Among poststroke morbidities, poststroke epilepsy (PSE) has been identified as a significant clinical issue. Although middle cerebral artery (MCA) infarct is the most common type of stroke among all vascular territories, very few studies specifically focused on the risk factors leading to PSE in patients with MCA infarct.A population study in Taiwan has been conducted, linking the National Health Insurance Research Database and Hospital Stroke Registry, from 2001 to 2015 and 2006 to 2010, respectively. Patients were divided into MCA and non-MCA groups, and the diagnosis of incident epilepsy between the groups has been compared. The multivariable Cox proportional hazard model was used to identify the risk factors for developing PSE. The distribution of time to PSE was estimated using the Kaplan–Meier method.In total, 1,838 patients were recruited, with 774 and 1,064 in the MCA and non-MCA groups, respectively. PSE incidence in the MCA group was 15.5% vs. 6.2% in the non-MCA group, with a hazard ratio of (95% CI) 2.06 (1.33–3.19). Factors significantly associated with PSE included atrial fibrillation, depression, National Institutes of Health Stroke Scale (NIHSS) scores of ≥ 16, and alert on arrival. For patients with MCA infarct, higher NIHSS and Glasgow coma scale scores, the presence of visual field defects and weakness, urination control impairment, and complications during hospitalization were associated with a higher risk for PSE development.This study established the conditions leading to a higher risk of PSE and identified the important clinical risk factors in patients experiencing MCA infarct. Efforts to manage these risk factors may be important in preventing PSE in patients with MCA infarct. Advances in stroke treatment resulted in a dramatic reduction in stroke mortalities; however, the number of stroke survivors living with morbidities increased significantly. Among these morbidities, seizures and epilepsy are not uncommon, and PSE has been identified as a significant clinical issue among stroke survivors. As we know, stroke is the most common cause of epilepsy in older adults and for patients aged more than 65 years, where PSE accounts for 30–50% of new-onset seizures . The incThe stroke severity, location, and type of pathological changes, genetic factors, and preinjury and postinjury exposure to nongenetic factors including exposome can be used and divide patients experiencing an ischemic stroke into different levels of susceptibility –6, whereThe middle cerebral artery (MCA) infarct is the most common form of stroke among all vascular territories . The cerThis study conducted a large-scale epidemiological study, linking a large dataset stroke registry and an administrative claims database to investigate the incidence and risk factors related to post-MCA infarct epilepsy in Taiwan to unravel the potential clinical risk factors and make a specific comparison with post-non-MCA infarct epilepsy.https://nhird.nhri.org.tw/en/]. For further details of Taiwan's NHIRD, readers can refer to Hsieh et al.  from 2001 to 2015 and the Hospital Stroke Registry from 2006 to 2010. The NHIRD is derived from the National Health Insurance program, which covers nearly all of the Taiwanese population. It includes baseline demographics for beneficiaries, outpatient care claims, inpatient claims, and claims for medication dispensed at pharmacies. Each claim contains the International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) diagnosis and procedure codes, expenditures per visit or admission, and details of drug prescriptions. The NHIRD used in this work was provided by the Ministry of Health and Welfare and is maintained by the Health and Welfare Data Science Center (HWDC) in Taipei City, Taiwan  included atrial fibrillation [2.65 (1.75–4.01) and 1.76 (1.06–2.91)], depression [2.24 (1.17–4.31) and 2.00 (1.02–3.91)], NIHSS scores of ≥ 16 [3.17 (1.99–5.05) and 3.21 (1.47–7.00)], and alert on arrival [1.6 (0.99–2.6) and 0.43 (0.21–0.88)] .P values for all interactions > 0.05).In the stratified analysis , the treP = 0.002) and Glasgow coma scale scores (P = 0.006)], the presence of visual field defects (P = 0.034) and limb weakness (P = 0.005), urination control impairment (P = 0.019), and complications during hospitalization  were associated with a higher risk for PSE development .In the univariable analysis using the Kaplan–Meier method , a signiIn this study, all patients with ischemic stroke (MCA infarct vs. non-MCA infarct) were first characterized, and the risk factors for PSE in all patients were investigated; then, HRs for PSE were stratified (MCA infarct vs. non-MCA infarct); finally, the risk factors for developing PSE in patients with MCA infarcts have been specifically evaluated. Furthermore, in our survival analysis, the incidence curves for the development of PSE in patients with MCA infarcts vs. non-MCA infarcts have been depicted. In addition to establishing the higher risk of PSE following an MCA infarct as compared to a non-MCA infarct, the important clinical risk factors associated with PSE in patients with MCA infarcts were identified: the disease severity .The MCA is the most common artery involved in an acute stroke . It branIn this study, patients with MCA infarcts exhibited more atrial fibrillation as compared to those with non-MCA infarcts, which was compatible with the findings of earlier studies showing atrial fibrillation to be associated with MCA infarcts , suggestRegarding the overall risk factors for PSE in patients experiencing an ischemic stroke, MCA infarcts were identified to exhibit the highest adjusted HR among all the variables. Atrial fibrillation, NIHSS scores of ≥16, alert on arrival, and depression were the other risk factors associated with PSE. The stratified specific comparison of the MCA infarct vs. non-MCA infarct groups on HR showed, in addition to an overall higher risk of PSE for the MCA infarct groups, a positive trend of an association was found between MCA infarct and PSE in some subgroups, namely, sex , age (60–79 years), hypertension, and using of antiplatelet agents, disease severity . The reason that the other risk factors did not show a strong positive trend is probably due to the strong HR of MCA infarct itself in this stratified analysis. The above findings suggested that, compared to non-MCA infarcts, MCA infarcts exhibited a higher HR for PSE.In patients with MCA infarcts, specific risk factors were identified. Disease severity, as expected, could represent brain damage and important risk factors that could predict PSE. Similarly, the presence of visual field defects, limb weakness, and urination control impairment all represented significant compromises in and neuronal damage to MCA vascular territory, namely, the temporal, parietal, and frontal territories. In another study specifically focusing on collateral flow in acute MCA infarcts , visual Depression has been regarded as the peri-injury exposome and risk of epileptogenesis after cerebral stroke , which iInterestingly, one study proposing another scoring system for PSE prediction did not include the stroke location as an important variable . NeverthAlthough the observations were retrospective, this study was based on prospectively registered patients with stroke who were admitted to National Cheng Kung University Hospital and Ditmanson Medical Foundation Chia-Yi Christian Hospital. The data collected in this stroke registry were prospectively recorded. Our study presents several additional limitations. The HR of acute seizure complications during hospitalization was not assessed precisely due to the small sample size. Performing long-term EEG monitoring on every patient with stroke is not practically feasible. Another limitation was the fact that the HR of neurosurgical intervention in PSE could not be evaluated due to the small sample size. Although patients who require neurosurgical procedures during the acute stage of a stroke typically represent a higher degree of severity, neurosurgical interventions, including hemicraniectomies, still require randomized clinical trials to prove their effects on functional recovery, especially in patients over 60 years of age and those who are severely disabled , 35. BesRegarding the effects of acute treatments for stroke (thrombolysis and thrombectomy), due to the extremely small number of patients, we did not verify the effects of acute treatments on PSE. Furthermore, according to the current database, we could neither differentiate the data based on the tracts of MCA occlusion (M1-M4) nor analyze the tandem occlusion stroke (MCA + ICA) in the MCA cohort. In addition, according to the database, at the current stage, we could only compare MCA infarcts with non-MCA infarcts ; we could not differentiate between the subgroups in patients with non-MCA . Whether different territories of MCA would carry the different risks of PSE is worth further investigation. Lastly, whether the results can be generalized to other racial/ethnic groups is unclear given that stroke and its complications may not be totally similar among different ethnic groups , 36.This study on a large dataset linking stroke registry and an administrative claims database established the higher risk of PSE and identified the important distinct clinical risk factors associated with PSE in patients with MCA infarcts: disease severity . Increased awareness and early management of these risk factors in patients with MCA infarcts may be important in PSE prevention and thus should be given attention.huangcw@mail.ncku.edu.tw.The data analyzed in this study was obtained from the National Health Insurance Research Database (NHIRD), the following licenses/restrictions apply: these datasets were provided by the Ministry of Health and Welfare (MOHW) and are maintained by the Health and Welfare Data Science Center (HWDC) in Taipei City, Taiwan. Requests to access these datasets should be directed to Chin-Wei Huang, The studies involving human participants were reviewed and approved by Institutional Review Board of National Cheng Kung University Hospital (IRB No. A-ER-108-563). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.C-YH, C-CS, EL, Y-SC, T-HH, Y-HK, C-HC, S-FS, and C-WH: substantial contributions to the conception or design of the work or the acquisition, analysis or interpretation of data for the work, provide approval for publication of the content, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. C-YH and C-WH: drafting the work or revising it critically for important intellectual content. All authors contributed to the article and approved the submitted version.This research was supported in part by grants from the Ministry of Science and Technology, Taiwan . The funding bodies did not play any role in the design of the study and collection, analyses, and interpretation of data or the writing of the 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.


Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence of chronic kidney disease (CKD). Our goal was to study the independent impact of uric acid and CKD on mortality.Methods: We retrospectively investigated 21,963 patients from the URRAH study database. Hyperuricemia was defined on the basis of outcome specific cut-offs separately identified by ROC curves according to eGFR strata. The primary endpoints were cardiovascular and all-cause mortality.Results: After a mean follow-up of 9.8 year, there were 1,582 (7.20%) cardiovascular events and 3,130 (14.25%) deaths for all causes. The incidence of cardiovascular and all-cause mortality increased in parallel with reduction of eGFR strata and with progressively higher uric acid quartiles. During 215,618 person-years of follow-up, the incidence rate for cardiovascular mortality, stratified based on eGFR  was significantly higher in patients with hyperuricemia and albuminuria  as compared to those with only one risk factor or none . Serum uric acid and eGFR significantly interact in determining cardiovascular and all-cause mortality. For each SUA increase of 1 mg/dl the risk for mortality increased by 10% even after adjustment for potential confounding factors included eGFR and the presence of albuminuria.Conclusions: hyperuricemia is a risk factor for cardiovascular and all-cause mortality additively to eGFR strata and albuminuria, in patients at cardiovascular risk. Serum uric acid (SUA) has been shown to predict the occurrence of cardiovascular (CVM) and all-cause mortality (ACM)  as well Chronic kidney disease is also a well-known risk multiplier in itself. Both reduced GFR and albuminuria independently entail an increased risk of mortality, especially from CV causes . Many riCKD and HU often coexist as glomerular filtration rate (GFR) reduction is one of the main determinants of UA increase. Thus, it is difficult to sort out the independent role of each one of these conditions.We have previously reported on the specific threshold of SUA associated to a significant increase in CVM and ACM  in a larOur aim was to investigate the relationship between SUA and CKD components in causing mortality.The Uric Acid Right for Heart Health (URRAH) project is based on a multicenter retrospective, observational cohort study, which involves data collected on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension. Participant centers who collected the data included in the general database are listed under Acknowledgements. The study protocol has been previously extensively described . A natioThe URRAH was performed according to the Declaration of Helsinki for Human Research . The processing of the patients' personal data collected in this study comply with the European Directive on the Privacy of Data. All data to be collected, stored and processed are anonymized, and all study-related documents are retained in a secure location. No personal information is stored on local personal computers. Approval was sought from the Ethical Committee of the coordinating center at the Division of Internal Medicine of the University of Bologna (no. 77/2018/Oss/AOUBo). Informed consent was obtained from all individuals at recruitment.Hypertension was defined according to ESH-ESC guidelines as a BP at least 140/90 mmHg or by the presence of antihypertensive treatment. Systolic and diastolic BP was measured twice, in a quiet room, after 5 min resting and with the participant in sitting position. The second measure was used for all analyses.n 8,607; 4,697 men, 3,910 women) for whom the SUA was not available or the estimation of eGFR was not possible or follow-up data were not complete were excluded from analysis. Data obtained from the remaining 21,963 patients  form the basis of the present study.Data on the patients  for skewed variables. Logarithmically transformed values of skewed variables were used for the statistical analysis. Comparisons between groups were made by analysis of variance. Comparisons of proportions among groups were made using the χGiven the known difference in SUA levels along with eGFR strata, we tested SUA for an interaction with eGFR in its association with the two clinical outcomes.Furthermore, three CKD-specific cutoff points were identified, and their prognostic value for CVM and ACM was tested. To this purpose, the survival receiver operating characteristic curve was implemented using Kaplan-Meier estimates and was used to search for prognostic cut-off of SUA that optimized the combination of sensitivity (true-positive) and 1-specificity  for CVM and ACM by the presence of CKD . Youden'Time to event analyses were performed using: (i) Kaplan-Meier method for survival curves estimation and log-rank test to compare them; (ii) univariate and multivariate Cox regression models: risk was reported as hazard ratios (HR) along with their 95% confidence intervals (CI). Covariates included all available clinical variables with biological plausibility. Time variable was defined as the interval time between baseline date and the date of endpoint occurrence or the last available follow-up.n = 21,963) represented a sample largely sufficient to avoid b error also after stratification by CKD.Power analysis showed that the number of individuals in the database . The null hypothesis was rejected for values of n = 14935) and 7% (n = 1537) had a positive history for hypertension and diabetes, respectively. Office systolic BP was 144 ± 23 mm Hg, and diastolic BP was 85 ± 13 mm Hg. Mean SUA was 5.03 mg/dl and mean eGFR was 81.5 ± 20.0 ml/min/1.73 m2. When we analyzed the baseline clinical characteristics across eGFR stage  we found that patients with preserved eGFR  were younger, more frequently males, without a positive history of hypertension and diabetes and with lower BMI, BP levels, fasting glucose and a more favorable lipid profile as compared to those with impaired renal function. As for mean SUA levels, HU, gout and use of Allopurinol they were all lower in patients with eGFR above 90 ml/ min  patients with available data about albumin excretion at baseline, we found a prevalence of micro- and macro-albuminuria of 9.3 and 0.9%, respectively. The characteristics of these patients stratified by eGFR stage and albuminuria are depicted in In the overall study population, median follow-up was 9.8 years. During 215,618 person-years of follow-up, 1,063 patients developed non-fatal cardiovascular events , 1,582 patients died due to cardiovascular disease  and 3,130 patients died from all causes .The 1,582 patients dead for CV and the 3,130 dead for ACM  were old2) and with the increasing of SUA quartiles. Patients treated with Allopurinol showed mean SUA levels higher than non-treated patients  and developed CVM and ACM with an incidence of 15 and 25%, respectively.To better understand the relationship between HU, renal function and outcomes, we analyzed the incidence of CV an ACM on the basis of CKD strata and SUA quartiles . The prop < 0.0001, data not shown).A Cox regression interaction analysis using the two mortality outcomes assessed the interaction between SUA levels and eGFR in determining cardiovascular and all-cause mortality (2). p = 0.0014; 1.13 CI 95% [1.08–1.19], p < 0.0001; 1.05 CI 95% [0.99–1.12], p = 0.1189, respectively) and all-cause mortality .To investigate the specific predictive role of serum uric acid for CVM and ACM according to eGFR strata, we performed univariate and multivariate Cox survival analysis splitting the cohort on the basis of three eGFR strata , and ACM . These are summarized along with ROC curves parameters in ROC curve analysis yielded plausible eGFR stage specific cut-off values of SUA for CVM . For each eGFR strata the additive presence of CKD specific definition of HU at baseline significantly decreased the survival proportion both for CV and ACM  and the relatively long follow-up period, do contribute to make our results a reliable representation of real-life clinical condition.In conclusion, HU is a risk factor for CVM and ACM additively to eGFR strata and albuminuria in patients at CV risk. These data suggest that although CKD is a major determinant of the presence and degree of HU, these two conditions may have, at least in part, different pathogenetic mechanisms by which they both contribute to the excess of CV morbidity and mortality. Moreover, a higher threshold values (≥7 mg/dl) should be applied to define asymptomatic HU in the presence of CKD.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 the Ethical Committee of the coordinating center at the Division of Internal Medicine of the University of Bologna (no. 77/2018/Oss/AOUBo). The patients/participants provided their written informed consent to participate in this study.CB, GG, RP, MC, FV, ER, AV, MM, and CF: research idea and study design. ER, FV, RP, MC, and GL: data analysis/interpretation. ER, FV, and GL: statistical analysis. CB, GG, RP, MC, FV, ER, AV, MM, CF, and GP: supervision or mentorship. Each author contributed important intellectual content during manuscript drafting or revision, accepts personal accountability for the author's own contributions, and agrees to ensure that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.This work has been conducted with an unrestricted grant from the Fondazione of the Italian Society of Hypertension (Grant Number: MIOL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the 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.


Klebsiella pneumoniae strains increased their pathogenicity and antibiotic resistance, thereby becoming a major therapeutic challenge. One of the few available therapeutic options seems to be intravenous fosfomycin. Unfortunately, the determination of sensitivity to fosfomycin performed in hospital laboratories can pose a significant problem. Therefore, the aim of the present research was to evaluate the activity of fosfomycin against clinical, multidrug-resistant Klebsiella pneumoniae strains isolated from nosocomial infections between 2011 and 2020, as well as to evaluate the methods routinely used in hospital laboratories to assess bacterial susceptibility to this antibiotic. Materials and Methods: 43 multidrug-resistant Klebsiella strains isolates from various infections were tested. All the strains had ESBL enzymes, and 20 also showed the presence of carbapenemases. Susceptibility was determined using the diffusion method (E-test) and the automated system (Phoenix), which were compared with the reference method (agar dilution). Results: For the reference method and for the E-test, the percentage of strains sensitive to fosfomycin was 65%. For the Phoenix system, the percentage of susceptible strains was slightly higher and stood at 72%. The percentage of fosfomycin-resistant strains in the Klebsiella carbapenemase-producing group was higher (45% for the reference method and E-test and 40% for the Phoenix method) than in carbapenemase-negative strains . Full (100%) susceptibility categorical agreement was achieved for the E-test and the reference method. Agreement between the automated Phoenix system and the reference method reached 86%. Conclusions: Fosfomycin appears to be the antibiotic with a potential for use in the treatment of infections with multidrug-resistant Klebsiella strains. Susceptibility to this drug is exhibited by some strains, which are resistant to colistin and carbapenems. The E-test, unlike the Phoenix method, can be an alternative to the reference method in the routine determination of fosfomycin susceptibility, as it shows agreement in terms of sensitivity categories and only slight differences in MIC values. The Phoenix system, in comparison to the reference method, shows large discrepancies in the MIC values and in the susceptibility category.Introduction: Over the past few decades,  Fosfomycin, a natural bactericidal antibiotic and a derivative of phosphoric acid, has been used worldwide for more than 40 years. Currently, there is a revival of its use in antibiotic therapy. It gained renewed interest due to an increase in infections caused by multidrug-resistant bacteria, where therapeutic options are very limited ,2,3.N-acetylglucosamine-enolpyruvyltransferase), which is responsible for the synthesis of the pentapeptide mediating the synthesis of peptidoglycan . At the same time, i.v. fosfomycin, which has the smallest hydrophilic molecule among all antibiotics, has good pharmacokinetic properties, including excellent distribution to many tissues. This antibiotic achieves clinically relevant concentrations in the serum (does not bind with plasma proteins), kidneys, lungs, bones, heart valves, bladder, prostate gland, and seminal glands. It penetrates the placenta, as well as the blood-brain barrier, reaching high concentrations in the cerebrospinal fluid. It also demonstrates very good penetration into abscesses. It is nearly completely (95%) excreted unchanged in the urine within 24 h, and its half-life is relatively long (4–8 h). Due to its different chemical structure and characteristic mechanism of action, for the time being, there is no cross-resistance observed with other antibiotics commonly used in clinical practice [Pseudomonas aeruginosa and Staphylococcus aureus strains [Fosfomycin is a bactericidal antibiotic whose unique properties are owed, among other things, to its mechanism of action. It is involved in inhibiting cell wall synthesis, but in a different way than in the case of β-lactam or glycopeptide antibiotics. It inhibits the MurA enzyme , mainly in the treatment of uncomplicated urinary tract infections (UTI). Intravenous fosfomycin  was not registered by the European Commission until 2015 and initially was used in such EU countries as Spain, Germany, and France . In PolaStaphylococcus aureus (MRSA), Enterococcus strains resistant to glycopeptides [Enterobacterales [Pseudomonas aeruginosa, noting however its low effectiveness when used in monotherapy [Intravenous fosfomycin gained increased interest in the second decade of the 21st century, as it remains active against many very problematic pathogens such as methicillin-resistant peptides , and mulcterales ,12,13. Motherapy ,7,14. Thotherapy .Currently, clinicians and scientists are conducting a number of studies testing the susceptibility of different organisms to fosfomycin , hoping for its application in combination treatment of severe infections caused by multidrug-resistant pathogens that have very limited or no therapeutic options. However, there is a great need for modern research into the activity and range of action of fosfomycin, as well as into optimal methods for routine determination of in vitro resistance. Klebsiella pneumoniae strains are among the pathogens posing a major therapeutic problem [Klebsiella bacilli have undergone a unique evolution over the last few decades. They greatly increased their pathogenicity and reduced their susceptibility to antibiotics through acquiring new virulence features and resistance mechanisms. This has led to their transformation from bacteria commonly found in the environment, in the gastrointestinal (GI) tract, and in the upper respiratory tract of humans into dangerous pathogens with very high pathogenic potential and limited therapeutic options [Multidrug-resistant  problem ,3,4. Kle options ,16,17. The greatest evolution took place in the production of broad-spectrum enzymes breaking down many classes of antibiotics, such as the ESBL enzymes. In the present decade, the strains often produce several types of ESBL, where on one plasmid ESBL, there are genes that inactivate other groups of antibiotics, and sensitivity remains only to carbapenems and colistin ,17. CurrKlebsiella strains currently pose a high risk, in both in-hospital and out-of-hospital settings, causing pneumonia; infections of wounds, the urinary tract, the central nervous system (CNS), and soft tissues; and septic infections (blood infections), which are particularly dangerous and have high mortality rates [Drug-resistant ty rates ,16,17. Mty rates .The proliferation of new antimicrobial resistance mechanisms in common pathogens is a growing concern and warrants the search for new therapeutic options. However, testing bacterial susceptibility to fosfomycin poses a certain problem because the reference method , which is the most reliable and recommended by EUCAST , is labor-intensive and difficult for routine use in hospital laboratories ,20,21.Klebsiella pneumoniae isolated from nosocomial infections over the past ten years. Another important goal was to evaluate the methods of determining bacterial susceptibility to fosfomycin routinely used in hospital laboratories: the diffusion methods  and the automated method of serial dilutions in a liquid medium ; the goal was to compare them with the method recommended by specialists—dilution in a solid medium. The use in microbiological laboratories of simpler and cheaper diffusion methods or the determination of fosfomycin susceptibility in automated systems raises doubts and is associated with the risk of obtaining false results, leading to incorrect antibiotic therapy of patients [In view of the above facts, the main objective of this study was to evaluate the antimicrobial activity of fosfomycin against clinical multidrug-resistant strains of patients ,21.Klebsiella pneumoniae. The antibiograms obtained using the automated BD Phoenix system showed that the tested strains were highly resistant to routinely used antibiotics. All tested Klebsiella were characterized by complete resistance to aminopenicillins, penicillins with inhibitors of β-lactamases (excluding piperacillin/tazobactam—12% of sensitive strains), cephalosporins, quinolones, and, significantly, tigecycline and tobramycin. For the remaining aminoglycosides, the sensitivity of the tested Klebsiella isolates was higher . The degree of sensitivity of the isolated bacilli to cotrimoxazole also varied, but resistant strains prevailed (86%).All the test strains were identified by BD Phoenix as Klebsiella pneumoniae isolated at the clinical centers selected for the study.Differences were noted in susceptibility to carbapenems , which correlated with the production by the tested strains of carbapenemases, although some carbapenemase-negative bacilli (six strains) also showed reduced susceptibility or resistance to these antibiotics, especially ertapenem. The tested strains showed the highest susceptibility to colistin (81% S), fosfomycin (71% S), imipeneme (65% S), and meropeneme (53% S). Six strains from a relatively small colistin-resistant group (19%) showed at the same time susceptibility to fosfomycin. Klebsiella strains were isolated rather infrequently at the hospitals selected for this study. In the next five years (2016–2020), as many as 33 of such multidrug-resistant strains were isolated. Most isolates were fosfomycin-susceptible strains. The comparisons conducted in individual years of the number of strains resistant to this antibiotic with the susceptible strains and with all isolated strains did not show any clear trend of increasing fosfomycin resistance in Klebsiella strains (Over a period of five years (2011–2015), ten strains showing resistance to the majority of antibiotics used were collected for investigation. At that time, such multidrug-resistant  strains . The lowKlebsiella pneumoniae strains (80%), and KPC enzymes were found in four strains (20%) . MBL enzymes were detected in 16 of the tested ns (20%) . In the Klebsiella strains was determined using three methods: the agar dilution method (reference method) (Fosfomycin sensitivity of multidrug-resistant  method) , the gra method) , and then = 20) and in the group which does not produce this enzyme . In the Klebsiella group of carbapenemase producers, the percentage of fosfomycin-resistant strains was significantly higher (45% using the reference and E-test methods and 40% using the Phoenix system) than in the group which does not produce carbapenemases   .The E-test method and the reference method showed 100% agreement in terms of the susceptibility category. The agreement between the automated system and the reference method was 86%. Four VME (very major errors) and two 2 ME (major errors) were detected in the case of the Phoenix automated system. The VME rate and ME rate for the Phoenix system were 33% and 17%, respectively .p < 0.000001). This is confirmed by the maximum value of phi coefficient Φ = 1, which indicates a perfect association between the reference method and the E-test. In the comparison between fosfomycin susceptibility results obtained using the reference method and the automated Phoenix system, the p-value is very low (p = 0.00008) and the phi coefficient Φ = 0.63, which indicates a correlation with a moderate correlation strength.A comparison of results obtained using the reference and E-test methods showed a statistically significant correlation . Pearson’s correlation coefficient for MIC values obtained in the Phoenix method, and the reference method is r = 0.59, indicating a moderate correlation. Klebsiella pneumoniae strain and its fosfomycin resistance  did not show a statistically significant relationship between the site of isolation of the sistance .Klebsiella pneumoniae is an important etiological factor in nosocomial and non-nosocomial infections, which are a serious threat to patients’ lives. For many years, these bacteria were a major challenge for clinicians around the world. Of particular concern is the fact that the organisms are able to survive and spread easily in hospital settings. An important role in the spread of the bacteria is played by gastrointestinal carriage, occurring in as much as 5–38% of the general population and in up to 77% of hospitalized patients [Klebsiella pneumoniae can be carried in the GI tract for one or even two years, despite previous assumptions of that period being three months [patients ,22. The patients . Accordie months .Klebsiella is illustrated in the statistics presented in the Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) for most European countries [Klebsiella pneumoniae [Enterobacterales (CPE) are among Europe’s most serious medical and epidemiological problems. The number and rate of the appearance of carbapenemase-producing strains indicate a high epidemic risk for hospital environments [Klebsiella pneumoniae strains. In the country of these authors, strains producing KPC enzymes (Klebsiella Pneumoniae Carbapenemases) appeared as the first ones, and their rapid spread was noted in 2010–2013. Since 2016, there was a marked increase in the occurrence of Klebsiella strains with NDM-1 carbapenemases , and from 2017 this was also observed with OXA-48 enzymes (Carbapenem-hydrolysing Class D β-lactamases) [Klebsiella pneumoniae studied in this paper, in addition to ESBL enzymes, mainly KPC carbapenemases were detected .The extremely rapid development of resistance mechanisms in these bacteria led to the elimination of almost all antibiotics from effective therapy . Recentlountries . The repeumoniae . Strainseumoniae . Today, ronments ,31. In ttamases) ,33,34. Idetected . Among tKlebsiella pneumoniae isolated from four multi-specialty hospitals between 2011 and 2020. Like colistin, fosfomycin is a drug for which new applications have now been found [Klebsiella pneumoniae, but also to verify the reliability of laboratory determinations of susceptibility to this drug.This paper presents analyses of the sensitivity to fosfomycin of multidrug-resistant strains of en found ,37,38. DEnterobacterales’ ability for easy transmission of resistance genes significantly limited the options for effective antibacterial therapy. The above is confirmed in the review of antibiograms made for the tested pathogens using the automated Phoenix system  and to monobactams. As many as 47% of these strains produced carbapenemases hydrolysing antibiotics with β-lactamase inhibitors, other cephalosporins, and carbapenems , but still lower than for E. coli strains (above 95%) [Klebsiella pneumoniae isolates, reported that as many as 81% of them showed susceptibility to fosfomycin [Thanks to the specific pharmacokinetic properties and the unique mechanism of action, i.v. fosfomycin can be successfully used in combination therapy. Except for urinary tract infections, monotherapy with i.v. fosfomycin is not recommended due to the risk of development of resistance ,41. A go and CPE ,41,42. Aove 95%) . SeventeKlebsiella pneumoniae. The organisms were isolated from various clinical sources such as CNS infections, pneumonia, urinary tract infections, sepsis, bone and joint infections, and soft tissue infections. Therapeutic success in the use of fosfomycin was noted for as many as 81% of all infections and for 80% of infections caused by Enterobacterales. Fosfomycin was mainly used in combination with, depending on the case, carbapenems or cephalosporins [In 2010–2016, studies were conducted in Germany by Putensen et al. on the use of intravenous fosfomycin in daily clinical practice . The resosporins .Klebsiella multidrug-resistant strains to fosfomycin, were obtained in the research carried out for the purposes of this paper. Data reliability was verified by comparing the obtained determinations with the reference method (agar dilution), which is recommended by EUCAST , inactivating the tested drug, is relatively rare [Klebsiella pneumoniae conducted in Taiwan is among many supporting this thesis. Among the group of fosfomycin-resistant bacteria, 70% had a MurA amino acid substitution, and 96% of this group had functionless transporters [Klebsiella pneumoniae showed a higher resistance rate in carbapenemase-producing strains than in strains producing extended-spectrum β-lactamases. This phenomenon is related to the transfer of the plasmid carrying fosA3 genes and the gene responsible for the production of carbapenemases [Klebsiella. Fosfomycin susceptibility analysis conducted for carbapenemase-positive strains performed as part of our research , alteration of bacterial proteins that are antimicrobial targets (receptor resistance), and limitation of drug uptake or active drug efflux (transport resistance). Amino acid changes at the drug binding site are caused by a mutation in the ely rare . Researcsporters . Studiesenemases . Given tresearch  shows a Enterobacterales to the test antibiotic is pivotal to effective therapy. The variety of available methods is the subject of many studies [Enterobacterales (including Klebsiella pneumoniae), obtained by the reference method and by alternative methods. All experiments lead to the same conclusion—the lack of satisfactory concordance of results of tests carried out using different methods. The studies compare diffusion methods (strips with a gradient of drug concentrations and antibiotic-soaked discs) and broth dilution methods (automated) with the reference method—dilution of the drug in a solid medium. Regarding all alternative methods, the authors [A separate problem, already indicated above, is the choice of laboratory method for the determination of fosfomycin resistance. Despite EUCAST’s recommendation of agar dilution as the reference method, there is a certain freedom of choice of methods used by microbiological laboratories related, for example, to their use of specific apparatuses, which carries a risk of inconsistency of results between methods. The method’s reliability in determining susceptibility of  studies ,40,45,46 authors ,36,40,45 authors ,35,40. O authors . There i authors . BallestKlebsiella pneumoniae susceptibility to fosfomycin presented in this paper , Teaching Hospital in Wroclaw (n = 14), Regional Specialist Hospital in Wroclaw (n = 3), and Regional Specialist Hospital in Legnica (n = 2). The organisms were collected from 43 patients showing clinical signs of nosocomial infections and from hospitalized asymptomatic carriers. Klebsiella strains were isolated from urine samples (n = 15), bronchial aspirates (n = 9), other clinical materials  (n = 7), and from the fecal matter of carriers (n = 12)  . Only muIdentification of strains and determination of drug sensitivity and resistance mechanisms were performed using an automated system—Phoenix 100™  with ID402 panels  containing a set of 20 antibiotics  based on the method of serial dilutions in a liquid medium.MIC determinations for fosfomycin were also made using the gradient method (E-test) Fosfomycin FM 0.064–1024 μg/mL  according to EUCAST guidelines  for all isolates . The plaThe dilution method in the Mueller–Hinton agar (MHA)  was used as the reference test. This method is the only one recognized by the American Clinical and Laboratory Standards Institute (CLSI) for the purposes of determination of susceptibility to fosfomycin, and is the one most recommended by the EUCAST ,49,50. TVarious β-lactamases of Klebsiella bacilli were screened using combination discs . ESBL enzymes were identified with DDT (Double-disk test) using combination discs  with cefotaxime (30 µg), ceftazidime (30 µg), cefepime (30 µg), and amoxicillin with clavulanic acid (30 µg). MBL carbapenemases were identified using DDST (double-disk synergy test) with discs with imipenem (10 µg), ceftazidime (30 µg), and EDTA (Standard). KPC enzymes were identified using a review method using the following discs: meropeneme 10 µg and meropeneme 10 µg with 10 µL boronic acid  ,51. IdenEscherichia coli ATCC 25922 (MIC range 0.5–2 μg/mL) and Pseudomonas aeruginosa ATCC 27853 (MIC range 2–8 μg/mL). All identifications were performed in triplicate [Quality control for all methods was performed using the following reference strains: https://www.statsoft.pl/ (accessed on 24 March 2021). Categorical agreement was calculated, and discrepancies were described as very major error  and major error . The VME rate was calculated by dividing the number of errors (VME) by the number of all resistant isolates. In the case of susceptible isolates, the ME rate was calculated analogically. Fisher’s exact test was used to compare the relationships between categories. Pearson’s correlation coefficient was used to compare the MIC values obtained by the three methods. Due to limitations of the methods, it was not possible to determine the MIC in an identical concentration range. For the purposes of correlation analysis, the values indicated by the inequality sign were replaced with integers. A replacement of value does not affect the diagnostic decision. For “greater than” values, the nearest MIC value on the logarithmic scale was assumed . Values "less than or equal to" were replaced with "equal to" values (≤16 was assumed as 16). For all statistical analyses, the p-value of <0.05 was adopted as significant. The charts were made using Microsoft Excel, Microsoft 365, https://office.microsoft.com/excel (accessed on 22 March 2021).Statistical analysis was performed using TIBCO Software Inc. (2017) Statistica , version 13, Klebsiella strains, as over 65% of strains are susceptible to this drug. Some strains resistant to colistin and carbapenems are also susceptible, although the percentage of resistance in carbapenemase-producing strains is higher. The E-test can be an alternative to the reference method in routine determination of fosfomycin susceptibility, as it demonstrates agreement in terms of sensitivity categories and, for the most part, only slight differences in MIC values. Subjectivity of the reading is its disadvantage. On the other hand, the serial dilution method employed in the automated Phoenix system seems to be of little use for determining susceptibility to this antibiotic. In comparison to the reference method, it shows large discrepancies in the MIC values and in the susceptibility category.Fosfomycin appears to be the antibiotic with a potential for use in the treatment of infections with multidrug-resistant


N = 1677 people, 44% women. In contrast with men, in women, cancer was less prevalent (64.4% vs. 73.9%) (p < 0.001), cognitive impairment was more prevalent  and professional caregivers were much more common . Women over 80 showed less complexity in the following subareas: symptom management , emotional distress , spiritual distress , socio-familial distress  and location of death . Men were more complex in the subareas of “practice” OR = 1.544 (1.25–1.90 p = 0.000) and “transcendence” OR = 1.52 (1.16–1.98 p = 0.002). Observed complexity is related to male gender in people over 80 years of age. Women over the age of 80 are remarkably different from their male counterparts, showing less complexity regarding care for their physical, psycho-emotional, spiritual and socio-familial needs.This study analyses gender differences in the complexity observed in palliative home care through a multicentre longitudinal observational study of patients with advanced disease treated by palliative home care teams in Catalonia (Spain). We used the HexCom model, which includes six dimensions and measures three levels of complexity: high (non-modifiable situation), medium (difficult) and low. Results:  There is currently a certain consensus that, beyond the vital prognosis or the disease, the backbone of palliative care should be the level of care complexity required by the person with advanced disease . ComplexThe complexity and uniqueness of each patient and each situation calls for an open and multiple approach, bearing in mind that the application of conventional approaches—such as reductionism and compartmentalisation—can be potentially counterproductive .To this end, a systemic understanding of these situations emphasises the ecological framework in which they unfold , taking Over time, androcentrism in biomedical sciences has invisibilised women, assimilating them to men . To giveStanding at the crossroads of biomedical and social research and practice, palliative care has not escaped this tendency to ignore women’s singularities. For instance, Gott et al. have recently shown that while cancer guidelines recommend an early administration of palliative care, women have shown lesser improvements in quality of life and emotional status than men . SimilarCurrently, there is a lack of studies on these gender dynamics in the practice of palliative home care. In this article, we explore the role of gender in the process of defining the complexity of each case. To do so, we draw on the Hexagon of Complexity (HexCom) ,17, whicOur objectives were to analyse differences by gender in the complexity of patients registered by a home palliative care team and describe the role of age in these differences.Design: Longitudinal observational study of a multicentre cohort.Population: Patients requiring advanced illness and/or end-of-life treatment provided by home care support teams in Catalonia (PADES) .Inclusion/exclusion criteria: Patients requiring advanced illness and/or end-of-life treatment provided by PADES teams in their own home. Patients receiving care in a residential institution were excluded. Consecutive sampling was used during the recruitment period (January 2016–December 2019) to assign the patients who met the inclusion criteria to any of the PADES teams who agreed to participate in the study.Complexity was assessed after the demise of the patient by the interdisciplinary PADES teams using the HexCom model.HexCom includes six dimensions  and 18 subareas, with three levels of complexity: low, medium and high. High complexity occurs when the team cannot respond to the need and has to refer the case and/or assume that they can only act as support. Medium complexity occurs when the management is considered difficult and requires the support of other services. In cases of low complexity, the need of the patient and/or family can be easily managed . The HexDisease groups: Medical diagnosis (ICD-10) and advanced disease groups: cancer, advanced chronic organ failure, advanced neurological disease, dementia and geriatric frailty/multimorbidity. The PADES team had to agree on the main diagnosis associated with death.Socio-demographic data: Age; gender; relationship with caregiver: partner, yes or no; professional caregiver: yes or no.Patient status: Functional status (Barthel index) and mental status (Pfeiffer test).Procedure: To standardise data collection, the 43 PADES teams (74.3% teams accepted our invitation to participate) received 10 h of face-to-face training, a user guide, and were able to call the researchers during fieldwork if necessary.p ≤ 0.05. SPSS  for Windows statistical package, version 25.0, was used for all analyses.Statistical analysis: Gender  was analysed in relation to complexity, using a logistic regression analysis, adjusted for age. Each specific subarea was considered for the analysis. Except for length of care, all variables analysed were categorical and are described with their absolute and relative frequencies. To compare proportions, we used Pearson’s Chi Square test. The significance level was set at Ethics Committee Approval: The study was approved by the Clinical Research Ethics Committee of the Institute for Research in Primary Care (IDIAP) Jordi Gol (registration number P15/171) and by the Clinical Research Ethics Committees of all participating centres. All participants read and signed an informed consent form.p < 0.001), more cognitive impairment , less partners as primary caregivers  and more professional caregivers A total of 1677 patients were recruited (44% women) . Only 19p = 0.011), of psycho-emotional , spiritual  and socio-familial distress , and in relation to the location of the death . In the group of 80 years and under, the only subarea with a statistically significant difference was transcendence, which relates to fear of death or the future, with less complexity detected for women than for men . Logistic regression (p = 0.54), and that men are more complex especially in the socio-family subarea “practice” OR = 1.544 (1.25–1.90 p = 0.000) and the spiritual subarea “transcendence” OR = 1.52 (1.16–1.98 p = 0.002).As a result of statistically analysing the six dimensions of complexity as a whole, observed complexity was significantly lower in women than in men in all areas except for ethics . The dimgression  shows thThe results of this study highlight important gender differences in observed complexity in patients from palliative home care over 80 years of age. In this group, there are more women who, compared with men, have a lower prevalence of cancer, more cognitive impairment, less partners as primary caregivers and more caregivers who are professional. The complexity observed by the professionals in this group of women was lower than in men regarding location of death, management of symptoms and psycho-emotional, spiritual and socio-familial distress.Currently, more men than women require specialised home palliative care , in agreement with the literature and with predictions of the World Health Organisation based on the different causes of death according to gender . HoweverObserved complexity is higher for both men and women under 80 years of age. The inverted association between age and complexity, also observed in other studies , may resFinally, we should underscore that the subgroup of women over 80 years shows less complexity. In the Catalan context, this could be explained by the resilience of this subgroup, which has endured wars, post-war hardship, dictatorship, emigration and widowhood, and have been great fighters and caregivers. In addition, this could be related to different approaches to end of life. Most women have lost their partners (only 8.4% have their partner as primary caregiver versus 45.9% of men), and might have accepted that death is the next step in their biography, adopting coping strategies focused on problem solving and help seeking, whereas men draw more on avoidance and disengagement . SimilarThe higher prevalence of dementia (46.9% versus 36.5% of men) might also contribute to the lower levels of observed complexity in women. The impact of having a partner might partly explain these differences: emotional ties are crucial for older cancer patients, and male patients, unlike women, depend mainly on the social support of their partners . DistresStudies indicate that men and women face the end-of-life situation differently . NormatiAccording to our results, spirituality is more used by women than by men as a coping mechanism for extreme situations such as death. In our study, women show less fear of death and the future. Many studies conducted in various cultural settings  confirm Finally, we should emphasise that no differences were found between men and women in relation to ethics, even though the literature shows that while more women sign advanced directives , reject Gender biases and inequalities exist at multiple levels of health research and practice, affecting each other’s significance ,43. For Intersectionality is one of the strengths of this study , as reflWe should also ask whether a change in traditional patterns is taking place. For instance, while the number of women caregivers is higher than men, a recent national survey conducted in Sweden indicated an equal number of men and women acting as informal caregivers . The expOur results aim to raise awareness of gender inequities amongst palliative care professionals to prevent pattern perpetuation, feelings of guilt and to provide unconditional support to the “obligated caregiver”. This is one of the most extensive and comprehensive series published, which underlines the lack of resources in home palliative care derived from the inequalities and iniquities inherent of a patriarchal and neo-liberal socio-political context , where pOur study highlights the need to address the social determinants of health with active and all-encompassing policies, as well as an intersectional viewpoint. That is, public health policies should not focus exclusively on the economic determinants, nor consider a gender perspective only and in isolation within organisational development plans or research programs.As we have shown, especially regarding men over 80 years old, gender stereotypes increase patients’ needs and the necessary resources to address them, insofar as these cultural representations normalise lacking coping strategies and a healthier acceptance of death. Consequently, developing a “pedagogy of death and dying” with a gender perspective and at a population level would be adequate. This would be particularly urgent and timely in the Spanish context, since the passage of the euthanasia law has brought to the fore a social debate on death and dying.Finally, more research that is inclusive is also needed, taking into account aspects such as non-binary categories and the gender of the formal and informal caregivers, who are key figures in palliative home care.


Objective: This study aimed to undertake a rigorous psychometric evaluation of the nine-scale Norwegian version of the Health Literacy Questionnaire (HLQ) based on data from a sample of people with psoriasis. Methods: Cross-sectional survey data were collected from 825 adults with psoriasis who previously participated in the Norwegian Climate Heliotherapy programme. To investigate the factorial validity of the Norwegian HLQ, confirmatory factor analyses were carried out using Stata. Results: A highly restricted model fit with no cross-loadings or correlated residuals was acceptable for three of the nine scales . After minor model adjustments of the other scales, one-factor models were acceptable. All scales showed acceptable internal consistency, with Cronbach’s alpha ranging from 0.71 to 0.87. Except for three items, all items had high to acceptable factor loadings. Conclusions: This study of the Norwegian HLQ replicates the original factor structure of the Australian HLQ, indicating the questionnaire has cogent and independent scales with good reliability. Researchers, programme implementers and policymakers could use the Norwegian version of the HLQ with confidence to generate reliable information on health literacy for different purposes. Fifteen million deaths attributed to non-communicable diseases (NCDs) occur between the ages of 30 and 69 years, and people from all age groups are vulnerable to the risk factors that contribute to NCDs . The UN 2Low HL has been reported to be associated with increased mortality, hospitalisation, lower use of preventive health-care services, poor adherence to described medication, difficulty communicating with health professionals and poorer knowledge about disease processes and self-management skills among people with NCDs. Furthermore, research also suggests that strengths and weaknesses in HL abilities may explain observed health inequalities among people of different races and with different educational attainment . These rWhile many different HL measurements exist, a main feature of the measurements is whether they are subjective or objective in scope. In objective measurement, people are challenged by standardised test stimuli to measure an underlying trait. In subjective measurement, people self-report their responses to questions about their experiences and skills. Furthermore, HL measures can be characterised as uni- or multidimensional. However, despite promising recent work developing tools in tandem with definitions, the disconnect between definitions and what the tools measure has been a persistent conceptual stumbling block, which has led to several conundrums that will need to be solved for the field to progress in a coherent manner .There is a need for robust HL instruments to be used for health promotion, the prevention of diseases and in disease management in research and practice. The Health Literacy Questionnaire (HLQ) is a generic, subjective, multidimensional instrument (nine domains) measuring HL, developed in Australia by Osborne et al. . The queThe HLQ has shown psychometric robustness in the original development process (English language) where nine conceptually distinct areas of HL are defined to assess the needs and challenges of a wide range of people and organisations. Across the European versions of the HLQ , confirmatory factor analysis (CFA) has been performed and support the initial nine-factor model –13. ThesData from a cross-sectional study of 825 adults with psoriasis who had previously participated in the Norwegian Climate Heliotherapy (CHT) programme was used to investigate the psychometric properties of the HLQ. The CHT is one of the therapeutic options available to Norwegian patients with moderate to severe psoriasis. A three-week multidisciplinary programme is provided in the Canary Islands , which includes tailored sunlight ultraviolet (UV)B radiation, physical exercise, group discussions and comprehensive education.A total of 1275 individuals  were invited to participate in the study. The data collection period was from March to August 2017. Invitations were sent by post, together with a consent form and the survey. At six weeks following the initial post, a reminder letter was sent. Of the 1275 individuals, 825 (65%) returned a completed survey.In addition to HLQ data, the present paper draws on self-reported data on sociodemographic information  and self-reported health status, co-morbidities, number of CHT treatments and duration of the disease. Reports on associations between these variables and HL, based on the same sample, are published elsewhere .The Regional Committee for Medical Research Ethics for Southern Norway (ID 2016/1745) approved the study. In addition, the administrative leaders of the Section for Climate treatment and the Centre for Privacy and Information Security at Oslo University Hospital approved the study. The study was conducted in accordance with the Declaration of Helsinki.The HLQ comprises 44 items representing nine independent HL domains. For further information on the development and the questionnaire, see Osborne et al. . The domEach domain comprises four to six items. The first five domains are scored using response options indicating the level of agreement, ranging from 1=strongly disagree to 4=strongly agree. Four domains report on the capabilities, from 1=cannot do or usually difficult to 5=very easy). The domain scores are calculated as the average of the item scores, with higher scores indicating better HL.Analyses were carried out using Stata v16 . Descriptive analyses were carried out to describe the sample. Further, Cronbach’s alpha was calculated to investigate each scale’s internal consistency.In order to investigate the factorial validity of the Norwegian version of the HLQ, CFAs were performed. As the structure of the original HLQ has been described previously , the facModel evaluation was based on chi-square tests for model fit and further model fit indices, including the root mean square error of approximation (RMSEA), the comparative fit index (CFI), the Tucker–Lewis index (TLI) and the standardised root mean square residual (SRMR). For model fit to be interpreted as ‘acceptable’, a RMSEA of <0.05 was considered a close fit, while a RMSEA and a SRMR of up to 0.08 were considered acceptable. Comparing the fit of a target model to the fit of an independent or null model, the CFI has a cut-off for good fit CFI of ⩾0.90. A TLI of 0.95 indicates the model of interest improves the fit by 95% relative to the null model, and the cut-off for good fit was sat at TLI ⩾0.95. Furthermore, the correlations of residuals to improve model fit when fitting the nine one-factor models were considered. Correlated residuals <0.2 were considered acceptable when fitting the models ,17. PoteTo obtain a clearer idea of the data and potential problematic items, a full nine-factor model and nine one-factor models were fitted to the data. To test whether modifications, in terms of correlated within-factor residuals, led to significant model improvement, modification indices were obtained using the ‘estat mindices’ command in Stata.SD=12.4 years). About 61% of respondents had only formal education of up to 13 years, which is the universal benchmark in Norway.Sample characteristics are shown in SD=2.5).The median disease duration was 27 years, ranging from 0 to 77 years. Mean self-assessed health was 3.33 on a scale ranging from 1 to 5, with a higher number indicating better health. The mean number of co-morbidities was 4.4 (2 (866)=3351.98, p<0.001; RMSEA=0.063 ; CFI=0.849; TLI=0.835; SRMR=0.071.Nine one-factor models were fitted to the data, and results are shown in All factor loadings were high to acceptable  in domain 4 , three adjustments  in domain 7  and one adjustment (0.280) in domain 9 . After respective model adjustments, the one-factor models were acceptable. All nine HLQ scales showed satisfactory to good internal consistency, with Cronbach’s alpha ranging from 0.71 to 0.87 see .This study of the Norwegian version of the HLQ supports the original Australian nine-dimension HLQ using robust CFA procedures (both full-model and one-model approaches). The model fit (RMSEA and SRMR) for the full nine-factor model is acceptable, although the CFI and TLI is just below 0.85, which is somewhat lower than the original Australian version . HoweverOur results are also in accordance with similar studies from other countries investigating the HLQ structure. Despite differences in samples and statistical programmes/procedures, the Danish, German, Slovakian and French versions of the HLQ all demonstrated comparable results –13 with When adapting the questionnaire into a language-specific context, such as Norwegian, the procedure of translation and adaption has been highly standardised across countries, including transparent translation steps, the use of item intents and cognitive interviews ,14. The Today, the HLQ is used in many studies across countries and health contexts, and gives valuable information on HL from a broader and more in-depth perspective compared to traditional and functional measures of HL ,21–30. G21N=825), the use of robust CFA procedures and a well-developed original questionnaire. A weakness maybe the homogenous sample, including only individuals with psoriasis. While the patient group may not represent the broad Norwegian population, participants had an average of more than four other co-morbidities and may well be similar to common groups with chronic conditions. The response rate was reasonable high (65%), with good variation with regard to sociodemographic characteristics, and participants were situated in different parts of Norway. Although the present study supports the use of the HLQ in Norway, studies in other NCD groups and in the general population are warranted.Validity testing of instruments such as the HLQ is comprehensive and ongoing work, including qualitative and quantitative techniques in order to build evidence. The present study focuses on psychometric properties of the Norwegian version of the HLQ and includes a large number of respondents (There is mounting evidence that supports the interpretation and use of the HLQ in Western cultures, including Norwegian and other European settings. Our study builds upon growing evidence of the measurement properties of HLQ and that it is a valuable tool for researchers, programme implementers and policymakers to use to explore HL in diverse populations.


Recently, camel milk (CM) has been considered as a health-promoting icon due to its medicinal and nutritional benefits. CM fat globule membrane has numerous health-promoting properties, such as anti-adhesion and anti-bacterial properties, which are suitable for people who are allergic to cow’s milk. CM contains milk fat globules with a small size, which accounts for their rapid digestion. Moreover, it also comprises lower amounts of cholesterol and saturated fatty acids concurrent with higher levels of essential fatty acids than cow milk, with an improved lipid profile manifested by reducing cholesterol levels in the blood. In addition, it is rich in phospholipids, especially plasmalogens and sphingomyelin, suggesting that CM fat may meet the daily nutritional requirements of adults and infants. Thus, CM and its dairy products have become more attractive for consumers. In view of this, we performed a comprehensive review of CM fat’s composition and nutritional properties. The overall goal is to increase knowledge related to CM fat characteristics and modify its unfavorable perception. Future studies are expected to be directed toward a better understanding of CM fat, which appears to be promising in the design and formulation of new products with significant health-promoting benefits. Camelus dromedarius) and two-humped camels (Camelus bactrianus) . CMCM fat was reported to act as an emulsifier more than human or cow milk because it contains almost 1% of its total lipids as phospholipids (PLs) . FurtherOn the basis of the aforementioned information, it is evident that the CM fat components are quite comparable to human and cow milk. Nevertheless, the majority of studies have focused on the fat composition of cow and human milk, with less reported regarding CM. The objective of the present review is to highlight the reports currently available on the detailed composition and nutritional value of CM fat for improved utilization in dairy industries with focus on the recent findings of its applications.n-3 and n-6 FAs due to the consumption of modern fast and processed food + in a variety of molecular systems, most notably in the relative splint magnitude of a sequence of linolyte and arachidonate TAGs [The determination of CM fat physicochemical and nutritional properties provides insight into the structure of TAGs, which is defined by the types, quantities, and distribution of FAs. Differences in diet, season, lactation stage, and animal species can lead to changes in the amount and composition of milk TAGs. Only one study reported on the composition of milk TAGs for both types of camel milk . Previouate TAGs . In addiate TAGs . Severalate TAGs ,20,85,91ate TAGs  found thOdd-chain FAs are widely present in CM fat and constitute about 13.5% of TAGs , allowinsn-2 position, whereas UFAs are primarily at sn-1 and sn-3 positions. The majority of palmitic acid is present at the sn-1,3 locations [sn-2 positions, contrary to most natural fats. As a result, the distribution of the three main FAs in natural fats significantly differs from that in human milk and standard vegetable oils [sn-2 location has been linked to the enhanced fat and calcium absorption, intestinal comfort, and the growth of intestinal microorganisms [To date, relatively few studies have reported TAG distribution and composition in CM compared to extensive reports focused on cow and human milk. The acyltransferase specificity and activity are responsible for the non-random FA distribution. Thus, by comparing experimental to theoretical TAG distributions, researchers have shown the non-random distribution of FAs in CM . FA distocations ,15. Thusble oils , whereasrganisms ,115. OthThe most abundant sterol in CM fat is cholesterol, whose level is determined by the overall fat content in milk . CholestTo date, CM cholesterol has been a subject of debate because it appears to be completely different from that of the cow milk, especially in terms of the total cholesterol level. The cholesterol level of CM fat was found to be lower than that of cow milk fat ,23, alsoOn the other hand, a greater proportion of small fat globules is associated with a higher concentration of cholesterol in milk, due to the greater surface area of MFGM per fat unit . FollowiFrom a nutritional point of view, earlier studies have shown that the CM (fresh or fermented milk) exhibits a hypocholesterolemic effect on animals’ lipid profiles ,26,27,28PLs are one of the essential lipid components that can be used as functional ingredients by industries involved in either agro-food or clinical nutrition. The PL content in CM has not received much attention in comparison with human and cow milk. The major PLs present in camel MFGM were found to be phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM), phosphatidylinositol (PI), and phosphatidylserine (PS), similar to those reported in cow MFGM ,110,124.31P nuclear magnetic resonance (31P NMR) methods demonstrated comparable results for evaluating PLs in dietary matrices [matrices . Morrisomatrices . They fo31P NMR spectroscopy method succeeded in identifying and measuring 12 PLs, including some lysophospholipids of CM, human milk, cow milk, and mare milk, with ease of sample preparation, high precision, and strong sensitivity [According to the literature, the sitivity . It was sitivity , the resZou et al.  comparedBriefly, studies presented here indicate that the content of PLs in CM was higher than in all other studied animal species. Nevertheless, the major PLs present in the CM MFGM are PC, PE, SM, PI, and PS, similarly to those in all studied species. On the basis of composition, CM exerts a better emulsifier action than human and cow milk, since it contains almost 1% of total lipids as PLs . Thus, CCM butter is one of the dairy products made from CM. In various regions around the world, such as Algerian Sahara , northersn-1, sn-2, and sn-3 positions, as well as by the ripening temperature [C. dromedarius milk butter generally ranges from 64 to 65% and 49 to 58%, respectively [C. dromedarius were at 6.7, 43.2 °C, and 1.4, respectively [C. dromedarius milk butter is less prone to rancidity because of the lower acid degree value. The high level of LC-FAs (C14-C18) and low percentage of SC-FAs (C4-C6) in C. dromedarius milk butter may have contributed to its high melting point, and high refractive index value.Butter flavor and aroma, as well as its rheological properties, have a large impact on consumer acceptance. Its properties are determined by the types of FAs found in butter. SC-FAs play a significant part in butter flavor. The lower content of butyric acid in CM butter resulted in a less intense flavor relative to cow milk butter . Anotherperature . The conectively ,138. Dueectively . As a reectively . The aciThe selected technology for the manufacturing of CM butter is a major challenge. Indeed, traditional churning presents some criticisms because it shows a slight tendency to cream up, due to the lack of the agglutinin protein in the CM . The eugsn-2 position, whereas UFAs are primarily at the sn-1 and sn-3. CM has a higher concentration of total PLs than human and cow milk, and it may be used to substitute human milk since it delivers equal quantities of plasmalogens and SM to infants, even if the cholesterol content is a controversial issue. The main actual challenge is to better understand the properties of CM fat so that products with bioactive ingredients derived from milk can be designed and formulated.The recent advances in understanding the composition of CM fats is important in understanding not only their nutritional value but also their functional properties and health benefits. The most abundant protein in the CM fat globule membrane (MFGM) was found to be lactadherin-like protein, which has anti-sticking and anti-bacterial qualities, and moreover it is suitable for consumers with an allergy to cow’s milk. The small size of the camel MFG resulted in its high-fat digestibility but led to difficulties in obtaining butter. CM has a low level of SFAs (C4-C6) and a high content of UFAs and LC–FAs. Hence, it contains an adequate number of components that are useful in reducing inflammation and decreasing the incidence of lipid-related cardiovascular diseases. The higher concentration of SFAs in CM fat is at the


Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age. Langerhans cell histiocytosis (LCH) is a rare disease  and its origin was long a matter of debate. LCH is characterized by the infiltration of tissue, such as skin, bone, brain, lung, and liver tissue, by the hallmark CD1a+ CD207+ cells, such as Langerhans cells (LCs), eosinophils, neutrophils, macrophages, and lymphocytes. The hallmark cells are present in variable percentages in LCH lesions, ranging from 1% to 70% [Systemic histiocytic neoplasms differentiate LCH from non-LCH diseases, including, in the latter group, Erdheim–Chester disease (ECD), juvenile xanthogranuloma, and Rosai–Dorfman disease. However, at least partially, they share some mutations. To reflect these overlaps, the most recent classification ,3 identiLCH is frequently associated with a paraneoplastic syndrome, such as diabetes insipidus, because of the infiltration of the hypophysis-surrounding tissue by LCH cells. The clinical features of the disease can be variable and their evolution over time is unpredictable. Multisystem LCH is frequently recognized in adults and children. LCH is a chronic disease and therefore can affect patients’ and their families’ quality of life. Therapeutic options are lacking and the recruitment of patients for research studies is difficult given the rarity of the disease. There are only clinical guidelines for children with LCH, which are extremely aggressive and require high-dose chemotherapy and/or bone marrow transplantation.Imatinib mesylate is a small molecule analog of adenosine triphosphate with 2-phenylaminopyrimidine as an active part, and was created specifically to block the binding site of ATP in the BCR/ABL protein. It is also a platelet-derived growth factor receptor (PDGFR) and a KIT CD117) kinase inhibitor. The PDGFR family consists of two receptors, an alpha and a beta-receptor, that signal through the cell surface of the tyrosine kinase receptors (PDGFR) and stimulate various cellular functions including growth, proliferation, and differentiation . Its kin kinase iPDGFR-β and other proteins, such as p-Akt (Ser-473), p-mTOR (Ser-2448), and p-p70S6K (Thr-389), that are part of PDGFR-β signaling, contribute to an integrated circuit that fuels histiocyte growth and apoptosis resistance .Moreover, preclinical, and clinical data support a role for imatinib in inducing not only direct on-target, but also indirect off-target effects.During imatinib treatment, through c-KIT signaling, NK cells are activated, a favorite production of Th1 over Th2 cytokines is induced, and tolerogenic mechanisms are suppressed ,12. As sImatinib mesylate was shown to be effective in PDGFRα/β positive LCH with brain involvement  and in CIn this report, the immunohistochemical evaluation of KIT/PDGFRβ on 10 LCH samples and the updated clinical results with imatinib in a separate series of LCH patients are described.Ten biopsies  were evaluated. Two biopsies of oral mucosa, performed at different times, were available for one patient.The tissues available were bone in 4 patients, skin in 2 patients, and 1 case each of oral mucosa, brain, lymph node, and ocular soft tissue. For the bone tissue, the fragments were processed without decalcification. A 4 μm section obtained from the formalin-fixed, paraffin-embedded specimens was incubated in a microwave oven for 15 min in 10 mmol/L, 6.0 pH buffered citrate following the immunohistochemical procedure for platelet-derived growth factor receptor beta (PDGFRβ)  and KIT (CD117) , diluted to 1:50 and 1:300, respectively. The conventional avidin–biotin complex procedure was applied according to the manufacturer’s protocol. The section was briefly washed and incubated with a primary antibody overnight at 4 °C, and then incubated with a secondary antibody. Positive staining was revealed using DAB chromogen, according to the supplier’s conditions, followed by counterstaining with Mayer Hematoxylin. The slide was cover-slipped with a xylene-based mounting medium. The diagnosis of LCH was based on the presence of a population of Langerhans cells showing an unequivocal positive reaction to CD1a and S-100 protein antibodies mixed with eosinophils and inflammatory cells. The immunostaining with PDGFRβ was scored from 1 to 3, with 1 corresponding to low expression and 3 to strong expression of the Langerhans cells in the cytoplasm. 99mTc-methylene diphosphonate, nuclear magnetic resonance (NMR), positron emission tomography (PET), and ortopantomography. Exclusion criteria were pregnancy, breastfeeding, absence of adequate contraception, unmeasurable lesions as the only site of disease , uncontrolled heart disease , or thromboembolism sequels , other uncontrolled diseases, chemotherapy in the 30 days before study enrollment, or inability to express informed consent and to follow study protocol. The primary objective of the study was the evaluation of drug activity based on the response evaluated by RECIST criteria. Secondary objectives were the evaluation of safety and effects on quality of life. Safety was assessed according to National Cancer Institute criteria. Twenty patients aged between 18 and 75 years old, with WHO performance status 0–1 and histological diagnosis of LCH were expected to be enrolled. The study protocol was approved by the Local Ethical Committee and was submitted to Agenzia Italiana del Farmaco (AIFA) . The TETimaX trial enrolled patients with refractory thymic epithelial tumors and LCH. Informed consent was required and obtained before study enrollment. Patients had received previous treatment and showed disease progression. Immunohistochemical evaluation of cKIT, PDGFRα, PDGFRβ, mTOR, or p-AKT was contemplated. At least one, measuring either ≥2 cm or ≥1 cm if identified by computed tomography (CT) scan, was necessary. Patients were required to have normal laboratory exams to assess bone marrow, renal, and liver function. Before study entry, patients were evaluated with appropriate scans such as X-rays, CT, bone scintigraphy with Imatinib mesylate was administered at a daily dosage of 400 mg for one year if an objective response was documented. Drugs interfering with isoenzyme CYP450 (2D6 and 3A4) can reduce the activity of imatinib, therefore they were allowed with caution. Furthermore, patients taking concomitant drugs metabolized by P-450 cytochrome underwent more follow-up visits because of the increased risk of toxicity. Concomitant use of acetaminophen was not allowed. Warfarin was not allowed because of P-450 cytochrome metabolism and was substituted with low-molecular-weight heparins. Time to tumor progression (TTP), defined as the time elapsed between treatment initiation and disease progression, was assessed. Response assessment by the same radiologic technique used at basal evaluation was performed every three months. Safety was evaluated according to NCI CTCAE v3.0 criteria and classified into grade 1: low risk, 2: moderate risk, 3: severe risk, and 4: life-threatening. Colony-stimulating factors (CSF) were allowed per protocol in the case of grade 4 febrile neutropenia, grade 3 and 4 neutropenia, and grade 4 neutropenia associated with diarrhea. In these instances, prophylactic use of CSFs was allowed in the following cycles. Radiotherapy and surgery could be used during the study if medically required.A comprehensive picture of the results obtained is shown in Tissue differential expression was not detected among the cases that included bone or oral mucosa. Four cases received an intermediate score for cytoplasmic expression and one case displayed a low cytoplasmic expression of PDGF-Rβ. The immunohistochemistry series also included the brain biopsy of the patient previously described and treated with imatinib mesylate . We evalThe protocol was stopped in 2013 because of low accrual. From 2008 to 2011, five patients , followed in a single Center, were enrolled. Given the small number of patients enrolled, as compared to expected, all patients were considered assessable for drug activity and efficacy. In Unfortunately, immunohistochemical evaluation of the patients enrolled in the clinical study was not performed because of a lack of available materials. The absence of the B-RAF mutation was only defined for one patient. This evaluation was performed through the amplification of a segment within exon 15 of BRAF and gene sequencing by Sanger.All patients were pretreated, as shown in The TTP was variable, ranging from 1 to 120 months (median 108 months). Three patients were free of treatment at the date of the last evaluation. The patient (n.3) who was pretreated with two lines of chemotherapy before study enrollment reported a complete brain and bone response and a partial response for lung disease as the best response and remained free of further treatment at the date of the last evaluation. Two patients received further treatment after imatinib. One of these was the patient that prematurely stopped imatinib (patient n.4). He received interferon for two years and three months, then relapsed and was treated with vemurafenib for two years and two months based on compassionate use. He was free of disease; however, he died because of end-stage renal disease, secondary to obstructive uropathy from retroperitoneal fibrosis. The other patient who had bone-only disease (Patient n.5) relapsed after one year and received vinblastine plus prednisone and etoposide following the relapse. All but one patient (Patient n.4) were alive at the date of last contact (July 2021). Treatment was well-tolerated, with mainly 1–2 graded nausea related to imatinib reported.Treatment of LCH encompasses several options, ranging from chemotherapeutics to immune-modulatory and targeted drugs. When evaluating activity and efficacy, clinicians should keep in mind the unpredictable behavior of the disease. Pediatric and adult LCH appear to be different in clinical features and response to treatments. Following the report of the successful treatment of a patient with neurological refractory LCH with imatinib, interest in imatinib use increased. The activity was shown in three patients without significant genomic correlation, because of a lack of materials and/or KIT/PDGFRA mutations . UncertaWe found a significant expression of PDGFRβ in LCH. All biopsies in the present study returned positive results. This finding encouraged us to explore the activity of imatinib in a series of LCH patients. A previously published series documented PDGFR expression in LCH. A positive PDGFR-β expression in histiocytes was found in 86.5% (32 of 37 samples) of ECD and 27.3% (3 of 11) of LCH biopsies . NeverthDespite the plan for 20 patients to be enrolled in the TETimaX trial, only five patients were recruited. All but one patient had multisystem involvement. Imatinib was shown to control the disease in all patients. A response was also achieved in the pretreated case. At a prolonged follow-up –more than a decade later three patients were free of treatment and all but one were alive. This study has several acknowledged limitations. The trial was originally designed to be multicentric, with 20 patients predicted to be enrolled. However, the study was prematurely stopped because of the low accrual and because it was only monocentric. Therefore, the limited number of patients enrolled and the lack of a control group reduce the relevance of our findings, as is easily acknowledged. However, in LCH more than in other diseases, it is particularly difficult to plan such studies. Unfortunately, none of the patients in the immunohistochemistry series were enrolled in the clinical part of the study. The critical limitation, while quite common, especially in retrospective series, was the lack of tissue from which to evaluate genomic alterations. In the clinical series, the biopsies available for pathological diagnosis included lung, eye, and temporal bone tissue. Biopsies from these sites are often only sufficient for diagnosis, and repeated sampling is not easily accepted by the patients. This issue can be overcome with liquid biopsies in the future. Moreover, we highlight that immunohistochemistry is limited to protein detection, and genomic studies to detect molecular aberrations are also needed. In addition, the choice to treat patients with an experimental drug for a definite, instead of indefinite, time (one year) may be disputable. We note that one of the two patients who relapsed stopped the imatinib treatement prematurely because of atrial fibrillation. Moreover, in this series, the choice of a 1 year treatment can be considered appropriate because the control of the disease was maintained in the responsive patients and they were protected from the toxicities related to longer-term therapies. This kind of treatment may be particularly convenient for LCH patients because of the unpredictable disease behaviour with flares alternating with dormancy that further complicated management and therapy. However, LCH may severely worsen quality of life because of the multiplicity of systemic symptoms and long-term morbidity. Despite the previously cited limitations, this study reintroduces the need for accurate basal genomic assessments of LCH and cooperative multicentric studies which can overcome the recruitment difficulties. The increasing efforts to define pathogenetic mechanisms and identify targeted drugs have focused attention on MAPK activation. A breakthrough in understanding the pathogenesis of LCH occurred in 2010 when a gain-of-function mutation in B-RAF (V600E) was identified in more than half of LCH patient samples . SimilarMEK, also known as mitogen-activated protein kinase MAP2K1, and ERK phosphorylation were also found in 100% of examined cases . The ERKThe discovery of additional mutations in LCH including A-RAF, N/KRAS, PIK3CA, and gene fusions involving B-RAF, ALK, and NTRK  enrich tThe identification of the specific MAPK pathway mutation present in each patient with LCH could enable personalized approaches to medication and the design of treatment sequences. In line with this logic, the Pediatric MATCH Screening trial (NCT03155620)  imposes The present study started before the identification of the role of the BRAF mutation in LCH. In our small series of LCH patients, imatinib mesylate was able to produce a significant clinical benefit rate and prolonged progression-free survival. Imatinib treatment was also found to produce an objective response in a patient with brain and bone LCH involvement previously treated with two lines of therapy. It is important to note that one patient from the present series is not evaluable for progression-free survival as he stopped the treatment prematurely.Imatinib blocked multiple downstream signaling pathways activated by cKIT, PDGFRA, and bcr-abl, including those mediated by phosphatidylinositol 3-kinase (PI3K)/Akt, Ras/RAF/MEK/ERK, and the signal transducer and activator of transcription (STAT), which are involved in cell proliferation. We suppose that the effect of imatinib is also mediated through interference with the MAPK pathway, which is frequently involved in LCH. The role of c-KIT in comparison to BRAF mutations in LCH is not well defined. In one recent study, c-KIT and MAP2K1 mutations were evaluated in skin pathological samples of patients with cutaneous LCH labeled as BRAF wild-type . MAP2K1 In conclusion, the crucial role of BRAF inhibition does not definitively exclude the role of imatinib in LCH. We can suppose the therapeutic relevance of the presence of cKIT mutations and/or synergistic activity together with other agents interfering with MAPK signaling. Larger studies, possibly including the identification of individual driver mutations, could contribute to defining the best-tailored approach.