Pediatric palliative care (PPC) is defined as the prevention and relief from suffering of families and children with life-limiting (LLDs) or life-threatening diseases (LTDs). These patients often experience pain, with morphine being the most widely used drug to treat it. Few studies investigated the role of methadone in PPC patients, although it is considered among the most effective and underutilized drugs in PPC.Our aim was to evaluate the efficacy, safety, and dosage of methadone in PPC.Between August and October 2021 PubMed, Scopus and the Cochrane Library were searched for studies on the use of methadone in children with LLDs and LTDs. Articles were included if they met the following criteria: published in the last 10 years, English language, patients aged 0–23 years; children enrolled in a PPC center or receiving declared support from a PPC service; reporting of specific data on methadone in interventional trials, observational studies, or case series on >10 patients. The reporting of the article was guided by the PRISMA guidelines, and a critical appraisal of the included studies was performed using the JBI-tool.After duplicates removal and full-text assessment, four studies were included and another one was added after checking the references of the retrieved papers. All were retrospective, and the literature is concordant in documenting the lack of evidence. A total of 116 children received methadone in PPC. From our review emerges the poor quality of data collection: in only one study pain was assessed with standardized scales. All studies documented the effectiveness of methadone in treating complex pain, either nociceptive or neuropathic. No serious adverse events were reported, with no cases of cardiac arrhythmias.Our results suggest that methadone could represent a suitable strategy for treating pain in PPC. However, the evidence base is insufficient, and further research is warranted. Pediatric palliative care (PPC) is defined as the prevention and relief from suffering of children with life-limiting or life-threatening diseases and their families . Pain isOpioids play a central role in the management of pain in PPC, with morphine being the most widely used drug , 5. AmonIn this systematic review, we evaluated the efficacy, safety, and dosage of methadone in PPC.A preliminary research was conducted in August 2021 to rule out the possibility of an already existing review on the topic and to identify the keywords and selection criteria. Articles published in the last 10 years in English language were considered for inclusion if they met the following criteria: patients aged 0–23 years , 13; chiA systematic review of literature was performed following the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines , and theThree databases  were browsed until October 30th, 2021. Searches used both controlled MeSH and free terms, and the descriptors were combined using Boolean operators. The search strategy and the key terms were adapted to the different databases .Titles and abstracts of the retrieved articles were independently assessed by three Authors  to identify the papers specifically referring to PPC; then, the full text of each paper was reviewed to assess the other inclusion criteria. The references of identified articles were screened to identify additional publications of particular relevance, even when not meeting all the selection criteria. Any disagreement was resolved by involving a fourth assessor (IA). Discarded papers could be considered for the Discussion on methadone therapy.We designed a data extraction form, which two authors used to extract data from selected studies. Extracted data were cross-checked. Disagreements were settled by discussion and, if necessary, with involvement of a third researcher.The extraction form included: name of first author, publication date, study design, study aim, sample size, setting, methadone treatment length, posology, method of administration, concurrent medications, efficacy, and adverse events. We sought data about efficacy/safety of methadone and its dosing. Any measure of pain was eligible for efficacy evaluation . We did not prepare a protocol and the review was not registered.The initial search identified 437 records; after duplicates removal, 343 articles were screened. Of them, 99 articles underwent full text evaluation for eligibility and 4 papers , 17–19 mIn the selected studies, a total of 116 pediatric patients received methadone; among them, 112 (96%) were affected by cancer pain.The main findings of the identified studies are summarized below. Studies are listed according to the number of patients evaluated.n = 2; 4%) or receiving only immediate-release opioid . Efficacy was assessed through an ad hoc pediatric symptom assessment system evaluating 11 physical and psychological symptoms. A five-point Likert scale (score 0–4) was used to register child and parent response for each symptom. Pain improved significantly over the entire follow-up period, as scored by the child (from a mean of 3.59 ± 0.61 standard deviation (SD) points to a mean of 1.80 ± 1.13 at the first follow-up) and the parent (from a mean of 3.46 ± 0.66 points to a mean of 1.35 ± 1.25 at the first follow-up). A similar trend was observed for insomnia and, partially, for fatigue. No cardiac arrhythmias, in particular no prolongation of QTc, or opioid-associated neurotoxicity  were reported.In a monocentric retrospective study, Madden et al.  evaluaten = 18; 90%) or neuropathic  advanced cancer pain during the last 4 weeks of life. Methadone was continued in 15 patients (75%) during the entire follow-up. Of the 20 patients, 8 (40%) received an ECG before starting methadone, and 6 had a monitoring of the ECG after initiation of therapy; no patient discontinued methadone due to an increased QTc interval. No other adverse events were mentioned.In a single-center, retrospective study, Hall et al.  evaluateIn a retrospective, monocentric study on 17 children with advanced cancer [median age 8.9 years (range 2–18)], Davies et al.  assessedn = 12; neurological conditions, n = 3; cardiac diagnosis, n = 1) received methadone for incomplete analgesia on other high-potency opioids (n = 9), adverse events from other opioids (n = 6) and desire to use oral analgesic (n = 3). Their mean age was 7.4 (1.3–16) years. Seven patients received methadone in a palliative care specialized setting and four were treated at home. Fifteen patients (94%) did not interrupt methadone and experienced improved pain control or reduced requirement of breakthrough medications. The most common symptoms reported in the early phase of the treatment were drowsiness, unsteadiness, itch, constipation, transient bradypnea and behavioral change. One patient had a treatment-emergent seizure with methadone being among the potential drugs involved. During methadone withdrawal, three patients experienced abstinence syndrome and pain rebound. In two patients, dose reduction was necessary due to adverse events.In a bicentric retrospective study , 16 chiln = 3; 27%) or mixed  pain and for whom first-line opioid therapy was ineffective  or associated with adverse events . Methadone was started in a hospital setting (n = 8) or at home (n = 3). Nine children received more than one administration of methadone . For three children, methadone was administered as the sole analgesic treatment. Five of the nine children who received more than one dose of methadone achieved adequate analgesia. The only adverse events reported were nausea  and tachycardia .In a monocentric retrospective study conducted in a low-resource setting in India, Palat et al.  evaluateIn the retrospective study of Madden et al.  the mediBoth Davies et al.  and MottIn the study by Mott et al. , one patn = 8, 50%), sublingual , intravenous  and subcutaneous . When given enterally, methadone was divided into three or four daily doses, while i.v. and s.c. formulations were given as a 24-h infusion.Routes of administration were enteral  including liquid formulation , safe usIndeed, in our systematic review, we were able to identify only five studies on methadone patients receiving PPC. Remarkably, all studies were uncontrolled and retrospective, and current literature is concordant in documenting the lack of evidence on this topic , 26–28.It must be pointed out, however, that interventional studies are not always feasible in the PPC setting and therefore anecdotal observations can have a role in providing evidence on drug therapy in this population .In the identified studies, the total population of children who received methadone in PPC was overall limited (116 patients), and the wide majority of them was affected with cancer-related pain. However, oncological patients represent only a minor proportion of children needing PPC , 29.As evidenced by the risk assessment, another finding emerging from our review is the poor quality of data collection. Indeed, in the studies by Hall et al. and Davies et al. , 20, thead hoc, non-validated pediatric symptoms assessment system. Only Palat et al.   , but theersion”) , while tersion”) , 25, calersion”) , 20; rapCurrent recommendations suggest a 1:1 conversion rate in case of lower and brief prior exposure to opioids, and ratios of 20:1 or higher in case of greater and longer prior opioid exposure , 18, 20.Available evidence, although collected in a limited number of patients and with an overall modest methodological quality, seems to suggest that methadone could represent a suitable strategy to treat complex pain in the PPC setting. It is however important to point out that no firm recommendation for its use can be made. Health care providers should be adequately trained before the use of methadone and careful monitoring of this treatment during the entire therapy course is crucial.To date, there is a large gap in the literature regarding the use of methadone in children with life-limited and life-threatening non-cancer conditions. The future goal will be to develop methodologically well-conducted interventional, if faisable, or observational studies with larger numbers that can lead to strong recommendations for the use of this drug, which, in the few studies conducted to date, has been shown to hold the potential for efficacy and safety for use in this population.Areas for further study on the use of methadone in pediatrics concern its use in intensive care and its use in the treatment of pain in oncology. However, most of the available literature concerns the adult population. Further evidence in PPC is needed for the correct use of methadone in pain management.On these bases, we believe that further research on methadone in the PPC setting is warranted. Randomized controlled trials may not be feasible, but high-quality prospective studies on the use of methadone in PPC should be planned and conducted.FBene, SZ, and AS accomplished the bibliographic review, selection and reading of articles, and drafted the manuscript. IA has revised the search strategy, resolved any disagreements, and reviewed the manuscript. FBeni supervised the entire research work and the writing of the article. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Welding fumes (WF) are a complex mixture of gas and particles. Action of occupational exposure to WF on cardiovascular system has been recently studied as for noise.The main objectives of our study are therefore to evaluate the impact of exposure to WF, noise, and combined WF and noise on autonomic nervous system as assessed by heart rate variability (HRV).The study groups were 16 welders and eight airport workers (as a control group). All the participants underwent ambulatory electrocardiogram, personal WF, and noise exposure monitoring, respectively, with dust track and calibrated noise dosimeter during workday. Atmospheric environmental assessments at workplaces have been also performed. HRV parameters were summarized for all the workday and hourly. Correlation tests were used to examine relation between HRV parameters and levels of noise exposure in the two population. Analysis of covariance (ANCOVA) was used for mean of each HRV parameters.p = 0.01) and RMSSD (p = 0.02) and decreases in LF/HF (p = 0.008). Indeed, the interaction between exposure to WF and mean noise levels for HF (p = 0.005), LF/HF (p = 0.01), and RMSSD (p = 0.007) was significant.For HRV parameters, we found significant higher levels for mean range of high frequency (HF), standard deviation of normal-to-normal R-R interval (SDNN), and root mean square of successive heartbeat interval difference (RMSSD) in welders which suggested an imbalance between sympathetic and parasympathetic nervous system in this population. For relation between noise and HRV parameters, we noted that levels of low frequency (LF), HF, and SDNN were significantly correlated with mean noise levels for welders , not in control group. Using ANCOVA, we found that working as a welder significantly increases mean of HF (This study shows an impact of WF and noise on ANS balance. One hypothesis is WF exposure could increase sensibility to noise exposure on autonomic nervous system or there is a synergic effect. A significant and positive correlation between exposure to WF and the risk of cardiovascular diseases (CVD), especially ischemic heart diseases, has been previously reported –3. WorkeTwo recent meta-analyses on the impact of noise on cardiovascular system concluded that living or working in an environment with noise exposure is associated with an increased risk of hypertension , CVD , and cardiovascular mortality  . Indeed,HRV is a non-invasive method to evaluate the balance of sympathetic and parasympathetic branches of the autonomic nervous system , 14. TimWelders are exposed both to WF and noise at work. However, we are not aware of studies reporting the combined effects of WF and noise in this population. The main objectives of our study are therefore to evaluate the impact of exposure to WF, noise, and combined WF and noise on autonomic nervous system as assessed by HRV.All participants were informed about the potential risks and discomforts associated with the study and gave their written informed consent prior to study enrollment. The protocol was approved by the Ethical Committee of the University Hospital of Brest and performed in accordance with the guidelines of the Helsinki Declaration for human research.This prospective study included two groups of workers: (1) ship repairing welders were exposed to noise and WF and (2) airport workers were exposed to noise only. We previously showed that airport workers had same cardiac status, educational level, and shift work conditions than welders . AirportThe study population was followed by the occupational health service. A special information session was provided by an occupational physician before inclusion. After acceptance, a complete medical and professional history, and a medical examination with blood pressure measurement were conducted by an occupational physician.WF exposure assessment was conducted by trained hygienists. Air samples were taken individually at work in a boat and at the airport (filter holder were placed on worker's shoulders) and environmental samples in different locations of the boat and the airport. Specific methods for air sampling are French-validated methods including Metropol M-274 for WF, M-43 for hexavalent chromium, and M-122 for other metals –26. For For noise exposure evaluation, employees wore a calibrated noise dosimeter  on their shoulders. The dosimeter allowed noise level measurements between 20 and 140 dB(A) every second. The measurements were A-weighted dB(A). All measurements were performed by an experimented occupational health technician. Data were analyzed with specialized software B&K 2245 Work Noise Partner. This process was in accordance with the AFNOR standard in ISO 9612 (May 2009). To assess noise exposure, we used two indicators: LAEq [average level of sound exposure per hour in dB(A)] and LPC [peak sound pressure level in dB(A)]. Workers from the two groups wore same type of ears' sound protection.We used an ECG Holter monitor . Workers wore a standard five lead ECG Holter monitor at work. HRV measurement was performed during all workday, began in the morning just before the beginning of the workday. For testing and references' values, the monitoring began by 10 min without physical activity. Digital recordings were analyzed by a trained cardiologist in the Cardiology Department of the University Hospital of Brest. The ECG recordings were made from three orthogonal leads of Frank. The SyneScope ECG Holter analysis software processed the data collected by the PCMCIA Sorin CRM Flash Sorin digital ECG recorders. An automatic and then manual reading of the R-R intervals was performed to ensure the correct identification and classification of each QRS complex as well as the removal of artifacts. Following the recommendations of the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, the presence of more than 20% of artifacts resulted in a rejection of the analysis . The samt-test was applied in case of normal distribution. The quantitative variables were described using the usual position and dispersion statistics. The differences for HRV among the two populations were initially assessed by a one-way analysis of variance (ANOVA) followed by an analysis of Covariance (ANCOVA) to statistically control the effect of covariates. The alpha risk was set at 5% for all analyses. Values in tables are expressed as mean ± standard deviation (SD).We studied the variation in HRV per 1-h time period as a function of the level of noise exposure. Due to the non-linear nature of sound exposure, responses of the ANS are not homogeneous. Therefore, we carried out an analysis by time segments. We measured the main HRV criteria on each of these fragments independently of each other. Statistical analysis was performed with R software . The Shapiro–Wilk test was used to test normal distribution of data. When variables were not normally distributed, non-parametric test (Mann–Whitney U-test) was used. The From the initial population of 17 welders and 10 airport workers, 16 welders and eight airport workers were finally included with available HRV and noise exposure measurements during a workday. The level of ECG artifacts was >20% in three subjects (one welder and two airport workers) who were excluded from the study. The mean age of welders' population was 42.4 years, they had 18.2 years of experience, and 67% were smokers. For blood pressure, in subject population of welders, blood pressure was, respectively, 71 mm Hg for diastolic and 125 mm Hg for systolic. All subjects were males without differences in smoking status, age, precedence at workstation, body mass index (BMI), and blood pressure between the two populations. No cardiovascular disease was present in all the included subjects. All population characteristics are summarized in 3 to 25.4 mg/m3. The mean concentration was 4.5 mg/m3, and the median was 1.8 mg/m3. We also evaluated the concentrations of respirable dust in the working environment in the ballasts and in the engine room where welders worked. Concentrations of respirable dust ranged from 0.2 mg/m3 to 7.5 mg/m3. The mean concentration was 1.6 mg/m3, while the median was 1 mg/m3. The results were below the recommended limit values for French professionals . The respirable dust concentrations at the workplace ranged from 0.4 mg/mssionals . The resp = 0.019) for airport workers than for welders not mean value for a workday.For noise exposure measurement, six participants of each group wore a dosimeter for a total of 76 acoustic sequences. The average workday noise exposure for welders was 83.1 and 83.6 dB(A) in the airport. We did not find differences for the average level of sound exposure per hour. For peak sound pressure level per hour, mean values, respectively, for airport workers and welders are 128 and 124 dB(A). However, LPC was statistically significantly higher (The results are summarized in p = 0.36 and p = 0.19). The mean heart rate during workday did not differ between the two groups .Considering the whole workday, no statistical difference was found in heart rhythm, conduction. or repolarization disorders between welders and airport workers. The maximum and minimum RR interval did not differ between the two groups (p = 0.04) and SDNN (p = 0.05) in welders.HRV measurements and comparison between mean values on 8 h in time and frequency domains are presented in We obtained 76 1-h time segments evaluating daily exposure and peak sound pressure (39 for airport workers and 37 for welders).First, the results of an univariate linear regression are described in p < 0.05), HF , and SDNN . No significant correlation with peak of noise was found.For welders' population, we observed a statistically significant positive correlation between 1-h time value of HRV and mean noise values for LF  in Leq was associated with, respectively, a concomitant increase in 0.97%, 2.08, 1.3, and 1.16% of SDNN, LF, HF, and LF/HF ratio, and in another study, the concurrent increases of 5 dB(A) in Leq were associated with increases in HR (1.48%) and LF/HF (4.89%) but decrease in LF (−3.77%) and HF (−8.56%) , 35. In According to the Babish's noise effect models, under the involvement of the limbal system and hypothalamus, exposure to noise influences the ANS either directly or indirectly through the stress hormones . Indeed,Moreover, significant interaction between working as welder and mean sound level on decrease in LF/HF and increase for HF strengthened interrogation. Is it due to cumulative or synergic effects? We could hypothesize that noise and WF exposure generated activation of baroreflexes with imbalance of ANS. In his review on the utility of LF in HRV, Reyes Del Paso concluded that HRV spectrum in frequency domains is predominantly determined by vagal activity and that HRV analysis is an estimation of the parasympathetic influences on HR . For GolIn case of acute exposure, autonomic nervous system could regulate the influence of the sympathetic tone, but after few minutes for noise and few hours for WF, this capacity is overloaded. The cavallary's study suggests that exposure to WF has a double time effect with a very short-term and short-term impact on the ANS balance . The co-The small number of subjects included in this study is the main limitation of our results. The design of the study allowed us to analyze 76 1-h noise and ECG measurements. Reducing these sequences to 5 min allowed us to analyze a larger number of them and thus increased the power of the study. This study did not include any women. Therefore, no analysis of gender effect is possible. Another limitation of this study is the lack of information on confounding factors such as temperature, external stimuli as light exposure, time of day, and food consumption , 45. CafThis study shows an impact of WF and noise on autonomic nervous system balance. It seems that cardiovascular system could react during a short time to noise and WF exposure through baroreflex regulation. After minutes or hours, regulation is overloaded with imbalance of ANS. According to ECG monitoring during working time, significant effect of workplace, and interaction between WF and noise exposures on HRV parameters, we could suggest that WF exposure could increase sensibility to noise exposure on ANS or there is a synergic effect. Further studies are needed to explain pathophysiological pathways and the possible cardiovascular impact of both factors or a potentiating effect of noise.Noise and welding fumes' exposure have an impact on heart rate variability and autonomic nervous system. It could explain higher risk of cardiovascular diseases in population exposed to noise and welding fumes.A possible combined effect of gas and fine particles (welding fumes) and noise on autonomic nervous system need confirmation and open questions on other pathways such as oxidative stress, endothelial dysfunction, and thrombosis when humans are exposed to these compounds.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comité de Protection des Personnes Ouest II ref 2017-AO1829-44. The patients/participants provided their written informed consent to participate in this study.FG, JM, and DL: study design. EJ: exposure assessment. PC: noise assessment. DL, SH, and FG: inclusion, clinical examination, and Holter ECG on participants. FG and DL: data analysis. FG, JM, and DL: article writing. EJ, SH, and PC: corrections on article. All authors contributed to the article and approved the submitted version.This study was funded by the Research and Innovation Unit Brest Teaching Hospital Brest, France.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.


The COVID-19 pandemic has undone years of progress in providing essential TB services and controlling the TB burden. Italy, a low TB burden country, has an incidence of 7.1 cases per 100,000 people. To control the TB spreading in Italy is critical to investigate the characteristics of patients with the worst outcomes and the highest risk of adverse events related to antituberculosis therapy. Therefore, we conducted a large retrospective study in TB patients admitted to the Clinic of Infectious Diseases University of Bari, Italy, in order to describe the clinical presentation and the factors associated with adverse events and outcomes.We retrospectively evaluated the patients admitted to the Clinic of Infectious Diseases from January 2013 to 15 December 2021. We stratified our cohort into two groups: <65 years of age and ≥65 years in order to assess any differences between the two groups. Two logistic regression models were implemented considering the dependent variables as: (I) the adverse events; and (II) the unsuccessful treatments.p-value < 0.05) for nationality , previous contact with TB patient , type of TB , unsuccessful treatment , length of hospitalization  and diagnostic delay . Adverse events related to TB drug regimen were reported in 24% (n = 49). Age < 65 years , non-Italian nationality , homeless , presence of respiratory symptoms , diagnostic delay  resulted associated with unsuccessful treatment outcome . Finally, age < 65 years , presence of pulmonary TB , length of hospitalization  and TB culture positive  were associated with adverse events in our populations.In total, 206 consecutive patients  were diagnosed and admitted with TB at Clinic of Infectious Diseases. Of the whole sample, 151 (74%) were <65 years and 55 (26%) were ≥65. Statistically significant differences between the two groups were detected (Mycobacterium tuberculosis, but also to the poverty or the social fragility. Our data suggest that young foreigners, the homeless, and the people with low social and economic status are at higher risk of an unfavorable outcome in low incidence TB countries. Targeted actions to support this highly vulnerable population both in terms of outcome and occurrence of adverse events are needed.The pharmacological approach alone seems insufficient to treat and cure a disease whose ethiopathogenesis is not only due to the  Tuberculosis (TB) is still one of the world’s leading killers and one of the most serious public health issues, with 10 million new cases diagnosed each year and 1.5 million deaths . Unfortu3116Therefore, we conducted a large retrospective study by evaluating patients with pulmonary TB admitted to the University Clinic of Infectious Diseases, University of Bari, Apulia region, south of Italy in order to describe the clinical presentation and the factors associated with adverse events and outcomes.M. tuberculosis from a respiratory sample  or other biological specimens; (2) on positive M. tuberculosis nucleic amplification test NAT  from biological specimens (without culture confirmation); or (3) on histopathological findings consistent with TB and presence of acid fast bacilli (AFB) in a tissue sample. Moreover, patients were classified as “clinical TB” if the diagnosis was based on clinical and radiologic criteria (having excluded other diseases) including appropriate response to standard anti-TB therapy.We performed a retrospective study in patients diagnosed with pulmonary TB admitted to the University Clinic of Infectious Diseases University of Bari, Bari, Italy, from 1 January 2013 to 15 December 2021. We retrospectively evaluated data from each patient admitted in our hospital with pulmonary active TB. According to the WHO guidelines, enrolled patients were classified as “active pulmonary TB” if the diagnosis was based: (1) on a positive culture for Patients were treated according to the institutional protocol drawn up following the WHO TB guidelines . The firPatient demographics; admission and dis-charge/death dates; and clinical variables: symptoms, tuberculosis diagnosis, M. tuberculosis drug resistance, TB location, treatment regimen, adverse events , and outcomes were the key data sources. The severity of adverse events was defined as light , moderate (necessitating limited non-invasive intervention), and severe  .a priori, since the study included all patients admitted during the study period. Continuous data were expressed as median and interquartile range (IQR), and categorical data as numbers and percentages. Chi-squared test or Fisher’s exact test as appropriate were used to compare categorical variables. We stratified our cohort into two groups: <65 years of age and ≥65 years in order to evaluate any differences between these two groups.No formal sample size was calculated p-value < 0.10 at the univariate analyses were included in the models. Multicollinearity among covariates was assessed through the variance inflation factor (VIF), taking a value of two for excluding a covariate. However, no variable was excluded according to the previous criterion.Two logistic regression models were implemented considering the dependent variables as: (1) the adverse events; and (2) unsuccessfully treated  while each of the available factors were considered as independent variables . All the factors with a Odds ratios (ORs) as adjusted odds ratios (Adj–ORs) with their 95% confidence intervals (CIs) were used to measure the association between factors at the baseline (exposure) and treatment failure (outcome).p value less than 0.05 were considered statistically significant. Statistical analysis was performed using STATA V.13.All two-tailed test Between January, 1 2013 and December, 15 2021, 206 consecutive patients  were diagnosed and admitted with TB at the Clinic of Infectious Diseases, and included in the study. Of the whole sample, 151 (74%) were <65 years. Median age was 32 years (16–63) and 71 years (65–92) for <65 years group and ≥65 years one, respectively. Among them, 51% (n = 105) had non-Italian nationality, 8% (n = 17) were homeless, and 65% (n = 135) had a pulmonary localization of TB. Notably, 60% (n = 124) had respiratory symptoms. Furthermore, 68% (n = 140) were culture positive and 16% (n = 34) showed at least one drug resistance. Fifty-seven percent (n = 117) successfully completed the treatment, while 1% (n = 4) died due to a TB-related cause. At the time of the study, treatment was still ongoing 10% (n = 20) of the sample. Furthermore, the treatment success rate in ≥65 years group was 84% (n = 46), while in <65 years was 45% (n = 71).Table 1 shows the characteristics of all participants on the whole sample and stratified by age-classes <65 or ≥65 years old. Differences in distribution of the variables collected between <65 or ≥65-year-old groups emerged  for nationality , previous contact with TB patient , type of TB , unsuccessful treatment , length of hospitalization  and diagnostic delay  as shown in Table 1.Table 2.Adverse events related to the TB drug regimen were reported in 24% (n = 49) of patients. Out of the 49 patients who reported an adverse event, 55% (n = 27) showed a liver disease. In 51% (n = 25) of the 49 patients, the event required minimal non-invasive intervention classified as mild while 49% (n = 24) of cases required a suspension of the suspect drug and change of the treatment. Further characteristics of adverse events reported in the sample are shown in Table 3. Age < 65 years , non-Italian nationality , homelessness , presence of respiratory symptoms , diagnostic delay  resulted associated with unsuccessful treatment outcome , as reported in Table 3.The multivariate logistic model on unsuccessful outcome considered the effects of age, gender, nationality, homelessness, presence of respiratory symptoms, diagnostic delay, length of hospitalization, acid-fast bacilli smear positive, drug resistance, treatment, TB localization (lung or extrapulmonary) and TB culture positivity. Significant predictors of unsuccessful outcome are reported in Table 4.The multivariate logistic model on the adverse events considered the effects of age, gender, nationality, homelessness, presence of respiratory symptoms, diagnostic delay and length of hospitalization, acid-fast bacilli smear positive, drug resistance, treatment and TB culture positivity, TB localization (lung or extrapulmonary). Age < 65 years , presence of pulmonary TB , length of hospitalization  and TB culture positive  resulted associated with adverse events in our populations, as reported in Figure 1 shows the temporal trend (2013–2021) of admitted TB patients and lost one to follow-up.Furthermore, Our study describes a cohort of patients admitted in a referral hospital for TB in Italy referred to a large time period (2013–2021). According to the WHO definitions, 140 out of 206 patients were microbiologically confirmed with pulmonary TB. A global successful treatment was reported in half of our sample, while one out four reported an adverse event related to TB drug regimen and 16% presented at least of one drug resistance. Stratifying our data by age classes <65 or ≥65 years old, differences were found in: nationality, previous contact with TB, length of hospitalization, diagnostic delay.Quite surprising are the results concerning the factors associated with an unsuccessful outcome. In fact, in our sample, age < 65 years, non-Italian nationality, homelessness, presence of respiratory symptoms, and a diagnostic delay resulted associated with an unsuccessful treatment outcome .In line with European data, in our cohort there is a slight prevalence of male subjects 11 and al12This result is due to the fact that 51% of our patients were foreigners and 94% of them were less than 65 years. In our case, the role of the migrant population is greater than in the rest of Europe. In fact, the latest 2021 report records that approximately one third (34.5%) of TB cases reported in the EU/EEA in 2019 were of foreign origin 14.Several authors showed as being elderly is a risk factor for a worse outcome and expose to a major risk of adverse events 16. This 13In EU countries, the average treatment success rate for active TB has been reported as 60%–87%. Our data globally showed a 57% of successful treatment, but with a notably difference between the two groups . In fact20Moreover, Apulia and the other regions of South Italy are located in the middle of the Mediterranean migration route with high prevalence of migrant population that represents a pivotal key to TB burden control .Furthermore, in our cohort one out four patients showed an adverse event related to TB drug regimen. Around half of them showed a hepatitis and half of these patients changed treatment. Factors associated with adverse events were age < 65 years, pulmonary TBC, length of hospitalization and TB culture positive.This is in contradiction with the literature which shows a variable percentage of 15–75% of adverse events in the over 65 and especially over 75 population 24. This 26Furthermore, our data show that patients under 65 have a higher diagnostic delay than patients over 65 (76 days vs. 43 days) and also higher hospital length of stay (43 vs. 24). Our study found a median TD of 76 days in line with other regions of our country  . This fiThere may be several reasons for what has been observed: in a country with low endemicity for tuberculosis there is a low awareness of the disease both by the patients and by the general practitioners; in our case series, the extra-pulmonary forms, which are characterized by a more specific symptomatology and do not present the classic clinical pattern of the respiratory forms, are more frequent in the young population. Moreover, a large part of the young population is represented by migrants who, despite the presence in our country of a free national health system, may experience difficulties due to the condition of irregular migrants without access to the general practitioners and because of this the diagnosis is often only made after the access to the public hospitals due to the manifestations of the advanced clinical forms.Another statistically significant difference between the young and elderly population was found in the length of stay. In the younger the average length of stay is 43 days (with a wide range from 7 to 230 days) versus 24 days in the older population (from 5 to 120 days). As already observed in other studies, the risk of hospitalization is not only influenced by clinical factors, but also by social determinants and high hospitalization times is generally greater in: migrants who have been in the country of arrival for more than two years, the homeless and patients with multidrug-resistant TB 30. HoweverFigure 1 also allows for two reflections. The first is the reduction in TB diagnoses during the SARS CoV2 pandemic, as well as the lockdown periods with interruption and disruption of TB services due to the pandemic’s need and workload. As several authors have reported, this may have a negative impact on Tb burden control, with an increase in clinical severity, diagnostic delay, and, more broadly, a reduction in TB control, pushing the results obtained in the fight against tuberculosis back ten years.Furthermore, The second reflection is on the potential impact of establishing a tuberculosis-specific medical and nursing team for those who were lost to follow-up. In fact, as of 2019, a team specializing in tuberculosis is caring for patients in our hospital, which could explain the significant decrease in lost to follow-up over the last three years. Of course, studies focusing on this potential impact are required to demonstrate the intervention’s potential effectiveness.We acknowledge that our study has some limitations. First, the inclusion of the patients diagnosed at a single institution may limit the generalizability of the results. Moreover, due to the study’s retrospective nature, other factors potentially influencing outcomes, such as lack of comorbidity data, radiological findings, and other risk factors, were not considered. Furthermore, in our study, we only considered total diagnostic delay, with no distinction made between healthcare system and patient delays.the Mycobacterium Tuberculosis, but also to the poverty. The establishment of a dedicated medical and nursing team for tuberculosis could improve outcomes and reduce lost to follow-up for this vulnerable population, but more integrated social actions are required. Hospitalization in tertiary referral hospitals with clinical multidisciplinary expertise in TB diagnosis and treatment can be useful to improve outcome in the elderly. Concentrating elderly TB patients to referral facilities is important to ensure a better outcome for this fragile population, which is different from the previous one and requires dedicated expertise on TB care.In conclusion, our data suggest that young foreigners, the homeless, and people with low social and economic status are at higher risk of an unfavorable outcome in low incidence TB countries. According to the WHO, one of the pilot keys for high-income countries to control TB burden is to target TB vulnerable groups 343536. T3435Furthermore, new treatments and short regimens should be specifically evaluated in vulnerable populations to increase adherence, reduce the risk to lost to follow up, reduce the pill burden and treatment time, and improve outcome and safety. Future research is therefore needed to evaluate targeted interventions to assist vulnerable populations and to effectively control and eliminate tuberculosis as a goal of sustainable development.All authors confirm that the data supporting the findings of this study are available within the article. All datasets generated and/or analyzed during the current study are available from the corresponding author on request. Data request can be made through the corresponding author’s email.


Laparoscopic liver resection (LLR) is a widely practiced therapeutic method and holds several advantages over open liver resection (OLR) including less postoperative pain, lower morbidity, and faster recovery. However, the effect of LLR for the treatment of hepatocellular carcinoma (HCC) in elderly patients remains controversial. Therefore, we aimed to perform the first meta-analysis of propensity score-matched (PSM) studies to compare the short- and long-term outcomes of LLR versus OLR for elderly patients with HCC.Databases including PubMed, Embase, Scopus, and Cochrane Library were systematically searched until April 2022 for eligible studies that compared LLR and OLR for the treatment of HCC in elderly patients. Short-term outcomes include postoperative complications, blood loss, surgical time, and length of hospital stay. Long-term outcomes include overall survival (OS) rate and disease-free survival (DFS) rate at 1, 3, and 5 years.P < 0.00001, I2 = 0%), less blood loss , and shorter hospital stay , whereas operation time  was insignificantly different. Furthermore, there were no significant differences for the OS and DFS rates at 1, 3, and 5 years.A total of 12 trials involving 1,861 patients  were included. Compared with OLR, LLR was associated with lower postoperative complications (OR 0.49, 95% CI 0.39 to 0.62, For elderly patients with HCC, LLR offers better short-term outcomes including a lower incidence of postoperative complications and shorter hospital stays, with comparable long-term outcomes when compared with the open approach. Our results support the implementation of LLR for the treatment of HCC in elderly patients.https://inplasy.com/inplasy-2022-4-0156/, identifier INPLASY202240156. Liver cancer is one of the most common cancers and a major global health challenge . AccordiSurgical resection is one of the most effective treatments of choice for early HCC. Since Reich et al. reported the first laparoscopic liver resection (LLR) in 1991 , this miHowever, several factors such as the presence of comorbidities and the age of the patients may have a significant effect on the efficacy and safety of this minimally invasive technique. Age is a challenging feature given the significant heterogeneity of general conditions among individuals of the same age range and the growing number of elderly patients in good clinical condition presenting with HCC . Also, eAccordingly, in order to summarize the present high-quality evidence, we performed a meta-analysis of PSM studies to compare the short- and long-term outcomes of LLR versus OLR for the treatment of HCC in elderly patients.We conducted our study on the basis of the updated PRISMA statement  (SuppleThe inclusion criteria were as follows: 1) population: elderly patients (≥65 years old) with pathology‐confirmed HCC; 2) intervention: LLR; 3) comparison: OLR; 4) outcomes: short-term outcomes including postoperative complications, blood loss, surgical time, and length of hospital stay and long-term outcomes including 1-, 3-, and 5-year overall survival (OS) rates and 1-, 3-, and 5-year disease-free survival (DFS) rates; and 5) design: PSM.Two authors (SW and HY) independently searched relevant studies and extracted data. The characteristics of the included studies  are recorded in Two authors (GY and SW) independently evaluated the methodological quality of the included studies by using the Newcastle–Ottawa Scale for cohort studies. The Newcastle–Ottawa Scale contains three categories (including eight subcategories), and each study is able to acquire a maximum of 9 stars. The detailed grading standards are as follows: a score of 7 to 9 stars is graded as a high-quality study, a score of 4 to 6 stars is considered an average-quality study, whereas a score of 0 to 3 stars is classified as a low-quality study.I2) statistics  with 95% confidence interval (CI) for dichotomous outcomes and the mean difference (MD) with 95% CI for continuous outcomes. For survival data, we used the hazard ratio (HR) with 95% CI reported in the included studies. If the HR data were not reported in the original study, we imputed the HR by digitizing the Kaplan–Meier survival curves . The hetatistics . Substansymmetry . We consSubgroup analysis stratified by types of hepatectomy  and ageThe initial search identified 608 articles . Among them, 376 were duplicated articles, and 147 studies were excluded by screening the abstracts. During the evaluation of the full text, 73 studies were further removed for various reasons. Eventually, a total of 12 trials –31 involIn addition, the length of hospital stay, surgical time, and blood loss were expressed as median with range or interquartile range. Thus, we converted the above data into mean and standard deviation by utilizing the methodology that was developed by Wan et al. .P = 0.92), blood loss (P = 0.4164), length of hospital stay (P = 0.8368), or surgical time (P = 0.5373). Furthermore, since the number of trials in the analysis of long-term outcomes was limited, we could not reliably assess the publication bias.Funnel plots and Egger regression test for all short-term outcome measures were used to further test for potential publication bias . Overall, the incidence of postoperative complications in the LLR group was lower than that in the OLR group, 31.8% (236/741) versus 45.2% (356/788), respectively. Our meta-analysis demonstrated that LLR was associated with a lower incidence of postoperative complications  for minor hepatectomy and 0.55  for combined hepatectomy. The results indicated that LLR was associated with a lower incidence of postoperative complications for patients with minor or major hepatectomy. Moreover, for patients with minor hepatectomy, LLR was associated with less blood loss , shorter length of hospital stay , and comparable surgical time . However, for patients with combined hepatectomy, there was no significant difference in blood loss  and length of hospital stay , but a longer surgical time  was observed. However, the significant heterogeneity and limited number of studies in this subgroup weakened the credibility of this conclusion.The pooled ORs for postoperative complications in the two subgroups were 0.44 , and the subgroup of ≥70 years old showed similar results with the overall analysis. However, the subgroup of ≥65 years old showed no difference in the length of hospital stay  but had longer surgical time .Furthermore, since there were three different definitions of elderly patients , we performed a subgroup analysis based on the age groups. The subgroup analysis showed that the incidence of postoperative complications was similar in three different subgroups , we divided the data of postoperative complications into minor and major complications. The results indicated that both major and minor postoperative complications were in favor of LLR , which may lead to a small study effect bias .Secondly, there was a significant between-study heterogeneity in several outcomes, which might be derived from the differences in age ranges, liver function, number and location of lesions, general condition of the individual patient, surgeons’ experience, perioperative care protocols, pre- and postoperative chemotherapy, and other factors. Some studies included patients at wide study intervals, which may introduce biases due to advances in the mastery of surgical skills and improvements in surgical instruments . NoteworLast but not the least, our meta-analysis only evaluated the overall and pulmonary complications. Some specific and important complications including bile leak, abscesses, and intra-abdominal infection between the two therapies could not be adequately compared, which should be further evaluated in the future.In conclusion, our meta-analysis of PSM studies suggests that LLR has improved short-term outcomes including a lower incidence of postoperative complications, less blood loss, and shorter length of hospital stay, with comparable long-term outcomes for elderly patients with HCC when compared with the open approach. However, most of the existing data are about the results of minor hepatectomy, and laparoscopic major hepatectomy in elderly patients should be carefully evaluated and preferably performed in expert centers. Furthermore, considering the limited number of included studies with small sample sizes, significant heterogeneity and potential bias were found among the included studies. Well-designed, multicenter RCTs with a large sample size are needed to further evaluate the short- and long-term outcomes of LLR versus OLR for elderly patients with HCC.The original contributions presented in the study are included in the article/SW and HY conceived the idea, performed the analysis, and wrote the initial draft of this paper. GY, JW and SX contributed to the collection and interpretation of data. QY helped to frame the idea of the study and provided technical support. HY contributed to the revision of this paper and the final approval of the version to be published. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The importance of health is well documented in the development economics literature because of its increasing effects on economic growth in the long-run. Financial development and financial globalization are essential resources for health. This study examines the role of financial development and financial globalization in the rapid rise of life expectancy in China, India, and Japan by using the annual data covering the period of 1991–2019. The ARDL bounds testing approach confirm the long-run relationship between financial development, financial globalization, and life expectancy in the presence of GDP, health expenditure, and the internet. The long-run findings indicate that financial development positively affects life expectancy by 0.599% in China. The novel findings also indicate that financial globalization positively affects life expectancy by 1.247% in Japan and 1.121% in India. Our findings offer new empirical insights to policymakers crucial to improving life expectancy in China, India, and Japan. Life expectancy is used to represent a nation's health and used as a vital indicator to verify the development of a country by various international agencies. Therefore, the life expectancy rate can have long-lasting effects on the level of national income, fertility rate, transfer payments, pension schemes, and public finance , 2. FurtThere are various channels through which financial development can affect the health status of a nation . The firOn the other side, financial development may reduce life expectancy if a poor family requires excessive collateral to acquire financial services. To cope with high collateral, the poor family is bound to sell its valuable assets that cause their income to fall and, as a result, their health condition deteriorates. Besides, if the financial services are only available for the privileged class of the society, in that case, it leads to a financial crisis resulting in slow economic growth over a long period of time . In the Over the past few decades, globalization has become the central focus of social scientists and international leaders. As a result, the impact of globalization on various economic and social indicators has been extensively studied. However, there are not many studies available that have analyzed the relationship between globalization and a country's health system , 12. GloThe above-mentioned literature proposes that the impact of financial development and globalization on health is not yet conclusive. Previous studies mainly focus on overall globalization ignoring financial globalization. To our information, no past study has explored financial globalization with health. The prior studies have only found the long-run effect of financial development and globalization on health ignoring short-run effects. Consistent with the views mentioned above, we aim to investigate the impact of financial development and financial globalization on the health outcomes of three Asian economies, namely China, India, and Japan. These three economies are among the largest economies of Asia and hold better healthcare infrastructure and systems among Asian economies. None of the past studies have targeted these economies while analyzing this relationship. Hence, this study is an effort to plug this gap into the literature. For empirical analysis, we have relied on the ARDL model, which is the best sample size model if small, and it provides short and long-run estimates simultaneously.Following the health economies literature, the two most important determinants of health are financial development and financial globalization. This research work proceeds under a theory of neoliberalism, first familiarized by Friedrich Hayek in the 1920s. In doing so, we follow , 24 and via various channels such as income, education, gender equality, infrastructure, and clean energy effects, thus estimate of φ1 could be positive. Similarly, financial globalization is a source of capital inflows, which improves health outcomes. Consequently, an estimate of φ2 is expected to be positive. Economic development, health expenditure, and the internet are possible key determinants of life expectancy observed in the field of health economies, thus estimates φ3, φ4, and φ5 are expected to be positive. On the other hand, φ0 represents constant term and εt is the white noise error term. The basic model has given us only long-run estimates by ignoring short-run. To differentiate the long-run impacts of financial development and financial globalization on health from its short-run effects, again following Pesaran et al. (Specification (1) is the health function that depends on financial development (FD), financial globalization (FG), gross domestic product (GDP), health expenditure (HE), and internet users (Internet). We have employed life expectancy as a proxy of health outcomes. Claessens and Feijen  reportedn et al.  we expreω2ω6 normalized on ω1. We can assess cointegration for the validity of estimates by using an F-test and ECM or t-test. The null hypothesis of the F-test in the equation is H0: φ1 = φ2 = φ3 = φ4 = φ5 = φ6= 0, which infers the non-existence of long-run connection. While the alternative hypothesis is H1: φ1≠0, φ2≠0, φ3=0, φ4≠0, φ5≠0, φ6≠0. ARDL model assuming all variables to be integrated of either I(0) or I(1), even blend of two. This approach accommodates I(0) and I(1) variables, and it is also robust to small samples. To confirm the model's goodness of fit, some diagnostic and stability tests are applied. For instance, testing for serial correlation (LM), functional form (RESET), heteroscedasticity (BP) is robustly linked with the selected model. We can use cumulative sum (CUSUM) and cumulative sum of squares (CUSUM-sq) for stability. The next section can estimate Equation (2) for three larger Asian economies.Specification (2) is similar to Engle and Granger . It is lThe study examines the impact of financial development and financial globalization on the health outcomes of selected Asian economies from 1990 to 2019. These economies contain the sample of China, India, and Japan. 2 emissions. Before performing regression analysis, the study confirms the order of integration for life expectancy, financial development index, financial globalization index, GDP, health expenditures, and internet. For that purpose, the study employs two-unit root tests: Augmented Dickey-Fuller (ADF) and Phillips Perron (PP) tests. In the long-run, findings show that financial development has a positive and significant impact on life expectancy at a 10% level in China only, while the impact is statistically insignificant in the case of Japan and India. It shows that a 1% upsurge in financial development increases life expectancy by 0.599% in China. In our study, findings display that the impact of financial development on health outcomes is significant and positive. This means that easy access to finance through financial globalization enables people to choose a better and healthier lifestyle, foods, medical treatment, and accommodation. Meanwhile, financial development expands the life expectancy through the channels of gender equality, infrastructure, education, and per capita GDP. This finding is also supported by Levine , who notIn contrast, financial globalization shows a positive and significant impact on life expectancy at 10% level in Japan and 5% level in India, while in the case of China, findings display insignificant results. It shows that in the long-run, a 1% upsurge in financial globalization increases life expectancy by 1.247% in Japan and 1.121% in India. These findings infer that the Chinese government can adopt financial development as a policy measure to enhance their life expectancy, while Japanese and Indian governments should adopt financial globalization as a policy tool to enhance their life expectancy level. Our study observed that the impact of financial globalization on health outcomes is significant and positive. This finding is also backed by Cornia , who argGross domestic product displays a significant and positive impact on life expectancy in China and Japan at a 1% significance level. It shows that a 1% rise in GDP increases life expectancy by 2.614% in China and 1.842% in Japan in the long-run. Findings reveal that current health expenditures have a significant and positive impact on life expectancy at 1% level in Japan and 1% level in India. It infers that in the long-run, a 1% expansion in health expenditures increases life expectancy by 0.252% in Japan and 0.166% in India. Long-run findings display that the internet has a significant and positive effect on life expectancy at a 1% level in China and Japan, revealing that a 1% increase in the use of the internet increases life expectancy by 0.019% in China 0.013% in Japan.The relationship between financial development and life expectancy is significant and positive at 5% in China and at 10% in India in the short-run. However, the impact of financial globalization on life expectancy is statistically insignificant in Asian economies in the short-run. The impact of GDP is positive and statistically significant on life expectancy at a 10% level in the short-run. Health expenditures have a significant and positive impact on life expectancy in India at a 1% level. At the same time, the internet has a significant and positive effect on life expectancy at a 10% level in Japan in the short run. The lower panel of The importance of life expectancy on economic growth is well established in the existing stock of literature. However, no study has documented the impact of financial globalization and financial development on health outcomes in Asian economies. Thus, our study aims to fill this vacuum using the ARDL approach to explore the long-run cointegration among financial globalization, financial development, and life expectancy. The study considers three Asian economies, namely China, Japan, and India, from 1990 to 2019. The study uses current health expenditures, GDP per capita, and the internet as control variables. The empirical findings indicate that financial development tends to improve life expectancy in China in the long-run, while it improves life expectancy in China and India in the short-run. In contrast, financial globalization improves life expectancy in Japan and India in the long-run. However, financial globalization produces no impact on life expectancy in the short-run. Moreover, health expenditures, GDP per capita, and the internet are positively associated with life expectancy in the long-run and short-run, revealing that these determinants positively contribute to enhancing the health outcome of individuals.Our findings put forward some important policy implications for Asian economies. It is found that financial globalization and financial development improve health outcomes, suggesting that these two measures can be adopted as effective policy tools to enhance individuals' life expectancy. It is suggested that the governments and policymakers in Asian economies should not undervalue the role of financial globalization and financial development while designing health-related policies. Findings also suggest that financial sector improvement should be considered key to enhancing life quality, productivity, and economic growth for Asian economies. Findings reveal the positive impact of GDP per capita on life expectancy, suggesting that policymakers should adopt economic development to improve individuals' health outcomes. Moreover, digitalization shows positive effects on life expectancy, suggesting that smart technologies should be increased in the health sector. Additionally, current health expenditures in the government budget should be increased to improve individuals' life expectancy.The study has identified some limitations, such as energy sector and environmental sector variables are not included in the analysis. Although, environmental and energy-related issues are highly affecting health outcomes. It is suggested that in future research, these variables should be included. Another future direction is that the impact of financial inclusion should be investigated for the health industry. A similar objective can also be tested for regional and group-wise economies in the future.https://data.worldbank.org/.Publicly available datasets were analyzed in this study. This data can be found here: GS: conceptualization, software, data curation, and writing—original draft preparation. DW: methodology, writing—reviewing, and editing. MA: visualization and investigation. All authors contributed to the article and approved the submitted version.This study was supported by Education Department of Jilin Province, Project Name: Research on Financial Risk Early Warning and Prevention in Jilin Province in the Post-Pandemic (Project Number: JJKH20211381SK).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.


Burnout among nurses is a significant problem in healthcare establishments and has negative implications on clinical outcomes. International studies have shown the prevalence of burnout ranged from 10 to 70%. However, this is unknown among nurses in private hospitals in Addis Ababa. The study was intended to assess the levels of burnout and the associated factors among nurses working in private hospitals in Addis Ababa, Ethiopia, 2020.p < 0.25 on bivariate analysis were taken into multivariate logistic regression, and then variables with p < 0.05 were considered statistically significant.An institution-based cross-sectional study was used. A probability sampling, specifically, a simple random sampling technique was employed to collect data, and the Maslach burnout inventory human services survey (MBI-HSS) instrument was adapted to measure the levels of burnout. The data obtained was edited manually and entered into EPI-data version 4.6 and then exported to SPSS version 25 for analysis. Logistic regression was used to identify the association between the dependent and independent variables and variables with A total of 385 questionnaires were distributed to participants, but only 368 (96%) of them were collected and included in this study. The majority 56% and 69.8% of them were females and belonged to the age group of 20–29 years, respectively. Two hundred seven (56.5%) of them reported suffering from a high level of burnout. In the multivariate logistic regression analysis, night duty shift , excessive workload , staff shortage , persistent interpersonal conflict , and nurses' poor health status  demonstrated a statistical significant association with the professional burnout.Nurses' burnout in private hospitals of Addis Ababa was highly prevalent. Therefore, ensuring adequate staffing and minimizing the workload of nurse professionals are mandatory to prevent it. Burnout is conceptualized as a psychological syndrome that occurs in response to interpersonal stressors in the work environment. It is an individual-level phenomenon and can be viewed as a negative emotional experience which is a chronic, ongoing affective response . BurnoutNursing burnout is more likely related to job demands, and burned out health professionals believed that their objectives are not achieved, which is accompanied by physical depletion, feelings of helplessness, disillusionment, decreased motivation, dysfunctional behavior, negative self-concepts, and negative attitudes toward work and life itself. To prevent further energy depletion, employees distance themselves mentally from their work by developing depersonalizing attitudes. Due to this reason, their work performance tends to diminish and they may feel incompetent and in efficacious, leading to a decrease in the quality of the health care facilities, which ultimately affects the satisfaction of the patient. Most of the time, burnout can occur due to a widening gap between the individual and demands of the job .Burnout can affect every occupation. However, it is thought to be more prevalent among human professionals as the services offered by them are in response to the needs of the society. Among health professionals, professional nursing, in particular, is a service for the promotion of human and social welfare. Comparatively, nurses are the first line of contact; they spend the most time with patients and are constantly exposed to the emotional strains of dealing with the sick and dying. Such stressors when left unchecked lead to burnout. Burnout syndrome among nurses in hospitals has become a worldwide phenomenon that negatively impacts the quality of care, safety of patients and working staff. An estimated range of 10–70% of nurses are affected by burnout throughout the world , 5.In a multi-country, cross-sectional study conducted in 10 European countries among staff nurses, high levels of burnout were reported in England (42%) and low levels of burnout were in Switzerland (15%) . MoreoveBurnout has been associated with reduced organizational efficiency and work-related problems such as low morale, poor quality of care, lowered productivity, absenteeism, interpersonal problems, and employee turnover . A 10% iDespite the existence of numerous studies conducted in Ethiopia on the prevalence and associated factors of burnout among nurses who are working in public hospitals, as far as our knowledge, there is found a lack of studies conducted in private hospitals in Addis Ababa administration. Although the healthcare industry in Addis Ababa expanded drastically, this expansion has taken place mostly in the private sector. Many hospitals are established throughout the city which opened employment opportunities for the professionals in large numbers, but at the same time could not meet the demand of the number of hospitals required to provide better services to the people at large. In private hospitals, a high number of patients is seen in every hospital from morning till late evenings and this increases the number of duties of the nursing staff because most of the private hospitals in Addis Ababa cover many tasks with the minimum number of nurses. The current duty shift during data collection period was alternate, day, night. In our study, the nurses perception about the presence of work-load burnout was 79.7%. The variation of burnout across the various nursing disciplines/departments were the nurses' perception about the presence of work load, nurses' perception about the presence of nursing staff shortage, the presence of persistent interpersonal conflicts, nurses' perception about the management of their organization's support nursing staff, whether or not they got any professional recognition, respect, or reward from their hospital administrator. The information from the study result provided input for the planner and policymaker to consider the extent of the problem and develop a well-standardized guideline and policy to tackle the problems that cause burnout among nurses to improve its work-related consequences. To address the gap in the research for various health care institutions, the study was intended to assess burnout syndrome and its determinant factors among nurses in private hospitals of Addis Ababa, Ethiopia.The study was conducted at private hospitals in AA city. Addis Ababa is the capital city of Ethiopia and seat of the Africa Union. It is the largest city in Ethiopia, with a population of 3,475,952 according to the 2007 population census with an annual growth rate of 2.7%. In Addis Ababa, there are around 40 private hospitals that provide health care services not only for Addis Ababa residents but also serve as referral facilities for the nation. Out of these ten hospitals  were selected for this study, and data collection working units were ward (inpatient department), intensive care unit, emergency department, outpatient department, and operation Room. The study was conducted from 1 November to 30 December 2019.An institutional based cross-sectional study was employed. For this study, the source population was all nurses who are working in Addis Ababa private hospitals. The study population was all nurses who are working in different departments in selected private hospitals of Addis Ababa, which fulfill the inclusion criteria. All nurses who are assigned in the departments with work experience of 12 months and above were included in this study.To determine the sample size, the following assumption was used. Prevalence and determinant factors of nurse's burnout were taken from a previous related study which is 54.8%, with confidence levels 95%, and 5% margin of error , the final sample size was 385. To achieve the representativeness of the study participant simple random sampling technique was employed to draw the sample size from 40 private hospitals currently functioning in Addis Ababa. Due to the scarcity of resources, only ten hospitals were selected by the lottery method and considered to participate in the study. The ten hospitals were . Then the final sample was selected from the respective hospitals by using proportional to size allocation formula:The non-response rate  was taken to be 10% using previous related research response rate = 350N: total number of nurses in the selected hospitals.where; ni: number of nurses in each selected hospital, nf: final sample of the study, *385/924 = 103, Nordic hospital = 101*385/924 = 42, T/Haymanot hospital = 88*385/924 = 37, Halelujah hospital = 104*385/924 = 43, Bethzatha hospital = 51*385/924 = 21, Kadisco hospital = 86*385/924 = 36, Yerer hospital = 65*385/924 = 27, Addis Hiwot hospital = 43*385/924 = 18, Landmark hospital = 47*385/924 = 20, Girum hospital = 91*385/924 = 38.Korea hospital = 248N/n, where N: the population sample size in the selected hospital, n: required sample size, and K: interval.Then systematic sampling was performed to select samples from each hospital by using the formula K = Korea hospital = 248/103 = 2.4 ≈ 2, Nordic hospital = 101/42 = 2.4 ≈ 2, T/Haymanot hospital = 88/37 = 2.37 ≈ 2, Halelujah hospital = 104/43 = 2.42 ≈ 2, Bethzatha hospital = 51/21 = 2.43 ≈ 2, Kadisco hospital = 86/36 = 2.39 ≈ 2, Yerer hospital = 65/27 = 2.41 ≈ 2, Adishiwot hospital = 43/18 ≈ 2, Landmark hospital = 47/20 = 2.35 ≈ 2, and Girum hospital = 91/38 = 2.39 ≈ 2. Therefore, the selection was every second unit in the population in each hospital from the nurse's roster.Data were collected through 24 h, both in working time and night duty time. Data collection was conducted by the trained data collectors and the supervisor. Training was given to data collectors and supervisors for 1 day. Two B.Sc. data collectors and one M.Sc. supervisor were recruited based on previous experience of data collection. After identifying the study subjects, informed consent was obtained to confirm willingness, and confidentiality was ensured to all the study subjects and the self-administered structured questionnaire was administered. Non-respondents were encouraged to fill in the questionnaire and were revisited at least twice. The respondents were encouraged to respond to all items in the questionnaire within the time they devoted as much as possible to minimize a large non-response rate.A self-administered standardized questionnaire was adapted by the principal investigator after reviewing different related literature. The questionnaire has two sections that is used to obtain information relevant to the study: the first section asked about participant's personal information which includes sociodemographic, work related, and organizational related factors of an individual. The second section was a standard question used to assess the levels of burnout, the English version of Maslach's Burnout Inventory Human Services Survey (MBI-HSS), which comprises 22 items regrouped into 3 sub-scales: emotional exhaustion , depersonalization , and personal accomplishment . Each item was answered on a 7-point Likert scale ranging from “never” (=0) to “daily” (=6). The results of the inventory consisted of three separate scores, one for each factor or subscale. A combination of high scores on EE and DP, and a low score on PA, were considered to correspond to a high level of burnout. Scores were considered high if they are in the upper third of the normative distribution, middle if they are in the middle third, and low if they are in the lower third. The MBI-HSS was a self-administered questionnaire, which has been reliable  in the pretest.Burnout syndrome.Sociodemographic characteristics: age, sex, marital status, educational qualification, years of work experience, salary/wages.Work-related factors: work load, working unit, inter-personnel conflict, and night shift duty.Organizational factors: lack of management support, lack of professional recognition, respect, or reward, and personal/material resources.Emotional exhaustion: low (≤16), moderate (17–26), high (≥27).Depersonalization: low (≤6), moderate (7–12), high (≥13).Personal accomplishment: low (≤31) moderate (32–38), high ≥39) ( (9).Burnout: It is a psychological condition characterized by emotional exhaustion (EE), depersonalization (DP), and low personal achievements (LPA) (ts (LPA) .Emotional exhaustion: Leading indicator of burnout and defined as feelings of fatigue and of being drained by one's work.Depersonalization: The negative attitude toward and a dehumanizing treatment of one's clients in the workplace (having a negative view about their clients).Low personal accomplishment: Reduced competence and achievements in one's work a feeling of lower capability in doing personal duties) ( duties) .High levels of burnout: High scores on emotional exhaustion (EE) and depersonalization (DP) subscales, and a low score on personal achievement (PA) subscale.Moderate level of burnout: Represents burnout score an average number on three dimensions .Low levels of burnout: Low scores on emotional exhaustion (EE) and depersonalization (DP) subscales, and a high score on personal achievement (PA) subscale  variable was measured on a dichotomous scale and had multiple independent variables; it used logistic regression. Prior to performing regression analysis, data were checked for multicollinearity, normality, linearity, independence of residuals and outliers. No major violations of the assumptions of the regression analysis were found. Model adequacy was checked by omnibus tests of coefficients and Hosmer-Lemeshow goodness-of-fit test. The squared multiple correlation coefficients were 0.564, which was between zero (0) and one (1), and indicated that 56.4% of the variation in an outcome variable is explained by the variation in the predictor variables. To explain the study population in relation to relevant variables, descriptive statistics such as frequencies and percentages were calculated. The data were analyzed by using logistic regression with step-wise model selection method to identify the association between burnout and determinant factors. To control confounder, all predictors that have been associated with the outcome variable on bivariate logistic regression with a To maintain the reliability of the questionnaire, Cronbach's alpha test was done and reliability reported at 0.83, 0.76, and 0.80 for emotional exhaustion, depersonalization, and personal accomplishment sub-scale, respectively. The quality of data was assured through careful design and pretesting of the questionnaire. A pretest was conducted on 5% of the sample size on the same source population in Yordanos hospital. The result of the pretest was analyzed and modification was made prior to the actual data collection. A 1-day training was given for both the data collectors and supervisor on the objective of the study and methods of data collection. The supervisor and principal investigator closely followed the day-to-day data collection process and ensured completeness and consistency of the collected questionnaires on a daily basis.Ethical clearance was obtained from the Ethical Review Committee of Debre Berhan University, Institution of Medicine and Health Sciences, College of Health Sciences prior to beginning of the study. A letter of cooperation to secure permission of access was given to the selected hospitals included in the study. After obtaining permission from the hospital directors and unit coordinators, informed (written) consent was obtained from the study subjects who have equal chance to participate in the study. To ensure the autonomy of the study participants, their willingness prior to their participation was confirmed after explaining the objective of the study. Information obtained from individual participants was kept secure and confidential. Names and other identifying data of respondents were made anonymous or eliminated throughout the study process to maintain confidentiality.A total of 385 questionnaires were distributed to the nurses working in ten different private hospitals in different departments, three hundred sixty-eight (96%) participants responded to the questionnaires and were considered for the study. Two hundred six (56.0%) of the respondents were females. Majority (69.8%) of them belonged to the age group of 20–29 years. With respect to the respondent's marital status, 205 (55.7%) were single. With regard to their educational status, 291 (79.1%) were B.Sc. in nursing. The result illustrates that in regard to years of work experience of the respondents in their facilities, 152 (41.3%) had between 3 and 5 years of work experience. With regard to the working unit, 179 (48.6%) were in inpatient departments (ward). In the duty shift, 236 (64.1%) were in alternate shifts, whereas, the rest 56 (15.2%) were in the night shift. Participants were asked a question, “Do you perceive satisfied with the current monthly salary?” Three hundred forty-six (94.0%) of the respondents were dissatisfied with their current monthly salary. Participants were asked a question, “Do you think to leave the current working unit within the next 12 months related to your work?” Two hundred nine (56.8%) of them reported having the intention to leave their current working unit. Participants were asked a question, “How do you perceive your current health status?” One hundred and fifty-eight (42.9%) of the respondents perceived their health status as fair and 135 (36.7%) as good, while the rest 75 (20.4%) perceived their health status as poor. Participants were asked a question, “How do you perceive health problems have you experienced in relation to your work?” One hundred and seventy-nine (48.6%) of the respondents perceived as experiencing backache, 110 (29.9%) had depression, and 108 (29.3%) had headache. While the rest, 28 (7.6%) and 2 (0.5%) were perceived as experiencing insomnia and hypertension, respectively see .Two hundred seven (56.5%) of the participants were suffering from high levels of burnout (PB) during the study period. Two hundred nine (56.8%), 84 (22.8%), and 75 (20.4%) of them had high, moderate, and a low scale of emotional exhaustion (EE), respectively. On the other hand, 207 (56.3%), 94 (25.5%), and 67 (18.2%) of them had high, moderate, and low scale of depersonalization (DP), respectively. Regarding the scale of personal accomplishment (PA), 79 (21.5%), 82 (22.3%), and 207 (56.3%) of them rated as having high, moderate, and low scores, respectively.p < 0.25) were selected as candidate variables for multivariable logistic regression analysis. Nurses age, educational level, service area, service year, current duty shift, presence of work overload, presence of interpersonal conflict, staff nurses shortage, presence of management support, professional recognition/respect or reward, intention to leave within 12 months, nurses perception about their current health status, and depression were significantly associated with nurse professional burn out (at p < 0.25). All variables that have association (at a significance level of 0.25) with the outcome variables in bivariate logistic regression analyses were included in the multiple logistic regression models. After controlling for the effects of potentially confounding variables using multiple logistic regression, duty shift, workload, staff nurse's shortage, interpersonal conflict, and nurse's perception about their current health status were significantly associated with nurse professional burnout (at p < 0.05).To investigate the association of independent variables with burnout, both bivariate and multivariate analyses were used. Those variables that showed association with outcome variables in the bivariate analysis ] more likely to develop professional burnout as compared to those who were working at day duty shift, and nurses who were working at alternate duty shifts were 81%  less likely to develop professional burnout as compared to those who were working in day duty shifts. Nurses who had suffered from excessive work overload  and not working with the standard proportion  were comparatively 6 times more likely to develop professional burnout. Moreover, burnout levels were comparatively 2 times  higher among nurses those who had persistent interpersonal conflict at their workplace. In addition to the above factors, staff nurses those who had perceived their health status as poor  and fair  were 3.8 and 2.8 times more likely to develop professional burnout as compared to staff nurses who had perceived their health status as good, respectively see .To successfully tackle burnout problems in Ethiopia, particularly in the present study area, there appears a need to investigate the level of burnout and associated factors among nurses. The finding of this study showed that from the total, 56.5% of nurses who were working in Addis Ababa private hospitals experienced burnout. Among the study participants, 56.8 and 56.3% were high on emotional exhaustion (EE) and depersonalization (DP) sub-scale, respectively. On the other hand, 56.3% was low on the personal accomplishment (PA) sub-scale.Nurses' level of burnout in this study was higher compared to a previous finding reported in Thailand and Singapore, which were 50.2 and 55%, respectively , 15. FurIn this study, a work-related factor has an association with the nurse's professional burnout, which was in the selected private hospitals, for example, nurses who had night duty shifts were significantly associated with burnout as compared to day duty shift. This finding is consistent with the findings of previous studies done in Portuguese . The posIn this study, the organization-related factor has an association with the nurse's professional burnout, which was the selected private hospitals, where staff nurses' shortage has significant association with professional burnout in the study population. Nurses who had not worked with standard proportion were more vulnerable to experience professional burnout than their counterparts. This finding is consistent with the findings of previous studies done in the USA and South Africa , 26. TheIn addition to the above factor's burnout is significantly associated with nurse's perception about their health status. Perception of the health status of the participant nurses, indicating that nurses who perceived their health status as poor have high levels of burnout and vice versa. Decreased wellbeing among nursing staff was associated with burnout syndrome. This finding is supported by a study done in Lebanese and South Africa , 27. It The strength of the present study is that it utilized a strong theoretical basis, using reliable and valid instruments to collect data.The primary limitation of the study is that this study is a cross-sectional study design and can only reflect experiences of nurses at the time of assessment, and therefore, a causal relationship cannot be established between burnout and its predictors.The other limitation of the study is the utilization of self-reported measures, which may increase the possibility of response bias.This study presents strong evidence that a significant proportion of nurses working in private hospitals in Addis Ababa experienced high levels of burnout. There was noted a significant association identified between nurse's burnout with certain work profile , organizational factor (nursing staff shortage), and nurses' perception about their health status. On this ground, it can be concluded that a lot of reforms are required at the organizational and work environment levels.Based on the results of this study, the following recommendations are forwarded by the researcher.Reforms for the human resources for health: One of the major recommendations is for the policymakers to increase the nursing strength as per the current patient load of the hospital. This requires a time-to-time revising of the nursing positions in hospital as per emerging demands, that is, reforms in terms of recruitment rules.Clear job description: Clear-cut guidelines for nursing duties and role clarification at all the levels of staff nurse help them prevent vulnerable to extraordinary pressure at the workplace.The hospital's nursing managers and authorities in different levels should be paid for making a friendly communication with the staff, team work encouragement, and reducing occupational conflicts at workplace.They should ensure adequate staffing of nurses to minimize their workload.They should reduce the number of night duty shifts of staff nurses and make alternate shifts.Finally, further and rigorous studies about levels of burnout among nurses in private hospitals in Addis Ababa using other study designs are recommended.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical clearance was obtained from Ethical Review Committee of Debre Berhan University, Institution of Medicine and Health Sciences, College of Health Sciences prior to beginning of the study. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.DF worked on designing the study, training and supervising the data collectors, interpreting the result, and preparing the manuscript. EC, MH, BD, and ST played their role in analyzing and interpreting the result and wrote the manuscript. All authors were involved in reading and approving the final manuscript.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.