Drug–drug interactions (DDIs) pose new challenges beyond traditional pharmacodynamics in the context of optimizing the treatment options with immune checkpoint inhibitors (ICIs). To alleviate cancer-related pain, analgesics are of absolute vital importance as chronic medications used by cancer patients. However, the possible outcome of ICI treatment concomitant with analgesics remains unclear.χ2-based Q-test. Publication bias was examined by funnel plot analysis.Original articles describing the possible influence of analgesics use on ICI treatment published before December 1, 2021 were retrieved from PubMed, Embase, and the Cochrane Library. Odds ratio (OR) with 95% confidence interval (CI) for objective response rate (ORR), hazard ratio (HR) with 95% CI for progression-free survival (PFS), and overall survival (OS) were calculated using the random-effects or fixed-effects model, and heterogeneity was assessed using the p < 0.001). Compared to patients who did not receive opioids, opioid users had an increased risk of progression and mortality . Furthermore, the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) was not significantly associated with differences in ORR, PFS, and OS in patients treated with ICIs .A total of 11 studies involving 4,404 patients were included. The pooled OR showed that opioid use decreased the response of opioid users to ICIs compared to non-opioid users (OR = 0.49, 95% CI = 0.37–0.65, The concomitant use of opioids during ICI treatment has an adverse effect on patient prognosis, while the use of NSAIDs is not significantly associated with the prognosis in patients treated with ICIs. Drug–drug interactions (DDIs) are an important concern in the context of anticancer therapy due to the narrow therapeutic index and inherent toxicity of anticancer agents . ConcomiSeveral studies have highlighted the link between DDI and the response to ICI therapy. Steroids, antibiotics, and proton pump inhibitors (PPIs) have been demonstrated to influence prognosis in patients treated with ICIs compared to those receiving ICI treatment –10. Furtvia their inhibition of cyclooxygenase-2 (COX-2), NSAIDs may be beneficial for the treatment of ICIs, since overexpression of COX-2 has been found in a wide range of tumors, and is associated with malignant tumor phenotypes and negative regulation of anticancer immunity  guidelines . We desiWe systematically conducted an electronic search using PubMed, Embase, and the Cochrane Library to identify potentially relevant studies. Results from International conferences, such as the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), and the American Association for Cancer Research (AACR) were also selected to avoid any loss of information. Studies were identified using free text including the following terms: neoplasm, malignancy, ICIs, anti-PD1, anti-PD-L1, opioids, and NSAIDs, as well as specific drug names. The search was limited to studies published in English and published before December 1, 2021. Two authors (ZM and XJ) established the comprehensive search strategy, which is presented in A study was included when all the following criteria were met: (a) involved patients with solid tumors or hematological malignancy treated with ICIs; (b) explored the DDI between ICIs and analgesics (opioids and NSAIDs); (c) involved primary endpoints, such as objective response rate (ORR), progression-free survival (PFS), and overall survival (OS); and (d) provided sufficient data to calculate the odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI). Accordingly, the exclusion criteria were as follows: (a) lack of related or sufficient data; (b) designed as single-arm or dosage-finding studies; and (c) published as a meta-analysis, editorial, review, or case report. Two authors (ZM and XJ) checked the studies, and disagreements were decided by two senior investigators (HG and ZL).The studies that met the inclusion criteria were selected and analyzed by two authors (PJ and QW). The following elements were extracted for each included study: first author’s surname, publication year, country of origin, sample size, type of concomitant analgesics received, type of study design, analysis, cancer type, ICIs type, line of treatment, median PFS and OS, OR for ORR with 95% CI, HR for PFS, and OS with 95% CI. Discrepancies were solved by the other two authors (YZ and YL).Three independent authors  assessed the quality of the included studies by using the Quality Assessment of Newcastle–Ottawa Scale (NOS) for cohort studies . Discrepχ2-based Q-test and quantified using the I2 test. If p was < 0.10 for the Q-test or I2 was >50%, we recognized significant heterogeneity, and the random-effects model was utilized to synthesize the data. Otherwise, the fixed-effects model was adopted  was used for all pooled analysis and GraphPad Prism, version 9.0.0  was used to construct graphical charts.ORs with 95% CI for ORR from included studies were utilized to calculate the pooled OR. HRs with 95% CI for PFS or OS were synthesized in this meta-analysis. ORR was defined as proportion of complete response (CR) and partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) . PFS was adopted . SubgrouAll included studies –36 were p < 0.001) .Five studies reported the influence of opioid use on ORR in patients treated with ICIs. The pooled OR showed that the use of opioids decreased the response of opioid users to ICI treatment compared to non-opioid users  .Four studies used PFS as an indicator of outcome. The analysis of this study showed that compared to non-opioid users, the use of opioids increased the risk of progression by 61% among opioid users  in these studies, we used a random-effects model for analysis. The pooled data for HR showed that the concomitant use of opioids was significantly associated with a poorer OS in patients receiving ICIs  ; thus, the random-effects model was adopted for analysis. The pooled OR showed that the use of NSAIDs did not significantly influence ORR in patients during ICI treatment   .Five studies reported PFS data. Our analysis showed that compared to non-NSAID users, NSAID use did not significantly influence PFS among NSAID users , a random-effects model was used for the analysis. The pooled HR data showed that the concomitant use of NSAIDs was not significantly associated with OS in patients treated with ICIs  (OS data were available in seven studies. Due to the high heterogeneity (p = 0.020).A further subgroup analysis was performed according to the following variables: cancer type (NSCLC and melanoma) and ICI type . The results are presented in Regarding the comparison between opioid users and nonopioid users, the pooled ORs for ORR were stable in the sensitivity analysis, ranging from 0.42  to 0.55Comparison of NSAID users and non-NSAID users showed that the pooled ORs for ORR were stable in the sensitivity analysis, ranging from 1.11  to 1.61 [95% CI = 0.93–2.87, after excluding Cortellini et al., 2020  or 95% CFunnel plots were used to determine whether there was evidence of publication bias for pooled HRs for ORR, PFS, or OS analysis. In general, the funnel plots were distributed symmetrically, and the publication bias was modest , which results in a decrease in afferent nociceptive neuronal depolarization, thus producing the analgesic effect . Howeverinvasion . Morphininvasion . Furtherinvasion . In summin vitro study has shown that morphine can block IL-2 transcription, an iconic cytokine involved in the activation of CD8+ T cells  levels in peripheral blood mononuclear cell samples by approximately five times in the rhesus monkey , which can be an impediment to treatment with ICIs. An  T cells . Furtheron stage . In termactivity . Not allactivity . Cornwels monkey . In addis monkey .In vivo and in vitro, morphine has been shown to destroy the intestinal epithelial integrity by damaging the distribution of tight junction protein (ZO-1) in intestinal epithelial cells. As a result, the risk of Escherichia coli bacteria translocation to the mesenteric lymph nodes of mice increases after morphine treatment, inducing damage to the immune system  . Substan+ T cells. As a result, there is a marked decrease in the content of aspartic acid and of various enzymes in the MAS system, resulting in the growth arrest of CD8+ T cells  cells and the expression of CCR5 and XCR1 in conventional type 1 dendritic cells (cDC1), which can impair the function of NK cells and the accumulation of cDC1 in the TME, which are responsible for tumor immunity  system is critical to maintaining the redox equilibrium between mitochondria and cytoplasm in various cells . COX-2/P T cells , 25. Thiimmunity . Furtherimmunity . Taken tStudies evaluating NSAIDs have also reported a lack of beneficial effect of concomitant use with ICIs [such as Miura et al., 2021 , Kanai eTo our knowledge, this is the first meta-analysis to assess the influence of analgesics on the treatment of ICIs. Our study provides some useful information to oncologists in their clinical practice. Chronic use of opioids should be limited or replaced with NSAIDs as much as possible, to prevent the negative impact on concomitant treatment with ICIs and improve survival rates. For patients experiencing severe pain that is inadequately treated with NSAIDs, proper management of opioids is crucial to balance a pain-free period without influencing the outcome of ICI treatment. Opioids with weak or no immune modulation, such as buprenorphine, oxycodone, hydromorphone, and tramadol should be given before morphine, fentanyl, or codeine, which possess powerful immunosuppressive effects . In addiCertainly, our study has some intrinsic limitations. First, all included studies were retrospective designs, possibly lacking scientific control over variables, which could have led to deviations between results and actual clinical practice. Second, all studies included in this meta-analysis were published in English, which may have introduced a certain degree of bias. Third, some important characteristics, including age, sex, PD-L1 expression, line of ICI treatment, and pain grade, were not included in the subgroup analysis due to unavailability, and may have affected the universality of our findings.In summary, this study revealed that concomitant use of opioids is associated with a poor prognosis in patients treated with ICIs, while use of NSAIDs did not alter the efficacy of ICI treatment. Our findings provide important information for balancing management of cancer pain relief and efficacy of ICI treatment.The original contributions presented in the study are included in the article/HG and ZL designed the study. ZM and XJ performed literature search and wrote the original manuscript. PJ and QW conceived the project and prepared the figures and tables. YZ and YL participated in the drafting and editing of the manuscript. XF and MJ provided statistical analysis. LJ committed to interpreting the results. HG revised the manuscript. ZM and XJ revised the draft and approved the final version to be submitted. All authors had full access to all data, critically revised the paper, approved the final analysis, and took responsibility for all aspects of the work.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 compare the efficacy of two different surgical approaches during and after pyeloplasty according to the degree/severity of hydronephrosis factor.n = 20), while those who received transperitoneal laparoscopic pyeloplasty (TLP) were selected as Group B (n = 40). Clinical parameters, including gender, age, laterality of UPJ obstruction, degree/severity of hydronephrosis, body weight, operation time, drainage tube indwelling time, complete oral feeding time, and length of hospital stay, were compared between the two groups.Sixty child patients with UPJ obstruction admitted to our hospital from August 2019 to October 2021 were collected. Patients who underwent retroperitoneal laparoscopic pyeloplasty (RPLP) were enrolled into Group A (P < 0.001). The differences in complete oral feeding time, drainage tube indwelling time, and length of hospital stay were statistically significant between the two groups, and RPLP was superior to TLP in terms of postoperative recovery time (P < 0.001). A stratified comparison showed that there were no statistically significant differences in anteroposterior diameter ≤ 20 mm, while there were statistically significant differences in anteroposterior diameter >20 mm. Hydronephrosis is reviewed after 3 months of the operation, degree/severity of hydronephrosis have been reduced.All 60 child patients were operated upon successfully without conversion to open surgery. There were no statistically significant differences in gender, age, laterality of UPJ obstruction, and body weight between the two groups, while the operation time of TLP was shorter than that of RPLP, indicating a statistically significant difference (Both RPLP and TLP are safe and feasible in the treatment of UPJ obstruction, and their overall surgical effects are equivalent. For child patients with anteroposterior diameter ≤ 20 mm, RPLP is available, while patients with anteroposterior diameter >20 mm, TLP is recommended. Pediatric hydronephrosis mainly resulting from ureteropelvic junction (UPJ) obstruction can be treated by the Anderson-Hynes operation, which is viewed as the gold standard . Currentn = 20) and the TLP group B (n = 40). Clinical parameters including gender, age, laterality of UPJ obstruction, body weight, degree/severity of hydronephrosis, operation time, drainage tube indwelling time, complete oral feeding time, and length of hospital stay were compared between the two groups.Clinical data of 60 child patients with UPJ obstruction admitted to our hospital from August 2019 to October 2021 were collected for retrospective analysis. The diagnostic standard used in this study are: ultra sound (SFU classification) , 8, intrPreoperative routine preparation, gastrointestinal preparation, indwelling of urethral catheter, and general anesthesia with endotracheal intubation were given to patients. An experienced Pediatric surgeon have done all the operations used in this study.RPLP was performed in Group A. The patient was placed in a lateral position on the unaffected side with the waist padded on the operating table. First, a 1.5-cm skin incision was made at 1–2 transverse fingers above the iliac spine at the axillary midline. Next, hemostatic forceps were used to bluntly separate muscles, lumbodorsal fascia, and the psoas major muscle, with the index finger moving closely along to the location below the 12th rib at the posterior axillary line, followed by placing a 0.5-cm trocar. The index finger pushed the anterior peritoneum back to the ventral side and then pressed against and below the costal arch at the axillary front line, followed by placing a 0.5-cm trocar, and then a 0.5-cm trocar was inserted above the iliac spine with silk thread fixing the muscle and skin. Subsequently, the perirenal fascia was longitudinally cut to expose the dorsal side of the lower pole of the kidney, followed by separation and exposure of the renal pelvis and upper ureter to clarify the location and cause of stenosis. Then the stenosis portion was resected completely, and a double-J tube was placed after anastomosis , 9. At tTLP was performed in Group B. The patient was placed on the operating table with the waist padded on the affected side. Three 0.5-cm trocars were inserted into the umbilicus (midline of the abdomen), 2.0 cm away from the upper and lower umbilicus margins, and were arranged in a straight line. Surgical treatment was carried out through the paracolonic sulcus, which is located at the lower edge of the mesenteric vein. The medial edge of the colon was left free to fully expose the paracolonic sulcus, and the perirenal fascia was open at the lateral edge of the genital vein to expose the lower pole of the kidney and to expand the renal pelvis, followed by separation and exposure of the renal pelvis and upper ureter to clarify the location and cause of stenosis. The upper pole of the renal pelvis was suspended and dilated. Then the stenosis portion was resected, and a double-J tube was indwelled after anastomosis. At the end of operation, an abdominal drainage tube was placed into the pelvic cavity , 5, 10, t-test, while those not conforming to normal distribution were expressed as the median and interquartile ranges (lower quartile—upper quartile) and compared by an independent-samples non-parametric test.SPSS 25.0 software was adopted for statistical analysis. Categorical variables were compared by a chi-square test. Continuous variables were subjected to a normality test. Those normally distributed data were expressed by the mean ± standard deviation and compared by an independent-samples All 60 patients were operated upon successfully without conversion to open surgery. The results of comparative analysis revealed that mean average age, operation time, drainage tube indwelling time, complete oral feeding time, and length of hospital stay were [51 (36.5–96) months vs. 41.5 (23.75–63.75) months], [152.5 (146.25–182.5) min vs. 140 (126.25–150) min], [29 (27.25–30) h vs. 40 (38–41.75) h], [(40.65 ± 2.89) h vs. (50.05 ± 3.94) h], and [6 (5–6) d vs. 7 (6–7) d], respectively, between Groups A and B. No patients required blood transfusion during and after the operation in the two groups. Among the patients in Group A, one suffered abdominal pain and fever following removal of a double-J tube after operation. When anastomotic stenosis was proven by inspection, a secondary operation was performed and the patient recovered well postoperatively.P = 0.001). The differences in complete oral feeding time, drainage tube indwelling time, and length of hospital stay were statistically significant between the two groups, and RPLP was superior to TLP in terms of postoperative recovery time , while the differences in complete oral feeding time, drainage tube indwelling time, and length of hospital stay were statistically significant between the two groups, and RPLP was superior to TLP in terms of postoperative recovery time (P < 0.001). In the case of hydronephrosis with an anteroposterior diameter ≤ 20 mm, there was no statistically significant difference in operation time between the two surgical approaches (P = 0.701), while the differences in complete oral feeding time, drainage tube indwelling time, and length of hospital stay were statistically significant between the two groups, and RPLP was superior to TLP in terms of postoperative recovery time  the gastrointestinal gut will be influenced for long time operation; (B) the complete healing time is longer than that of the retroperitoneal laparoscopic pyeloplasty; (C) there is a certain possibility of internal hernia after the operation . The resvantages –30: (A) This was a single-center study with a small sample size. Considering the changes in the learning curve of retroperitoneal laparoscopy and the fact that retroperitoneal laparoscopy has been adopted in few hospitals in China for the treatment of UPJ obstruction, many samples are still needed for further research. Besides, given that the follow-up period in this study was short, a long-term follow-up is also needed to further investigate the postoperative outcomes. We will further improve our study by conducting multi-center experiments and increasing samples numbers to make the conclusion more accurately.Both RPLP and TLP are safe and feasible for the treatment of UPJ obstruction, and their overall surgical effects are equivalent. For child patients with mild hydronephrosis (with an anteroposterior diameter ≤ 20 mm), no notable difference is shown in the operation time of the two surgical approaches, but RPLP is superior to TLP in terms of postoperative overall recovery, so RPLP is available to treat UPJ obstruction. For child patients with severe hydronephrosis (anteroposterior diameter > 20 mm), the operation time of TLP is significantly shorter than that of RPLP, so TLP is recommended to treat UPJ obstruction.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.Study conception and design and critical revision: BL. Data acquisition: CW, KM, ZL, GZ, and YL. Analysis and data interpretation: HT, HL, YM, HM, and XS. Drafting of the manuscript: PZ. All authors contributed to manuscript revision, read, and approved the submitted version.This study was supported by the National Natural Science Foundation of China (Grant No. 82060277), the Guizhou Provincial Health Committee Support Program (Grant No. gzwjkj2019-1-005), and the Doctoral Startup Fund of the Affiliated Hospital of Zunyi Medical University, Project Number: 2020-04.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.


Mycobacterium bovis burden across the globe. The aim of this study was to describe zTB surveillance programs in selected WHO signatory countries and to assess the relationship of the disease with the country’s income level and the risk of M. bovis transmission.Little is known about zoonotic tuberculosis (zTB) due to We searched the main articles databases and grey literature for guide documents published between 1980 and 2019. For inclusion, the articles and guide documents had to be in English, French, Portuguese, Spanish, or Italian. Only original articles and narrative and systematic reviews were accepted and the guide documents were required to be available on official websites. We excluded articles that did not focus on epidemiology, control and surveillance. We used bovine TB cases in livestock and wildlife populations as a proxy for the country’s risk of zTB using data from the World Organization for Animal Health (OIE) published from 2015 to 2018. Countries were classified according to income level (World Bank’s classification) and strength of zTB surveillance. The study was registered in PROSPERO under number CRD42018090603.We included 13 articles and 208 guide documents including data from 119/194 countries (61.3%). We found a lack of surveillance data about zTB in over half (89.9%) of the 119 WHO signatory countries. Most surveillance systems perform passive surveillance and are not integrated into the One Health perspective, which was operating in 4/119 (3.4%) countries, all high-income. Many of these countries  have M. bovis circulating in their cattle herds, but only ~10% of them have implemented zTB surveillance activities.M. bovis transmission. To meet this challenge, efforts will be needed to promote intersectoral policies, implementing the One Health strategy.Our findings highlight weaknesses in zTB surveillance worldwide, with a consequent lack of information that could support an adequate understanding of disease burden, especially in countries at major risk for  Mycobacterium bovis, ie, zoonotic tuberculosis (zTB). Insufficient data are a major challenge for developing strategies for the control of zTB, in particular in low-income and middle-income countries. Surveillance data are essential to develop effective TB control strategies, quantifying disease burden, and identifying risk factors and vulnerable groups. Strengthening the One Health approach is essential for making zoonotic disease control strategies highly effective by promoting concerted actions across human and animal health programs and integrated surveillance. A systematic review was conducted to describe existing zTB surveillance and the degree of its coordination with animal TB surveillance in countries of low-income, middle- and high-income, accounting for the country risk of M. bovis transmission. We found that zTB surveillance is highly conditioned by country’s income level, and identified a discrepancy between the level of risk of animal-human TB transmission and the extent of surveillance. In addition, less than 5% of the countries assessed have implemented integrated human and animal TB control programs, which suggests low adoption of the One Health approach across the world. Without adequate surveillance for zTB, across the world, it will be unlikely to guarantee diagnosis and treatment for all TB patients.Little is known, across the world, about of tuberculosis in humans caused by  Sustainable Development Goals (SDG) [Zoonotic diseases have gained importance due to their impact on human health and the economy, with their inclusion in the global public health agenda becoming a priority. The successful control of zoonotic diseases depends to a large extent on the implementation of long-term intersectoral public policies, which act synergistically by promoting social and economic development and a better quality of life and health of the population . To thisls (SDG) . Strengtls (SDG) .Mycobacterium bovis, which belongs to the M. tuberculosis complex [Mycobacterium orygis, a new member of the complex described in 2012, has been associated with zTB especially in Asia. However, robust estimates of its prevalence in humans and animals are lacking [The World Health Organization (WHO) defines zoonotic tuberculosis (zTB) as a form of TB in humans that is predominantly caused by  complex . Recentl lacking .M. bovis but other animal species are also involved in disease transmission, a fact that renders it a highly complex process [M. bovis infection in cattle should be the pillar of disease prevention in humans and should be achieved by the inspection of slaughterhouses and the application of the tuberculin test to animals [Cattle are the most important reservoir of  process . Accordi process . This da process . Histori animals .Insufficient data and knowledge are a major challenge for developing strategies for the control of zTB, in particular in low-income and middle-income countries where people are more vulnerable due to a greater risk of TB . SurveilM. bovis transmission.To the best of our knowledge, there are no published reports based on global data to support approaches to the strengthening of zTB surveillance and control in different countries. In an attempt to fill this knowledge gap, we conducted a systematic review aimed at describing the existing zTB surveillance systems and the availability of data, including their characteristics, basic components and degree of coordination with animal TB surveillance in countries of low, middle and high income, accounting for the country’s risk of http://prisma-statement.org/PRISMAStatement/Checklist.aspx) (Register of Systematic Reviews (PROSPERO) (protocol number CRD42018090603) (https://www.crd.york.ac.uk/prospero/)).We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  animal TB infection; iii) bacterial genetics, phylogeny, and genotyping; iv) pathogen isolation and detection, diagnosis, pathogenesis, or disease transmission; v) interdisciplinary research on other zoonotic diseases; vi) immunology, vaccination, treatment, and drug resistance, and vii) clinical case presentations.We excluded articles focusing on: i) infections and/or diseases associated with mycobacteria other than We searched PubMed, Embase and Index Medicus for the South-East Asian region, Web of Science, African Index Medicus, Index Medicus for the Eastern Mediterranean region, and SciELO and Lilacs for Latin America, comprising the period from 1980 to 2019. We considered a broader period in the search for scientific articles in an attempt to find countries that have traditionally published data on zTB, thus creating a timeline of continuity of surveillance services for these countries.M. bovis as a zTB agent, our search terms were “Mycobacterium bovis,” “surveillance,” “control” and “epidemiology,” adjusted for each database  evaluated and selected the articles. They independently read the titles and abstracts of the articles retrieved and then reviewed the full text of the selected articles for relevance, methodological rigor and inclusion/exclusion criteria. Disagreements were resolved by a third researcher (EAW). We conducted additional searches to locate the references cited in the articles retrieved and other publications were selected based on our inclusion and exclusion criteria.https://www.equator-network.org/) to assess the study design of the articles and potential biases. This checklist did not apply to guide documents.We used the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist  and/or surveillance programs on Ministry of Health websites from 194 WHO signatory countries. All available documents were included in the study.M. bovis, basic surveillance components  [M. bovis as a potential causative agent, description of transmission modes, reservoir characterization, identification of risk groups, and description of clinical forms.Two researchers (RMC and GOS) independently reviewed the data extracted from all documents and articles, namely: country, study design (for articles only), study population (for articles only), exposures associated with human transmission of esearch) ,11, and http://www.oie.int/wahis_2/public/wahid.php/Diseaseinformation/statusdetail)). We grouped each country according to income classification and strength of zTB surveillance.We adopted the World Bank classification of 2018 for the categorization of countries by income level (databank.worldbank.org/data/download/site-content/CLASS.xls), which divides groups according to gross national income per capita, calculated using the World Bank Atlas method. The groups are: low income, $1,035 or less; lower middle income, $1,036–4,045; upper middle income, $4,046–12,535; high income, $12,536 or more. We considered cases of TB in livestock and wildlife populations as a proxy for the country’s risk of zTB; these data were obtained from the World Organization for Animal Health (OIE) database for the period from January 2015 to December 2018  to generate thematic maps according to the country’s income level and risk of zTB and the R software (version 3.6.1) for creating graphs.Thirteen articles were selected from the data sources searched for this study .Application of the language exclusion criterion resulted in the exclusion of 75/194 (38.7%) WHO signatory countries, 5/75 (7%) low income; 21/75 (28%) lower middle income; 22/75 (29%) upper middle income; and 27/75 (36%) high income. Thus, we searched for documents on the websites of the respective Ministries of Health from 119/194 (61.3%) countries, whose income distribution is presented in Based on information collected from the articles and guide documents included in the study, we reached a consensus and divided the countries into five groups  as folloM. tuberculosis in the Netherlands [Surveillance activities carried out in countries from group A involved three basic components : i) estaherlands .M. tuberculosis) or the definition of suspected cases of zTB (only reporting that cases were confirmed by culture isolation of M. bovis). Ten out of 12 countries (83%), all of which were high income, reported using genotyping as an important adjunct diagnostic test to identify the source of infection [Surveillance of zTB was passive in countries from group A. Only 2/12 countries (17%), both high income, reported routine active human case-finding from confirmed animal TB cases ,19. The nfection .undercooked meat or consuming unpasteurized dairy products from infected animals  [M. bovis (United Kingdom) [Surveillance can be considered effective in these countries since it provides scientific data informing about disease control strategies including: i) indication of targeted tuberculin testing in people exposed to animals with respiratory infection or aerosol-generating procedures with the potential for airborne transmission of infection (Canada) ; ii) indIreland) ,21,22, aKingdom) . In addiKingdom) ,19,23–30Coordination between animal and human health sectors incorporating core concepts of the One Health approach was evidenced in 4/12 countries (33%), all of which were high income. The key aspects included: i) laboratory-based surveillance focused on cross-transmission between humans and animals with genotyping of all human and animal isolates (The Netherlands) ; ii) croMycobacterium bovis is described as a possible causal agent of TB cases in guide documents from 3/29 (10%) countries in group B  [M. bovis isolation–Lowenstein-Jensen medium with sodium pyruvate (India) [i Lanka) –35. Theri Lanka) ; ii) impi Lanka)  and gasti Lanka) ; iii) spi Lanka)  and highi Lanka) , and iv) (India) .The data analysed for countries in groups C, D and E made no reference to zTB surveillance in routine TB surveillance activities of the NTPs, either because there was no mention in the guide documents (group C) or because there were no guide documents available in the sources searched (groups D and E). It is noteworthy that countries in group D were either low income or middle income . On the other hand, countries in group E were medium-to-high income islands or small territories with low population density  .For the period from 2015 to 2018 , there were reports of TB in livestock and/or wildlife populations in 9/12 countries in group A (75%), 26/29 in group B (90%), 24/41 in group C (58%), 10/12 in group D 83%), and 2/25 in group E (8%), for a total of 71/119 (59.7%)  of the 119 WHO signatory countries accessed. Additionally, most surveillance systems perform passive surveillance and are not integrated into the One Health perspective.M. bovis circulating in their cattle herds, but only ~10% of them have implemented zTB surveillance activities. On the other hand, ~25% of these countries point out the importance of M. bovis for TB control in their guide documents, recognizing how zTB surveillance is essential for controlling TB in humans, yet, they are mostly high-income or middle-income countries. It is important to point that, unlike human tuberculosis, TB in livestock is not a notifiable/controlled disease in many low- and middle-income countries and therefore there is often a lack of data on TB in the livestock population in these countries, underestimating the dimension of the disease. Therefore, the zTB risk may be underestimated in our analysis and the probability of underestimation is likely higher for countries that have large numbers of cattle herds.Many of these countries  have It is accepted that effective zTB surveillance and control rely to a large extent on concerted actions based on the One Health approach in human and animal populations ,6. Yet, ultidrug-resistant TB surveillance [We identified data gaps even in the few countries with zTB surveillance, such as lack of a clear definition of suspected cases, which would be a valuable tool to improve surveillance sensitivity ,11, and eillance .M. bovis in their national TB programs, recent M. bovis infections continue to occur even after the introduction of control measures for the sanitary control of herds (including the compulsory testing of dairy cattle), or for the sanitary control of food products (including milk pasteurization), indicating that these animals are likely to have acquired infection from other sources or other transmission routes. Thus, trends and risk factors should continue to be monitored [In countries that have implemented a specific surveillance component for onitored ,26,29. Aonitored . Buying onitored .Since our results indicate that zTB surveillance is carried out predominantly in high-income countries, it is possible that this disease is being neglected in many low- and middle-income countries. Some important risk factors associated with disease transmission occur especially in these countries, where the disease is more prevalent. In many African countries, milk pasteurization is not used regularly and 80%–90% of the volume produced is sold by small dairy farms and pastoral communities .M. orygis [M. orygis as a potential zoonotic TB agent and others that may yet be identified.We must acknowledge some limitations in interpreting the findings of our study. Nearly one-third (38%) of WHO signatory countries were not assessed in this study, with a large proportion (64%) being low-income and middle-income countries. More studies including central, eastern Europe, Russia and middle east countries are necessary, in order to access zTB surveillance data. It is important to mention that specially in these countries, despite previously falling TB incidence, there was an upsurge of TB cases and deaths throughout the region after the economic recession and other crises . Neverth. orygis , which w. orygis ,11 such gaps exist in surveillance data. New diagnostic technologies are urgently needed to differentiate M. bovis from M. tuberculosis disease, improving routine diagnosis of M. bovis in human cases of TB, making possible quantify zTB burden. Similarly, surveillance systems need improve zTB case definitions, incorporating suspected case definition. These limitations show that zTB will be an additional challenge along the path to reach the goal of ending TB in 2030 if no urgent action is taken [M. tuberculosis or M. bovis, will count towards the achievement of this ambitious goal [Our findings provided quantitative data supporting the literature claim that significant is taken . Findingous goal ,2,4,10.M. bovis. Countries must intensify their efforts to incorporate the One Health approach by integrating surveillance in humans, animals and environmental areas. To make the SDG Agenda a reality, broad ownership must translate into a strong engagement by all stakeholders.zTB continues to negatively affect both the health and economy of a considerable number of people, and the health and welfare of animals. Since the risk of zTB occurrence is intrinsically related to the occurrence of cases in domestic animals, and that the occurrence in these animals is related to the spread of the disease from wild reservoirs, identifying wild hosts and mapping the occurrence in these animals is fundamental for the control of the transmission of S1 PRISMA Checklist(DOCX)Click here for additional data file.S1 Data(DOCX)Click here for additional data file.S1 PRISMA Flow Diagram(DOCX)Click here for additional data file.S2 PRISMA Flow Diagram(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 TableDistribution of countries classified in Groups A, B, C, D and E by income level, available academic articles and manuals and reported tuberculosis in animals.(DOCX)Click here for additional data file.


Precise examination of breast cancer survivors’ lifestyles can lead to improved planning and implementation of care and counseling interventions to increase their survival rate and improve their quality of life. Therefore, a valid and reliable instrument needs to be developed. Therefore, the present study aimed to determine the psychometric properties of the Persian version of the Healthy Lifestyle Instrument for Breast Cancer Survivors (HLI-BCS).This methodological study was conducted on 420 Iranian breast cancer survivors between May and November 2022. Participants were selected using convenience sampling. The face, content, construct validity, convergent, and reliability of the Persian version of the HLI-BCS were assessed.p < 0.001, r = 0.832), physical health (r = 0.786), and mental health (r = 0.809).After assessing face, content, and construct validity, the Persian version of the HLI-BCS with five factors and 20 items was provided. The total Cronbach’s alpha and intra-class correlation coefficient (ICC) were calculated as 0.86 and 0.79, respectively, which were at acceptable levels. A healthy lifestyle in breast cancer survivors was observed to have strong and significant relationships with quality of life in general (The Persian version of the HLI-BCS has favorable properties, is consistent with the conditions of breast cancer survivors, and is valid and reliable. This version of the scale can provide adequate and precise information on the lifestyles of these patients. Breast cancer is the most common invasive cancer among women and involves one in every eight women. It is considered the leading cause of cancer-related deaths among women worldwide, including in Iran , 2.The importance of breast cancer as a disease with high incidence and mortality rates is thought-provoking, particularly in developing countries, because 58% of deaths occur in less-developed countries . In addiTherefore, given the high prevalence and survival rate of breast cancer, the importance of status examination, treatment follow-up, and lifestyle of individuals with this cancer after completing the treatment is emphasized. Cancer survivors further adhere to self-care recommendations to improve long-term treatment outcomes compared to the time of diagnosis , 6. MoreOne way to check an individual’s healthy lifestyle is to measure elements that are considered as the lifestyle’s objective manifestations . InstrumCurrently, there is a dedicated Healthy Lifestyle Instrument for Breast Cancer Survivors to evaluate their post-treatment status. The Healthy Lifestyle Instrument for Breast Cancer Survivors (HLI-BCS) was designed by Wang et al.  and usedTherefore, given the high prevalence of breast cancer in Iran, a standard and indigenous lifestyle assessment instrument for planning and providing care interventions for breast cancer survivors has become increasingly evident. Also, in Iranian society, there is no indigenous Persian version of the instrument for patients with breast cancer, consistent with Iranian Islamic culture. Therefore, this study was conducted to determine the psychometric properties of the Persian version of the HLI-BCS in Iranian society.The current methodological study was carried out on female breast cancer survivors referred to hospitals affiliated with Mashhad University of Medical Sciences from May to November 2022.The sample used in this study was selected through convenience sampling. Women with breast cancer had the following inclusion criteria: a history of at least two years of breast cancer, having no recurrent or metastatic disease, receiving treatment in one of the stages of surgery, chemotherapy, or radiotherapy, consenting to participate in the study, and having the ability to answer the questionnaire items. The exclusion criteria were no mental disorder, not using psychiatric medications, and reluctance to participate in the study. According to Kellar and Kelvin 2012), the minimum sample size to perform factor analysis is five to ten times higher than the number of items in the intended instrument , the min. Thus, tData were collected using the demographic information form, Persian version of the HLI-BCS, and SF-12. The demographic information form included age, marital status, education level, employment status, economic status, health insurance, type of treatment, cancer stage, and duration of breast cancer.HLI-BCS was developed by Wang et al in 2015 . This inThe SF-12 is the short form of the 36-item Short Form Health Survey (SF-36), designed by Ware et al. in 1996. For the reliability of the questionnaire, the calculated Cronbach’s alphas for the physical and mental dimensions were 0.89 and 0.76, respectively, showing the favorable reliability of the questionnaire items . MontazeThe translation was performed using a forward–backward translation protocol from English to Persian using the World Health Organization WHO, 2016) method [ method [A cognitive interview and pretest were performed with the target group to ensure translation validity. Accordingly, ten patients with breast cancer who met the criteria to fill out the questionnaire were interviewed individually regarding the clarity of every single item and the precise measurement of the real variable using the Persian instrument. The target group was asked to express their opinions and suggested words to better understand each item or to replace words .A group of 15 experts calculated the content validity ratio (CVR) and content validity index (CVI) to assess the relevance, clarity, and simplicity of the items. The group of experts consisted of faculty members from the nursing department, oncologists, oncology nurses, oncology surgeons, clinical nutritionists, psychiatrists, and social workers. When the number of experts was 15, the minimum acceptable CVR was 0.49, based on Lawshe’s table . The min2/df < 5), the root mean square error of approximation (RMSEA < 0.08), the comparative fit index (CFI > 0.9), the goodness of fit index (GFI > 0.9), parsimonious normed fit index (PNFI > 0.5), and the Tucker–Lewis index/non-normed fit index (TLI/NNFI > 0.9). Items with factor loadings less than 0.4 were removed from the model [CFA was performed using the maximum likelihood estimation method and the most common goodness-of-fit indices for 220 participants to evaluate the structural factors of the Persian version of the HLI-BCS. Model fit indices were evaluated according to .Internal consistency was examined using Cronbach’s alpha to check instrument reliability. Cronbach’s alpha ranged from 0 to 1. Higher values indicate higher reliability, and a minimum level of 0.7 is recommended for alpha. In addition, the test–retest method and intraclass correlation coefficient (ICC) were used to determine reliability, and 30 patients who met the criteria for completing the instrument responded to the questions of the Persian version within two weeks. The ICC rate is between zero and one, the reliability coefficient of 0.6 is acceptable, and reliability coefficients of 0.8 and higher denote the instrument’s great stability , 22.p < 0.001 were considered as multivariate outliers. All statistical analyses were performed using IBM SPSS Statistics version 24 and IBM SPSS Amos version 25. A significance level of p < 0.05 was considered for all statistical tests [Univariate and multivariate distributions were assessed for skewness and kurtosis, and Mardia’s coefficient for outliers. One of the signs of deviation from the normal distribution was a Mardia’s coefficient > 8. Multivariate outliers were evaluated by assessing the Mahalanobis distance. Items with a Mahalanobis distance of al tests .Four hundred and twenty women with breast cancer participated in this study (mean age = 47.63 ± 11.08 years). Most participants (83.1%) were married, 71.6% had an under-diploma education, and the mean number of years of disease was 3.37 ± 1.27. Other demographic, social, and cancer-related information about the patients is provided in Table After completing the translation process, the face validity of the items in the Persian version of the questionnaire was approved by 10 patients with cancer. Understanding the difficulty of the items, understanding the expressions, and the items’ apparent fit with the central objective of the questionnaire was acceptable for the patients. In addition, none of the items underwent semantic changes owing to semantic differences, and all items entered the content validity process.Regarding CVR, obtaining scores lower than acceptable values in Lawshe’s table for 15 experts (less than 0.49) omitted the items, but all items with acceptable CVRs were between 0.8 and 1. The CVIs of all items were acceptable (0.7<). Finally, S-CVI/Ave was calculated to be 0.92.Skewness, kurtosis, and Mardia’s coefficient of the data were assessed to determine the CFA type. The skewness values of all the variables were between −3 and + 3, and their kurtosis values were between − 10 and + 10. Therefore, an assumption of normality was established.2/df and fit indices indicated that the five-factor model of the Persian version of the HLI-BCS had a good fit for patients with breast cancer , physical health (r = 0.786), and mental health (r = 0.809) , environment and physiology (3 items), health responsibility and stress management (5 items), social and interpersonal relations (3 items), and spiritual growth (4 items). The results indicated that the HLI-BCS had satisfactory validity and reliability with appropriate model fit indices, high levels of internal consistency reliability, and convergent validity to measure healthy lifestyles in breast cancer survivors in Iran.To evaluate the validity of the Persian version of the HLI-BCS, face validity was used in breast cancer survivors, and content validity was used in a group of experts experienced in caring for cancer patients. The S-CVI/Ave index of 0.92 for the Persian version shows that the questionnaire’s content has been confirmed, considering the sociocultural status of breast cancer survivors in the Iranian community. Acceptable CVR and CVI for the Persian version indicate that the questionnaire’s content has appropriate quality, given the clinical characteristics of these patients in the Iranian community. In the original version of the questionnaire, content validity was assessed by five experts, but there needs to be a report on calculating CVR and CVI. In addition, HLI-BCS is yet to be assessed psychometrically in other communities.The current research confirmed the structural factors of HLI-BCS in the Iranian community using CFA. The factors and 20 items were confirmed in the original version using CFA and favorable fit indices. The five factors of the Persian version of the HLI-BCS are dietary habits, environment and physiology, health responsibility, stress management, social and interpersonal relations, and spiritual growth. Dietary habits refer to the survivors’ dietary habits and preferences and the nutritional value of the selected foods. Environmental and physiological factors are related to perceived physiological problems and the perception of probable contamination sources in the current environment. Health responsibility and stress management factors indicate one’s perceived responsibility and the emotional and stressful reactions survivors face in their daily life or work. Social and interpersonal relationship factors reflect survivors’ general perceptions and feelings regarding social and interpersonal relations. The spiritual growth factor refers to survivors’ willingness to provide feedback and accept others in their lives , 24.The convergent validity of the Persian version of the HLI-BCS was confirmed by its correlation with the SF-12 quality of life. A significant correlation was observed between a healthy lifestyle and quality of life scores in breast cancer survivors. In similar studies, having a healthy lifestyle, including adequate exercise, proper consumption of fruits and vegetables, weight loss, and satisfactory sleep, effectively improved the quality of life concerning the health of breast cancer survivors –28. ImprIn the current study, the dimensions of social and interpersonal relations and spiritual growth had the highest correlations with mental health. In addition, the total quality of life score was highly correlated with spiritual growth in the Iranian population with breast cancer. Some studies have indicated that increasing spiritual/religious activities and, in particular, increasing the frequency of attending spiritual/religious activities, the social support present in religious groups, and relaxation by attending homogeneous groups regarding the disease are related to improving health status –31. In aThe internal consistency and stability of the scales were measured to determine their reliability. Internal consistency was evaluated by calculating Cronbach’s alpha coefficient. The alpha coefficient of the total scale was 0.84, which was acceptable. For all factors, the Cronbach’s alpha coefficient was higher than 0.7, indicating the consistency of the items in a factor and measuring similar properties. ICC was then calculated for the total scale to determine its stability. The ICC value was 0.79, indicating stability of the scale over time. In the HLI-BCS for internal consistency, a Cronbach’s alpha of 0.82 was obtained for the total instrument, and a test–retest reliability of 0.86, were obtained for the total instrument . TherefoThe first limitation of this study may be recall bias, because the data were collected using self-report questionnaires. Another limitation is that the validity and reliability of the Persian version is limited to a geographical region. It is better to conduct more methods of construct validity with more diverse samples to ensure strong psychometric properties of the instrument.Nurses are responsible for institutionalizing health in society worldwide, including Iran. For this purpose, they must create a culture in which individuals are unconsciously inclined toward healthy lifestyles. This effort requires a complex process based on a proper understanding of lifestyle and the relationships among various constituent elements of a healthy lifestyle. In other words, the prerequisite for achieving this goal is the ability of nurses to accurately recognize and assess how individuals behave and to compile an appropriate program based on a valid and reliable measurement. This study helped to develop a valid and reliable instrument with favorable characteristics compatible with the conditions of breast cancer survivors that can be used to provide adequate and precise information on the lifestyle of these individuals.


Non-specific building-related symptoms (NBRSs) describe various symptoms in those affected. Questionnaires are the first step in investigating suspected NBRSs in office environments and have been used for over two decades. However, changes in reporting of symptoms among office workers over time are currently unknown. The overall aim was thus to investigate if reported symptoms and perceived causality to the office environment have changed during 25 years of using the MM 040 NA Office questionnaire. A cross-sectional study of 26,477 questionnaires from 1995–2020 was conducted, where 12 symptoms and perceived causality to office environment were examined using logistic regression analyses of 5-year groups adjusted for sex and atopy. Reporting trends in the year groups varied slightly among symptoms, but eight symptoms were statistically significant in the 2015–2020 group compared to the 1995–1999 group. Seven symptoms had increased: fatigue, heavy-feeling head, headache, difficulties concentrating, itchy/irritated eyes, congested/runny nose, and dry/red hands. One symptom decreased: hoarseness/dry throat. Perceived causality of symptoms to the office environment decreased to a statistically significant degree in 2015–2020 for 11 symptoms, and there was an overall trend of decreasing perceived causality throughout the year groups for most symptoms. The observed time trends suggest a need for up-to-date reference data, to keep up with changes in symptom reporting in office environments over time. Most people spend the majority of their time indoors, which places demands on interior environments to facilitate health and wellbeing ,2,3. IndBRI includes diseases, such as Legionnaires’ disease, where air contaminations or other clear environmental problems cause a specific pathological condition in the exposed individuals, and objective findings support the diagnosis ,8,9. NBRPersonal factors such as atopy and female sex have been previously shown to also be important risk factors for NBRSs ,8,12. AtPsychosocial stress in the work environment is of significance for symptom reporting. Work-related stress was associated with more symptoms in previous studies ,15. A reExposure to adverse environmental factors in the office environment, such as air pollutants, insufficient ventilation, uncomfortable temperatures, poor air quality, excessive noise, harsh lighting, vibration, or psychosocial stress, can affect perception of the office environment and reporting of symptoms ,9,16,17.Assessment strategies typically involve systematic investigations of the building, involving technical aspects and questionnaires about environmental perceptions and perceived symptoms among workers—including temporal symptom patterns—to rule out other medical causes. Investigation methodologies utilized in Sweden are, e.g., the SWESIAQ methodology and the Örebro model ,21. The It can reasonably be assumed that patterns of questionnaire responses have been affected by changes over time in the office environment. For example, methods for construction of buildings, office layouts, climate comfort systems, emissions and chemicals emitted from available materials, and choices of furnishing all contribute to indoor air quality, as do other factors, such as noise and psychosocial contexts. The objective of this study was to investigate if reported symptoms and attribution to the office environment from the Örebro model questionnaire have changed over time between 1995 and 2020 in Sweden.This was a cross-sectional study of “MM 040 NA Office” questionnaires, collected by the Department of Occupational and Environmental Medicine in Sweden between the years 1995 and 2020. The questionnaires were completed by Swedish office workers in cases where symptoms attributed to the office environment were suspected among the employees, which was why the workplace had initiated contact with the Department of Occupational and Environmental Medicine and requested a survey. The questionnaire answers for the study were retrieved from a database at the Department in Örebro, which included questionnaires collected nationwide from year 1995 to 2014, and thereafter from four out of 21 counties  from the years 2015 to 2020.The initial dataset consisted of 26,478 questionnaires completed between 1995 and 30 April 2020. Exclusion criteria were age below 18 or over 70, excluding one questionnaire where the person was under 18. The final study material consisted of 26,477 questionnaires originating from 432 Swedish office workplaces.The questionnaire was administered in Swedish and contained items about the respondents’ background , working conditions , perceived office environment , psychosocial working conditions, and symptoms  . The queQuestionnaires were subdivided into five 5-year groups based on year of filling in the questionnaire: 1995–1999, 2000–2004, 2005–2009, 2010–2014, and 2015–2020. The year group 1995–1999 was selected as reference group for the analyses. Logistic regression analysis adjusted for sex and atopy status was used to study associations of questionnaire answers between the reference year group and later year groups. Answers regarding symptoms and perceived causality were dichotomized, i.e., all answers “Yes often” to symptom and of those, “Yes” answers to perceived causality to the office environment, were included in the analyses. Logistic regression analysis was also used to study associations of sex (women vs. men) and atopy (atopy vs. no atopy) on symptom reporting in years 2000–2020 compared to 1995–1999. The results are presented with odds ratios (OR) with 95% confidence intervals (CI). Considering the possibility that each respondent would not answer all questions in the questionnaire, an internal loss throughout the material was presupposed. The significance level was set at 0.05. Statistical analyses were performed with IBM SPSS Statistics version 27.This study was carried out in accordance with the Declaration of Helsinki. An application to the Swedish Ethical Review Authority was not necessary for this study since the material consisted of anonymous data, collected nationally in Sweden between 1995 and 2020. Questionnaire answers were collected and stored in a register with permission from the National Board of Health and Welfare, and the physical questionnaires destroyed. The respondents had not received information about the register. Answers are only shown at a group level, and since there is no code key they cannot be linked to a specific city, workplace, or person, and the risk of invasion of privacy is therefore low. This research can add information on symptoms in office environments and enable future research on the subject, for example, on groups with increased risk. Consequently, important knowledge can be added, concurrently, as the risk of harm to individuals is considered very low.General characteristics of the respondents and year groups are shown in Among all respondents, 50% reported having at least one of the 12 symptoms often (at least once every week), and 64.6% of those reported that they believed the work environment was the cause of the symptom. Among the 13,244 respondents from all year groups who reported at least one symptom, fatigue was the most frequently reported symptom during the time period, with an average of 58% of respondents, followed by heavy-feeling head (31.5%), itch/stinging/irritation in eyes (30.0%), irritated/congested/runny nose (28.2%), headache (22.2%), hoarseness/dry throat (19.7%), dry/red skin on face (19.7%), dry/itchy/red skin on hands (16.8%), scaly/itchy scalp or ears (14.6%), difficulties concentrating (12.4%), cough (11.6%), and nausea/dizziness (3.8%).A perceived causality to the office environment among the reported symptoms was on average most often reported for itch/stinging/irritation in eyes (76.5%), followed by hoarseness/dry throat (72.4%), heavy-feeling head (71.2%), difficulties concentrating (69.4%), headache (64.0%), dry/red skin on face (61.2%), irritated/congested/runny nose (59.4%), cough (58.1%), fatigue (53.3%), dry/red skin on hands (46.6%), nausea/dizziness (45.0%), and scaly/itchy ears or scalp (35.4%). Year group frequencies and percentages of the 12 symptoms from the questionnaire and the perceived causality to the workplace for each symptom are presented in The reporting of general symptoms increased slightly over time, with the exception of nausea/dizziness . The repOf the three skin symptoms, the reporting of dry, itchy, or red skin on hands increased to some extent in the year group 2015–2020 compared to 1995–1999, whereas the other two symptoms varied slightly over the whole time period and were at about the same level in the year group 2015–2020 as in 1995–1999.The reporting of the perceived causality of the symptoms to the office work environment decreased in general between 1995 and 2020. The only exception is the reporting of nausea/dizziness, which varied more over time and also increased in the year group 2015–2020 compared to 1995–1999.p-values < 0.001. Previous or current eczema, allergic rhinitis, or asthma—indicators of atopy—were also associated with greater odds for reporting any symptom in this study, with the smallest effect on difficulties concentrating, OR 1.49, and the greatest effect on scaly or itchy ears or scalp, OR 3.33, all p-values < 0.001 . Women had greater odds than men for reporting any of the 12 symptoms in the office environments of this study, as presented in  < 0.001 . Sex hadp < 0.01), fatigue significantly increased in three of the year groups , but not in 2005–2009 (p > 0.05), and heavy-feeling head , as well as headache , increased significantly only in the last year group, 2015–2020. The reporting of itchy, stinging, or irritated eyes significantly increased in the last year group  as well as irritated, congested, runny nose  and cough only in 2010–2014 . A significant decrease in reporting of hoarseness/dry throat occurred in three of the year groups between 2005 and 2020 . Of the skin symptoms, only dry, itchy, or red skin on hands significantly increased in the last year group, 2015–2020 , having significantly decreased in year group 2005–2009 . Dry or red skin on face significantly decreased in 2005–2009  and 2010–2014 .Associations between year groups and reported frequencies of symptoms and perceived causality to the office environment were examined with logistic regression analyses adjusted for sex and atopy, and with the earliest year group, 1995–1999, as reference (OR 1). Unadjusted analyses are shown in p < 0.05). Nausea/dizziness significantly decreased in 2005–2009  and 2010–2014 , as did difficulties concentrating in 2010–2014  and 2015–2020 . The significantly largest reductions over time (between 2005 and 2020) for reporting perceived causality to the office environment occurred for hoarseness/dry throat , dry or red skin on face , itchy, stinging, or irritated eyes , irritated, congested, runny nose , heavy-feeling head , and cough —see In ten of 12 symptoms, the reporting of perceived causality to the office environment resulted in statistically significant decreased reporting in all year groups compared to the 1995–1999 year group , 18% of participants reported a work-related symptom . In thatThe descriptive results show that the proportion of respondents with frequent symptoms at least once every week varies over time depending on the type of symptom. For the vast majority of symptoms, there are small changes in symptom prevalence between 1995 and 2014, but during the period 2015–2020, the prevalence increases somewhat more, mostly for difficulties concentrating, thereafter for dry, itchy, or red skin on hands, headache, itchy, stinging or irritated eyes, irritated, congested, or runny nose, heavy-feeling head, and fatigue. The results for the perceived causality of symptoms to the office environment show an opposite trend. For a majority of the symptoms, a decrease in reporting was seen over time—mostly for cough, hoarseness, or dry throat, dry or red skin on face, and irritated and congested or runny nose, but there are also reductions among the other symptoms.Adjustments of data were performed for sex and atopy, both presumed to influence symptom reporting. There were more women than men in the present study, and women and persons with suggested atopy had greater odds for reporting symptoms in the office environments, comparing respondents of all years (2000–2020) to the reference year group (1995–1999). More symptoms reported among women are in accordance with other studies ,25,26,27Logistic regression analysis of time trends for reported symptoms adjusted for sex and atopy of the 12 examined symptoms in the present study showed some statistically significant increased reporting between 2000 and 2020 compared to the period 1995–1999. In particular, the results over time showed an increasing trend of difficulties in concentrating, but also fatigue. Furthermore, five of the symptoms—headache, heavy-feeling head, eyes, nose, and hands—increased significantly in the last year group 2015–2020 compared with 1995–1999. Conversely, hoarseness decreased significantly between 2005 and 2020, and nausea/dizziness between 2010 and 2014. The observed time trends strongly suggest a need for recurrent audit of the questionnaire, e.g., to enable capture of the most up-to-date reference data, in order to keep up with changes in symptom reporting in office environments over time. The outcome of the time trends was, however, not affected by the adjustments of data. Results from logistic regressions of unadjusted data are shown in Possible reasons for the observed time trends of reported symptoms in the present study could be multifactorial, involving, for example, workload of the office workers that may not have been consistent over time, as well as changes in office landscapes, construction, and building materials—affecting indoor climate and concentration patterns of air pollutants. Occupants of offices with higher concentrations of selected air pollutants have been shown to be more likely to report health symptoms in several recent studies ,28,29,30Other possible reasons which might explain the time trends could stem from outside of the actual offices, especially considering the findings of this study that respondents in later year groups less often viewed the office environment as cause for their symptoms. Firstly, Internet usage and social media have become significantly more common in recent years, and many workers are often online or reachable for a large part of the day. Research on the effects of this on mental health, such as increased tiredness and depression, has increased in recent years . This coLimitations of the present study should also be discussed. The 2015–2020 year group included four more months than the other groups, but was the only group encompassing only four counties, resulting in a numerically smaller year group. Previous studies showed a slightly higher asthma prevalence in northern parts of Sweden (8.5% compared to 7%) , and anoThe intention in the present study was to include childhood and current eczema, rhinitis, and asthma, as this would suggest atopy. Atopy and the pathogenesis of development of asthma are linked. There are, however, non-allergic forms of eczema, rhinitis, and asthma, e.g., adult-onset asthma, which are less associated with atopy. In this study, answering “yes” to, e.g., asthma would automatically include the respondent in the “atopy group”, without distinguishing between types of asthma. Non-allergic asthma in one study was prevalent in 39% of adult asthmatics, and was more common among women than men . Adult-oSelf-administered questionnaires are based on subjectively based information, and exaggerations, understatements, and recall bias are all possible. Furthermore, internal loss is difficult to avoid with this sort of study design. However, the internal loss of 0–5.0% per question in this study with 26,477 questionnaires was considered an acceptable amount, with no significant impact on the results.This study found changes over time where reporting of the majority of symptoms in the questionnaire increased in the later years. Conversely, the perceived causality to the office environment had decreased over time for all symptoms but one. The reasons behind the time trends are most likely multifactorial, involving the inherent reporting bias of self-administered questionnaire data and altered characteristics of the work environments, as well as societal changes related to the digital media landscape affecting health and the public’s view on causality with indoor environments. Further research is required to confirm these results, identify specific causes to the time trends, and enable suitable measures and preventive actions for improved health in office environments. Accordingly, the results strongly suggest a need for recurrent audit and development of the utilized questionnaire, e.g., enabling capture of the most up-to-date reference data, in order to keep up with changes in symptom reporting in office environments over time.


Hemorrhage transformation (HT) is the most dreaded complication of intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). The prediction of HT after IVT is important in the treatment decision-making for AIS. We designed and compared different machine learning methods, capable of predicting HT in AIS after IVT. A total of 345 AIS patients who received intravenous alteplase between January 2016 and June 2021 were enrolled in this retrospective study. The demographic characteristics, clinical condition, biochemical data, and neuroimaging variables were included for analysis. HT was confirmed by head computed tomography (CT) or magnetic resonance imaging (MRI) within 48 h after IVT. Based on the neuroimaging results, all of the patients were divided into the non-HT group and the HT group. Then, the variables were applied in logistic regression (LR) and random forest (RF) algorithms to establish HT prediction models. To evaluate the accuracy of the machine learning models, the models were compared to several of the common scales used in clinics, including the multicenter stroke survey (MSS) score, safe implementation of treatments in stroke (SITS) score, and SEDAN score. The performance of these prediction models was evaluated using the receiver operating characteristic (ROC) curve (AUC). Forty-five patients had HT (13.0%) within 48 h after IVT. The ROC curve results showed that the AUCs of HT that were predicted by the RF model, LR model, MSS, SITS, and SEDAN scales after IVT were 0.795 , 0.703 , 0.657 , 0.660  and 0.655 , respectively. The RF model performed better than the other models and scales. The top four most influential factors in the RF importance matrix plot were triglyceride, Lpa, the baseline NIHSS, and hemoglobin. The SHapley Additive exPlanation values made the RF prediction model clinically interpretable. In this study, an RF machine learning method was successfully established to predict HT in AIS patients after intravenous alteplase, which the sensitivity was 66.7%, and the specificity was 80.7%. Stroke is a major global public health issue with high morbidity and mortality. According to China's Ministry of Health, 77.8% of strokes are ischemic . CurrentPrevious reports have indicated that there are a number of clinical, laboratory, and radiographic factors associated with the risk of HT after alteplase. A systematic review and meta-analysis of 55 studies have reported on factors that are associated with HT, and these included age; the severity of the stroke; the baseline glucose; the use of antiplatelet drugs or statins; leukoaraiosis; early signs of infarction on head CT; the presence of atrial fibrillation, diabetes, previous ischemic heart disease or cerebral vascular diseases; and congestive heart failure . LipoproMachine learning (ML) is a branch of artificial intelligence that can establish ideal models for classification, prediction, and estimation by allowing computers to “learn” from large, noisy or complex input and output datasets . In receAIS patients treated with rt-PA therapy after admission to Zhongda Hospital Affiliated to Southeast University between 1 January 2016 and 30 June 2021 were enrolled in this retrospective study. Inclusion criteria were as follows: (1) age ≥ 18 years, (2) AIS confirmed by magnetic resonance imaging (MRI), and (3) onset of stroke symptoms within 4.5 h and treated with rt-PA. Exclusion criteria were as follows: (1) additional endovascular therapy after intravenous thrombolysis, (2) no head computed tomography (CT) or MRI patients within 48 h after intravenous thrombolysis, (3) patients treated with urokinase thrombolytic therapy. This retrospective study was approved by the Research Ethics Committee of Affiliated ZhongDa Hospital and the Southeast University .The clinical data were collected by a certified stroke neurologist. Overall, 61 clinical variables were initially selected for the model construction.The study collected demographic data including patient sex, age, body weight, past history , clinical characteristics, including baseline indicators , the time from onset to thrombolytic therapy (OTT), the rt-PA dose (0.9 or 0.6 mg/kg), the NIHSS score (1 h after IVT), the NIHSS score (2 h after IVT), and the laboratory test results on the second day after IVT.The SEDAN, MSS, and SITS scores were used for the measuring the HT scores, all of the patients were evaluated based on the scale, and they were evaluated after IVT and after having medications for 48 h. When the score was higher, there was a greater risk that the AIS patient would develop HT after IVT.To compare the machine-learning risk algorithms, the study population was split into a “training” cohort from which the HT risk algorithms were derived and a “validation” cohort in which the algorithms were applied and tested. The “training” cohort was derived from a random sampling of 80% of the AIS patients, and the “validation” cohort was comprised of the remaining 20% of the AIS patients. The machine learning models were trained with all of the variables as inputs to classify the patients who were likely to have HT after IVT for AIS. Two of the commonly used classes of machine-learning algorithms were utilized: logistic regression, and random forest. To evaluate the accuracy of the machine learning models, we calculated three of the common scales used in the clinic as references: the MSS score, SITS score and SEDAN score. An ROC (receiver operating characteristic) curve was used to evaluate the performance of the models.The effects of the features on the RF prediction model were measured using the functions of the SHapley Additive exPlanations (SHAP) Python package (version 0.40.0), which assessed the importance of each feature using a game-theoretic approach .t-test or a non-parametric test. Categorical data were compared using the χ2 test. P-values were corrected for multiple testing with the Benjamini-Hochberg false discovery rate (FDR) correction using the Statsmodels package in Python. In all cases, FDR-adjusted P < 0.05 was considered to indicate statistical significance.SPSS 22.0 was used for the descriptive analysis and the comparison of clinically defined groups. Continuous variables are expressed as means ± SD or as medians (interquartile range). Categorical variables are expressed as percentages. Continuous data were compared between the groups using p-value: 0.026), had higher baseline NIHSS scores , NIHSS scores 1 h after IVT , NIHSS scores 2 h after IVT , PT values , and INR values , and they had lower RBC counts , hemoglobin , lymphocytes , and triglycerides after IVT . Also, more of patients who developed HT had cardioembolic events  compared to the non-HT group. However, there were less HT patients that had small vessel occlusion  compared to the non-HT group. The demographic and clinical characteristics of this study population are shown in A total of 498 patients who received IVT with rt-PA within 4.5 h of stroke onset were included in the cohort during the study period. Ultimately, 345 patients were included , after eThe ROC curve results showed that the AUCs of HT, as predicted by the RF model, LR model, MSS, SITS, and SEDAN scores after IVT in AIS patients were 0.795 , 0.703 , 0.657 , 0.660  and 0.655 , respectively. When the optimal cutoff value of the RF model was 0.169, the sensitivity was 66.7%, and the specificity was 80.7%. When the optimal cutoff value of the LR model was 0.140, the sensitivity was 60.0%, and the specificity was 78.0%. The RF model performed significantly better than the other models. The AUCs are presented in A SHAP summary plot was used to illustrate the positive or negative effects of the features attributed to the RF model . The SHAIn this retrospective cohort study, we developed and validated machine learning algorithms using 61 features to predict HT after IVT for AIS. The results demonstrated that the use of machine learning models can accurately predict HT. The RF model performed better than the LR model in predicting HT.Numerous factors affect, with varying significance and mechanisms, the development of HT after IVT in AIS patients. To avoid HT as much as possible, it is important to consider as many influential factors as possible before proceeding with IVT. Unfortunately, the scales that are commonly used in the clinic, such as the MSS score , SITS scMany risk factors have been confirmed to be associated with HT after IVT. A systematic review and meta-analysis of 55 studies reported that age, severity of the stroke, baseline glucose, use of antiplatelet drugs or statins, leukoaraiosis, early signs of infarction on head CT, and the presence of atrial fibrillation, diabetes, previous ischemic heart disease or cerebral vascular diseases, and congestive heart failure were associated with HT after IVT . In addiThe NIHSS score is widely used to assess the clinical stroke severity. It has been suggested that the baseline NIHSS score is an independent risk factor for HT after IVT and that a high NIHSS score is a predictor of HT , 29. MorThe patient's blood pressure , especiaA high NLR was reported to predict HT in AIS patients after IVT in previous studies , 26–28. Our study also obtained some new findings. The factors that were ranked in the top four factors in the present study were triglyceride, Lpa, the baseline NIHSS and hemoglobin, among which, triglyceride, Lpa, and hemoglobin were negelected by commonly used scales in clinic currently.Several studies have shown that a high level of triglycerides contributes to atherosclerosis –37, whilThe results from previous reports on the association between Lpa and stroke are controversial. Several studies have shown that there is no evidence of an association between the Lpa levels and stroke , 40. HowIt has been demonstrated that lower hemoglobin levels on admission are associated with hematoma expansion (HE) after intracranial hemorrhage and worse clinical outcomes . As indiThere are several limitations in the present study. First, this was a single-center retrospective study, and this study requires validation with larger datasets from other sources. Additionally, the data was too small to further analysis the prediction of SICH. Second, the algorithm was built from the input features, and some hidden relationships may have been ignored because unknown or neglected features were not evaluated by physicians. Third, the patients did not have susceptibility-weighted imaging (SWI), which might have led to an underestimation of HT.This study demonstrated that machine learning algorithms, especially the RF model, can improve HT prediction for ischemic stroke patients after intravenous alteplase. It may aid clinicians, as well as patients and families, in the process of decision-making when determining the AIS patient's eligibility for thrombolytic treatment.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Research Ethics Committee of Affiliated ZhongDa Hospital and the Southeast University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.YX and XL conceived and designed the research. ZZ and AJ provided technical assistance. YX and DW performed the experiments and plotted the figures. YX wrote the manuscript. XL checked the manuscript and made final modifications. All authors have read and approved the submitted version.This study was supported by the Nanjing Medical Science and Technique Development Foundation (No. YKK21217).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.


Multicomponent physical exercise is the most recommended type of physical intervention in older adults. Experimental data suggest the relevance of the muscle-brain axis and the relationship between muscle contraction and release of brain-derived neurotrophic factor, however, the impact of this relationship on cognition remains unclear, especially in people with diagnosis of cognitive impairment. This study assesses the effect of multicomponent physical exercise on global cognition in people with mild cognitive impairment or dementia.Randomized controlled trials published until January 2021 were searched across three electronic databases . Data about exercises included in the multicomponent intervention , the inclusion of aerobic exercise, and the change in global cognition were extracted. The effect size was represented as a standardized mean difference. Risk of bias was assessed by the RoB2 tool.A total of 8 studies were included. The overall effect size suggested an effect of multicomponent exercise on global cognition. However, the subgroup analysis showed an effect only when aerobic exercise was included in the intervention. No effect when mild cognitive impairment and dementia were assessed separately was found.This study suggests that multicomponent physical exercise could have an effect on global cognition in people with mild cognitive impairment or dementia only when aerobic exercise is included in the intervention. Our results support the inclusion of structured physical exercise programs in the management of people with cognitive impairment.The online version contains supplementary material available at 10.1186/s12877-022-03302-1. In recent decades we are living a paradox, we have experienced a steady increase in life expectancy, which has been accompanied by an increase in chronic conditions and associated with a high functional cost . This fuCurrently, there is not enough evidence available for disease-modifying pharmacological treatments , and theAmong the effects of the different types of physical exercise on the cognition of people with cognitive impairment, some questions remain unanswered, such as the effect of multicomponent physical exercises. This type of exercise includes endurance, strength, balance, and flexibility training , and is The effects of multicomponent physical exercise on cognitive function, especially in people diagnosed with cognitive impairment, are still unclear. Therefore, the aim of this systematic review and meta-analysis is to estimate the effect of multicomponent physical exercise on global cognition in people with MCI or dementia.The protocol of this systematic review was registered at the International Prospective Register of Systematic Reviews (PROSPERO), with the register identification CRD42020184660. In addition, the protocol was approved by the Ethics Committee of the Pontificia Universidad Javeriana and the Hospital Universitario San Ignacio.A search was performed on MEDLINE (via PubMed), Scopus, and Cochrane Database up to January 2021. The search was aimed to identify published randomized controlled trials assessing the effect of multicomponent physical exercise on global cognition in people with dementia and MCI. Global cognition was considered the outcome because it is the best measurement of the cognitive function in patients with dementia and MCI and is the most common way to assess cognition in the included randomized controlled trials. We examined the reference list of eligible studies to expand the search. The complete MEDLINE search strategy is displayed in Supplementary material (Supplementary Table SThe studies included in this systematic review met the following inclusion criteria: (i) Participants: adult participants with dementia or MCI secondary to either. (ii) Intervention: multicomponent physical exercise defined as an exercise program including endurance, strength, balance, or flexibility . We inclAfter defining the search strategy, all records were imported into the reference management system  to exclude duplicate records. Two authors (LVS and CAB) independently performed the search literature and data extraction, with the intervention of a third author in case of disagreement (ICR). The following data were extracted from the selected studies using an ad-hoc form: author, publication year, country, sample size, losses, female proportion, mean age in control and intervention group, type of cognitive impairment, types of physical exercises included in the intervention, length of the intervention (weeks), number of sessions per week, duration per session (minutes), type of control group, the intensity of the multicomponent exercise (as reported by each study), cognitive assessment tool and effect on global cognition.The risk of bias was assessed independently by two authors using the revised Cochrane risk-of-bias tool for randomized trials (RoB2) . The RoB2 statistic [2 statistic was calculated and interpreted as low when τ2 was lower than 0.04, moderate when was from 0.04 to 0.14 and as substantial when it was from 0.14 to 0.40 [The effect size (ES) and 95% confidence intervals (CIs) for the effect of physical exercise programs on global cognition were calculated using the Cohen’s d index. A pooled ES was estimated using a random-effects model based on the Der Simonian and Laird method . We constatistic , whose v to 0.40 . In caseThe small study effect was graphically assessed using a funnel plot, additionally, the Egger test was estimated. Finally, the trim-and-fill analysis was used to estimate the number of studies needed to remove publication bias, and to estimate the ES without publication bias. Stata/IC software, version 16.1 for Windows was used for statistical analysis.A total of 2789 records were found following the search strategy. After removing duplicates, and reviewing the title and abstract, 31 relevant papers were chosen for full reading. Finally, only 8 articles met the inclusion criteria  . Dependi2 = 41.21%). Between-trials heterogeneity was considered moderate (τ2 = 0.06).The ES of multicomponent physical exercise on global cognition in MCI and dementia was 0.34 . We found a moderate inconsistence  for dementia and 0.34  for MCI. For the subgroup analysis by the inclusion of aerobic exercises in the exercises protocol, the ES was 0.32  for those multicomponent physical exercise including aerobic exercise and 0.44  for those not including aerobic exercise, respectively  and Kwak et al. . Omitting the study of Kemoun et al., the only study that did not include strength exercises in the intervention, the effect size was 0.27 (95% CI: 0.02–0.52). . The trim-and-fill analysis showed that only one study was needed to remove the small study effects and that the ES of observed and imputed studies would be 0.274   and brain-derived neurotrophic factor (BDNF), a factor that promotes the growth and differentiation of neurons and supports the survival of existing neurons, was previously explored. It seems that blood levels of BDNF are not affected by the multicomponent physical exercise intervention . This reThis study shows the importance of included a physical exercise intervention in the management of patients with cognitive decline including both aerobic and multicomponent exercise , independently of the stage of cognitive impairment. As far as we know, this is the first systematic review and meta-analysis that explores the effect of multicomponent physical exercise intervention on cognition in patients with MCI and dementia, using the accepted definition of multicomponent physical exercise in the inclusion criteria. However, our study has some limitations. First, no information on independent cognitive domains was found, so only data on global cognition was reported. Second, few primary studies were found with a small sample size and therefore small study effects was found in the analysis. Third, only two studies did not include aerobic exercise as part of the intervention and presented a high heterogeneity between them. Finally, only published papers in English and Spanish were included, so no information on other languages was included.This systematic review and meta-analysis suggests a positive effect of the multicomponent physical exercises on global cognition in people with MCI or dementia specially when aerobic exercise was included in the exercise protocol. However, due to the limitations of the included studies, these findings should be cautiously interpreted. Well-designed clinical trials comparing aerobic exercise to multicomponent exercise should be conducted to clarify the true effect on cognition. However, our results support the needed to include physical exercise in the cognitive rehabilitation protocols and cognitive impairment therapies.Additional file 1: Supplementary Table S1. PubMed search strategy until January 2021. Analogous search strategies were used for Scopus, and Cochrane Database. Supplementary Table S2. Articles excluded. Supplementary Figure S1. Risk of bias using the Cochrane Collaboration´s tool for assessment of risk of bias (RoB2): A. Intention-to-treat effect; B. Per-protocol effect. Supplementary Figure S2. Publication bias.