Sudden cardiac death (SCD) is the most common cause of death in children with hypertrophic cardiomyopathy (HCM). The European Society of Cardiology (ESC) recommends consideration of an implantable cardioverter-defibrillator (ICD) if two or more clinical risk factors (RFs) are present, but this approach to risk stratification has not been formally validated.P = 0.34), with a positive and negative predictive value of 19% and 90%, respectively. The C-statistic was 0.62 (95% CI 0.52–0.72) at 5 years.Four hundred and eleven paediatric HCM patients were assessed for four clinical RFs in accordance with current ESC recommendations: severe left ventricular hypertrophy, unexplained syncope, non-sustained ventricular tachycardia, and family history of SCD. The primary endpoint was a composite outcome of SCD or an equivalent event , defined as a major arrhythmic cardiac event (MACE). Over a follow-up period of 2890 patient years (median 5.5 years), MACE occurred in 21 patients (7.5%) with 0 RFs, 19 (16.8%) with 1 RFs, and 3 (18.8%) with 2 or more RFs. Corresponding incidence rates were 1.13 [95% confidence interval (CI) 0.7–1.73], 2.07 (95% CI 1.25–3.23), and 2.52 (95% CI 0.53–7.35) per 100 patient years at risk. Patients with two or more RFs did not have a higher incidence of MACE (log-rank test The incidence of MACE is higher for patients with increasing numbers of clinical RFs. However, the current ESC guidelines have a low ability to discriminate between high- and low-risk individuals. The incidence of an arrhythmic event increases with additional clinical risk factors, however, the current European Society of Cardiology (ESC) 2014 guideline for risk stratification in childhood hypertrophic cardiomyopathy (HCM) has a low ability to discriminate between high- and low-risk individuals.The positive predictive value of the ESC treatment threshold is low, leading to unnecessary implantable cardioverter-defibrillator implantation in many patients.Large-scale, multi-centre, collaborative approaches to risk stratification in childhood HCM are needed to develop robust risk stratification algorithms.,Hypertrophic cardiomyopathy (HCM) is the second commonest cardiomyopathy occurring during childhood, with an estimated annual incidence of 0.24–0.47 per 100 000 and prevalence of 2.7 per 100 000.z-score ≥+2), which could not be solely explained by abnormal loading conditions.Longitudinal clinical and outcome data were collected from a retrospective multi-centre cohort of children diagnosed with HCM in the UK between 1980 and 2017. Complete data were available from 13 out of the 14 UK specialist paediatric cardiac centres. Patients aged 16 years or younger meeting the diagnostic criteria for HCM were eligible for inclusion. This included patients with phenocopies of sarcomeric HCM . The diagnosis of HCM was made in the presence of left ventricular wall thickness >2 SD above the body surface area (BSA)-corrected population mean (A single researcher (G.N.) visited each site to assist with data collection and confirm diagnostic classification. Anonymized, non-invasive clinical data were collected from baseline evaluation, including demographics, aetiology, symptoms, family history, resting and ambulatory ECG, two-dimensional Doppler and colour transthoracic echocardiography, and device interrogation of arrhythmic events. Aetiology was classified as non-syndromic in the absence of a diagnosis of a RASopathy syndrome , neuromuscular disease (including Friedreich’s ataxia), or inborn error of metabolism.In accordance with the 2014 ESC guidelines,All patients were routinely evaluated every 6–12 months up to 1 October 2017. The primary patient outcome, taken from last clinic appointment, was a composite outcome of SCD or an equivalent event , defined as a major arrhythmic cardiac event (MACE).z-scores relative to the distribution of measurements vs. BSA in normal children, using previously published normal values.Body surface area was calculated from height and weight.Figure 1). The ESC guidelines assign each clinical RF equal weight and the overall clinical risk profile is calculated as the sum of RFs present. For the purpose of assessing the discriminatory ability of the ESC algorithm, missing data for RFs were coded as absent to reflect the use of the guideline in clinical practice.For the purpose of analysis, patients with syndromic HCM were excluded as they are a heterogeneous population with variable long-term outcomes, which are partly determined by the underlying aetiology. However, as the ESC guidelines do not specifically exclude patients with non-sarcomeric disease, separate analyses were also performed including these patients  . Baseline clinical characteristics are shown in Table 1. Median age at diagnosis was 10 years (IQR 3–13); 60 patients (14.6%) presented under the age of 1 year. Pathogenic mutations in sarcomeric protein genes were reported in 94 patients (23%). One hundred and ten patients (26.8%) had an ICD implanted during follow-up for primary prevention [n = 99 (90%)] and secondary prevention [11 (10%)]. Of those with a secondary prevention device, the indication for ICD implantation was an aborted SCD in nine patients and sustained VT on ambulatory ECG monitoring in two.From the total cohort of 687 patients,Table 2. Two hundred and eighty-two patients (68.7%) had no traditional clinical RFs, 113 (27.5%) had a single clinical RF, 14 (3.4%) had two clinical RFs, and two patients (0.5%) had three clinical RFs. No patients had all four clinical RFs. Complete data for all clinical RFs were available for 295 patients (71.8%), data were missing for one or two RFs in 111 patients (27%) and 5 patients (1.2%), respectively.The prevalence at baseline of each of the four major clinical RFs described in the 2014 ESC guidelines is shown in n = 3) or an implantable ambulatory ECG device (n = 2).Median length of follow-up was 5.5 years (IQR 2.4–10.6). Over a total follow-up period of 2890 patient years, 43 patients had a MACE with an event rate of 1.5 per 100 patient years at risk. The MACE was SCD in 17 (4.1%); aborted cardiac arrest in 9 (2.2%); appropriate ICD discharge in 12 (2.9); and sustained VT associated with haemodynamic compromise in 5 (1.2%). Sustained VT was documented on ICD download (Table 3). Event-free survival at 5 years for patients with 0, 1, or ≥2 clinical RFs was 93.8% [95% confidence interval (CI) 89.3–96.5%], 87.6% (95% CI 79.1–92.8%), and 86.7% (56.4–96.5%), respectively . The corresponding incidence rates are shown in Table 3.A MACE occurred in 21 patients (7.5%) with no clinical RFs; 19 patients (16.8%) with one clinical RF; and 3 patients (18.8%) with two or more clinical RFs  had severe LVH; 22 (20%) unexplained syncope; 40 (35%) a family history of SCD; and 2 (2%) NSVT. The incidence of MACE in patients with a single clinical RF is shown in P = 0.34) .Patients classified as ‘high risk’ according to the ESC guidelines  did not have a higher incidence of MACE compared to ‘low risk’ patients . The PPV and NPV of the 2014 ESC treatment thresholds for primary prevention ICD implantation  at 5-year follow-up and end of follow-up were 12.5%/93.9% and 18.8/89.9%, respectively. A complete case analysis (n = 295) did not improve the discrimination performance of the guideline with a PPV and NPV of 23.1% and 89%, respectively, and C-statistic of 0.63 (95% CI 0.54–0.72) (n = 663) did not improve the discrimination performance of the guideline with a PPV and NPV of 23.5% and 92.9%, respectively, with a c-statistic of 0.63 (95% CI 0.557–0.703).The C-statistic, which represents the probability of correctly distinguishing between high and low risk patients using the 2014 ESC clinical risk profile, was 0.58 (95% CI 0.31–0.86) at 1 year and 0.62 (95% CI 0.52–0.72) at 5 years (54–0.72) . A sensiThis study is the first external validation of the current ESC guidelines for risk stratification in childhood HCM. We show that the current guidelines have only a modest ability to discriminate between patients with non-syndromic HCM at a low or high risk of an arrhythmic event, with a C-statistic of 0.62 at 5 years.The majority of patients (69%) in this cohort had none of the traditional clinical RFs for SCD historically used for risk stratification in adults, and only a small number of patients met the ESC threshold for ICD implantation . However, the overall rate of arrhythmic events was higher in childhood disease compared to adulthood (1.1 vs. 0.8%), particularly for those with non-syndromic disease (1.5 vs. 0.8%). This suggests that additional, or alternative, clinical RFs for SCD are important in childhood onset disease. Indeed, although a large number of potential RFs for SCD in childhood HCM have been reported in the literature, the lack of consistent definitions and sufficiently large, suitably designed population studies means that the evidence for individual RFs, including those endorsed by the ESC guidelines, is not robust. A meta-analysis of published clinical RFs for SCD in childhood HCMAs each traditional clinical RF included in the ESC guidelines is a marker of more severe disease, it is perhaps not surprising that the risk of an event increased incrementally with summative RFs. However, the incidence rate did not significantly differ between those classified by the guideline as high risk or low risk, meaning that the ability of the guideline threshold to distinguish between those patients at high and low risk was limited. Although the arrhythmic incidence rate was lowest for patients with no clinical RFs, the majority of events (63%) occurred in this low-risk group. Furthermore, the low PPV (18.8%) means that the majority of patients in whom an ICD is recommended will not experience an event but will be exposed to the potential complications associated with ICD implantation. In this cohort of 110 patients with an ICD, only 11% had an appropriate discharge to treat a malignant arrhythmia. The low number of patients receiving appropriate therapy likely highlights the difficulties in identifying patients at increased risk. Indeed, over half (56%) of MACE occurred in patients not judged to be at increased risk by clinicians who therefore did not undergo ICD implantation. Application of the ESC clinical guideline did not improve patient identification with 93% of arrhythmic events occurring in patients with 0 or 1 clinical RFs. This is a particular problem for childhood HCM, as it has been shown that younger patients are at higher risk of ICD-related complicationsTable 4). However, the high NPV of the ESC treatment threshold (89.9%) supports the notion that patients with 0 or 1 clinical RF are at a low risk for ventricular arrhythmias and can be reassured. Large multi-centre collaborative studies are required to investigate the role of individual RFs in childhood HCM.The current guidelines do not specifically exclude patients with syndromic HCM  and excluding these patients from the analysis did not improve the discriminatory power of the guidelines. Of note, current North American guidelines,Childhood HCM is recognized to be a heterogeneous disease.This study is limited by inherent problems of retrospective studies, in particular missing or incomplete data. Although the classification of missing RF data as absent is a source of potential bias, this reflects real world practice where absence of a RF is often taken to mean absence of risk. This approach to analysis replicates that used by other retrospective validation studies in adult HCM Ref. in whichAs childhood HCM is a rare disease and SCD a relatively rare outcome, despite this study containing one of the largest populations of childhood HCM to date, there were a small number of events and small number of patients classified as ‘high risk’ according to the ESC guidelines. This reduced our power to detect statistically significant differences and, as a result, the reported confidence intervals are wide. The relatively short mean follow-up time of 5.5 years (range 6 months–25 years) could partly explain the low number of events. However, it is important to note that the current guidelines do not provide an estimate of risk at a particular time point. Relatively little is known about the sample size requirements for external validation of prediction models, although a sample containing at least 100 events and 100 non-events has been suggested.In this cohort, only 23% of non-syndromic patients had a confirmed pathogenic mutation in a cardiac sarcomere protein gene. This is almost certainly an underestimate of the true prevalence as previous studies have shown that most cases of HCM are caused by sarcomeric mutations, even in young children.This study is the first validation of the 2014 ESC risk stratification guidelines for childhood HCM. The results suggest that the current guidelines have a limited ability to distinguish between high- and low-risk patients. Although the incidence of an arrhythmic event increases with additional RFs, the PPV of the treatment threshold is low with unnecessary ICD implantation in many patients. Large-scale international collaborative studies are required to overcome the challenges of small patient numbers inherent to rare diseases.This work was supported by the British Heart Foundation (grant number FS/16/72/32270 to G.N. and J.P.K.). E.F. and J.P.K. are supported by Max’s Foundation and Great Ormond Street Hospital Children’s Charity. This work is (partly) funded by the NIHR GOSH BRC. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. R.Z.O. and T.D. work at University College London Hospitals/University College London who received a proportion of funding from the United Kingdom Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.Conflict of interest: none declared.euz118_Supplementary_DataClick here for additional data file.


Hydatid disease is an important public health problem in many Mediterranean and Middle East countries . “This dThe aim of the present study was to identify the epidemiological, diagnostic, and therapeutic features of pulmonary hydatidosis in children. Thirty patients under the age of 14 yr, operated between Jan 2009 and Dec 2016 due to pulmonary hydatid cysts, were evaluated retrospectively. All patients had chest radiographies and abdominal ultrasonography scans. Computed tomography scan was performed in 11 (36.6%) patients.Written informed consent was obtained from the legal guardian of each patient to publish the case and accompanying images in scientific journals for research and educational purposes.There were 21 boys and 9 girls. The mean age of our patients was 8.12 ± 2.5 yr. Twenty-eight (93.3%) patients were of rural origin. The symptoms at the time of presentation were coughing in 30% (n=9), hemoptysis in 20% (n= 6), and chest pain in 40% (n=12). The diagnosis was made incidentally on chest radiography in 10% (n=3). The average cyst diameter was 6.36 ± 1.8 (3–10) cm. The cysts involved the left lung in 16 (63.6%) patients, the right in 11 (36.4%). Three (10%) patients had bilateral lung cysts .The most common location of cysts was in the left lower lobe . Serological tests were positive in 22 (73.3%) patients. Twelve (40%) patients had perforated cysts. A liver hydatid cyst was found in 3 (10%) patients. One patient had multiple cysts with involvement of the lungs, the liver and the left kidney . All of Although hydatid disease has been controlled in many countries, this zoonosis remains endemic in some regions, especially in developing countries. A high index of suspicion is needed to make the diagnosis. During surgical removal of hydatid cysts, we must avoid spillage of cyst contents to prevent anaphylactic reaction, recurrence and multiple hydatidosis. Prophylactic Community-based measures are crucial to treatment strategy. These measures include people education, treatment and control of all dogs, and proper hand washing after contact with dogs or their feces.


Plasmodium falciparum exposure during pregnancy, we dissected IgG responses against VAR2CSA, the parasite antigen that mediates placental sequestration. We used a multiplex peptide-based suspension array in 2,354 samples from pregnant women from Mozambique, Benin, Kenya, Gabon, Tanzania, and Spain. Two VAR2CSA peptides of limited polymorphism were immunogenic and targeted by IgG responses readily boosted during infection and with estimated half-lives of <2 years. Seroprevalence against these peptides reflected declines and rebounds of transmission in southern Mozambique during 2004–2012, reduced exposure associated with use of preventive measures during pregnancy, and local clusters of transmission that were missed by detection of P. falciparum infections. These data suggest that VAR2CSA serology can provide a useful adjunct for the fine-scale estimation of the malaria burden among pregnant women over time and space.Pregnant women constitute a promising sentinel group for continuous monitoring of malaria transmission. To identify antibody signatures of recent  Plasmodium falciparum infection among pregnant women are sensitive to changes in transmission  against a quantitative suspension array containing VAR2CSA and general parasite antigens. We first selected IgG responses that were rapidly acquired after P. falciparum infection, did persist in circulation, and were sensitive to the level of parasite exposure in pregnant women from Mozambique and Spain. We then used the serologic assay to quantify the relationship of VAR2CSA antibody responses with P. falciparum infection as well as with temporal, spatial, and intervention-driven changes in malaria burden among pregnant women.The utility of serosurveillance depends mainly on specific properties of the antigen, including immunogenicity, polymorphism, cross-reactivity, and longevity of the antibodies. Because different VAR2CSA domains elicit IgG responses with varying magnitudes and dynamics (https://www.bd.com) and centrifuged; plasma was stored at −20°C. From a subset of pregnant women in Mozambique who delivered during 2011–2012, peripheral blood samples were also collected at the first antenatal visit and before administration of the second IPTp dose. We geocoded the households of women in Mozambique by using a global information system. Clinical malaria episodes were treated according to national guidelines at the time of the study .We included in our study pregnant women who participated in 3 clinical trials of intermittent preventive treatment during pregnancy (IPTp) during 2003–2005 in Mozambique (NCT00209781) , the Centers for Disease Control and Prevention , and national ethics review committees from each malaria-endemic country participating in the study. Written informed consent, which included permission to test for immune markers by using stored biological samples, was obtained from all participants.www.hemocue.com), Hemocontrol , and KX analyzer . Thick and thin blood films and placental biopsy samples were checked for Plasmodium spp. according to standard, quality-controlled procedures  targeting 18S ribosomal DNA  for 37% of pregnant women participating in the clinical trials with samples available. We constructed 2 multiplex suspension array panels  and 1 consisting of synthetic peptides (25 VAR2CSA peptides covering conserved and semiconserved regions of VAR2CSA and a circumsporozoite peptide [pCSP]) (We measured IgG in plasma (Benin and Mozambique) or on DBS  in appropriate conditions for plasma elution (y panels  (19), 1 P. falciparum positive by qPCR for Sanger sequencing of var2csa PCR amplification products covering peptides of interest (https://www.cgl.ucsf.edu); We used DNA extracted from 50 DBS that were interest . Sequenc>1 previous pregnancy) and categorized age as <20, 20–24, or >25 years  in multivariate models. We assessed the modification of the associations by HIV infection or parity by including interaction terms into the regression models. To control the false discovery rate in the selection of antigens, we computed adjusted p values  by using the Simes procedure (2×) IgG levels in the longitudinal cohort of pregnant women from Mozambique , R statistics software version 3.2.1 (https://www.r-project.org), and Graphpad Prism version 6 (https://www.graphpad.com).We included in the analysis pregnant women for whom all information was available for IPTp, date of delivery, HIV status, age, parity, and antibody responses. We classified women as primigravid (first pregnancy) or multigravid , among HIV-uninfected women was 46% (332/725) in Benin, 10% (9/89) in Gabon, and 6% (28/452) in Mozambique and among HIV-infected women was 8% (22/273) in Kenya and 4% (13/327) in Mozambique  in 2004–2005 to 2% (3/176) in 2010 and increased to 6% (4/72) in 2012. A subset of 239 pregnant women from Mozambique recruited during 2011–2012 was followed during pregnancy; prevalence of P. falciparum infection detected by qPCR was 16% (38/239) at first antenatal visit , 3% (8/239) at the second IPTp administration (25.9 ± 4.98 weeks), and 5% (13/239) at delivery (38.4 ± 2.26 weeks). P. falciparum infection was detected at unscheduled visits for 2% (5/239) of the women. Overall, P. falciparum infection was detected at any of these time points for 21% (49/239) of the women.The study areas represented 5 sites in sub-Saharan Africa with different intensities of malaria transmission. Prevalence of zambique . The pre>5% of the pregnant women from Spain who had never been exposed to P. falciparum  for p5 to 1.07 years (95% CI 0.60–5.23 years) for p27  years for p8 to 3.66 (95% CI 0.98–∞) years for p1 (2× (0.31 [95% CI 0.21–0.61] years) and half-life (0.66 [95% CI 0.42–1.65] years), whereas AMA1 IgG showed the highest T2× (1.76 [95% CI 0.76–∞] years) and half-life (4.18 [95% CI 1.86–∞] years).We assessed the dynamics of IgG responses in a longitudinal cohort of 239 pregnant women from Mozambique , panel Apeptides  Table 5.regnancy  Table 5.regnancy  Table 5. for p27  Table 6.s for p1  Table 6.P. falciparum during pregnancy compared with uninfected women , IgG against p5 (51 amino acids) and p8 (48 amino acids) showed the lowest half-lives  and the largest increase in women exposed to p5+8 0.27 [95% CI 0.11–0.68]), followed by an increase from 2010 to 2012 . Similar to P. falciparum prevalence determined by qPCR, seroprevalence rates were the highest in HIV-uninfected women from Benin, followed by those from Gabon (AORp5+8 0.31 [95% CI 0.21–0.47]) and Mozambique , decreased from 2004–2005 to 2010 . Geographic areas experiencing significantly higher seroprevalence rates than would be expected by chance were observed for p5  and p5+8  but not for MSP1and AMA1  Table 12and AMA1  Table 12P. falciparum testing of easily accessible pregnant women at maternal healthcare services has the potential to offer a rapid, consistent, and cost-effective method for evaluating the malaria burden in different communities and tracking progress of interventions. IgGs against 2 VAR2CSA peptides, selected according to their ability to maximize the information about recent P. falciparum exposure during pregnancy, reflected differences in malaria burden over time and space in multiple settings in Africa and changes in parasite rates associated with the use of different preventive regimens. Overall, our results indicate that in areas with well-attended maternal healthcare services, this pregnancy-specific serologic test may serve as a useful sentinel surveillance tool for flagging changes in malaria burden and progress in the path toward elimination.Routine P. falciparum isolates from a variety of regions of Africa, in accordance with estimates from previous studies for the DBL1X domain  is localized in the DBL1X domain and p8 (48 amino acids) in the ID1 region of VAR2CSA. Limited diversity (5%) of p5 sequence was observed in P. falciparum prevalence among pregnant women from Mozambique delivering during 2004–2012  mirrored trends in 19 and AMA1 were not able to identify these malaria transmission patterns because of saturation of antibody responses after lifelong exposure to P. falciparum. These results support the value of using VAR2CSA serologic testing to amplify signals of recent exposure and suggest its potential to trigger targeted interventions to persons living in close proximity to passively detected seropositive pregnant women.Geographic distribution of pregnant women from Mozambique who were seropositive against p5 and p5+8 revealed a serologic hotspot in an area close to the river and sugar cane plantations, where the density of anopheline mosquitoes can be expected to be higher. In contrast, antibodies against MSP1P. falciparum resurgence after local elimination.Our study has several limitations. First, the peptide array we used may have missed some conformational nonlinear epitopes. Second, different transmission dynamics and host genetic factors may affect the acquisition and decay of antibodies (P. falciparum infections. Our results suggest that inferring recent exposure through VAR2CSA serologic testing would amplify signals of ongoing malaria transmission and increase the power to detect changes, either natural or driven by deliberate efforts, as well as malaria hotspots, among pregnant women (In summary, this study shows that IgG against 2 VAR2CSA peptides from the DBL1X-ID1 domain reveal temporal and spatial differences in malaria burden among pregnant women and reductions in exposure associated with the use of preventive measures during pregnancy. These antibodies enable the identification of local clusters of transmission that are missed by detection of Plasmodium falciparum transmission patterns.Supplemental methods and results from study of VAR2CSA serologic testing to detect Plasmodium falciparum transmission patterns.Supplemental results from study of VAR2CSA serologic testing to detect


There is an alarming rise of chronic kidney disease prevalence globally associated with significant morbidity and mortality necessitating special attention as one of the major growing public health problems. Medication-related problems are common in hospitalized patients including chronic kidney disease and may lead to increase hospital stay and health care cost and augment the risk of morbidity and mortality.  To determine prevalence of medication-related problems and associated factors among chronic kidney disease patients admitted to Jimma University Medical Center from April to September 2018. p value <0.05.  A hospital-based prospective observational study was conducted among 103 chronic kidney disease patients admitted to Jimma University Medical Center from April to September 2018. Data regarding patient characteristics, medications, diagnosis, length of hospitalization, and laboratory results were collected through review of patients' medical charts. Data were analyzed by using Statistical Package for the Social Sciences (SPSS) version 21.0. Univariate and multivariate logistic regression was utilized to assess the associations between dependent and independent variables. Statistical significance was considered at  Out of 103 chronic kidney disease patients, 81 (78.6%) of patients had MDRs, on average 1.94 ± 0.873 per patient. The rate of overall MRPs was 30.95 per 100 medication orders. The most common MRPs among CKD patients were need additional drug therapy (62 (31%)), nonadherence (40 (20%)), and dose too low (36 (18%)). The most common cause of need additional drug therapy (52 (26%)) was untreated medical conditions; nonadherence (19 (9.5%)) was mostly due to that the patient/caregiver forgets to take/give the medication, and dose too low (29 (14.5%)) was mostly due to that the dose is too low to produce the desired response. Polypharmacy , number of comorbidities , and stage of CKD  were independent predictors for MRPs.  We have demonstrated that medication-related problems are high among chronic kidney disease patients. Marital statuses, stage of CKD, polypharmacy, and comorbidity were independent predictors for MRPs. Interdisciplinary health professionals should work to decrease the high prevalence of MRPs among chronic kidney disease patients. Chronic kidney disease is one of the global health problems requiring early detection and treatment to prevent its progression  and assoSince MRPs are very common in patients with CKD, identification, prevention, and management of these problems require a comprehensive, interdisciplinary approach –14. It iIdentifying MRPs is a major task which could be taken care of by a clinical pharmacist in coordination with other health care providers through medication reconciliation –33. On tThe study was conducted at Jimma University Medical Center (JUMC), which is the only referral hospital for the south region, serving 20 million catchment areas. The study was conducted from April 1 to September 30, 2018, among CKD patients admitted to JUMC. Patients were eligible for inclusion if they were greater than 18 years of age and willing to give their informed consent. The dependent variable was MRPs and independent variables included patients' related factors: age, sex, BMI, educational status, residence, monthly income, marital status, and occupation; disease-related factors: stage of CKD, length of hospital stay, comorbid condition, past medical history, and reason of admission; drug-related factors: number of drugs per prescription, past medication history, and drug class.p=81.5% [n = 231. 180 CKD patients admitted to JUMC in 2017. The final sample size, 103, was calculated using the correction formula.A hospital-based prospective observational study was used to determine the magnitude of medication-related problems and associated factors among CKD patients. The sample size was calculated by using simple proportion formula with estimated prevalence of MRPs among CKD patients, p=81.5% , 95 confPharmaceutical Care Practice: The Clinicians Guide [Well-designed questionnaires were prepared after reviewing different literatures. The questionnaire was translated from English to local language Afan Oromo and Amharic and back to English by a licensed linguist. Semi-structured interview was conducted to record patients' sociodemographic data, past medical and medication history, date of admission/discharge, and allergy/ADR history and the patient chart to collect comorbidities, current and discharge medications, and laboratory investigations. All drugs which were prescribed for CKD patients were recorded and evaluated for presence, types, and patterns of MRPs. Identified MRPs were recorded and classified using MRP registration format which was taken from ns Guide . MRPs wep value <0.25 were a candidate for multivariate analysis and those variables with a p value <0.05 were considered as significant in multivariate analysis. The ADR was assessed by using the Naranjo ADR Probability Scale [Data were checked for completeness, grouped, then entered to EpiData version 4.2.0.0 software, and exported to the Statistical Package of the Social Sciences (SPSS) version 21.0 for analysis. Descriptive statistics like mean and percentage were used to present sociodemography and clinical characteristics of participants. Binary logistic regression was used to see the association between independent and dependent variables, and variables with a ty Scale . Subsequty Scale . Then, tInstitutional review board approval was obtained from Jimma University and written informed consent was obtained from each study participant.CKD is defined as abnormalities of the kidney structure or function, present for 3 months, with implications for health .2)  Stage I: kidney damage with normal or increased GFR (≥90% mL/min/1.73 m2)  Stage II: kidney damage with a mild decrease in GFR (60–89% mL/min/1.73 m2)  Stage III: moderate decrease in GFR (30–59 mL/min/1.73 m2)  Stage IV: severe decrease in GFR (15–29 mL/min/1.73 m2) [  Stage V: kidney failure (<15 mL/min/1.73 m2) Diseases or disorders that exist together with an index disease, or co-occurrence of two or more diseases or disorders in an individual.Use of alcohol, cigarette smoking, and chewing khat for one or more than one year.Use of five or more medication concomitantly.Events involving drug treatment that are actually or potentially harmful to a patient's health or prevent patients to optimally benefit from treatment.Additional drug therapy is required to treat or prevent a medical condition or illness from developing.During the six month study period, 103 CKD patients were included. Most of the study participants were in age group of 18–40 years with a mean age of 45.83 ± 17.7. Majority of the study participants 72 (69.9%) were males, 65 (63.5%) had no regular income, 66 (64.1%) were living in rural area, and 73 (70.9%) were married. Most of the study participants were 53 (51.5%) farmers and 34 (33.0%) had secondary education .Majority of the study participants (69 (66.99%)) had <5 comorbidities, 90 (87.4%) were newly diagnosed CKD patients, 66 (64.1%) received <5 drugs per prescription, and 80 (77.7%) were stay in hospital for ≥7 days. Most of the study participants 44 (42.7%) had normal BMI. The prevalence of CKD in the study population according to the KDIGO classification was as follows: 2 (1.9%) were in CKD stage II, 18 (17.5%) were in CKD stage III, 16 (15.5%) were in CKD stage IV, and 67 (65%) were in CKD stage V .All of the patients were found to have one to seven comorbidities. The top five comorbid conditions were anemia (86 (83.5%)), hypertension (77 (74.8%)), dyspepsia (52 (50.5%)), electrolyte abnormality (36 (34.95%)), and infections (32 (31.1%)) .Out of 103 study participants, 81 (78.6%) of patients had MRPs, on average 1.94 ± 0.873 MRPs per patient. The rate of overall MRPs was 30.95 per 100 medication orders. The most common MRPs among CKD patients were need additional drug therapy (62 (31%)) and nonadherence (40 (20%)). The most common cause of need additional drug therapy was untreated medical conditions (52 (26%)), while for nonadherence, the patient/caregiver forgets to take/give the medication (19 (9.5%)) was the most common cause .A total number of 646 medications were prescribed, and the mean number of prescribed medications per patient was 6.26 ± 1.85. From these, 219 drugs were involved in 200 different types of MRPs. The most common drug classes associated with the occurrence of MRPs among study participants include cardiovascular medications (31.9%), gastrointestinal (19.1%), and analgesic (19.1%) .A total of 218 clinical interventions were undertaken at three levels of the intervention: prescriber level: 88 (40.4%); patient/career level: 56 (25.7%), and drug level: 74 (33.9%). Out of these interventions, 178 (81.6%) were accepted and 174 (79.8%) were totally solved .p value <0.25 in bivariate analysis were introduced to multiple logistic regression. The result of the multivariate analysis showed participants who were married were 62% times more likely to have MRPs compared to those who were single . Participants who took polypharmacy were 4.695 times more likely to have MRPs compared to those who did not took polypharmacy . Participants who have ≥5 comorbidities were 3.616 times more likely to have MRPs compared to those who have <5 comorbidities . Participants who were treated for stage V CKD were 3.941 times more likely to have DRPs compared to those in other stages of CKD   .In our study, most of the study participants 90 (87.4%) were newly diagnosed CKD patients (within 3 months of study enrollment) and 67 (65%) were in CKD stage V. The reasons for this were most study participants live in rural areas, had a history of many medical conditions, did not take their medications properly, and came to JUMC after developing ESRD. We found a high frequency of MRPs in 81 (78.6%) patients among CKD patients with an average of 1.94 ± 0.873 MRPs per patient. The rate of overall MRPs was 30.95 per 100 medication orders. This result is lower than the result obtained from studies conducted in Indonesian (42.7 MRP per 100 medication orders) . Each stOur analysis on MRPs showed need additional drug therapy , which is almost similar to the studies conducted in France (30%) , 27. In Overdosage was accounted for 14.5% of all MRPs identified, which was consistent with studies conducted in Canada 13.6%)  and Swit.6%  and Ineffective drug therapy contributed for 10% of all MRPs identified. In comparison, studies conducted in India, 40.6%) , Canada 0.6% , CaMarital status was significantly associated with the number of MRPs which is different from most findings , 27, 42 A total of 218 clinical interventions were undertaken at three levels of the intervention. Out of these interventions, 178 (81.6%) were accepted, 174 (79.8%) were totally solved, and 40 (18.3%) MRPs were partially solved due to lack of cooperation of prescriber and patient. Amongst the MRPs indentified, 78.1% were successfully resolved. Conversely, a study conducted in Nigeria [We have demonstrated that MRPs are high in CKD patients. Marital statuses, stage of CKD, polypharmacy, and comorbidity were independent predictors for MRPs.JUMC should implement strategies to decrease the high prevalence of MRPs among CKD patients and should assign an interdisciplinary health care provider in inpatient settings to decrease the prevalence of MRPs among CKD patients. Since CKD patients are at high risk to present with comorbidities, physicians should consider all while treating them. The health care provider should adhere to dose adjustment recommendationsand should prescribe essential medicines only to reduce polypharmacy, and if possible, polypharmacy should be avoided. CKD patients should adhere to their medications.


Rosuvastatin calcium (ROSCa) is a poorly soluble drug with bioavailability not exceeding 20%. Decreasing the particle size may enhance its solubility, dissolution rate and bioavailability. Therefore, the aim of the current study is to prepare ROSCa nanoparticles by wet milling technique using planetary ball mill. The codesign between formulation and stabilization of nanoparticles was studied to achieve both high dissolution as well as bioavailability.in-vitro dissolution test, XRPD and in-vivo study.ROSCa nanosuspensions was prepared by wet milling technique using planetary ball mill, by applying milling ball size of 0.1 mm at speed of 800 rpm for 3 cycles each cycle composed of 10 minutes. HPMC, PVP k-30, pluronic F-127, Tween 80 and PEG 6000 were used as stabilizers. The nanosuspensions were then freeze-dried, and the dried nanoparticles were evaluated for particle size, zeta potential, P < 0.05). The in-vivo study of ROSCa from the leading nanoparticle formula showed a significant enhancement in the Cmax after 2 h (82.35 ng/ml) compared to 9.2 ng/ml for untreated drug.ROSCa nanoparticles stabilized with 10% PVP (P3) had a good stability with smallest particle size, which in turn enhanced the dissolution rate. The particle size of the leading formula was 461.8 ± 16.68 nm with zeta potential of -31.8 ± 7.22 mV compared to untreated drug that has a particle size of 618μm. The percent of ROSCa dissolved after 1 hour enhanced significantly which reached 72% and 58.25% for leading nanoparticle formula and untreated ROSCa, respectively  was able to produce stable nanoparticle with small particle size which significantly enhance the dissolution rate and pharmacokinetics parameters of ROSCa. Rosuvastatin calcium (ROSCa) is the most effective antilipidemic drug and is called "super-statin". It decreases the low-density lipoprotein-C (LDL-C) by 63% after an administration of 40 mg dose , 2. ROSCThe principle of nanosization technology is based on size reduction. Drug nanoparticles are drugs in a nanosize range . KrishnaThe milling has been reported as a highly effective technique. It is a process of applying mechanical energy that affects particle size and thus specific surface area as well as shape of drug particles . ProlongThe aim of production of nanosuspension is to enhance both dissolution rate and bioavailability of ROSCa. However, physical stability of the prepared nanosuspension during preparation and shelf life storage should be ensured. The major problems of nanosuspension instability can be simplified as the aggregation of small particle size after size reduction. This is also known as Ostwald ripening in which small particles are recrystallized and forming large particles.The addition of stabilizers can enhance the physical stability of the nanosuspension by different mechanisms according to its properties. Ionic surfactant stabilizers stabilize the colloidal system by electrostatic effect . The ionThe aim of the present study was to prepare and characterize ROSCa nanoparticle by planetary ball milling technology to enhance both its dissolution rate as well as bioavailability. The effects of type and concentration of the nanoparticles stabilizers were also investigated. Design jointly (codesign) of enhancing the stability and dissolution by stabilizers was targeted in this study.® 80 was purchased from Merck Company . Poloxamer 407 (Pluronic F127®) was obtained from C.H. Erbesloh . Other chemicals were of reagent grade and were used as received.Rosuvastatin calcium (ROSCa) was purchased from Beijing Mesochem Technology CO. Ltd. . Hydroxypropyl methylcellulose, HPMC (Methocel E5 PREM LV) was obtained from DOW . Polyvinylpyrrolidone  was obtained by Loba Chemie (India). TweenPrior to wet milling, ROSCa was subjected first to dry milling using planetary ball mill . This step was done because the particle size of the starting material subjected to wet milling by the planetary ball mill was 618 μm. Zirconium balls with a size of 5 mm were used as the milling medium for the dry milling procedures in powder: ball ratio (1:10). The dry milled drug was further nanosized by wet milling.For the wet milling procedures, definite weight of dry milled ROSCa was mixed with the milling solution; water (with or without stabilizer) in different ratios. The dispersion was then nanosized by using zirconium ball of 0.1 mm size and milling speed of 800 rpm. This also done using three milling cycles (10 min of each) with a pause of 5 min after each milling cycle. The effect of stabilizers types namely: HPMC, PVP, Tween 80, Pluronic F-127 and PEG 6000 as well as their concentrations on the produced nanoparticles was also investigated. The prepared nanosuspension was subjected to freeze- drying and then solid nanoparticles was stored in a tight container at -30° for further characterization.In 10 ml volumetric flask, 10 mg of nanoparticles was dissolved in 10 ml methanol. One ml was taken in 10 ml volumetric flask and completed to the volume with 0.1N HCl. The absorbance was measures at λ 244 nm against a blank made of stabilizer only following the same procedure. The drug content experiment was carried out in triplicate.ζ of the nanosuspension were determined by using Malvern zetasizer .The particle size and zeta potential The crystallinity of the pure drug and nanoparticles was determined by using X-Ray diffractometry. The X-ray diffraction patterns of the powder samples were obtained using RIGAKU diffractometer  which is equipped with curved graphite crystal monochromater, automatic divergence slit and automatic controller PW/1710. The target used was CuKα radiation operating at 40 KV and 40 mA (λkα = 1.5418 Å). The diffraction pattern was achieved using continuous scan mode with 2Ɵ° ranging from 4° to 60° .−1.Fourier transform IR spectra were recorded for ROSCa raw material and nanoparticles. The samples were grounded separately and mixed thoroughly with potassium bromide. The ratio of sample and KBr was kept for all the preparations. The potassium bromide discs were prepared by compressing the powders at a pressure of 5 tones for 5 min in a hydraulic press. Scans were obtained from 4000 to 500 cmin-vitro dissolution profile of ROSCa nanoparticles was studied using a USP-II dissolution apparatus . The dissolution experiment was carried out in 500 ml of 0.1 N HCl as a dissolution medium at 37 C° and 50 rpm. Five ml aliquot samples were withdrawn at pre-determined time intervals  using poroplast-kerze filter and diluted suitably. The absorbance was measured spectrophotometrically at 244 nm against a suitable blank.The 60) was measured using the trapezoidal rule calculated from the area under the dissolution curve at time t and expressed as percentage of the area of the rectangle described by 100% dissolution in the same time [60) of the dissolution was calculated by determining the amount of ROSCa dissolved from tested samples and normalizing for the amount of drug dissolved from pure drug sample over the same time (60 minutes).Dissolution efficiency after 60 min  were obtained from the College of Pharmacy experimental animal care center . The animals were fasted for 24 hours prior the administration of the drug, the drug was administered using the oral route by oral gavage in order to assure the dose uniformity. The study was approved by the Ethical Committee (Protocol no. 80–23) by Experimental Animal Care Unit. The experimental protocol was in agreement with the Guide of the National Institution of Health (NIH) for the Care and Use of Laboratory Animals.max, Tmax, AUC, rate of absorption and rate of elimination using a non-compartmental model analysis.Drug administration: Two groups of animals were administered the calculated animal dose equivalent to 10 mg. Both raw ROSCa and nanoparticle formulation were suspended in 0.5% Na-CMC just before administration and administered orally via gastric tube. Aliquots of blood sample were collected at different time intervals for at least 24 hours. The blood samples were treated and analyzed using developed UPLC-MS/MS method . DiffereBlood sampling: At specific time interval , 1 ml blood was withdrawn from ear vein in heparinized tube. The blood sample was centrifuged at 6000 for 20 minutes to separate the plasma.Analysis of ROSCa in rabbit plasma:Sample preparation: The plasma samples were processed by protein precipitation method. Simply, 0.2 ml of plasma sample was combined with 50 μl internal standard Prednisolone (100 μg/mL) and 0.75 ml methanol, then vortexed for 1 min. After centrifugation at 15,000 rpm  for 10 min, 750 μl of the supernatant liquid was transferred to a sample vial and 5 μl was injected into the LC/MS/MS for quantitative analysis. Chromatographic conditions: In this study, a validated UPLC-MS/MS  was employed to determine the concentration of Rosuvastatin in rabbit plasma . The chrOne way analysis of variance (ANOVA) was used for comparison. A value of p < 0.05 was denoted significant throughout the current study.The effect of different stabilizers  and their three level of concentrations  on the particle size of ROSCa nanosuspensions were studied . UntreatThe particle size of nanosuspension stabilized with 2.5% HPMC was 500 ± 45.31 nm, which is lower than particle size observed in case of non-stabilized nanosuspension (750 ± 20.66 nm). Increasing HPMC level in the nanosuspension from 2.5% to 5% and 10% resulted in enlarging particle size to be 869.2 ± 63.99 nm and 1105 ± 81.79 nm, respectively. Increasing HPMC concentration might result in increasing solution viscosity, retardation in the movement of milling balls, and resulting in larger particle size . The enlThe three concentrations used of tween 80 as suspension stabilizers decreased the particle size of ROSCa nanosuspensions to range of 500 nm. Interestingly, the optimum surfactant concentration in decreasing the particle size was the 5% w/v, in which the particle size of 296.4 ± 9.62 nm was obtained.The low concentration of the tri-block co-polymer; pluronic F-127 (2.5%) did not produce a nanosized particles (1316.33 ± 73.2 nm). Differently, the higher concentrations (5 and 10%) were significantly produced nanoparticles . Pluronic F-127 at higher concentrations was able to decrease the aggregation of the particles by adsorption on the particle surface. The hydrophobic polypropylene oxide moiety may be adsorbed on the particle surface. In addition, the hydrophilic portion provides a steric hindrance property which is preventing the aggregation of the particles .All concentrations of PEG 6000 did not result in decreasing the particle size to nanosize range. This could be due to the high hydrophilicity of the polymer which prevents the adsorption on the particle surface for steric stabilization.ζ) can be defined as the potential difference between the stationary layer of fluid attached to the particles and the dispersion medium [Zeta potential . This value decreased to (-11.5 ± 5.77 mV) with increasing the HPMC concentration to 10%. Additionally, the zeta potential of nanosuspensions stabilzed by PEG 6000 increased from (-6.6 ± 4.81 mV) to (-29.4 ± 7.51 mV) by increasing the stabilzer concentration in the nanosuspension from 2.5% to 10%, respectively.Tween 80 stabilized nanosuspensions showed the lowest zeta potential values compared with other stabilizers. The low value of zeta potential value of these nanosuspensions (< -20 mV) could be due to the formation of thick adsorbed layer. This is due to the adsorption of the non-ionic surfactant to the nanosized particles resulting in covering and masking of the particle charge .Differently, freeze-drying of nanosuspension containing low concentration of PVP produced enlarged particles 1895.5±70 nm, while nanosuspensions stabilized with 5% and 10% PVP showed slight increase in their sizes upon freeze-drying. This could be attributed to high polymer weight ratio, which inhibits or at least decreases the mobility of drug particles and thus, inhibits its recrystallization . MoreoveFreeze-dried suspensions containing drug and different concentrations of stabilizers were prepared without milling. This step was done in order to investigate if the reduction in the particle size is due to the milling process or the properties of the polymer. The effect of stabilizer type and concentration are presented in The dissolution profile of ROSCa in 0.1N HCl (pH 1.2) showed that only 58.25 ± 1.6% was dissolved after 1 hour. The initial dissolution rate after 5 min (IDR) was 24.45 ± 2.6% and a DE% after 60 minutes was 42.7. The dissolution rate of non-stabilized ROSCa nanoparticles was slightly higher than that of untreated ROSCa after 1h (%DE 52.1), . Also, iThe percent of ROSCa dissolved after 60 minutes from nanoparticles stabilized with high HPMC concentrations (5 and 10%) was higher than that of untreated ROSCa or non-stabilized ROSCa nanoparticles. Nanoparticles stabilized by 5% HPMC showed increased drug dissolution rate by 1.2-folds in comparison to that of the raw drug powder. Also, nanoparticles stabilized by 10% HPMC showed increased dissolution rate by 1.6-fold (P < 0.05). The solubilizing effect of HPMC on the drug with the reduced particle size may participate for enhancing the dissolution rate of ROSCa nanoparticles stabilized by the polymer. In contrast, the dissolution rate of ROSCa non-milled freeze-dried suspensions in HPMC solutions prepared without milling exhibited a slight improvement in comparison to the untreated drug. However, they still slower than that obtained with the corresponding nanoparticles prepared by milling, . The perThe dissolution of ROSCa from nanoparticles stabilized by PVP showed a noticeable improvement in compared to that of the untreated drug, especially in case of using 5% and 10% PVP during nanoparticle formation. Nanoparticle formulations stabilized by 5% and 10% PVP significantly (P < 0.05) enhanced the dissolution rate of ROSCa in comparison with untreated raw drug powder. The values were 69.6 ± 3.3% and 72.08 ± 8.2% for 5% and 10%, respectively versus only 58.25 ± 1.62% for untreated ROSCa. In contrast, the dissolution of ROSCa non-milled freeze-dried suspensions in PVP solutions did not showed a significant enhancement of the drug dissolution compared to both untreated ROSCa and non-stabilized nanoparticle formula . TherefoThe non-ionic surfactant Tween 80 was extensively utilized to enhance the dissolution rate of poorly soluble drugs by micelle formation. Unfortunately, the freeze-dried non-milled suspensions of ROSCa in different tween 80 concentrations did not show a pronounced enhancement of the dissolution rate of ROSCa . The perTween 80 with the milling process produced nanoparticles with less than 500 nm in size. However, this marked decrease in the particle size did not greatly improve the drug dissolution rate compared to the untreated ROSCa . The lowThe milling of ROSCa in dispersions containing high concentrations (5% and 10%) of Pluronic F-127 succeeded to decrease the nanoparticles size to about 500 nm. However, this decrease in the particle size didn’t enhance the dissolution rate in case of nanoparticles stabilized by 5% pluronic F-127 solutions. In contrast, increasing the concentration of Pluronic F-127 to 10% resulted increasing the dissolution significantly from 39 ± 1.4% to 68 ± 3.8% in comparison to the untreated ROSCa dissolution (P < 0.05). The inefficiency of pluronic F-127 to enhance the dissolution rate of ROSCa in low concentrations could be attributed to nanoparticles agglomeration, which takes place after nanosization procedure resulting in slowing the drug dissolution rate .The dissolution rate of ROSCa from freeze-dried non-milled suspensions containing different pluronic F-127 concentrations significantly (P < 0.05) increased by increasing the polymer concentration. The enhancement in the dissolution rate of ROSCa from non-milled freeze-dried suspension containing higher concentration of pluronic F-127 could be due to the wettability and solubilizing effect of the polymer. Since pluronic F-127 is non-ionic surfactant capable of forming miceller in the solution that enhanced drug solubility . Thus, uThe dissolution profiles of nanoparticle formulations stabilized by different concentrations of PEG 6000 were slow . The resBased on the results of the particle size and the dissolution rate, it was found that nanoparticle formula stabilized by 10% PVP showed small particle size 461.8 ± 16.68 nm , along wIn order to investigate the crystalline nature of the raw material, physical mixture and nanoparticles XRD studies were carried out. The XRPD pattern of untreated ROSCa showed two distinctive diffraction peaks at 2θ degree of 31.8 and 45.5 degrees. These sharp peaks indicate the lower crystallinity form of ROSCa.The XRPD spectra of non-milled freeze-dried suspensions in 2.5% and 5% solutions of PVP showed the existence of ROSCa characteristics peaks. Differently, these peaks disappeared in case of 10% PVP solution suggesting that increasing the PVP concentration transform ROSCa to amorphous form even in absence of milling. The addition of PVP as stabilizer for nanoparticles has a rule in converting the crystal form of ROSCa to amorphous one . In addiP < 0.05) higher than those observed in case of raw ROSCa.The plasma concentration-time curve in rabbits after oral suspension administration of the prepared nanoparticle formula stabilized by 10% PVP was compared to raw drug . The ROSmax) increased significantly by 8.2 folds after administration of nanoparticle formula (P < 0.05), in which Cmax was 82.35 ng/ml compared to 9.2 ng/ml for the raw drug. The AUC0-∞ also increased by 21folds after administration of nanoparticles formulation (P < 0.05). The mean residence times (MRT) for nanoparticle formula and raw ROSCa were 80.24 and 30.11, respectively. The higher MRT may indicate that the drug may stay for long time inside the body as indicated by long half-life (55.06 ± 15.36 h) after nanoparticles administration. Moreover, lower elimination rate constant (0.013 ± 0.004) was observed in case of nanoparticle formulation compared to that observed for raw drug (0.04 ± 0.033).Pharmacokinetic parameters calculated from plasma concentration versus time profile of ROSCa are shown in max and AUC increased significantly by 8.2-folds and 21.1-folds in case of ROSCa nanoparticles stabilized by 10% PVP compared to the untreated ROSCa (P<0.05). Therefore, formulation of ROSCa stabilized nanoparticles resulted in enhancing the drug dissolution and improved its oral bioavailability.ROSCa nanoparticles were successfully formulated by wet milling technique using planetary ball mill. The type and concentration of stabilizers used in nanoparticle formulation could be monitored to attain the desired nanoparticles attributes such as particle size, zeta potential as well as dissolution parameters. The pharmacokinetic data showed that both C


EGDT  or some portion of EGDT has been shown to decrease mortality secondary to sepsis and septic shock. Our study aims to assess the effect of adopting this approach in the emergency department on in-hospital mortality secondary to sepsis/septic shock in Lebanon. Implementation of the EGDT protocol of sepsis in ED will decrease in-hospital mortality. Our retrospective study included 290 adult patients presenting to the ED of a tertiary center in Lebanon with severe sepsis and/or septic shock. 145 patients between years 2013 and 2014 who received protocol care were compared to 145 patients treated by standard care between 2010 and 2012. Data from the EHR were retrieved about patients' demographics, medical comorbidities, and periresuscitation parameters. A multivariate analysis using logistic regression for the outcome in-hospital mortality after adjusting for protocol use and other confounders was done and AOR was obtained for the protocol use. 28-day mortality, ED, and hospital length of stay were compared between the two groups. The most common infection site in the protocol arm was the lower respiratory tract (42.1%), and controls suffered more from UTIs (33.8%). Patients on protocol care had lower in-hospital mortality than that receiving usual care, 31.7% versus 47.6% (p=0.006) with an AOR of 0.429 (p =0.018). Protocol patients received more fluids at 6 and 24 hours (3.8 ± 1.7 L and 6.1 ± 2.1 L) compared to the control group (2.7 ± 2.0 L and 4.9 ± 2.8 L p=<0.001). Time to and duration of vasopressor use, choice of appropriate antibiotics, and length of ED stay were not significantly different between the two groups. EGDT-  based sepsis protocol implementation in EDs decreases in-hospital mortality in developing countries. Adopting this approach in facilities with limited resources, ICU capabilities, and prehospital systems may have a pronounced benefit. Sepsis is a life-threatening organ dysfunction caused by a dysregulation of host responses to infection . DespiteIn 2001, the early goal directed trial EGDT  introducThe primary outcome of our study is the 72 hours, hospital, and 28-day mortality to evaluate the implications of a structured sepsis protocol derived from the 2001 EGDT in patients presenting to the emergency department of a single tertiary hospital in Lebanon.Secondary outcomes includes length of stay, time to antibiotics, percent of ICU admission, amount of IV fluid use, and vasopressor use.μmol/L; urine output <0.5ml/kg/hr for 2hrs; creatinine>2mg/dl; platelet count <100,000/mm3; SpO2 <90%. Septic shock was defined as sepsis with any of the following: SBP <90mmHg or MAP <65mmHg despite 30ml/kg of crystalloid resuscitation . We excluded patients younger than 18 years of age, pregnant, or presenting with cardiac arrest or trauma.This is an IRB approved, single center, retrospective, cohort study conducted in a large tertiary care center in Lebanon. We reviewed the electronic health record using the ICD-9 coding system of patients presenting to the emergency department with severe sepsis or septic shock. Patients who were eligible for the study should meet the definition of severe sepsis or septic shock as per the 2012 Surviving Sepsis Campaign guidelines definitions . Severe We included 145 consecutive patients from January 2013 until May 2014 presenting to our ED with severe sepsis and/or septic shock who were managed by the EGDT sepsis based protocol, and these constituted the intervention arm. For the control cohort, 145 patients with sepsis and/or septic shock presenting to the ED between January 2010 and December 2012 were randomly selected from a large pool of database using computer software for random number generation. The AUBMC-ED volume of patients diagnosed with severe sepsis and started on the protocol during the years following implementation of a sepsis protocol (2012-2014) was used to determine the size of the study population. A rough estimate of each group size ranges between 200 and 300 patients.Medical records were used to retrieve data about patients' demographics including patients' age, gender and medical information regarding presence/absence of comorbidities, site of infection, microbiology findings, and site of disposition . Pertinent laboratory blood workup and vital signs upon presentation and the latter 6 hours after resuscitation were also collected. Antibiotics use and its appropriateness  were extracted. Data on the requirements of intravenous fluid resuscitation, vasopressor (use and duration) and steroid use were also retrieved. We also collected the length of stay in the ED, GPU and ICU along with in-hospital and 72-hr mortality.For the intervention cohort, patients were managed as per our ED sepsis protocol .Univariate analysis was carried out between the intervention and the control groups for comparison of patients' characteristics, preresuscitation parameters, resuscitation parameters, and length of hospital stay/mortality outcomes. Comparison was done between patients' demographics, comorbidities, severity of sepsis, site of infection, and microbiology isolate . PreresuA multivariate analysis was performed using logistic regression to find the best model that fits the data and explains the use of the EGDT-sepsis based protocol as predictor of in-hospital mortality while controlling for all possible confounders. A backward selection procedure, with significance level for removal from the model set at 0.1, was conducted by fitting in-hospital mortality with all risk factors found to be significant in the bivariate level, in addition to those considered as being clinically meaningful. The included variables were protocol use, age, gender, diagnosis (severe sepsis or septic shock), systolic congestive heart failure (CHF) EF<40%, diabetes mellitus (DM), coronary artery disease (CAD), hypertension (HTN), cerebrovascular accidents (CVA), chronic kidney disease (CKD), hemodialysis (HD), chronic obstructive pulmonary disease (COPD), central venous catheter (CVC) placement, endotracheal tube placement, MAP upon presentation to the ED, BUN, creatinine, and appropriate use of antibiotics.Two hundred and ninety patients were included in the final analysis with 145 patients in each arm. The protocol arm had a mean age of 71.9 ± 14.1 years compared to 72.9 ± 16.3 years in the control arm. 51.7% and 52.4% of the protocol group and control group, respectively, were male patients. All baseline demographics such as age, gender, and studied comorbidities in addition to diagnosis of severe sepsis or septic shock are presented . The mos2 saturation, SBP, or respiratory rate. Protocol patients had higher diastolic blood pressure (DBP=59.2 ± 16.3 mmHg vs. 54.7 ±16.0 mmHg p=0.019) and mean arterial pressure (MAP= 73.7 ±17.3 mmHg vs. 69.5 ± 17.6 mmHg p=0.043) and heart rate (HR= 106.2 ±24.2 bpm vs. 99.4 ± 25.3 bpm). When comparing initial laboratory results, most results were comparable between the groups except for creatinine  and BUN . Lactate levels did not differ between the two groups (3.9 ± 2.5 mg/dl in the intervention cohort versus 3.8 ± 4.1 in the control cohort). There was no statistically significant difference between the two groups in terms of temperature, OAll vital signs were comparable between the groups after treatment, except for MAP where protocol patients had a lower MAP than the control group at 6 hours . Patients who were managed using the sepsis protocol received more fluids at 6 and 24 hours (3.8 ± 1.7 L and 6.1 ± 2.1 L) compared to the control group (2.7 ± 2.0 L and 4.9 ± 2.8 L) p=<0.001. More vasopressors were initiated within the first 24 hours in the protocol arm as well (88 (60.6%) vs. 52 (35.8%) p=<0.001). The intervention group had more CVC placed (21.2% vs. 9.9% p=0.010). Both protocol and control cohorts have similar rates of mechanical ventilation. The time to vasopressor initiation and the duration of vasopressor use were not significantly different between the cohorts. Both cohorts had similar steroid and antibiotic use. The mean time of antibiotics initiation was 2.0 ± 3.6 hours in the protocol group compared to 2.8 ± 2.6 hours in the control group p=0.054. More antibiotics were initiated in the ED in the control arm than the protocol arm (99.3% vs. 93.8% p=0.010). Ninety-one patients (97.8%) in the intervention group received appropriate antibiotics compared to 75 (91.5%) in the control group (p=0.056). The length of stay in the ED was found to be 26.0 ± 29.0 hours vs. 19.4 ± 28.8 hours in the protocol and control group, respectively (p=0.051). ICU and GPU LOS did not differ between the two arms . Forty-sThis study attempts to evaluate the utility and efficacy of using EGDT-sepsis based protocol on sepsis management at a tertiary care centre in Beirut. The primary outcome is in-hospital mortality; the secondary outcomes were 28-day mortality, ED, and hospital length of stay. After the introduction of the EGDT in the USA, clinical outcomes of septic patients substantially improved  and mortAdherence to the sepsis protocol was associated with a relative risk reduction (RRR) on in-hospital mortality of 33.3%. This is in line with the findings of the Rivers  and otheSeveral studies questioned the effectiveness of the EGDT protocol versus standard care and showed that alternate strategies may have equal effect at reducing mortality without the increased costs –10. ThosPatient's length of stay in the ED and delayed transfers to the ICU have come under discussion in recent years , 26. SomOur study showed that fewer patients were started on antibiotics in the ED in the protocol arm despite a lower mortality in this group. This finding relates to ongoing antimicrobial stewardship efforts . It is cThis is the first study to be conducted in Lebanon assessing the effect of implementing an EGDT sepsis based protocol in ED on mortality outcome. The retrospective design of the study is a main limitation of the study as data collected from the electronic health records may sometimes be misinterpreted or missing. To minimize the information bias, frequent meetings were held between the investigators to standardize the data collection process. In addition, we were not able to use a matched control group. We included all patients who presented with sepsis between January 2013 and May 2014 to ensure a large sample size.The definition of “usual care” is not standard and was per the treating physician, thus comparing the management across the two arms is limited. The control group in our study did receive timely antibiotics, vasopressors, and IV fluids. Data about the paramedical care was not available; therefore we were not able to adjust for it in our analyses. The two cohorts were not matched, and the control arm subjects were sicker at baseline, showing worse hemodynamics upon presentation to the ED. These points might be explained by the inaccuracy of the non-invasive measurements. They had lower diastolic blood pressure (DBP=54.7 ±16.0 mmHg vs. 59.2 ± 16.3 mmHg p=0.019) and mean arterial pressure (MAP= 73.7 ±17.3 mmHg vs. 69.5 ± 17.6 mmHg p=0.043) when compared to the intervention arm. These findings might not be pertinent clinically as both groups had similar lactate and arterial pH. Those markers are indicators of end-organ hypoperfusion . MoreoveIn a single tertiary center in Lebanon, the introduction of an EGDT-based sepsis protocol decreased in-hospital mortality of patients presenting with severe sepsis or septic shock. 28-day sepsis mortality is also reduced after the implementation of the EGDT protocol. Although the utility of EGDT bundles has been under scrutiny in recent years, their benefits when used in countries with limited resources, ICU capabilities and pre-hospital systems may be pronounced. In conclusion, this study highlights several potentially important points. The introduction of a structured approach to sepsis is feasible in a resource limited setting; the results achieved in terms of reduced mortality are comparable to those demonstrated in developed countries. Outcomes could be further improved, especially regarding the baseline mortality by improving the existing pre-hospital infrastructure to ensure expedited and appropriate treatment of septic patients.


The aim of this study was to evaluate predictors of residual tumor and clinical prognosis in T1a-T1b  prostate cancer by analysis of specimens from men undergoing surgery for benign prostatic hyperplasia.We retrospectively reviewed medical records of incidental prostate cancer patients who had undergone radical prostatectomy. Patients whose tumor statuses were further confirmed by prostate biopsy, or who had used androgen deprivation therapy before radical prostatectomy, were excluded. Clinical and pathological parameters were analyzed to evaluate residual tumor and clinical prognosis. We used univariate and multivariate logistic regression analyses, as well as receiver operator characteristics, to predict residual tumor (pT0).The final analysis included 95 patients. Among these patients, 67 (70.53%) exhibited residual tumor, whereas 28 (29.47%) did not (pT0). Pathology findings showed that 44 (65.67%), 16 (23.88%), and 7 patients (10.45%) exhibited Gleason scores of G6, G7, and ≥G8, respectively. Fifty-seven and 10 patients exhibited pathologic T stages T2 and T3, respectively. Mean follow-up duration was 70.26 (±34.67) months. Biochemical recurrence was observed in 11 patients; none were pT0 patients. Multivariate logistic regression showed that low prostate-specific antigen density after benign prostatic hyperplasia surgery and invisible lesion on multiparametric magnetic resonance imaging were significantly associated with pT0. Additionally, a combination of these factors showed an increase in the diagnostic accuracy of pT0, compared with mpMRI alone ; this combination showed sensitivity, specificity, and positive predictive values of 71.6%, 89.3%, and 94.1%, respectively.Our results suggest that patients with incidental prostate cancer who have both prostate-specific antigen density ≤0.08 after benign prostatic hyperplasia surgery as well as invisible cancer lesion on multiparametric magnetic resonance imaging should be considered for active surveillance. Prostate cancer (PCa) is one of the most prevalent cancers worldwide; moreover, it exhibits the highest incidence among all cancers in males in the United States, especially in elderly individuals . As PCa Notably, the probability of finding no residual cancer (pT0) among patients with IPCa who undergo RP has been reported in several studies ,8–10. InV2 was used as a standard when the image was reviewed again by radiologists. Clinical characteristics of these patients included age, body mass index, PSA before and after BPH surgery, and prostate volume (measured by TRUS) before and after BPH surgery [We retrospectively reviewed the clinical and pathological data of 107 individuals with PCa who underwent BPH surgery before RP at our institution between June 2006 and December 2016; patients whose tumor statuses were further confirmed by prostate biopsy during surgery for BPH, or who had used androgen deprivation therapy before RP, were excluded. Therefore, 95 patients were included in this analysis; all included patients underwent mpMRI before RP. All images were retrospectively reviewed by three experienced uroradiologists who were blinded to pathologic results; they conducted a consensus review of the mpMRI images of all patients. The mpMRI images included standardized criteria for Likert scoring of multiparametric sequences using a 3.0-T MRI system  . From 20 surgery . In addiPostoperative PSA follow-up was performed monthly for the first 6 months, every 3 months for the second year, and every 6 months thereafter. Biochemical recurrence (BCR) was defined as any two consecutive increases in serum PSA ≥0.2 ng/ml following RP . BCR-freAll procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required. Data were collected after approval from the Institutional Review Board at Yonsei University College of Medicine (protocol number 4-2018-0669).Informed consent was not required from individual participants included in the study due to its retrospective design involving review of medical records.2 tests for dichotomous variables. Univariate and multivariate logistic regression analysis were performed to assess the association between baseline parameters and residual cancer. Significant variables from univariate analysis were included in the multivariate analysis. Moreover, the Kaplan-Meier method, combined with log-rank tests, was performed to estimate and compare oncologic outcomes with respect to pT0. Receiver operator characteristic (ROC) curve analysis was performed to determine the optimal cut-off value via the area under the curve (AUC). Comparisons where p < 0.05 were considered statistically significant. These statistical analyses were performed with SPSS Statistics software, version 23.0 . In addition, assessments of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with 95% confidence intervals were performed with Medcalc .We compared clinical and pathological characteristics between groups by using Mann–Whitney U tests for continuous data and χ2, respectively. The mean resection volume was 11.17±10.35 ml; the mean PSA and PSA density values after BPH surgery were 1.58±1.40 ng/ml and 0.06±0.06 ng/ml2. Among specimens following BPH surgery, 75 exhibited GS 6 (76.1%), 13 exhibited GS 7 (17.4%), and 7 exhibited GS ≥8 (6.6%). Forty-nine patients (51.6%) showed no suspicious lesions during MRI performed to evaluate the presence of PCa. Of the 46 patients (48.4%) with suspicious lesions, 33 showed lesions in the peripheral zone, 9 showed lesions in the transitional zone, and 4 showed lesions in both the peripheral and transitional zones.A total of 95 incidental PCa patients were included. At the time of surgery for BPH, patients were classified as stage T1a (n = 49) or T1b (n = 46), in accordance with the 8th edition of the American Joint Committee on Cancer TNM staging system. The mean age for all patients was 67.31±4.93 years. The mean prostate volume, as measured by TRUS, was 39.88±16.97 ml; the mean PSA and PSA density values were 4.45±3.63 ng/ml and 0.13±0.14 ng/mlThe median follow-up from RP was 68.37±41.83 months. Among specimens following RP, 67 (70.53%) exhibited residual tumor and 28 (29.47%) did not (pT0). When dividing the two groups on the basis of residual tumor, there were significant differences between the two groups in PSA after BPH surgery, PSA density before and after BPH, and suspicious lesions in MRI. T stage, according to BPH surgery and PSA before BPH surgery, did not significantly differ between the two groups .p = 0.027) (p = 0.001) and pathologic T stage ≥ T3  were independent prognostic factors for BCR. In contrast, PSA, PSA density, and T1a or T1b were not statistically different.Among 67 RP specimens (excluding those with pT0), 44 exhibited GS 6 (65.7%) and 16 exhibited GS 7 (23.9%). Furthermore, GS ≥8 was present in 7 (10.4%). The median tumor volume of specimens following RP was 0.76±1.1 ml. Pathologic stage ≥T3 was recorded in 10 cases (14.9%). Extracapsular extension (ECE) was present in 10 cases (14.9%); surgical margins were involved in 4 (6.0%). Invaded seminal vesicles were observed in 1 case (1.5%). Perineural invasion was reported in 1 case (1.5%); lymphovascular invasion (LVI) and lymph node metastasis were not reported. During the follow-up period, BCR was not observed in pT0 patients; in the residual PCa group, BCR was observed in 11 cases (16.4%). Furthermore, there were no cancer-specific deaths during the observation period . Additio= 0.027) . Univarip = 0.048) and suspicious lesion on mpMRI  constituted independent predictors of the presence of residual cancer at RP in both univariate and multivariate models. After BPH surgery, invisible lesion on mpMRI and low PSA density showed a significant correlation with pT0  and 0.711 , respectively. Diagnosis of pT0 with mpMRI alone revealed sensitivity of 64.2% , specificity of 89.3% , PPV of 93.5% , and NPV of 51.0% . We enhanced the diagnostic accuracy of mpMRI by adding PSA density values. Notably, PSA density ≤0.08 showed the best correction value. The AUC of the ROC curve for this combination of predictive factors was 0.805 . Diagnosis of pT0 with the combined predictors revealed sensitivity of 71.7% , specificity of 89.3% , PPV of 94.1%  and NPV of 56.8%   Table 4Table 4.pT0 is a well-known rare phenomenon, occurring in <1% of all patients who undergo RP for PCa . This isSeveral studies have reported the prevalence of pT0 cases in patients with T1a–T1b treated with RP; these range from 2% to 48% in patients without previous neoadjuvant therapy ,8–10,21.V2 recommendations. There were 38 patients from 2006 to 2009, and 57 patients from 2010 to the end of the study period. There was no significant difference with regard to suspicious lesions in the accuracy of mpMRI between the two groups .Our study has several limitations. First, this was a retrospective review of data from patients treated at a single institution; therefore, multi-center, prospective studies are needed. If we conduct a multi-center study and collect more cases, we may be able to generate a nomogram for residual tumors in patients with IPCa . Second,Despite these limitations, our study remains informative for clinicians who treat patients with IPCa. With regard to the strengths of our study, to the best of our knowledge, this is the first investigation to include mpMRI of IPCa for prediction of pT0. Furthermore, we investigated long-term follow up oncologic outcomes of IPCa with an established protocol. No patients were treated with adjuvant androgen deprivation therapy or radiotherapy until BCR; this allowed us to observe the natural history of BCR after RP. In this study, we determined the oncologic outcome according to the presence of residual tumor in IPCa. Because the oncologic outcome of IPCa patients who exhibit pT0 is good, it is important to predict pT0 where possible. Therefore, we believe that the proposed diagnostic tool is a method to reduce overtreatment in pT0 patients. We believe that our study will help clinicians to determine the direction of treatment in IPCa.Our results demonstrate that patients with pT0 in IPCa showed a good prognosis; therefore, radical treatment may constitute overtreatment. In our study, lesions invisible on mpMRI, combined with PSA density after BPH surgery, were significantly associated with pT0. Therefore, in IPCa, patients with PSA density ≤0.08 after BPH surgery and with invisible cancer lesion on mpMRI should be considered for active surveillance.


Objective: While Hungary is often reported to have the highest incidence and mortality rates of lung cancer, until 2018 no nationwide epidemiology study was conducted to confirm these trends. The objective of this study was to estimate the occurrence of lung cancer in Hungary based on a retrospective review of the National Health Insurance Fund (NHIF) database.Methods: Our retrospective, longitudinal study included patients aged ≥20 years who were diagnosed with lung cancer (ICD-10 C34) between 1 Jan 2011 and 31 Dec 2016. Age-standardized incidence and mortality rates were calculated using both the 1976 and 2013 European Standard Populations (ESP).Results: Between 2011 and 2016, 6,996 – 7,158 new lung cancer cases were recorded in the NHIF database annually, and 6,045 – 6,465 all-cause deaths occurred per year. Age-adjusted incidence rates were 115.7–101.6/100,000 person-years among men (ESP 1976: 84.7–72.6), showing a mean annual change of − 2.26% (p = 0.008). Incidence rates among women increased from 48.3 to 50.3/100,000 person-years (ESP 1976: 36.9–38.0), corresponding to a mean annual change of 1.23% (p = 0.028). Age-standardized mortality rates varied between 103.8 and 97.2/100,000 person-years (ESP 1976: 72.8–69.7) in men and between 38.3 and 42.7/100,000 person-years (ESP 1976: 27.8–29.3) in women.Conclusion: Age-standardized incidence and mortality rates of lung cancer in Hungary were found to be high compared to Western-European countries, but lower than those reported by previous publications. The incidence of lung cancer decreased in men, while there was an increase in incidence and mortality among female lung cancer patients. Lung cancer was the most commonly diagnosed tumor in 2018 and the first cause of cancer death worldwide in both sexes  projected the incidence of lung cancer to be 109.3/100,000 standardized person-years (SPYs) among men and 46.5/100,000 SPYs among women in 2012 . The NHIF database is a nationwide insurance system covering close to 100% of the Hungarian population, which collects patient ID and ICD-10 code information about all in- and out-patient visits, as well as about all prescription of drugs which are reimbursed in Hungary. The study was approved by the National Ethical Board for Health Research (10338-5/2019/EKU).Our analysis included patients with lung cancer (ICD-10:C34) who were newly diagnosed between 1 Jan. 2011 and 31 Dec. 2016 and were above 20 years of age at the time of diagnosis . To avoin), and as incidence rates per 100,000 persons at risk. The annual number of deceased patients was also determined. All-cause mortality was expressed as crude numbers of death and crude all-cause mortality rates per 100,000 person-years in the respective sex- and age-specific group of the population. We also calculated standardized incidence and mortality rates. Incidence and mortality data were adjusted for age using the ESP from 2013  and the mid-year population published by Hungarian Central Statistical Office , the explanatory variables were the year, age group, gender, and their paired interactions. The size of the at-risk population was determined based on the difference between mid-year population sizes and the number of previously diagnosed lung cancer patients on 1 January each year. The same method was used for incidence, prevalence, and mortality rates. The outcomes were the rates for 100,000 person-years standardized for the European population (standard ESP 2013).In all regression models mentioned above we estimated annual trends with 95% confidence intervals (95% CI). As data were not independent , a block-based bootstrap method was used for time series with a fixed block size of two.We also studied the association between smoking prevalence in the population and the incidence and mortality of lung cancer in an ecological analysis. For age-standardized incidence and mortality rates per 100,000 person-years, the source of regression analysis was the age-standardized incidence rate of lung cancer in European countries reported by Ferlay et al. and the prevalence of smoking prevalence in the population aged ≥15 years based on a WHO report from 1998 to 2002 . SignifiSD ± 9.85) and 64.9 years in women (SD ± 11.2) in 2011, which increased to 65.8 years (SD ± 9.41) and 66.0 years (SD ± 10.5)  .SD ± 10.4) to 68.0 (SD ± 9.68) years between 2011 and 2016, and was higher among females during the whole study period .The annual number of patients who died of lung cancer was between 6,045 (2011) and 6,465 (2016) during the study period . The meap = 0.028). Consequently, we did not find any significant change in incidence rates in the whole lung cancer population during the study period (p = 0.075). When applying ESP 1976, age-standardized incidence rates were 84.7 (in 2011) and 72.6 (in 2016) per 100,000 person-years in male lung cancer patients and 36.9 (in 2011) and 38.0 (in 2016) in female patients  was 115.7/100,000 person-years (95% CI: 112.3–119.1), while in 2016 it was 101.6/100.000 person-years (95% CI: 98.5–104.7), resulting in an absolute change of −13,9% . On the patients .p = 0.01) (p = 0.067). When using ESP 1976, age-standardized mortality rates were found to be 72.8–69.7 among males and 27.0–29.3 among females  of lung cancer varied between 103.8 (95% CI: 100.52–107.00) and 97.2 (95% CI: 94.12–100.25) per 100,000 person-years in men and between 38.3 (95% CI: 36.6–39.9) and 42.7 (95% CI: 41.0–44.4) in women . There w = 0.01) . We did  females .Using ESP 1976 for standardization calculations to compare our results to previously reported values for Hungary, the age-standardized incidence rate per 100,000 person-years in men was 78.3 and age-standardized mortality was 72.8 in 2012. These results are different from those reported by Ferlay et al. for European countries from the same year, 2012 (109.3 and 96.4), as seen in In the ecological study of age-standardized incidence rates of European countries in 2012 from Ferlay in relation to smoking prevalence in 1998–2002 based on WHO data, only the Hungarian incidence rate was out of the 95% predictive range as seen in Our nationwide, retrospective, longitudinal study provides comprehensive information on the epidemiology of lung cancer in Hungary using the database of the NHIF.The main findings of this large-scale evaluation can be summarized as follows:Hungarian age-standardized incidence and mortality rates of lung cancer were high but lower than those reported in earlier publications both among men and women.The age-standardized incidence of lung cancer significantly decreased in men, while we found a significant increase among women during the study period.The decreasing trend in the incidence of lung cancer in men is well-documented, which was preceded by a decreasing trend in smoking starting from the 1950s , 9. We fDifferences in trends among males vs. females could be explained by a number of factors including genetic and epigenetic differences, gender-specific lifestyle behaviors, or differences in sex hormone activity . HoweverThe mean age at the diagnosis of lung cancer was 64.7 years in 2011, which increased to 65.9 by the end of the 6-years study period. The mean age of patients at the time of death was about 2 years higher than the mean age at diagnosis, and showed an increasing trend between 2011 and 2016 (from 66.5 to 68.0 years). Our study supports previous findings showing an increase in the mean age at the time of lung cancer diagnosis , the age-standardized prevalence of smoking among Hungarian men was found to be lower in the population aged ≥15 years than in several other Eastern European as well as Balkan countries including Serbia, Romania and Montenegro . SimilarTo summarize, relevant differences can be observed between the present findings and previous reports, which could be explained by differences in data collection methodology and the high autopsy rate for hospital deaths in Hungary  leading Our study has certain strengths and limitations. The robust number of identified lung cancer patients, the carefully cleaned data, the 6-year-long follow-up period, the nationwide nature of the NHIF database all provide a solid foundation for drawing conclusions from our analysis. Nevertheless, the applied exclusion criteria may have led to the exclusion of patients who had other cancer types besides lung cancer. However, according to our estimations, the size of this patient population was not significant . MoreoveIn conclusion, our study is the first nationwide investigation which describes the incidence and mortality rates of lung cancer in Hungary, showing lower rates than those reported in previous reports which were typically based on estimations. It should be emphasized that although the incidence and mortality of lung cancer are probably lower in Hungary than previously reported, they are still very high. Our analysis also highlights the importance of using datasets of similar quality and similar methodology of estimation for international comparisons. Our study could also provide guidance on the revision and/or validation of previous reports on lung cancer in countries where lung cancer registries were not available.All datasets generated for this study are included in the manuscript/The studies involving human participants were reviewed and approved by National Ethical Board for Health Research, Hungary (10338-5/2019/EKU). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.ZK, AV, ZN-E, and ZP are employees of MSD Pharma Hungary Ltd. KH is a research fellow at Eötvös Loránd University, in employed in the framework of a joint research programme of Eötvös Loránd University and MSD Pharma Hungary Ltd. BN and ZV are employees of Eötvös Loránd University where their contribution to this project was financially compensated. KB, JM, and GO are employees of National Korányi Institute of Pulmonology. GG is employee of Oncology Center of Törökbálint. LT and VM are employees of Semmelweis University. LU is employee of Mátra Gyógyintézet. NB is employee of University of Debrecen. VS is employee of University of Pécs, where their contribution to this project was not financially compensated. GR and ZA-T are employees of RxTarget Ltd., where their contribution to this project was financially. The programme is financed by MSD Pharma Hungary Ltd.