 (95%CI 1.6–4.3); 5.9 (95%CI 1.3–27.9); 1.9 (95%CI 1.0–3.6)) in children living in the HMT area compared to those residing in the LMT area. Overall, forty-four children died during hospitalization  with the highest fatalities in children admitted with respiratory distress (26.0%) and those with hypoglycaemia (25.0%).In total, 921 children with severe malaria cases were enrolled in the study. The mean age was 33.9 (± 1.3) and 36.8 (± 1.6) months in lower malaria transmission (LMT) and higher malaria transmission (HMT) areas (p = 0.15), respectively. The geometric mean of asexual The study showed that children in the HMT area have a higher risk of presenting with coma, shock/dehydration, haemoglobinuria, hypoglycaemia, and respiratory distress. Case-fatality rate is higher among patients with respiratory distress or hypoglycaemia. Hospital surveillance provides a reliable and sustainable means to monitor the clinical presentation of severe malaria and tailor the training needs and resources allocation for case management. Despite the recent progress in malaria control in many countries across the globe, malaria remains the main public health threat in sub-Saharan Africa. Globally, there were an estimated 229 million malaria cases in 2019 in 87 malaria endemic countries, with about 94% of cases accounted for in the World Health Organization (WHO) African Region [Burkina Faso is one of those countries where progress in controlling the disease has stalled despite full-scale deployment of available interventions which include case management using artemisinin-based combination therapy (ACT), vector control through large-scale distribution of long-lasting insecticidal nets (LLINs); and seasonal malaria chemoprevention (SMC) targeting the marked seasonality of the disease transmission. The country is one of the high-burden nations as defined by the WHO and is part of the high burden to high impact initiative .The clinical epidemiology of severe, life-threatening malaria was characterised in Burkina Faso during the 1990s  at a timTo tailor interventions to maximize impact, it is important to obtain up to date information on the epidemiology of severe malaria. This study describes the current burden of severe malaria in children admitted at hospital level in two areas with distinct malaria transmission. The information on prevalence and lethality of severe malaria in hospitalized children is useful to the National Malaria Control Programme (NMCP), to health workers and may contribute to fine tuning the malaria control strategies and resources allocation.Anopheles gambiae, Anopheles arabiensis and Anopheles funestus, and Plasmodium falciparum is responsible for more than 90% of all clinical malaria cases [The study was conducted at two regional referral hospitals, the Regional Hospital of Koudougou and the Regional Hospital of Banfora, respectively. The Regional Hospital of Koudougou  is located 100 km Centre West of the capital city of Ouagadougou. Malaria transmission in this central part of the country is markedly seasonal and intense during the rainy season from June to October. The entomological inoculation rate (EIR) was estimated at 31.4 infective bites/person/year in a study conducted in the neighbouring zone of Saponé . The Bania cases , 8.The recruitment of children took place from August 2017 to August 2018 with an interruption from April to June 2018 (representing the dry season). For all consecutive children aged 0 to 15 years presenting at the paediatric emergency room at any time with a clinical presentation suggestive of severe malaria, an informed consent was obtained by study personnel from parents/legal representatives. Patients were further assessed by paediatric ward clinicians (who benefited from a refresher protocol specific training prior to the study start) and observations recorded using a standardized case report form. Data collected included the medical history, vital signs, a complete physical examination for signs of severity . Finger prick blood sample was taken for malaria smear , haemoglobin and glucose measurements using point of care devices . If the RDT was positive, anti-malarial treatment was immediately initiated based on the NMCP guidelines.Children received parenteral artesunate at 2.4 mg/kg body weight on admission (time zero), then after 12 and 24 h and then once a day, or artemether Injection at 3.2 mg/kg on admission, then 1.6 mg/kg body weight per day. In both cases, parenteral administration continued until the child improved and was able to take full course of oral ACT, using artemether-lumefantrine or artesunate-amodiaquine. Supportive therapy recommended for severe malaria includes the treatment of hypoglycaemia with dextrose when glucose < 2.2 mmol/l, blood transfusion for children with haemoglobin less than 5 g/dL. All treatments were free of charge. No adjusted dose of parenteral artesunate for children weighing less than 20 kg was adopted by the NMCP at the time of the study conduct.Plasmodium asexual forms were found, a total of two hundred thick film fields were screened for Plasmodium species other than P. falciparum. If P. falciparum was present, a count of asexual forms against leukocytes was made using a tally counter. Counting was conducted based on at least two hundred leukocytes in consistence with WHO standards. If less than 10 parasites were identified from the two hundred leukocytes screened, the count was extended to 1,000 leukocytes. On the other hand, if P. falciparum gametocytes were seen, a gametocyte count was performed against 1,000 leukocytes. All slides were read by two independent microscopists with a third reading in case of discordant results. The final result was based on the two most concordant readings. All readers are certified competent/expert by an external quality assurance system with Clinical Laboratory Services (http://www.cls.co.za), South Africa.Blood films were managed as described elsewhere . All RDTSevere malaria was defined based on presence of one or more criteria outlined in box Box 1 Features of severe malariaClinical features of severe malaria.Impaired consciousness (including unrousable coma);Prostration, i.e. generalized weakness so that the patient is unable to sit, stand or walk without assistance.Multiple convulsions: more than two episodes within 24 h;Acute pulmonary oedema and acute respiratory distress syndrome.Circulatory collapse or shock, systolic blood pressure.Clinical jaundice plus evidence of other vital organ dysfunction.Abnormal bleeding.Haemoglobinuria (dark urine or coca cola);Laboratory findings.Hypoglycaemia (< 2.2 mmol/l or < 40 mg/dl);Severe anaemia (haemoglobin < 5 g/dl).Danger signs as per NMCP guidelines.Incoercible vomiting.Lethargy.Inability to drink or suck.Data were entered into a MS ACCESS database and analysed using STATA software . Analysis included all paediatric admissions meeting the study eligibility criteria. Frequency were used for qualitative data and mean or geometric for quantitative data. The Clopper–Pearson method was used for calculating binomial confidence intervals. For computing the case fatality rates (CFR), only individuals with known in hospital outcome were included. Multivariable regression analysis was done to assess association between clinical features and transmission intensity. The significance level was set at P < 0.05.The study protocol and associated documents were reviewed and approved by CNRFP institutional bioethics committee , the Ministry of Health Ethical Committee for Biomedical Research . All study participants’ parents or legal representatives gave documented informed consent before any study procedures were performed. The study was conducted according to the principles of the declaration of Helsinki and International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines.Characteristics of enrolled children are presented in Table The mean time of illness before hospital admission was 3.0 days (95% CI 2.7–3.4) and 4.0 days (95% CI 3.5–4.5) in the LMT and the HMT areas, respectively. A high proportion of children admitted (38.4%) had also received a beta lactam antibiotic prior to hospital admission. There was a statistically significant difference between the HMT and LMT areas . Antibiotics administered include ceftriaxone (59.2%); ampicillin (29.6%) and amoxicillin (8.5%). Overall, almost half (43.1%) of children who had received an antimalarial were also given an antibiotic.The age of recruited children was 33.9 (± 1.3) and 36.8 (± 1.6) months in respectively LMT and HMT areas (p = 0.15)). For children enrolled with convulsions, the mean age was 29.5 months in LMT area compared to 38.3 in the HMT area. The difference was statistically significant.P. falciparum density was significantly higher in the LMT area compared to the HMT area . In total 58 (6.3%) of enrolled cases were harbouring P. falciparum gametocytes. The proportion of patients with gametocytaemia were 4.9% and 7.9% in LMT and HMT areas (p = 0.06), respectively. The geometric mean of gametocytes density was 44.7 gametocytes/µL (95% CI 25.4–78.7) and 81.3 gametocytes/µL (95%CI 52.2–126.5) in the LMT and HMT areas, respectively.The geometric mean of asexual Clinical presentation and overlap between the top three predominant syndromes are presented in Fig. The mean haemoglobin level was 5.7 (± 2.7) g/dL in study participants. Severe anaemia was present in 448 children (49.2%). On admission, other clinical features recorded included 8 cases (0.9%) of abnormal bleeding (epistaxis), 11 (1.2%) cases of circulatory collapse/shock, 80 (8.9%) patients with haemoglobinuria, 99 (10.7%) children with incoercible vomiting, 184 (19.9%) cases of lethargy, 37 (4.0%) children unable to drink/suck and 385 (41.8%) children with prostration. Among those with haemoglobinuria, only 7 (13.9%) have reported Quinine intake during the episode. The mean glucose level was 5.8 mmol/l (± 2.8). Severe hypoglycaemia was present in 43 (4.8%) children. The proportions of children presenting with one (01), two (02), three or more (≥ 3) severe features were 48.8%, 33.2% and 18.0%, respectively.Children living in the HMT area tend to present with three or more severe features compared to those from the LMT area . The association between clinical presentation and malaria endemicity is presented in Table Table This study investigated the burden of severe malaria in two hospitals located in two areas with different malaria transmission covered by same malaria control strategies as deployed the country NMCP.The predominant clinical presentations were anaemia (49.2%) and convulsions (21.8%); almost at the same level as reported in Burkina more than 20 years before by Modiano et al. . This isP. falciparum infection and prevalence of malaria-related anaemia [SMC consists of 4 rounds of administration of sulfadoxine/pyrimethamine + Amodiaquine given at intervals of one month to children aged between 3 and 59 months during the peak transmission season (July to October). This strategy has been shown to drastically reduce incidence of uncomplicated and severe malaria due to  anaemia –14 in ch anaemia , 16. In  anaemia . The preP. falciparum erythrocyte membrane protein 1 (PfEMP1) specific immunity which has been described to play a significant role in the susceptibility to CM [The odds of presenting with coma was significantly higher in children living in the higher malaria transmission area compared to those in lower malaria transmission area. This finding is in line with the inversely correlated geometric mean parasite. These findings corroborate previous report from Uganda , but arety to CM .Shock/dehydration was the second clinical presentation more observed in HMT area compared to LMT area (adjusted OR = 5.3 (1.1–24.6)). There are many potential causes of hypotension or shock in severe malaria. These include secondary bacterial sepsis, dehydration from vomiting or fever, haemorrhage from gastrointestinal bleeding, splenic rupture, and cardiac dysfunction. This was an unexpected finding which calls for further investigations to understand the potential causes of the difference if confirmed.P. falciparum-endemic areas who took quinine, the glucose-6-phosphate dehydrogenase (G6PD) deficiency have been described as potential causes of haemoglobinuria. Occurrence of haemoglobinuria have also been described in patients with normal erythrocyte G6PD activity who were administered quinine for severe malaria [Haemoglobinuria was one of the clinical syndromes significantly associated with the transmission intensity. The odds of presenting with haemoglobinuria was almost 3 times in HMT area although the overall incidence was similar to what was reported elsewhere in west Africa . A numbe malaria , 24. How malaria . Another malaria , 27. In The overall CFR recorded in this study is relatively high (5.0%) but remains within findings reported elsewhere –17, 28. More than half (51.4%) of cases referred by peripheral health clinics, who were admitted and managed as severe malaria cases based on HRP2 RDT results turned out to be negative by microscopy probably due to the high proportion (44.6%) among them who had received pre-referral anti-malarial treatment or alternatively to the low specificity of the HRP2 based RDT in our geographical context , 30, 31.In two areas of Burkina Faso with different ecology of malaria transmission, hospital-based surveillance of severe malaria clinical presentations has shown that children in the HMT are more significantly at risk of presenting with coma, prostration, shock/dehydration, haemoglobinuria, hypoglycaemia, and respiratory distress. Case-fatality rates are high among patients with respiratory distress and those with hypoglycaemia. Most of the deaths have occurred in children aged less than five years. Hospital surveillance provides a reliable and sustainable means to monitor the clinical presentations and lethality of severe and tailor the training needs for health workers at the frontline of cases management in different transmission patterns.


Soft tissue sarcoma (STS) is a malignant tumor of highly heterogeneous mesenchymal origin. STS has a biological pattern and clinical transformation with localized invasive growth and is susceptible to hematogenous metastasis. Local therapeutic strategies may treat recurrent and oligometastatic STS, including surgery and radiation therapy. This study aimed to evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for recurrent and oligometastatic STS.We retrospectively analyzed 37 recurrent and oligometastatic STS patients with 58 lesions treated with SBRT from 2009 to 2019 at our institution. Oligometastatic is defined as metastatic lesions less than or equal to 3. The primary endpoint was local control (LC); secondary endpoints were survival and toxicity.The median follow-up was 21.0 months (3.0 to 125.0 months). Among 37 patients, 18 were recurrent patients, and 19 were oligometastatic patients. Median LC was 25.0 months (95% CI 20.0–45.0). The 1-, 2-, and 3-year LC rates were 80.2%, 58.3%, and 46.6%, respectively. Median overall survival (OS) was 24.0 months (95% CI 13.0–28.0), and the survival rates after SBRT were 71.5%, 40.0%, and 29.1% at 1, 2, and 3-year, respectively. Median progression-free survival (PFS) was 10.0 months (95% CI 8.0–15.0 months), PFS rate after SBRT was 43.6%, 26.8%, and 18.4% at 1, 2, and 3 years, respectively. Late grade 3 radiation dermatitis was observed in one patient (2.7%). Using univariate and multivariate COX analysis, better OS, PFS, and LC were obtained in the histologic grade 1(G1) group, and tumor size and a number of lesions influenced LC.SBRT is a safe and effective treatment for patients with recurrent and oligometastatic STS. Histological grade influences local control and survival. SBRT may be a promising treatment option for recurrent and oligometastatic STS. Sarcomas are a rare and heterogeneous group of tumors, a general term for a class of solid mesenchymal tumors. In 2021, it was estimated that in the USA 13,460 people were diagnosed with STS and 5350 died [SBRT uses rigid fixation, advanced image guidance, and complex treatment planning and delivery systems, resulting in a highly conformal dose distribution that reduces treatment volume relative to conventional radiotherapy. This, in turn, allows each fraction to deliver large doses of radiation and increase the BED compared to the traditional treatments . It playThus, theoretically, SBRT may be an attractive alternative to surgical resection, conventional radiotherapy or other palliative measures in certain patients with metastatic or recurrent soft tissue sarcoma. In the current study, we report our early institutional experience with SBRT in patients with recurrent and oligometastatic STS.We retrospectively searched our patient database for patients who received SBRT at the Radiotherapy Center of Jinling Hospital between December 2009 and December 2019. Inclusion criteria included the diagnosis of STS; experienced recurrence (defined as tumor recurrence at a site previously treated for a STS) after surgery or oligometastatic (defined as a condition characterized by a progression in a maximum of 3 metastatic sites). Exclusion criteria included patients with multiple metastases. This study was approved by the ethics committee of hospital. Medical records have been assessed for eligibility.SBRT used the Cyber-Knife Radiation Therapy System . The CK can use the human skeleton, gold fiducials as a reference and monitor the target areas of the patient’s body in real time during treatment, for moving organs . Six-dimensional cranial tracking is used for intracranial, head, and neck tumors, while the “X-ray spine” tracking method is used for spinal metastases. Moving organs can implant one to three gold fiducials inside or near the tumor. One week after fiducial placement, CT simulation was performed for treatment planning .The PTV was obtained by isotropic expansion of 2–7 mm around the macroscopic lesion  outlined on a 1.0 mm thick simulated CT scan. The dose was opened to the outer line of the PTV and 75–85% isodose line. We gave the prescription dose according to the grading and the location of the lesion. The total dose of SBRT ranged from 30 to 75 Gy over a period of 2 to 10 days. A linear-quadratic model was used for dose equivalence, assuming α/β = 10 Gy for the tumor. The median BED was 85.5 Gy, ranging from 51.3 to 187.5 Gy. Treatment planning was based on each patient’s status, tumor size, pathological type, and lesion’s location. Dosimetric indices for the 58 lesions during SBRT are listed in Table Efficacy was assessed using the revised solid tumor response assessment criteria  . ClinicaLocal failure (LF) was defined as a minimum 20% increase in the diameter of the treated volume. The local control rate was calculated for 58 lesions from the start of radiotherapy to LF or last follow-up. OS was measured from the start of radiotherapy to death from any cause or the last follow-up visit. The PFS was calculated from the start of radiotherapy until disease progression or death. Acute toxicity and late toxicity  were assessed using the Common Terminology Criteria for Adverse Events .P values < 0.05 considered significant. Statistical analysis was performed using SPSS software, version 22.0  and MedCalc software, version 19.6.The LC and OS curves were estimated by Kaplan-Meier analysis and were compared using the log-rank test. The influence of variables on LC and survival was investigated using univariate analysis (Cox model). These significant variables in univariate analysis and covariates considered clinically influential were then analyzed by multivariate cox regression to identify significant variables. Cox proportional hazard survival regression was used for the multivariable analyses of histological grade association with LC outcomes. Histological grade lesions size and disease setting (recurrent and oligometastatic) were selected for the models. For all analyses, two-sided tests of significance were used with We reviewed a total of 68 patients with recurrent and oligometastatic who were treated with SBRT between December 2009 and December 2019 at the Radiotherapy Center of Jinling Hospital. We excluded patients with multiple metastases, unclear pathological type or imaging data and incomplete treatment plans. Finally, 37 patients who could not or refused surgery due to difficulty of reoperation, low patient willingness, and underlying diseases with 58 lesions who completed SBRT were enrolled in our study   . Multivariate analysis showed that histological grade, and lesions size also influenced LC . Overall, the 1-, 2-, and 3-year LC rates were 80.2%, 58.3%, and 46.6%., respectively. The LC of the recurrent and oligometastatic STS is shown in Fig. p = 0.016), histological grade (p = 0.0001) and the number of lesions at the time of first SBRT (p = 0.028) (Table The median OS was 24 months (95% CI 13.0–28.0 months). The 1-, 2-, and 3-year OS rates were 71.5%, 40.0%, and 29.1%, respectively. A Kaplan-Meier plot for OS is shown in Fig. p = 0.003), histological grade (p = 0.0001), and number of lesions at the time of first SBRT (p = 0.009) were significant factors for PFS (Table p = 0.003) was significant factor for PFS (Table The median PFS was 10.0 months (95% CI 8.0–15.0 months). The 1-, 2-, and 3-year PFS rates were 43.6%, 26.8%, and 18.4%, respectively . Acute grade 2 radiation pneumonitis occurred in one patient (2.7%), and acute grade 1–2 radiation enteritis was observed in two patients (2.7%). Late grade 3 radiation dermatitis was observed in one patient (2.7%) 6 months after SBRT.STS are rare and heterogeneous mesenchymal neoplasms, with more 70 histological subtypes . 40 to 5p = 0.017) [p = 0.001) [SBRT has been increasingly used for patients with tumors that are not candidates for surgery in recent years. For instance, it is now the standard treatment option for early-stage inoperable non-small cell lung cancer due to its superior efficacy . Good re= 0.017) . A recen= 0.001) , 20. In = 0.001) . For pat= 0.001) . In resp= 0.001)  study sh10 (range 60–150). Rates of LC were 84% at 2 years and 78% at 4 years. On univariate analysis, only the first relapse within 24 months was significantly correlated with reduced local control (p = 0.022), and no mention of the impact of EQD2 on LC. Stragliotto CL et al. [p = 0.018). The study includes STS and other osteosarcomas, all in patients with metastases, including oligometastases and multiple metastases. The most frequent pathological staging in STS was leiomyosarcoma, with lung metastases being the most common (97/136), and OS, PFS, and LC results were comparable to this study. Moureau-Zabotto et al. reported on 83 patients with first local recurrences, of whom 38 patients received surgery alone, 25 surgery and additional RT without prior RT, and 20 surgery with reirradiation mainly via brachytherapy to cumulative doses of 95–115 Gy. Local control after a median follow-up of 59 months was significantly improved by additional RT (64% vs. 45%) with an overall 5-year OS of 54% [Current studies on the role of radiotherapy in STS focused on local recurrences and oligometastatic lesions. Loi M et al.  reportedL et al.  reportedBased on common sense speculation, the relevant factors affecting the efficacy of SBRT may be tumor size, prescribed dose, and histology. The prognosis of STS is inferred by the interaction of multiple factors, including varying characteristics of the patient, varying characteristics of tumorigenesis and presentation and specificity of the different modalities, sequences, and combinations of combination therapy , 26. TheThere are several limitations to the current study. First, the number of cases in this study is small. Second, we did not analyze the effect of different pathological types on local control. Moreover, as a retrospective study of patients treated over a long period of time, selection bias cannot be excluded. Due to the rarity of the disease, a multicenter, clinically controlled study is necessary.SBRT is a safe and effective treatment for recurrent and oligometastatic STS and may be a promising treatment strategy for patients who are difficult to operate for various reasons. Patients with histologic G1 may have better local control and survival than those with histologic G2 and G3. Further research in multicenter prospective studies is needed.


The identification and mapping of at-risk populations at a lower administrative level than the district are prerequisites for the planning, resource allocation and design of impactful control intervention measures. Thus, the objective of the current study was to conduct sub-district precision mapping of soil-transmitted helminthiasis (STH) and schistosomiasis in 29 districts of north-western Tanzania using the current recommended World Health Organization criteria.Schistosoma haematobium eggs, whereas quantification of Schistosoma mansoni and STH eggs was done using the Kato–Katz technique. Microhaematuria was examined using a urine dipstick.A cross-sectional survey was conducted in 145 schools between March and May 2021. A urine filtration technique was used for the quantification of S. mansoni was 8.7% (95%CI 8.1–9.3), and 36.4%, 41.6%, and 21.9% of the children had low, moderate, and heavy infections, respectively. The overall prevalence of S. haematobium was 6.1% (95%CI 5.5–6.5), and 71.7% and 28.3% of the infected children had light and heavy intensity infections, respectively. The prevalence of microhaematuria was 7.3% (95%CI 6.7–7.8), with males having the highest prevalence . The prevalences of Trichuris trichiura, Ascaris lumbricoides and hookworm were, respectively, 1.3% (95%CI 0.1–1.5), 2.9% (95%CI 2.5–3.3) and 6.2% (95%CI 5.7–6.7). Most of the children infected with STH had light to moderate intensities of infection. The overall prevalence of co-infection with STH and schistosomiasis was 19.1%. The prevalence of schistosomiasis (P < 00.1) and STH (P < 0.001) varied significantly between schools and sub-districts. Schistosoma mansoni and S. haematobium were observed in 60 and 71 schools, respectively, whereas any STH was observed in 49 schools. In schools where schistosomiasis was observed, prevalence was < 10% in 90.8% of them, and ranged from ≥ 10% to < 50% in the other 9.2%. In schools where any STH was observed, the prevalence was < 10% in 87.7% of them.The overall prevalences of any STH and schistosome infections were 9.3% [95% confidence interval (95%CI) 8.6–9.9] and 14.6% (95%CI 13.9–15.4), respectively. The overall prevalence of The data reported here show that schistosomiasis and STH are widely distributed around Lake Victoria. In most of the schools where schistosomiasis and STH occurred the transmission thresholds were low. These data are important and need to be taken into consideration when decisions are made on the implementation of the next round of mass chemotherapies for schistosomiasis and STH in Tanzania.The online version contains supplementary material available at 10.1186/s13071-022-05547-6. Schistosoma haematobium and Schistosoma mansoni, respectively, are endemic at varying transmission levels in all administrative regions and districts , with prevalence higher for male than female participants . However, the prevalence of the S. mansoni infection did not differ by age group (P = 0.48) . No difference in mean eggs per gram of faeces was observed by age group . In total, 36.4%, 41.6% and 21.9% of the SAC infected by S. mansoni had light, moderate and heavy intensity infections, respectively.The overall prevalence of S. haematobium was 6.1% (95%CI 5.5–6.5). Male participants had the highest prevalence  . The overall geometric mean eggs/10 ml of urine was 19.05 eggs/10 ml (95%CI 16.7–21.6). Male participants had the highest geometric mean eggs/10 ml . Similar to prevalence of S. haematobium, the oldest age group (11–13 years) had a higher geometric mean eggs/10 ml of urine than the younger age group (9–10 years) . Overall, 71.7% and 28.3% of the participants had light and heavy intensity infections, respectively. The overall prevalence of microhaematuria was 7.3% (95%CI 6.7–7.8), with males having a higher prevalence than females .The overall prevalence of P = 0.2) . The overall geometric mean eggs per gram of faeces was 153.7 epg (95%CI 129.2–182.9), with no statistically significant difference between age groups  or sexes . In total, 98.7% and 1.3% of the SAC had light and moderate intensities of infection, respectively.The overall prevalence of hookworms was 6.2% (95%CI 5.6–6.6). There was no difference in prevalence according to sex  (Table P = 0.4). However, the youngest age group, 9–10 years, had the highest prevalence of A. lumbricoides . The geometric mean eggs per gram of faeces was 670.2 epg (95%CI 555.8–808.2). The youngest age group (9–10 years) had the highest geometric mean eggs per gram of faeces . In total, 92.4% and 7.6% of the participants had light and moderate ascaris infection intensities, respectively.The overall prevalence of T. trichiura was 1.3% (95%CI 0.1–1.5) (Table P = 0.012). The overall geometric mean per gram of faeces was 143.5 epg (95%CI 11.98–171.8), with no statistically significant difference between age groups  or males and females . Most participants had low intensity infections (97.4%), while only 0.8% had moderate and 1.6% heavy intensity infections.The overall prevalence of 5) Table , and theS. haematobium and S. mansoni) and the overall combined prevalence of STH species  stratified by gender and district. The overall combined prevalence of schistosomiasis was 14.6% (95%CI 13.9–15.4) and ranged from 0 to 53%; males (16.2%) had the highest prevalence  (P < 0.001). Significant differences in prevalence of schistosomiasis were noted between districts (P < 0.001), wards/sub-districts (P < 0.001) and schools (P < 0.001). Ukerewe district had the highest prevalence of schistosomiasis (53%) of all the districts. Schistosoma mansoni was common in Kigoma, Mwanza and Mara regions, whereas S. haematobium was common in Simiyu and Shinyanga regions.Table P = 0.56). STH were common in Kagera region and Kigoma region. Hookworm was also common in dry areas of Simiyu region and Shinyanga region.The overall prevalence of any STH infection was 9.3% (95%CI 8.6–9.9), with no statistically significant difference between females and males  occurred in all the regions of north-western Tanzania examined here. Schistosoma mansoni was observed to be endemic in districts bordering Lake Victoria to the south, west and east, and on an island in the lake. It was also endemic in a district bordering Lake Tanganyika and was found in schools/sub-districts located close to water bodies away from the lake. Schistosoma mansoni was a lesser problem in districts located beyond the shorelines of the large water bodies, particularly Lake Victoria and Lake Tanganyika, with prevalence declining as the distance from the lake basins increased; these results generally corroborate the findings of previous surveys [This study reports the distribution of schistosomiasis and STH prevalence in 29 districts of north-western Tanzania. At least one of the forms of schistosomiasis  mass preventive chemotherapy should continue at the same frequency and be reduced at the interruption of transmission, and (ii) in areas that do not have access to mass preventive chemotherapy, a test-and-treat approach should be used instead [The geographical prevalences of schistosomiasis and STH in the current study have several implications for MDA in terms of planning, implementation, and evaluation with the aim of shrinking the schistosomiasis and STH map in Tanzania. The WHO have set criteria for schistosomiasis prevalence and morbidity control , with annt views . To reacnt views . For combidities . For com instead . To ensu instead . However instead . Environ instead . Several instead .T. trichiura and A. lumbricoides of < 1%, indicating that Tanzania is moving towards achieving WHO goals in eliminating STH as a public health problem [Similarly, STH are targeted for elimination as a public health problem by 2030, defined by the WHO  in their problem . However problem . As STH  problem , integra problem . Thus, tBased on the WHO criteria, the majority of the school/sub-districts included in the precision mapping survey had low prevalences (< 10%) for schistosomiasis and STH (< 20%) and moderate prevalences for schistosomiasis (between 10 and 49%) and STH (between ≥ 20% and 50%) in transmission areas. Thus, according to WHO recommendations, most of the schools located in these areas with moderate endemicity will require either a single annual round or a single round of treatment once every 2 years of ALB and PZQ. On the other hand, schools located in areas with low endemicity may not need annual MDA, but instead a single round of MDA every 2 years. To significantly reduce prevalence and interrupt transmission in areas classified as moderate risk it is important to intensify intervention measures in these areas in the future. Alternatively, a well-focused treatment strategy needs to be designed that is focused on schools/sub-districts in areas classified as moderate risk, instead of implementing the current approach which includes treatment in every school. However, for informed decision-making, the mapping of schistosomiasis and STH in all schools in an implementation unit (district or ward) is recommended.The parasitological results used to define the prevalences and intensities of infection were based on single urine and stool samples collected from the study participants. This may have led to the underestimation of the true prevalences and intensities of infections. In addition, the sampling strategy mainly targeted schistosomiasis, which may have resulted in the underestimation of the prevalence of STH. The cross-sectional nature of the study design meant that data on causality could not be collected. However, using this design we were able to describe the prevalence and intensities of the targeted infections. Despite these limitations, the findings reported here allow for the following conclusions and recommendations to be made.The present study provides data on the geographical distribution of schistosomiasis and STH, their co-endemicity, and prevalences at different levels of intensities of infection with any schistosome or STH species in 29 districts across six regions of north-western Tanzania. Current MDA strategies can be reviewed and updated on the basis of these results. As some areas no longer require MDA, scarce resources can be saved. A focused MDA strategy targeting schools/sub-districts where the prevalence of schistosomiasis and STH is ≥ 10% and ≥ 15%, respectively, as shown here, would support Tanzania’s control and elimination goals. To achieve these elimination goals, complementary/supplementary strategies including health education and the provision of safe water and adequate sanitary facilities should be implemented concurrently.Additional file 1: Additional Tables S1–S58.Figure S1. Geographical locations of schools included in the precision mapping in five districts of Simiyu region, north-western Tanzania. Figure S2. Geographical locations of schools included in the precision mapping in three districts of Mwanza region, north-western Tanzania. Figure S3. Geographical locations of schools included in the precision mapping in four districts of Kigoma region, western Tanzania. Figure S4. Geographical locations of schools included in the precision mapping in five districts of Shinyanga region, north-western Tanzania. Figure S5. Geographical locations of schools included in the precision mapping in five districts of Mara region, north-western Tanzania. Figure S6. Geographical locations of schools included in the precision mapping in five districts of Kagera region, north-western Tanzania.


Heart neoplasms are rare tumors. Myxoma is the commonest primary benign tumor of the heart presenting with features of obstruction, arrhythmia, and embolism. Surgical excision of the tumor is the gold standard of treatment. The aim of the study is to find out the prevalence of cardiac myxoma among all cardiac surgeries operated during the study period.A descriptive cross-sectional study was done among 3800 patients undergoing surgery for cardiac tumors in a tertiary care center after obtaining approval from the Institutional Review Committee (Reference number- 36/(6-11)E2/077/078). The data was collected retrospectively from August 2012 to August 2020 using convenience sampling method. Statistical analysis was performed using Microsoft Excel 2016. Point estimate at 95% Confidence Interval was calculated along with frequency, percentage, mean and standard deviation.There were 26 (0.68%)  myxoma among 3800 cardiac surgeries performed over eight years. The mean age of the patients was 54.76±14.31 (range 17-75) years. Twenty (76.92%) patients were females. The commonest presenting symptom was shortness of breath in 19 (73.07%) patients. En masse excision with the closure of the atrial septal defect was the principal surgical technique. The mean Intensive Care Unit stay and hospital stays were 2.92±1.29 and 6.26±2.61 days respectively. There was no perioperative mortality.Cardiac myxoma was the most common cardiac tumor encountered as in other studies. This study is intended to find out the prevalence of cardiac myxoma among all cardiac tumors operated in our center during the study period.2/077/078). Convenience sampling technique was used and sample size was calculated according to the formula:This was a descriptive cross-sectional study conducted in the Department of Cardiothoracic Vascular Surgery in Manmohan Cardiothoracic Vascular and Transplant Center, Maharajgunj, Kathmandu, Nepal. The data was collected retrospectively from August 2012 to August 2020 through medical records. Ethical approval was obtained from the Institutional Review Committee (IRC) of Institute of Medicine (Reference number: 36/ (6-11)E2 × p × q / e2n = Z2 × 0.5 × (1-0.5) / (0.02)2  = (1.96)  = 2401Where,n = minimum required sample sizeZ = 1.96 at 95% of Confidence Interval (CI)p = prevalence taken as 50 % for maximum sample sizeq = 1-pe = margin of error, 2%Adding a 10% non-response rate, the calculated sample size was 2641. However, 3800 cases were taken.Data collected from patient files included patient characteristics-age, gender, New York Heart Association (NYHA) class, presentation of cardiac tumors, intraoperative tumor size, cardiopulmonary bypass time, aortic cross-clamp time, postoperative hours of ventilation, mediastinal drainage, postoperative complications, duration of hospital and Intensive Care Unit (ICU) stay, histopathology of a tumor, in-hospital and long-term survival. Long-term survival was studied by reviewing the follow-up record and telephonic interview.Data were recorded and descriptive statistics like frequency, percentage, mean and standard deviaton were calculated using Microsoft Excel 2016. Point estimate at 95% Confidence Interval was also calculated.Among 3800 cardiac surgeries, 26 (0.68%)  were performed for cardiac myxoma. The mean age of the patients with myxoma was 54.76±14.31 years (range 17-75). Eleven (42.30%) of the patients were in the 50-59 years group. The majority of the patients were females, with a female to male ratio of 3.3:1. The mean duration of symptoms was 119.84±134.11 days. Two cases were diagnosed incidentally while being worked up for hypertension. The presenting symptoms were shortness of breath, palpitation, cough, anorexia with weight loss, and features of embolism . Only siAll the patients with myxoma underwent complete excision of the tumor. A separate right and left atriotomy  was the most commonly employed approach . A totalThe majority of the patients were extubated the same day, had insignificant mediastinal drainage and stayed in ICU and hospital for an average period of 2.92±1.29 and 6.26±2.61 days respectively . Seven . One patThe patients followed up for a mean period of 1.49 years (range 7 days to 6.5 years). A review of medical records and telephonic interviews identified five late deaths.9 The incidence of cardiac myxoma is 0.3% in patients undergoing on-pump cardiac surgeries.10 Cardiac myxoma excision contributed to 0.68% of cardiac surgeries in our centre. Of the primary cardiac tumors, cardiac myxoma were 92.85% and 7.14% were malignant tumors. The majority of the patients, 20 (76.92%) with myxoma were females and the mean age was found to be 54.76±14.31 years. In a study by Mandal sc, et al. the female to male ratio of myxoma occurrence ratio was 1.9:1 and (43%) of patients were in the 4th to 5th decade of life.11 The mean age of the patients was 55 years (range 22-79 years) in a study by Keeling IM, et al.9 The mean duration of onset of symptoms to diagnosis was 119.84±134.11 in our population.In our study 89% of surgically treated cardiac tumors was myxoma similar to Keeling IM, et al. who found that 86% of surgically treated cardiac tumors were cardiac myxomas.12 Two (7.69%) patients had a preoperative stroke and two (7.69%) had femoral artery embolism in our center. In another study from Pakistan, 50% of patients had neurological symptoms at presentation including stroke and transient ischemic attack, and 14% had limb ischemia secondary to embolism.13 Similarly preoperative atrial fibrillation was seen in 3.84% in our study. Cianciulli TF, et al. found 9.3% patients had atrial fibrillation.5 Similar to our findings, 82.4%-86.6% of the myxoma was located in the left atrium attached to the interatrial septum.14 Protrusion of the tumor through the mitral/ tricuspid valve can give rise to symptoms of valvular obstruction, increased pulmonary artery pressure, and tricuspid regurgitation. Fourteen (53.84%) of our patients had myxoma protrusion through the mitral valve whereas eight (30.76%) patients had varying grades of tricuspid insufficiency.The most common presenting complaint of the patients included shortness of breath followed by palpitation and 16 (61.52%) patients were in NYHA class II, in our study which is similar to that reported in other studies. Fifty-one percent 51.0% presented with dyspnea and 65.78% were in NYHA Class II.2 All our patients underwent median sternotomy. The tumor size ranged from 2cm to 8cm, with a mean size of 4.13±1.39cm. The majority of the tumors 53.84% were broad-based. Tumor size ranged from 1cm to 12cm and 67.6% to 85.48% of the tumors were pedunculated in other studies.15 Complete excision of the tumor is of utmost importance in managing cardiac tumors. Hence the commonest approach for left atrial myxoma excision was the bicameral approach in 22 (84.61%) patients. 21 (80.79%) of our patients underwent en masse excision of the tumor and 13 (50%) underwent excision of the tumor along with a portion of the interatrial septum and the defect closure with an autologous pericardial patch. Similar approaches and techniques were followed by other surgeons.16 Various studies have shown patients with myxoma excision may need concomitant procedures like mitral valve and tricuspid valve repair or replacements, coronary artery bypass grafting.16 Tricuspid repair was done by Kay's annuloplasty in one patient and ring annuloplasty in another patient. One patient underwent mitral valve replacement with excision of the tumor and another patient underwent coronary artery bypass grafting to a distal right coronary artery. The mean cardiopulmonary bypass time and aortic cross-clamp time were found to be 46.19±18.19 minutes and 30.46±14.52 minutes in our study. However longer mean cardiopulmonary bypass time (80.7±39.0 minutes) and mean aortic cross-clamping time (51.3±27.5 minutes) have also been reported.17Various operative approaches to myxoma excision have been described in literature like minimally invasive, endoscopic, and robotically-assisted techniques, however, median sternotomy remains the most commonly performed one.The postoperative duration of ventilation was 7.91±6.27 hours in our patients. The mean mediastinal drainage was 272.50±192.66ml and the drains were placed for a mean duration of 1.57±0.64 days. However, packed cells transfusion was required in two patients only. One patient had hemiparesis; seven patients had arrhythmia in the post-operative period. Two patients had supraventricular tachycardia, two had atrial fibrillation with fast ventricular rate, managed by chemical cardioversion and two patients had ventricular fibrillation requiring electrical cardioversion. One patient had a run of ventricular tachycardia abolished by Lidocaine. One patient with postoperative cardiac failure with renal impairment responded well to medical management and three sessions of dialysis. None of the patients had re-exploration for bleeding or tamponade, sepsis, and surgical site infection.The mean postoperative intensive care unit stay and hospital stays were 2.92±1.29 days and 6.26±2.61 days respectively. In the hospital, perioperative mortality was not seen. Most of our patients were from remote areas and hence most of them did not follow up for a long period. The mean follow-up period was 1.49 years. Long-term survival was seen in 21 (80.76%) patients. There were two late in-hospital mortalities. One patient presented to the Emergency room with acute right lower limb ischemia of 24 hours duration and cardiac failure, one year after myxoma excision. The echocardiographic evaluation revealed recurrence of left atrial myxomatous tumor approximately 2cm in size. However, the patient crashed in an emergency and succumbed to the disease before she could be shifted to the operating theatre. Another patient had expired following tricuspid valve replacement for severe tricuspid regurgitation, three years after right atrial myxoma excision. In a telephonic interview, it was found that three patients (above 72 years of age) died at home.12 In a Greek study of 153 patients, the mean ICU stay and hospital stay were 2.0±0.9 days and 8.02±2.8 days respectively. Postoperatively, atrial fibrillation was seen in 5.9%, permanent pacemaker insertion was required in 5.2% and in-hospital mortality due to sepsis was 0.7%. Recurrence was found in 3.3% of patients in a mean follow-up of 3.7±4.3 years.14In a study from India, 7.89% of patients had supraventricular arrhythmias, 5.26% of patients had an atrioventricular block requiring temporary pacing and the early death rate was 5.88%. 15.78% of patients were lost to follow-up. There were no late deaths and recurrence.The limitations of the study were that the small sample size and it was a single-center study.Cardiac myxoma was the most common cardiac tumor in our study as in other published studies performed. Proper diagnosis and management of cardiac myxoma could result in complete and safe excision with low perioperative morbidity and mortality.


The saline groundwater level of many supratidal wetlands is rising, which is expected to continue into the future because of sea level rise by the changing climate. Plant persistence strategies are increasingly important in the face of changing climate. However, the response of seed persistence to increasing groundwater level and salinity conditions is poorly understood despite its importance for the continuous regeneration of plant populations. Here, we determined the initial seed germinability and viability of seven species from supratidal wetlands in the Yellow River Delta and then stored the seeds for 90 days. The storage treatments consisted of two factors: groundwater level (to maintain moist and saturated conditions) and groundwater salinity . After retrieval from experimental storage, seed persistence was assessed. We verified that the annuals showed greater seed persistence than the perennials in the supratidal wetlands. Overall, seed persistence was greater after storage in saturated conditions than moist conditions. Salinity positively affected seed persistence under moist conditions. Surprisingly, we also found that higher groundwater salinity was associated with faster germination speed after storage. These results indicate that, once dispersed into habitats with high groundwater levels and high groundwater salinity in supratidal wetlands, many species of seeds may not germinate but maintain viability for some amount of time to respond to climate change. Persistent seeds, as an important component in the soil seed bank, can represent a reserve of genetic potential that accumulates over time . Thus, tCoastal vegetation usually exhibits zonation patterns along an environmental gradient caused by the interaction of land and sea . SupratiThe ability of mature seeds to remain viable on the parent plant or on/in the soil referred to as seed persistence . To somePolygonum aviculare seeds were induced into dormancy by exposure to low moisture conditions . We used a factorial design with four replicates to test the effects of different groundwater levels and groundwater salinity on seed persistence of seven species. There were two groundwater levels  and four groundwater salinity levels .We simulated soil with quartz sand to eliminate the interference of physical and chemical factors. We added 400 g sterile quartz sand  in each 520-mL plastic tissue culture flask and drilled 32 small holes in the body and bottom of the flask. We put each plastic tissue culture flask into matching 1000-mL plastic bowl to simulate different groundwater levels by adding different amounts of water in plastic bowls. In addition, to test the effects of dry storage on seed persistence, seeds were also stored in dry quartz sand without any water storage treatment. The experimental device is shown in P. australis; 76.7 ± 3.0% and 79.7 ± 2.9% for S. salsa; 72.5 ± 3.9% and 76.7 ± 2.4% for C. chinense; 64.2 ± 1.6% and 72.5 ± 4.3% for C. album; 5.0 ± 1.0% and 47.5 ± 1.6% for A. venetum; 0.8 ± 0.8% and 61.7 ± 6.3% for I. cylindrica; and 5.0 ± 2.2% and 80.8 ± 1.0% for L. latifolium, respectively). We put 50 seeds of each species into small packets made of polyamide fabrics with 1-mm mesh width. After being tagged by colored clips, the seed packets were buried 1.5-cm below the top of the quartz sand in each tissue culture flask and stored in the different treatments for 90 days. To decrease the possible effect of strong light on germination, all devices were kept in the shade (20–30 μmol m–2s–1).Before storage, some seeds were used to determine the initial germination and viability percentages as a baseline for comparison  and 100% acetone. The samples were then placed overnight in labeled molds that were filled with 100% Spurr’s medium. The samples were vertically sectioned on a ultramicrotome  at 90 nm and then examined with a Hitachi SU8010 field-emission SEM .In addition, we selected the seeds with sharp changes in viability percentage to study the changes of seed internal morphological features. The seeds were fixed in 2.5% glutaraldehyde at room temperature for 2 h for subsequent analysis with a scanning electron microscope (SEM). After an extensive rinse with precooled phosphate buffer (pH 7.0), the samples were post-fixed in 1% OsOWe analyzed the germination percentage (GP), viability percentage (VP), dormancy percentage (DP), and mean germination time (MGT) of seeds after storages. We used the term “germinability” to represent the ability of seeds to germinate after storages under the lab culture conditions. Germinability was inferred based on the germinability index (GI), which represents the rate of germination conservation. We also used the viability index (VI), which represented the rate of viability conservation, to infer seed persistence based on the ability of seeds to maintain viability under storage conditions. The indexes were calculated as follows:where Nt represents the number of germinated seeds on day t and Dt represents the corresponding number of days.T-tests were used to examine the differences of seed GI and VI between the annual and perennial species, and the effects of groundwater level on GI and VI for each species. One-way ANOVA was used to examine the differences of GI and VI among treatments in each group . Group abbreviations are based on groundwater level and groundwater salinity of each set of conditions. For groundwater level, W0 indicates no water, W1 indicates low groundwater level, and W2 indicates high groundwater level. For groundwater salinity, S0 indicates no added salt; S1 indicates 10 g/L; S2 indicates 20 g/L, and S3 indicates 30 g/L. Tukey HSD tests were used for multiple comparisons when the data satisfied the homogeneity of variance test; otherwise, Games–Howell tests were used. Regression analysis curve estimation was used to build optimal models between DP and VI (dry treatment was included), and between DP, GI, VI, and MGT and groundwater salinity. Significance was set to P < 0.05.Statistical analyses were performed using SPSS Statistics version 25.0 . Prior to analysis, data were examined for normality, and they were log-transformed as needed. Transformed values were utilized in all subsequent statistical analyses. Untransformed values were presented for all means and standard errors. A two-way Analysis of Variance (ANOVA) was used to examine the effects of groundwater level, groundwater salinity, and their interaction on seed GI and VI (dry treatment was excluded). P = 0.024). After groundwater level and groundwater salinity treatments, the annual species had greater VI than the perennial species (P < 0.05). However, GI of the perennial species was significantly higher than that of the annual species after low groundwater level treatment (P = 0.032) (After storage treatments (including dry storage), seed germinability index (GI) of annuals and perennials had no significant differences, but seed viability index (VI) of annuals  was significantly higher than that of perennials   .C. chinense and L. latifolium seeds, which had higher GI and VI after low groundwater level storage  was analyzed, a clear trend in GI and VI was observed: dry storage  > high groundwater level storage (49.3% ± 9.9 and 51.9% ± 7.1%) > low groundwater level storage (30.1% ± 9.3 and 35.7% ± 5.4%) (The two-way ANOVA showed that groundwater level storage treatment had significant effects on GI in five of the seven species and VI in six of the seven species . Low gro storage . When th ± 5.4%) .I. cylindrica, whose seeds had better viability when stored in fresh groundwater (0 g/L) than higher salinity groundwater (20 g/L) (P = 0.004)   . Further< 0.001) .P. australis, S. salsa, and C. album seeds were stored in the low groundwater level treatments, a positive effect on seed GI was clearly observed for groundwater salinity treatments   (Both seed dormancy percentage (not shown in figures) and seed viability index were greater in three perennial species under high groundwater level storage treatment than under low groundwater level storage treatment  . Overall< 0.001) .P. australis seeds after W1S2 storage; S. salsa seeds after W1S0 storage; C. chinense seeds after W1S0 storage; C. album seeds after W1S1 storage; A. venetum seeds after W1S2 storage; I. cylindrica seeds after W1S2 storage; L. latifolium seeds after W2S0 storage), we found that the sections of seed embryos were reduced  maintaining greater seed persistence compared with moist conditions (low groundwater level storage treatment). The lower viability after moist storage was similar to the findings of Ruppia sinensis seeds because these conditions could inhibit seed germination. A possible reason for these results is that high salinity played a role in inhibiting microbial activity  in the supratidal wetlands of the Yellow River Delta .There has been some debate about the relationship between seed dormancy and seed persistence in soil. Previously, much work has been conducted on systematics to identify different species by seed characters using SEM , but theSupratidal wetlands are experiencing particularly rapid change as the shallow groundwater level rises . Our stuThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.LF and J-TL designed the experiment with the help of H-JY. LF, LP, QC, and J-ZM collected the seeds in the field and performed the lab experiments. All authors contributed significantly to the writing of the manuscript and approved the submitted version.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.


To analyze locally advanced rectal cancer (LARC) patients and tumor characteristics during the period of total neoadjuvant therapy (TNT) and explore the risk factors that may predict poor tumor regression in response to TNT.The data of 120 LARC patients who received TNT from December 2016 and September 2019 in our hospital were retrospectively analyzed. The clinicopathological characteristics of patients with different tumor regression responses were compared. Then we divided patients into two groups according to the carcinoembryonic antigen (CEA) clearance pattern after chemoradiation to explore risk factors that might predict the tumor regression response.P < 0.05). For those with elevated pretreatment CEA, fewer patients with poor response obtained normal CEA after chemoradiation . Besides, less patients’ CEA levels in the poor response group decreased by greater than 50% after chemoradiation when compared with that in the good response group . Stratified analysis by CEA clearance pattern after chemoradiation showed patients who obtained an elevated pretreatment CEA and decreased by less than 50% after chemoradiation were more likely to have poor response to TNT compared to others . Logistic multivariate analysis revealed that cN2 (95% CI 1.553-16.448), larger tumors (95% CI 2.250-21.428) and CEA clearance pattern after chemoradiation (95% CI 1.062-66.992) were independent risk factors for poor tumor regression response.Of 120 LARC patients, 34 (28.3%) exhibited poor regression. Stratified analysis by tumor response showed that patients with poor response to TNT were more likely to obtain elevated CEA during the course of TNT (all Approximately one-fourth of LARC patients with TNT achieved a poor regression response. Here, cN2, larger tumor size before treatment and elevated CEA levels were considered predictive features of a poor response. Active surveillance of CEA levels during the TNT course are potentially important, and CEA levels after chemoradiation might have important implications for the tumor response to TNT. Colorectal cancer is known as the third most common cancer in the world, and locally advanced rectal cancer (LARC) accounts for 70% of rectal cancers . LARC paUnder this circumstance, neoadjuvant therapy (TNT) was proposed to reduce distant metastasis. The current studies defined TNT as induction chemotherapy (chemotherapy followed by concurrent chemoradiation) or consolidation chemotherapy (systemic chemotherapy following concurrent chemoradiation) , 7. TNT P = 0.026). Therefore, early identification of patients who might not benefit from TNT and alterations in therapeutic approaches seemed to be essential for improving prognosis.However, although tumor regression appeared in most patients following TNT, approximately 20% were resistant to TNT, which manifested as slight or no tumor regression , 12. TheHowever, studies on risk factors suggesting tumor regression of LARC patients following TNT remain lacking . ChapmanThis study consisted of patients who underwent TNT for LARC at Beijing Chaoyang Hospital, Capital Medical University between December 2016 and September 2019. During the period, 151 LARC patients underwent TNT. The inclusion criteria were as follows: 1) distal extension less than 12 cm from the anal verge; 2) rectal adenocarcinoma determined by histology; 3) age: 18 to 80 years; 4) cT4N0 or cTxN1-2 rectal cancer with enlarged lateral nodes, extramural vascular invasion and mesorectal fascia positive based on pelvic MRI test; 5) patients who complete the whole course of TNT in our hospital; 6) American Society of Anesthesiologists (ASA) score I and II. The exclusion criteria were as follows: 1) recurrent cancer; 2) presence of unresectable cancer or acute intestinal obstruction before TNT; 3) the previous history of malignant tumor; 4) patients who refused surgery or underwent partial resection and 5) patients with missing important data . After exclusions, 120 patients were analyzed in the study Figure 12 twice daily. After chemoradiation, they received two cycles of CAPOX that consisted of oxaliplatin 130 mg/m2 on day 1, and capecitabine 1000 mg/m2 twice daily on days 1 to 14, every three weeks. Pelvic MRI was performed for all patients before surgery. Radical surgery was performed at least three weeks after the completion of consolidation chemotherapy. The median interval between radiation and surgery was 12 weeks.All patients were evaluated by coloscopy, computed tomography (CT) and pelvic MRI restaging before TNT. The patients had been selected for TNT by a multidisciplinary team (MDT). We performed TNT consisting of consolidation chemotherapy to patients. Patients were given IMRT once a day at 2.0 Gy/fraction per day, 5 days per week for a total dose of 50.0 Gy in 25 fractions, with concurrent oral capecitabine at 825 mg/mRadical surgery was performed in all patients regardless of the evidence of complete clinical response. Surgery was performed with total mesorectal excision and included low anterior resection (LAR), abdominoperineal resection (APR), or the Hartmann procedure depending on the distal extension from the anal verge to the tumor and intraoperative conditions.Follow−up evaluations were scheduled every 3 months for 2 years and every 6 months thereafter. Chest X−ray, abdominal CT, and pelvic MRI were performed annually to detect local recurrence or distant metastasis. Follow-up evaluations were performed in the outpatient department and by telephone. Follow-up ended in September 2022.Clinicopathological data and patient status were obtained from the medical records database. Measurement of the distance between the lower edge of the tumor and the anus, clinical TNM staging, mesorectal fascia (MRF) and extramural vascular invasion (EMVI) before TNT were all based on preoperative MRI. CEA was recorded before treatment and after chemoradiation and each cycle of CAPOX. Adverse events (AEs) during TNT were reported based on the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE) criteria. Body mass index (BMI) value was classified by applying the World Health Organization criteria.CEA ≥ 5.0 ng/mL was considered elevated. For patients with elevated pretreatment CEA level, the clearance rate of CEA was calculated, which was considered as: (pretreatment CEA level – follow-up CEA level)/pretreatment CEA level × 100%. The system used to assess tumor regression grade (TRG) was recommended by the Dworak grading systems . A good Survival outcomes were presented by 2- and 5-year overall survival (OS) and PFS. OS was defined as the interval from the date of surgery to the date of death from any cause. PFS was defined as the interval from the date of surgery to the date of death or tumor progression, such as local recurrence or distant metastasis.2 test were used to compare between-group differences. Long-term survival trends were estimated by the Kaplan−Meier method. Changes in CEA in the two study groups during the long-course of TNT were assessed by repeated-measures analysis of variance. The time trends of both groups and between-group comparisons across all time-points were shown due to no group-by-time interaction existed. Variables that had a statistically significant association at P < 0.05 with the regression response of patients in univariate analysis were entered into a logistic multivariable model. The area under the curve (AUC) is used as a summary measure of the receiver operating characteristics (ROC) curve and represents the discrimination ability. AUC is expressed on a scale of 0.5 to 1. The larger the AUC value, the better the classification effect. The results were reported as numbers (n) and percentages (%), means and standard deviations, or hazard ratios (HRs) with 95% confidence intervals (CIs), as appropriate, and were considered statistically significant at P < 0.05 in two-tailed tests.Statistical analysis was performed with SPSS 25.0  and GraphPad Prism 8 . The independent t test, Fisher’s exact test, and the χ A total of 120 patients with stage II or III LARC who received TNT were analyzed. The average age was 59.93 years old (standard deviation: 10.33), and 94 (78.3%) were male. The average BMI was 24.29 kg/m2 (standard deviation: 3.43), and the average tumor diameter before treatment was 5.14 cm (standard deviation: 1.81). The most common AEs were neutropenia (12.5%), thrombocytopenia (7.5%), anemia (5.8%) and rectal pain (5.8%). No grade 4 or serious adverse events were observed in this study. Overall, 86 (71.7%) patients showed a good tumor regression response, of whom 27 (22.5%) achieved pCR. The remaining 34 (28.3%) suffered a poor regression response. The median follow-up time was 36.5 (interquartile range 13.0-60.0) months in the GR group and 25.0 (interquartile range: 11.3-56.3) months in the PR group.These results are shown in P = 0.034], advanced cN stage  and greater MRF positivity  in patients in the PR group. A higher proportion of elevated CEA during TNT was observed in patients in the PR group than in those in the GR group .As shown in P < 0.001; ypN1-2: 67.6% vs. 14.0%, P < 0.001; positive CRM: 26.5% vs. 2.3%, P < 0.001; perineural invasion: 32.4% vs. 11.6%, P = 0.007).Regarding surgical results Table 1,P < 0.001). The 2- and 5-year OS rates in the two groups were not significantly different  patients in the PR group died, 4 (11.8%) suffered local recurrence, and 9 (26.5%) developed distant metastasis. In the GR group, 5 (5.8%) patients in the GR group died, and 8 (9.3%) suffered distant metastasis. The PFS rate at 2 and 5 years was 70.4% and 50.0% in the PR group compared with 90.4% and 88.7% in the GR group . Patients with good response achieved a greater clearance rate of CEA level than those with poor response (P = 0.045) (P < 0.001). Besides, more patients’ CEA levels in the GR group decreased by greater than 50% after chemoradiation when compared with that in the PR group .As shown in = 0.045) Figure 3According to the CEA clearance pattern after chemoradiation, patients were divided into two groups. Group A comprised patients with normal pretreatment CEA, or those of whom CEA was greater than 5 ng/ml before treatment but decreased by greater than 50% after chemoradiation. Patients in Group B obtained an elevated pretreatment CEA and decreased by less than 50% after chemoradiation. Groups A and B comprised 99 and 21 patients, respectively.P < 0.001; ypN1-2: 61.9% vs. 22.2%, P < 0.001; positive CRM: 28.6% vs. 5.1%, P = 0.003). Group B was more likely to achieve poor tumor response to TNT than Group A .As shown in P = 0.019). The 2- and 5-year OS rates in the two groups were not significantly different.The Kaplan-Meier curve of CEA clearance pattern after chemoradiation for OS and PFS are shown in P = 0.001), cN2  and CEA clearance pattern Group B after chemoradiation  as independent risk factors for poor regression response , 0.661 (95%CI 0.554-0.769) and 0.612 (95%CI 0.504-0.720). The AUC of all of these risk factors was 0.836 (95%CI 0.754-0.919) Figure 5TNT has been applied as the optional treatment for LARC patients ; howeverIn the current study, the most common AEs include neutropenia (12.5%), thrombocytopenia (7.5%), anemia (5.8%) and rectal pain (5.8%). No grade 4 or serious adverse events were observed. In addition, 27 (22.5%) patients achieved pCR in this study, which was consistent with the pCR rate reported by other studies , 11. TheIn this study, the PFS of patients in the PR group was inferior to that of GR patients. Other studies also reported that patients with pCR were likely to achieve better survival outcomes, indicating that relatively poor regression response was associated with worse survival outcomes , 19. TheP < 0.001). The author considered that the tumor diameter might be a clinical predictor of tumor response. In the study conducted by Yoon et al. (P = 0.044). A larger tumor diameter before treatment and cN2 might be indicative of a biologically more aggressive tumor.In the present study, patients with larger and node-positive tumors were more likely to have a poor regression response, and logistic multivariable analysis showed that tumor diameter ≥ 5.0 cm and cN2 before treatment were independent risk factors leading to poor response. Consistent with the findings of our study, the retrospective study by Chapman et al.  also iden et al.  with a tP < 0.05). Chapman et al.  for editing this manuscript.We thank American Journal Experts (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.


Kaplan–Meier method was employed to calculate drug retentions. Survival curves of treatment retentions were compared through Log-rank test between the studied subgroups. The hazard ratio for drug discontinuation was assessed through univariate cox regression models. In patients who started the first line TNFi therapy, the median treatment retention was 47.7  months for combination therapy and 22.7  months for TNFi monotherapy (p < 0.001). Estimated one-year survival was higher in patients on TNFi combined with csDMARDs as compared with TNFi monotherapy (75.3% vs 65.7%); two-year survival rate was 63.2% vs 49.2%, three-year survival rate was 55.4% vs 42.4% and five-year survival 44.9% vs 26.4% of patients. The estimated survival on the first TNFi was higher in patients taking combination therapy with methotrexate than with other csDMARDs (p = 0.003). Use of csDMARDs co-medication was associated with significantly better first TNFi drug survival compared to monotherapy. The combination of TNFi with MTX is more effective than the combination with leflunomide, which did not demonstrate a significant effect.The study aimed to compare treatment retention for first-line TNF inhibitor (TNFi) in the ATTRA registry patients receiving either combination with conventional synthetic DMARDs or TNFi as monotherapy. A retrospective multicenter study analyzed data of all adult patients with rheumatoid arthritis (The online version contains supplementary material available at 10.1007/s00296-021-05072-2. Convential synthetic disease-modifying drugs (csDMARDs) are according to current guidelines first-line drugs for the treatment of rheumatoid arthritis patients. Methotrexate (MTX) is the most common csDMARD used to treat rheumatoid arthritis. According to European League Against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA), it is the drug of choice that should be administered to all RA patients for whom it is not contraindicated. Where MTX cannot be given, rheumatoid arthritis therapy should be initiated with another csDMARD, most frequently sulfasalazine or leflunomide . ClinicaMTX combined with biological agents is more effective than either drug alone; in addition to the synergistic effect, the administration of MTX reduces their immunogenicity –12. WhilDespite current guidelines, approximately a third of patients currently taking a bDMARD receives it as monotherapy . There cThe presented study aimed to compare the real-world data on treatment retention in ATTRA (Anti-TNF Treatment in Rheumatoid Arthritis) registry patients receiving first-line treatment with a TNFi combined with csDMARDs and in those treated with a TNFi alone.n = 3032, female n = 2073; 77.3%) started on a first-line TNFi between January 1st 2012 and December 31st 2020. The ATTRA project is a clinical registry under the surveillance of the Czech Society for Rheumatology. It is a multicenter system for assessing the progress and outcomes of biological therapy of inflammatory rheumatic diseases. The observational, depersonalized and anonymous data were collected and stored after obtaining signed written informed consent for data collection from all participants. The registry is approved by the ethical committees . The study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments.A retrospective analysis included all ATTRA (Anti-TNF Treatment in Rheumatoid Arthritis) registry patients with RA  and median with 5th and 95th percentiles were presented for continuous variables. Categorical variables were described through absolute and relative frequencies (i.e. percentages). Statistical comparison of baseline characteristics between the subgroups was made using the non-parametric Mann–Whitney test or non-parametric Kruskal–Wallis test when comparing three groups. After testing of baseline differences through Kruskal–Wallis test, paired comparisons using the Mann–Whitney tests accompanied by Bonferonni correction were applied to discover which two subgroups differ. The relationship between categorical variables was evaluated by the Pearson’s chi-squared test or Fisher exact test when needed.P values < 0.05 were considered significant. Analysis was performed using IBM SPSS Statistics 25.0 and R (version 3.5.3).Retention rates of the first-line treatment were assessed by the Kaplan–Meier method, and the differences in survival curves were examined by the log-rank test. Univariate Cox regression models were employed to quantify the hazard ratio of treatment discontinuation. Bonferroni correction for multiple comparisons was applied when needed. p = 0.962). Combo-group used adalimumab in 43.7%, etanercept in 25.5%, golimumab in 11.4%, certolizumab in 9.9% and infliximab in 9.5%. Bio-originals represented 70.4% of TNFi. Mono-group used adalimumab in 46.9%, etanercept in 31.7%, certolizumab in 9.4%, golimumab in 6.9% and infliximab in 5.1% and bio-originals represented 71.7% of TNFi.Out of the total number of 3032 included, 2682 patients (88.5%) used a TNFi combined with any csDMARD , 350 patient used TNFi as monotherapy (11.5%). In the group of patients on MTX the initial mean dose (± SD) was 16.3 ± 5.6 mg, median dose  15 mg  weekly. Patients on combination therapy were slightly younger ; the mean disease duration was the same . The proportions of patients treated with any csDMARDs prior to initiation of first-line biological therapy were also statistically significant, namely 99.1% of combination therapy patients and 92.0% of those receiving monotherapy (p < 0.001). There were no major differences in either the numbers of swollen and painful joints or inflammatory parameters between the two groups. Similarly, the Disease Activity Score-28 for RA (DAS-28) with Erythrocyte Sedimentation Rate and the Simple Disease Activity Index at the initiation of TNFi therapy were comparable. Finally, there were no major differences in the EuroQol scale scores. In the Health Assessment Questionnaire Disability Index (HAQ-DI), there was a statistically significant difference between both groups . The characteristics of the patients and differences between csDMARDs and monotherapy subgroups are shown in Table Glucocorticoids were taken by a sizable proportion of patients, particularly those on combination therapy (68.5%), as compared to 59.4% of patients receiving a biological agent alone p < 0.00. The prop value < 0.001). Patients with csDMARDs combination have around 36% lower risk of TNFi discontinuation than patients with monotherapy  months for combination therapy with csDMARDs and 22.7  months for TNFi as monotherapy. Estimated one-year survival in patients on TNFi combined with csDMARDs as compared with TNFi monotherapy was 75.3%  vs 65.7%  of patients; two-year survival rate was 63.2%  vs 49.2% , three-year survival rate was 55.4%  vs 42.4%  and five-year survival 44.9%  vs 26.4%  of patients. Probability of staying on the first TNFi treatment is statistically significantly higher in the group of patients with csDMARDs combination than in patients with monotherapy; Log-rank test: During the study, first-line therapy with TNFi in combination with csDMARDs was discontinued by 1127 (42.0%) patients and in monotherapy by 184 (52.6%) patients. The most frequent reason for discontinuation was a loss of drug effect observed in 375 (33.3%) patients on combination therapy and 50 (27.2%) monotherapy patients. Primary ineffectiveness was noted in 220 (19.5%) and 40 (21.7%) patients, respectively. Treatment-related adverse events led to discontinuation in 169 (15.0%) patients receiving combination therapy and 33 (17.9%) monotherapy patients, pharmaco-economic reasons were observed in 90 (8.0%) in combination therapy and in 19 (10.3%) cases in monotherapy. Remission as a reason for discontinuation was noted in 10 patients (0.9%) in the combo group and in 2 (1.1%) in the monotherapy group. Finally, death was noted in 18 (1.6%) cases of combo- and in 2 (1.1%) in monotherapy groups. In 241 (21.4%) combination and in 33 (17.9%) monotherapy patients, the reason for discontinuation was assessed as other or unknown.The influence of csDMARDs on the retention of the TNFi differed in individual drugs. It was statistically significant in adalimumab and etanercept patients and not in certolizumab, golimumab and infliximab patients. However, these three drugs were rarerly used in monotherapy which might affect the statistical signicicance.n = 1172) vs adalimumab in monotherapy (n = 164) was 58.4 months  vs 17.9 months . Patients with adalimumab in combination with csDMARDs had a statistically significantly lower risk of treatment discontinuation represented by HR (95% CI) 0.510  than patients on monotherapy (p < 0.001).The median of retention of adalimumab in combination with csDMARDs (n = 685) vs etanercept in monotherapy (n = 111) was 44.8 months  vs 26.3 months , which is statistically significant longer for combination therapy with HR (95% CI) 0.699 ; p = 0.016.The median of retention of etanercept in combination with csDMARDs (n = 265) vs certolizumab in monotherapy (n = 33) was 66.4 months  vs 55.8 months , which is not significant result for combination therapy (HR (95% CI) 0.774 ; p = 0.371).The median of retention of certolizumab in combination with csDMARDs (n = 306) vs golimumab in monotherapy (n = 24) was 47.5 months  vs 60.8 months , risk for discontinuation did not differ statistically (HR (95% CI) 0.830 ; p = 0.555).The median of retention of golimumab in combination with csDMARDs (n = 254) vs infliximab monotherapy (n = 18) was 18.9 months  vs 15.2 months , with no statistical difference (HR (95% CI) 0.796 ; p = 0.397). Tables summarizing the reasons for the discontinuation of individuals TNFi could be found in the supplementary material (Supplementary Tables 1–5).The median of retention of infliximab in combination with csDMARDs  months for patients taking TNFi combined with MTX and 35.0  months for individuals on TNFi with other csDMARDs.p < 0.001 and p = 0.040). Further, MTX combination showed a significantly higher probability of staying on the treatment than other csDMARDs (p = 0.003). Patients with MTX co-therapy had 39% lower risk of TNFi discontinuation than patients on monotherapy (p < 0.001) and patients with other csDMARDs combination had 21% lower risk of TNFi discontinuation compared to patients on monotherapy (p = 0.015). Figure The estimated one-year survival rates on therapy accompanied by 95% confidence intervals were 76.0%  for patients taking MTX together with TNFi and 72.3%  for those using other csDMARDs; two-year survival rate was 64.6%  vs 56.4% , three-year survival rate was 56.9%  vs 48.1%  and five-year survival 46.4%  vs 37.8%  of patients. Probability of staying on the first TNFi treatment was statistically significantly higher in both combination groups  than in monotherapy (n = 184 (20.4%) vs n = 36 (16.0%), adverse events n = 139 (15.4%) vs n = 30 (13.3%), pharmaco-economic switch n = 78 (8.6%) vs n = 12 (5.3%), death n = 12 (1.3%) vs 6 (2.7%), remission n = 7 (0.8%) vs n = 3 (1.3%), other or unknown n = 192 (21.3%) vs n = 49 (21.8%).The loss of treatment effect was observed in 287 (31.8%) patients on MTX, 88 (39.1%) patients receiving other csDMARDs. Other reasons for discontinuation represented primary ineffectiveness n = 303). When comparing treatment retention for first-line TNFi in combination with MTX or LEF, patients receiving TNFi combined with MTX showed higher median retention compared to LEF-50.2 months  vs 28.2 months , Log-rank: p < 0.001. The probability of TNFi retention was slightly higher in LEF group compared to monotherapy, but the difference was not statistically significant  patients in the group on combination therapy and in 99 patients (28.3%) in monotherapy. The methotrexate, respectively, leflunomide co-therapy used bsDMARDs in 680 (30.5%), resp. in 80 (26.4%) of cases. The TNFi retention was not statistically different between bo- and bsDMARDs .The EULAR recommendations for the management of rheumatoid arthritis recommend the usage of csDMARD as a first-line therapy . BiologiThe presented retrospective study comes out from the legislation frame for RA therapy coverage in the Czech Republic. The drugs given in the studied period as the first-line biological therapy for RA were TNFi in the vast majority of cases; that is why they were chosen as the matter of interest for this investigation. The treatment was initiated in highly active disease (defined as DAS-28 ≥ 5.1) refractory to at least 6-month therapy with csDMARDs as recommended in the Czech guidelines for RA treatment . Even ifATTRA registry do not provide data about the reasons leading to the administration of TNFi in monotherapy, which complicates the interpretation of the results. Even so, the presented data underlined the high importance of co-medication of csDMARDs for better retention of TNFi. The estimated median retention time in patients treated with csDMARDs combination was in this study 47.7 months compared to 22.7 months for monotherapy. Patients with csDMARDs combination had around 36% lower risk of TNFi discontinuation, and their estimated 5-year survival (retention) rate was 45% against only 26% in patients with monotherapy.The differences that can be deduced from the characteristics of the two sets do not explain these facts. Patients on monotherapy were slightly older, had a slightly higher HAQ, a history of lower exposure to csDMARDs, and lower frequency of co-medication with glucocorticoids. This could indicate their poorer tolerance or compliance with drugs in general, which may then also contribute to worsening of the retention of biologic therapy.Another interesting finding of this study is the differences between individual TNFi. A significant effect of co-medication on the median retention was seen with adalimumab and etanercept, but not with certolizumab, golimumab or infliximab. This can be explained in the case of golimumab and infliximab used in monotherapy by the error of small numbers, as both drugs should be administered only in combination with csDMARDs as recommended for RA, the monotherapy groups were relatively small , which may represent specific situations of this choice.The positive effect of csDMARDs in this study is driven particularly by MTX, which demonstrated to be more effective in the comparison with other csDMARDs. Surprisingly, the second most commonly used csDMARDs, leflunomide, did not show a statistically significant effect on the median retention of TNF in this study. As data on the reasons for choosing MTX or LEF are not available in our register, we can obtain some insight from the description of both groups. In the case of leflunomide, these RA patients are older, with a longer duration of the disease, with a higher HAQ and with a higher anamnestic number of csDMARDs used before TNFi. This points to severe and more therapeutically resistant forms of the disease, indirectly to MTX intolerance, which appears to negatively affect retention.There is a lot of data in support of a better effect of TNFi when given in combination with methotrexate, less so with other csDMARDs. A meta-analysis of thirteen randomized trials showed that TNFi combined with MTX was more effective than the biological agents administered as monotherapy . PreviouTreatment retention analysis seems to be a practical tool for assessing drug effectiveness and safety. Unlike clinical trials, data from registries allow the study of broader patient populations with various drug combinations. In real-world clinical practice, treatment with TNFi tends to be discontinued for various reasons, most frequent adverse effects or a loss of treatment effect , 24. NumEvidence for the effect of leflunomide on TNFi retention is not so robust. Data from earlier studies –32 show Besides the main focus of the presented study it also shows some other aspects of bDMARD therapy in patients with RA. First, it should be noted that the persistence of patients with RA on the first TNFi is relatively good and in combination with csDMARDs reaches 75% after the first year and almost 45% after five years of follow-up. In patients in monotherapy, the annual persistence is 65% and 5-year-old 26%. The median survival was 47.7 months for combo group and 22.7 months for monothepray. This also corresponds to the literature sources, for example, the real-life data from a local registry of 583 RA patients on first-line TNFi demonstrated median survival of 53.5 months and overall twelve-year retention 23.4%. Concomitant MTX alo significantly increased TNFi retention .Second, the number of patients starting TNFi in monotherapy was relatively small and represented only 11.5%. Other registries indicate that bDMARDs alone can be given in 30–50% , 36. OurLast, but not least, a relatively large percentage of patients initiates TNFi in combination with glucocorticoids  The current recommendations are restrictive in terms of the length of glucocorticoids (GCs) administration. It is evident that chronic GCs therapy is administered relatively frequently in RA, although with a trend to decrease their administration in recent years . In our There are some limitations of the presented study. This is an analysis of real-world database from the registry, the absence of any randomization is a limiting factor in the interpretation of differences between individual TNFi. No data is available on the reasons that led physicians in individual cases to decide to administer TNFi alone or in combination with csDMARDs and no attempt was made to compare patients with similar input parameters. The intial activity of RA seems to be considerably high. In the years 2012–2018 the bDMARDs were reserved in Chech republic for RA patients with high disease activity despite csDMARDs treatment. Even if we cannot exclude a possible up-scoring in individual cases, we are convinced that this is only a marginal problem which did not influence the results of our observations. Since 2018 the bDMARDs are available in Czech Republic also for moderate RA activity and we think that possible up-scoring will play less and less important role. The trend towards earlier switches could be influenced also by the availability of other drugs with a same or different modes of action. In 2012, all five TNFi plus abatacept, tocilizumab and rituximab were available in the Czech Republic. Later also sarilumab became the choice. The possibilities of the switches were relatively extensive throughout the duration of our data collection. The advent of JAK inhibitors has expanded the range of drugs available in recent years. Sadly, in the Czech drug evaluation system, determining the reimbursement of a drug takes a long time. As a result, JAK inhibitors have only become more widely available since 2019. It can be assumed that expanding the range of drugs will motivate physicians and patients to more frequent switches, which could affect drug retention. However, in our opinion, only the following years will show whether it will be seen in ATTRA register as well.To conclude, the authors are convinced the study provides strong evidence that patients receiving TNFi in combination with csDMARDs have significantly better retention of first-line biologic therapy. This effect is mainly driven by MTX administration in most cases, but a statistically significant difference is also present in the set of other csDMARDs. Surprisingly, it was not confirmed for leflunomide. Another interesting finding is the difference in the effect of co-medication on the retention of individual TNFi, from which no broader conclusions can be drawn, since this requires the support of other observational data.Supplementary file1 (DOC 45 KB)Supplementary file2 (DOC 46 KB)Supplementary file3 (DOC 45 KB)Supplementary file4 (DOC 44 KB)Supplementary file5 (DOC 43 KB)Supplementary file6 (DOC 50 KB)Supplementary file7 (DOC 52 KB)Supplementary file8 Supplementary Fig. 1 Treatment retention in patients starting the first TNFi according the BMI (Body mass index) structure. The likelihood of treatment retention was estimated using the Kaplan-Meier method. Kaplan-Meier curves for patients treated with TNFi  were compared using the Log-rank test at the 5% level of a statistical significance (EPS 381 KB)Supplementary file9 Supplementary Fig. 2 Treatment retention in patients starting the first TNFi – comparison of bo- and bsDMARDs. The likelihood of treatment retention was estimated using the Kaplan-Meier method. Kaplan-Meier curves for patients treated with boDMDARDs vs bsDMARDS were compared using the Log-rank test at the 5% level of a statistical significance (EPS 366 KB)Below is the link to the electronic supplementary material.