Mycobacterium abscessus complex (MABC) lung disease.We aim to investigate the rate of spontaneous sputum conversion and reversion in patients with Among 241 patients diagnosed with MABC lung disease between July 2012 and December 2018, 126 patients with persistent sputum positivity for ≥ 6 months without treatment were enrolled at a tertiary referral center in South Korea. Patients were subdivided into two groups, depending on whether or not treatment was initiated within 2 years of diagnosis. The rates of spontaneous sputum culture conversion and reversion was investigated in patients who did not receive treatment within 2 years.Mycobacterium abscessus and Mycobacterium massiliense lung diseases. The Cox regression analysis showed that malignancy as a comorbid disease and the lower number of lobes involved were independent predictors of spontaneous sputum conversion. After spontaneous sputum conversion, reversion occurred in 27.8% patients at a median of 18.2 months after conversion.The mean age of 126 patients was 62.9 years. During a mean follow-up duration of 3.2 years, 33 (26.2%) patients received treatment within 2 years of diagnosis. Among the remaining 93 patients not receiving treatment within 2 years, spontaneous sputum conversion occurred in 24 (25.8%) patients during a mean follow-up duration of 3.7 years after diagnosis. No significant differences were observed in time to conversion between Among patients with MABC lung disease who did not receive treatment for at least 2 years after diagnosis, approximately one-fourth experienced spontaneous conversion. However, not a few patients experienced reversion after spontaneous conversion. Mycobacterium abscessus complex (MABC) is a rapidly growing mycobacterium associated with several diseases in humans, of which lung disease is the most common  for continuous variables, and numbers (%) for categorical variables. Data were compared via Student’s t-tests for continuous variables and χ2 or Fisher’s exact tests for categorical variables. All tests were two-sided and P values < 0.05 were considered statistically significant. The spontaneous conversion rates after diagnosis between the two species and radiologic types were compared using Kaplan–Meier method. The Cox regression analysis was used to calculate the adjusted hazard ratio (HR) and 95% confidence intervals (CIs) to predict spontaneous conversions. The variables used in the Cox analysis were those that had a statistical significance level of <0.05 in the univariate analysis. All data were analyzed using SPSS software .M. abscessus lung diseases and the remaining 67 had M. massiliense lung diseases. The mean age of the patients was 62.9 years, and 64.3% were female. NC-NB type was the most common radiological type that was noted in 67.5% (85/126) of patients. During a mean follow-up duration of 3.2 ± 1.7 years, 33 (26.2%) patients received treatment within 2 years of diagnosis, whereas the remaining 93 (73.8%) did not. The mean follow-up durations after diagnosis were indifferent for patients who did and who did not receive treatment within 2 years  Except for the higher rates of lung disease with cavity and radiologic type other than NC-NB in the patients who received treatment within 2 years, the clinical characteristics of the two groups were generally comparable . Among the 99 patients, one M. massiliense isolate was resistant to clarithromycin. Of the remaining 98 isolates susceptible to clarithromycin, inducible resistance was observed in 84.3% (43/51) of isolated M. abscessus strains and 6.4% (3/47) of M. massiliense strains.DST was performed for 99 patients (51 P = 0.075). M. abscessus and M. massiliense lung diseases by Kaplan–Meier analysis  of these patients during a mean follow-up duration of 3.7 ± 1.7 years, whereas the remaining 69 (74.2%) patients had persistent sputum culture positivity during a mean follow-up duration of 2.9 ± 1.6 years. For all 93 patients, sputum specimens were collected, on an average, 8.3 ± 5.7 times per patient during the follow-up period for AFB culture. Specimens were collected 6.5 ± 6.1 times for the 24 patients with spontaneous conversion and 8.9 ± 5.5 times for the 69 patients with persistent sputum positivity (P = 0.042) and the number of involved lobes  were independent predictors of spontaneous sputum conversion among these patients  patients at a median of 18.2 months  after spontaneous sputum conversion . After sIn contrast to MAC lung disease, in which spontaneous sputum conversion is known to occur in a considerable portion of patients ,17, therM. massiliense than in M. abscessus [M. abscessus is related to a functional erm(41) gene, which confers inducible macrolide resistance [The treatment of MABC lung disease is challenging because of the necessity for prolonged intravenous therapy and frequent side effects ,19. In sbscessus . The poosistance . In thisM. abscessus and M. massiliense (M. abscessus vs. M. massiliense) between the patients with spontaneous sputum conversion and those with persistent positivity  with M. abscessus lung disease underwent antibiotic treatment [M. abscessus lung diseases and 38.9% (21/54) of those with M. massiliense lung diseases [Of the 241 patients with MABC lung disease in this study, 32.4% (78/241), including 42 who received treatment within 6 months after diagnosis, 33 who received treatment within 2 years, and 3 who underwent surgical resection, received treatment for MABC lung disease within 2 years. This rate of 32.4% is lower than that shown in previous studies reported in other centers of South Korea. For example, Koh reatment . Moreovediseases  and 2006diseases  and 2011diseases , the attAmong our study subjects, malignancy and the lower number of lobes involved were independent predictors of spontaneous sputum conversion. The possible reason for the higher number of patients with spontaneous conversion who had malignancy as a comorbid disease was that the transient MABC infection that was associated with a weakened immunity owing to the malignancy itself or anti-cancer therapy  spontaneMABC manifests as two distinct phenotypic colony morphotypes: smooth and rough ,30. ConsM. bolletii from M. abscessus. However, M. bolletii is a very rare subspecies of MABC in South Korea [The present study had other several limitations of note. Most prominently, the analysis was conducted at a single referral center with a limited number of patients. Small number of patients included in the present study limited the statistical power of the analysis and the interpretation of the findings In addition, decisions regarding treatment initiation, follow-up interval, and requests for sputum examination were mainly made by the attending physician, without a pre-established protocol. Third, we did not differentiate between th Korea . Fourth,In conclusion, we found that approximately one-fourth of patients with MABC lung disease who did not receive treatment for at least 2 years after diagnosis experienced spontaneous conversion, suggesting that a watchfully waiting approach, without immediate treatment initiation, could be acceptable for some patients with MABC lung disease with a stable clinical course. However, continuous follow-up is needed for these patients because not a few patients could have reversion after spontaneous sputum conversion.S1 Table(DOCX)Click here for additional data file.


To date, there are no specific figures on the language-related characteristics of families receiving pediatric palliative care. This study aims to gain insights into the languages spoken by parents, their local language skills and the consistency of professional assessments on these aspects. Using an adapted version of the “Common European Framework of Reference for Languages”, the languages and local language skills of parents whose children were admitted to an inpatient pediatric palliative care facility (N = 114) were assessed by (a) medical staff and (b) psychosocial staff. Nearly half of the families did not speak the local language as their mother tongue. The most frequently spoken language was Turkish. Overall, the medical staff attributed better language skills to parents than the psychosocial staff did. According to them, only 27.0% of mothers and 38.5% of fathers spoke the local language at a high level while 37.8% of mothers and 34.6% of fathers had no or rudimentary language skills. The results provide important information on which languages pediatric palliative care practitioners must be prepared for. They sensitize to the fact that even within an institution there can be discrepancies between the language assessments of different professions. Communication is an integral component of health care worldwide. Looking at data on root causes for adverse events and patient harm in clinical practice, faulty communication is consistently among the top four ranks . Of all The obstacles of language barriers in pediatric palliative care have been reported by caregivers, especially in the context of accurate and complete dissemination of information ,12,13. FTo the best of our knowledge, there are no concrete numbers of language-related characteristics of parents whose children receive palliative care. However, a thorough knowledge of the languages and language skills of parents can provide a first significant insight into the cultures encountered in pediatric palliative care and thus contribute to culturally sensitive care. Therefore, this study aims to answer the following questions: (1) Which languages do families admitted to a pediatric palliative care unit speak? (2) If the local language is not spoken in the mother tongue: How good are the mother’s and father’s local language skills? Furthermore, and finally, (3) do staff members of different professions agree in their assessment of parental local language skills?The study was conducted on a pediatric palliative care unit which is affiliated to a pediatric hospital in a national conurbation of Germany. A multi-professional team annually cares for about N = 170 children and adolescents between 0–21 years with life-limiting diseases in a total of 8 patient rooms . AdditioThe following study is a full survey of all parents of children who were admitted to the pediatric palliative care unit in the year 2018. No further inclusion or exclusion criteria needed to be defined. Ethical approval was obtained by the Ethics Committee of the Children’s and Adolescents’ Hospital Datteln . It was confirmed that obtaining informed consent was not necessary as parents were only assessed by the staff during their regular stay and did not have to provide any further information about themselves or their child. Collected data was pseudonymized.A recording sheet to assess the spoken language(s) of each parent was compiled. If the parent did not speak the local language (German) as his or her mother tongue, the recording sheet furthermore assessed the parent’s local language skills. A version of the German “Common European Framework of Reference for Languages” (“Gemeinsamer Europäischer Referenzrahmen für Sprachen”) adapted by the research team was used for this purpose. The Common European Framework of Reference for Languages and its German version is divided into three superordinate competence levels which in turn can be subdivided into six language skills levels. In addition, the framework can be supplemented with intermediate levels if necessary. Each language skills level is explained by a short text describing what a specific person can do in terms of their language skills . Figure As an additional source of information, the assessment forms, which are routinely filled in by the parents when admitted to the pediatric palliative care unit, were reviewed, as they also ask for data on spoken languages.During the study period, both parents were individually assessed by the two professions once during or shortly after their child’s inpatient stay on the unit. The assessment was based on the clinical contacts with the respective parent. Obviously, parents could not be assessed if they were not present during their child’s inpatient stay. To determine to what extent staff members of different professions agree in their judgement, an assessment of (1) a member of the medical staff  and (2) a member of the psychosocial staff  was obtained for each parent. All staff members were native speakers of German .Data were descriptively analyzed. The local language skills assigned to mothers and fathers by the two professions and their respective frequencies  were determined. Each existing assessment made by the two professions was included in the analyses.The concordance between the two professions was examined at the individual person level by means of a Kappa statistic to test interrater reliability. The ranges of kappa can be interpreted as follows: <0.00 (poor), 0.0020130.20 (slight), 0.21–0.40 (fair), 0.41–0.60 (moderate), 0.61–0.80 , 0.81–1.00  . Each paIn the year 2018, N = 114 families were admitted to the pediatric palliative care unit. Of these, n = 49 (43.0%) did not speak the local language as their mother tongue. All following analyses and findings refer to this subgroup. For n = 44 (89.8%) parents an identification of spoken languages was possible, n = 4 parents spoke more than one language other than the local language .For the medical staff, an assessment of language skills was possible for n = 38 (77.6%) mothers and n = 32 (65.3%) fathers. The psychosocial staff could assess n = 37 (75.5%) mothers and n = 26 (53.1%) fathers.According to the medical staff, 36.8% of mothers and 25.0% of fathers spoke at the A Level (lowest level), 21.1% of mothers and 21.9% of fathers at the B Level (medium level) and the majority of mothers (42.1%) and the majority of fathers (53.1%) at the C Level (highest level).Overall, the psychosocial staff more frequently assigned poorer language levels to mothers and fathers. From their perspective, the majority of mothers (37.8%) and 34.6% of fathers spoke at the A Level (lowest level), 35.1% of mothers and 26.9% of fathers at the B Level (medium level) and 27.0% of mothers and the majority of fathers (38.5%) at the C Level (highest level). Considering the two extremes of the language skills levels , the medical staff attributed the A0 Level to 7.9% of mothers and 6.3% of fathers. The C2 Level was attributed to 23.7% of mothers and 31.3% of fathers. For mothers, the three most frequently assigned language skill levels were C2 (23.7%), C1 (18.4%) and A0+ (18.4%). For fathers, levels C2 (31.3%), C1 (21.9%) and B1 (12.5%) were the most common.According to the psychosocial staff, 18.9% of mothers and 15.4% of fathers spoke at the A0 Level; 16.2% of mothers and 19.2% of fathers spoke at the C2 Level. Mothers were most often assigned levels B2 (24.3%), A0 (18.9%) and C2 (16.2%). Levels C2 (19.2%), C1 (19.2%) and B2 (19.2%) were the three most common levels allocated to fathers. For 37 (75.5%) individual mothers and 26 individual (53.1%) fathers, it was possible to determine an agreement between the assessments of the medical and the psychosocial staff.κ = 0.59). When the professions coincided in their assessment, in 44.4% of the cases they jointly assigned an A-Level, in 22.2% a B-Level and in 33.3% a C-Level. Mothers, on whom the two professions disagreed, were mostly given the better competence levels by the medical staff (70%) in contrast to the psychosocial staff.For 73.0% of the mothers it revealed an agreement between the two professions. Kappa statistics confirmed a moderate agreement between the two professions . Here, the professions consistently assigned an A Level in 36.8% of cases, a B Level in 15.8% and a C Level in 47.4% of cases.Among fathers, the two professions matched in 73.1% of individual cases  who assigned the better competence levels. κ = 0.31). When assessments matched, the professions most frequently awarded the A0 Level (20.0%), the A0+ Level (20.0%) and the C2 Level (26.7%). When disagreeing, it was again mostly the medical staff who gave the better language skills levels to mothers (72.2%).The two professions agreed in 40.5% of mothers regarding their language skills levels . The agrκ = 0.36, fair; For 46.2% of fathers, the assessments of the two professions matched  collecting national and international data on languages spoken in pediatric palliative care, (b) based on these data and complementary research projects, relevant cultures in pediatric palliative care must be identified, (c) relevant characteristics and the dealing with the cultures identified should be integrated into education and training curricula for pediatric palliative care, and (d) in this context, pediatric palliative care providers need to be made aware of the different perception bias of individuals and professions.


Patients with renal replacement therapy or creatinine clearance (CrCl) of <70 mL/min had high rates of target attainment with the standard dosing regimens. There was a low number of patients with a CrCl >100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment. Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem,  Despite numerous advances in modern medicine, bacterial infections are still associated with high morbidity and mortality in intensive care units (ICUs) ,2,3. The>MICf T), and recent studies suggest targets of 100% >MICf T up to 100% >8-10xMICf T to be more appropriate for the critically ill [Beta-lactam antibiotics exhibit time-dependent antimicrobial activity above the minimal inhibitory concentration (MIC)  patients at the Department of Anaesthesiology of the University Hospital, LMU Munich, Germany. We retrospectively assessed the frequency of subtherapeutic and toxic concentrations of antibiotics in critical illness in relation to kidney function. In addition, the concentrations were examined over the course of one year to determine to what extent routine beta-lactam TDM and the experience of the attending physicians could improve the target attainment rate within the approved dosage regimens of the summary of product characteristics (SmPC) as short infusions. Furthermore, we aimed to derive dose recommendations for different sectors of renal function for both antibiotics.In total, 200 patients treated with meropenem and 89 patients treated with piperacillin were included in the present evaluation . The most frequent reasons for admission to the intensive care unit were (in descending order) lung transplantation, acute respiratory distress syndrome, and liver transplantation. The study population had a median age of 61 years (range 21–97 years), and 68.1% of the patients were male ones, which was in line with the overall patient cohort treated at our ICU. Renal function on the first day of sampling was well preserved in 196 patients without renal replacement therapy, with a median creatinine clearance (CrCl) of 90 mL/min (range 10 to 170 mL/min). The median sepsis-related organ failure assessment (SOFA) score was 12 (range 0 to 24). Detailed demographic and clinical data are given in p-value < 0.01, median 10.6 mg/L versus 11.7 mg/L). The detailed information can be found in There were 1834 TDM measurements performed for meropenem. Two samples had to be excluded from the evaluation due to incorrect sampling. For the remaining 1832 samples, 70.2% of the trough levels were obtained for the 1 g , and 29.8% of the trough levels were obtained for the 2 g (q8) dosage regime. The total median trough level was 10.9 mg/L. The target concentration of ≥8 mg/L was not reached in 39.3% of the samples, and 2.1% of the samples exceeded the toxic breakpoint of 45 mg/L. The median trough concentration for the 1 g (q8) dosing scheme was significantly lower than for the 2 g dosing scheme  or 0.5 g (q8). The rates of subtherapeutic levels in the different groups based on renal function were as follows: group 1 = 12.4%, group 2 = 11.1%, group 3 = 37.5%, and group 4 = 69.4%. The rates of toxic levels in these groups were: group 1 = 4.5%, group 2 = 7.4%, group 3 = 1.4%, and group 4 = 0.1%. Patients in group 1 had high rates of target attainment in both dosing regimens (86.2% after 1 g (q8), 93.3% after 2 g (q8)) and low rates of toxic levels (3.1% after 1 g (q8), 10.1% after 2 g (q8)). In group 2, the trough levels after 1 g meropenem (q8) were occasionally subtherapeutic (13.4%) and sparsely toxic (2.8%) in contrast to 2 g meropenem (q8), which demonstrated many toxic levels (22.1%). In group 3, high rates of target attainment were seen after 2 g meropenem (q8) (83.2%) combined with less toxic levels (3.8%). In group 4, none of the dosing regimens led to sufficient rates of target attainment (17.7% after 1 g (q8), 45.0% after 2 g (q8)). For detailed results, see r = 0.53. The correlation coefficient for 1 g meropenem was r = 0.68 and for 2 g meropenem was r = 0.58.The correlation analysis of all meropenem trough levels without renal replacement therapy combined with CrCl showed a strong correlation with p-value < 0.01, median 23.5 mg/L versus 65.9 mg/L), and the trough concentrations in q8 were also significantly lower compared to q12 . The detailed information can be found in There were 644 TDM analyses performed for piperacillin, and eight samples were excluded from the evaluation due to sampling errors. The dosing regimens of piperacillin-tazobactam as a short infusion ranged from two to four times a day. For the remaining 636 samples, 12.6% were quantified after a six-hourly (q6) period, 77.8% after a q8 period, and 9.3% after a q12 period. The total median trough level was 44.3 mg/L. The target concentration of ≥22.5 mg/L was not reached in 33.6%, and 11.0% exceeded the toxic breakpoint of 150 mg/L. The trough concentrations in q6 were significantly lower compared to q12  and the q12 dosing scheme . In group 2, the trough levels after q12 had lower rates of subtherapeutic levels (4.5%) and a low number of toxic samples (18.2%). In group 3, neither the dosing interval of q8 nor the dosing interval of q6 led to sufficient rates of target attainment (60.6% and 40.0%). Group 4 demonstrated similar results with inadequate rates of target attainment . For detailed results, see r = 0.63. The correlation coefficient for piperacillin (q6) was r = 0.56, for piperacillin (q8) was r = 0.65, and for piperacillin (q12) was r = 0.28.The correlation analysis of all piperacillin trough levels without renal replacement therapy combined with CrCl showed a strong correlation with In period 2, the total meropenem median increased from 10.5 to 11.3 mg/L, and the fraction of subtherapeutic trough levels decreased from 40.9% to 38.0%. The portion of 2 g (q8) dosages rose from 19.1% to 41.8% in period 2. Detailed information can be found in The total piperacillin median increased from 28.3 to 61.5 mg/L, and the fraction of subtherapeutic trough levels decreased from 42.4% to 26.1% in period 2. For detailed information, see Our data showed that renal function was an important influencing factor on beta-lactam antibiotic blood concentration. Dosing algorithms might be helpful in situations when routine therapeutic drug monitoring is not available or as a cost-saving measure. The main condition of a dosing algorithm was that it must be easy to implement, as it should be used in clinical practice. Such an algorithm can be found in To the best of our knowledge, this is one of the largest retrospective analyses of routine beta-lactam TDM in intensive care patients ,28,29. MOn average, 40% of meropenem samples did not achieve a sufficient trough concentration of 8 mg/L. We thought that the chosen high breakpoints for target attainment were necessary due to the high number of immunocompromised patients who underwent lung or liver transplantation and had special pathogens with higher MICs than other patients ,32. The Typically, beta-lactam dosage should be adapted based on renal function. However, there are no standardized breakpoints for dose adaption. The German SmPC, for example, recommends a dose reduction for meropenem if CrCl <50 mL/min  and for The criteria for an appropriate breakpoint of dose adaption in intensive care unit patients are high rates of target attainment and low rates of toxic levels. Therefore, we decided to use the breakpoints of CrCl <70 mL/min or renal replacement therapy (RRT), CrCl 70–100 mL/min, and CrCl >100 mL/min. Other authors in similar settings have also used different breakpoints like CrCl <50 mL/min and >100 mL/min  or CrCl We observed that up to a CrCl of <70 mL/min or renal replacement therapy, a dosage of 1 g meropenem eight-hourly as a short infusion was sufficient in the majority of cases, whereby a dosage of 2 g meropenem eight-hourly led to high rates of toxic levels (22.1% for group 2 and 10.1% for group 1) with the risk of nephrotoxicity and neurotoxicity ,44. For Augmented renal clearance is a well-known risk factor for target failure in antibiotic dosing ,45, and r-score >0.6). Patients with a CrCl <70 mL/min or renal replacement therapy had high rates of target attainment with 12-hourly dosing. In contrast, 28.2% of the patients with eight-hourly dosing and a CrCl <70 mL/min had toxic trough levels. Toxic side effects are often underestimated [Approximately one-third of all piperacillin trough samples did not reach the target. Similar to meropenem, there was also a higher risk for subtherapeutic trough levels with increasing CrCl  after initiating the TDM-program, explaining the relatively small changes. We assumed that these changes were attributable to the growing experience of the physicians with the TDM-program. Nevertheless, our results suggested that special instructions and SOPs were needed after initiating a TDM-program, especially at large ICUs with many physicians. There were limitations to the present study. Due to the retrospective setting, there were no regulations for the antibiotic TDM requests and no requirements for dose adjustment. The data set represented the true situation as it was observed in everyday clinical life in intensive care units, where several doctors often participate in the therapeutic process. Despite meticulous examination, we could not rule out that a minor proportion of falsely designated trough level samples were included in the present evaluation. Our recommendations for different dosage regimens depending on renal function were based on retrospective data. Unlimited application to other patients was not possible. Therefore, prospective data must be generated. This was a monocentric, retrospective study, investigating the appropriateness of short infusion dosage regimes of meropenem and piperacillin in ICU patients with a routine antibiotic TDM program. Clinical and laboratory parameters, including beta-lactam antibiotic serum concentrations, were documented between January and December 2018. The study was conducted in accordance with the Declaration of Helsinki, and the local Ethics Committee (registration number 18-578) approved the protocol. The study was registered at clinicaltrials.gov (NCT03985605).Patients aged ≥18 years, admitted to the ICU, treated with either meropenem or piperacillin-tazobactam, and subjected to TDM in routine clinical practice were eligible for study inclusion. Patients were only enrolled when at least three individual serum trough samples were taken in the pharmacokinetic steady state. Patients were excluded if less than three trough samples were subjected to antibiotic TDM.The dosage of meropenem and piperacillin administered was at the discretion of the treating physician with varying doses of 1 or 2 g of meropenem given 8-hourly (q8) and 4.5 g piperacillin-tazobactam given 6-, 8-, or 12-hourly , with each dose administered intravenously over 30 min (denoted as short infusion). No other dosing regimens like prolonged infusion were used due to the German SmPC and the resulting standard operating procedure at our intensive care units. Demographic data and clinical variables, such as vital parameters and weight and organ-support extracorporeal therapies, were collected from the medical record. In addition, different laboratory variables were collected from the laboratory information system. Based on these values, the sepsis-related organ failure assessment (SOFA) score was calculated on the first day of blood sampling. The creatinine clearance (CrCl) was calculated with Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) . PatientTrough levels and dosing schemes of the first half of the year after initiation of the TDM program (denoted as period 1) were compared with the second half of the year (denoted as period 2). g for 10 min. The serum supernatant was subjected to a TDM analysis with a previously published isotope dilution HPLC tandem mass spectrometry (HPLC-MS/MS) method [Meropenem and piperacillin trough blood samples were immediately transferred to the laboratory and centrifuged at 2000 ) method ,56. The >4xMICf T (>8 mg/L) due to the clinically sensible breakpoint against the pathogenic Pseudomonas spp. at 2 mg/L [>MICf T  due to the clinically sensible breakpoint against the pathogenic Pseudomonas spp. at 16 mg/L [Pseudomonas spp. was used as the reference pathogen as it is associated with high mortality in immunocompromised patients [Non-species-related  breakpoints were used as the lower limit of the therapeutic range. For the attending physicians, the target concentration for meropenem was 100% t 2 mg/L . Trough t 2 mg/L . The tar 16 mg/L . In acco 16 mg/L . Pseudompatients .Measurement results for inadequately documented drug administration or erroneously collected blood samples were excluded from the evaluation. Exclusion criteria were blood sampling during antibiotic administration and measurement despite the cessation of antibiotic therapy. Statistical analysis was performed with IBM SPSS statistics . The data set was evaluated with respect to the distribution of antibiotics trough sample concentrations for different dosage regimens, the impact of creatinine clearance on drug concentrations, and the changes during the year. Estimates of significance between different CrCl subgroups, dosage regimens, and time periods were obtained with the Mann–Whitney U-test and defined as significant by using a p-value of <0.01. The coefficient of correlation (r) was calculated using a Pearson correlation analysis.Daily therapeutic drug monitoring of meropenem and piperacillin in critically ill patients is necessary when their renal function is normal or augmented. Furthermore, a short infusion regimen is not suitable for this group. At our ICU, patients with impaired renal function or renal replacement therapy had high rates of target attainment with standard dosing; however, therapeutic drug monitoring is necessary if toxic side effects are assumed. Experience in the TDM-program leads to higher rates of target attainment in the second half of the year.


The Ga-containing BMGs still hold soft magnetic properties and exhibit large plastic strain of 1.53% in compression. Local melting during shearing produces molten droplets of several µm size throughout the fracture surface. This concept of local melting during shearing can be utilized to produce BMGs with self-healing ability. The molten regions play a vital role in deflecting shear transformation zones, thereby enhancing the mechanical properties.A new concept of soft ferromagnetic bulk metallic glass (BMG) with self-healing ability is proposed. The specific [Fe Among several bulk metallic glass (BMGs) systems, Fe-based BMGs are considered as a class of engineering materials with enormous potential for many fields of application due to their unique combination of excellent magnetic properties, good corrosion resistance, high hardness, high fracture strength, and low cost ,2,3. How36Co36B19.2Si4.8Nb4 base alloy (hereafter named FeCoBSiNb) with Ga. Since the compositional variation of the Ga content in steps of 0.1 at.% is very difficult, we considered adding Ga in steps of 0.5 at.%. In previous works, Ga was employed as a main alloying element to improve the glass-forming ability (GFA) in a few glass-forming alloy systems yσ, elastic strain yɛ, fracture strength fσ and plastic strain plɛ are almost the same as for the FeCoBSiNb parent glass, i.e., 3.95 ± 0.02 GPa, 2.80%, 4.06 ± 0.02 GPa and 0.43%, respectively. For higher amounts of Ga addition, the plastic deformation is improved. The yield stress is 3.71and 3.62 ± 0.2 GPa for the 1 and 1.5 at.% Ga-added samples and their corresponding elastic strain values are 2.73% and 3.30%, respectively. The fracture of all Ga-added samples occurs at nearly the same value of true stress, around 4 GPa, but the corresponding fracture strain is different: 3.87% for 1 at.% Ga- and 4.83% for 1.5 at.% Ga-added samples. The plastic deformation of the samples extends up to 1.07% and 1.53% for 1 at.% and 1.5 at.% Ga-added samples. The improvement in the plastic deformability of the glassy rods containing Ga can be explained based on the ordered zones observed in the TEM investigations. The dispersed ordered zones seem to be responsible for promoting plastic deformability in the Ga-containing samples, which is not observed for the Ga-free samples loaded under the same conditions. The ordered zones present in the Ga-containing samples affect the localized deformation in the glassy matrix. They may hinder shear band propagation by acting as pinning centers or by deflecting the shear bands into multiple small branches. The volume and density of these ordered zones also play a crucial role in deflecting the shear bands. If they are distributed densely in a narrow zone, then the deflection will be very less leading to brittle failure. The plasticity increase in the stress-strain curves reveals that the volume fraction and density of these ordered zones are large enough for affecting the shear band propagation through the material but not too high to cause distinct ductile failure. Sarac et al. [For the 0.5 at.% Ga-added sample, the yield strength c et al.  in theirThe fracture surface morphology of the samples after the compression tests was investigated using SEM. The fracture surface of the FeCoBSiNb and FeCoBSiNb + 0.5Ga samples consists of a number of small fracture zones and their zone planes appear to be inclined by about 70°–90° to the direction of the applied load. This kind of failure is mainly due to the simultaneous generation of a large number of small facture events at many sites, at a very high stress level close to 4.0 GPa. The high fracture strength of these glasses is mainly due to the covalent bonding nature of their constituents ,23. AlthMore interesting features are observed for the samples containing 1 and 1.5 at.% Ga. 100−x(Ga)x  alloys are ≈1310 K [ ≈1310 K  (supplem ≈1310 K  no such  ≈1310 K ,27,28. F36Co36B19.2Si4.8Nb4 glass; it improves glass-forming ability as well as plastic deformability to about 1.07% and 1.53% plastic strain for 1 and 1.5 at.% Ga addition without deteriorating the magnetic properties. Furthermore, for the first time we reported the presence of molten regions of several µm size throughout the facture surface in Fe-based BMG. Local melting at crack tips accompanied by fast cooling can be considered as a promising healing mechanism for improving industrial applications of Fe-based BMGs in many ways.In summary, we have revealed that Ga can be considered as a potential doping element for Fe


To determine the changes produced in mitral valve morphology after Percutaneous Trans-Venous Mitral Commissurotomy.Patients with mitral stenosis who underwent PTMC at the cardiology department of Lady Reading Hospital, Peshawar, Pakistan, from 2006-2016 were included in this study. All the data were manually obtained from the electronic medical record (M.F.E.). Wilkin’s echocardiographic scoring system was used to assess the severity of mitral valve thickness, leaflet mobility, valvular calcification, and Subvalvular disease. The student t-test was used for mean comparison. P-value < 0.05 was considered significant.2 to 1.78 ± 0.44 cm2 (P=0.001). Left Atrium diameter was 5.16±0.75 mm prior to PTMC, significantly decreased to 4.7± 0.7 mm (p=0.005) after PTMC. Ejection fraction (Left Ventricular Ejection Fraction) changed from 60.45± 8.25 mm Hg to 62.76±10 mm Hg (p=0.001). Mean Right Ventricular Ejection Fraction (RVEF) of patients before PTMC was 48.7 ± 4.7%, did not change significantly immediately after PTMC.Of the total 229 patients, males were 96(41.9%), and females were 133(58.1%). The mean [SD] age of the patients was 25 ± 11years. The total Wilkin score was 7 ±1.5. 151(65.9%) were in New York Heart Association (NYHA) functional class III, and 78(34.1%) were in NYHA class IV. There was no immediate change after PTMC in systolic myocardial velocities (SV) measured at the lateral tricuspid annulus. The 2D mitral valve area increased from 0.98±0.94 cmPTMC is associated with significant changes in mitral valve morphology in terms of splitting of the fused mitral commissures, increased MVA, improved leaflet excursion, and splitting of the subvalvular structures. One of the most well-known cardiac complications of rheumatic fever is mitral stenosis. Rheumatic heart disease (RHD) is still quite common in the world. The prevalence of the disease was estimated to about 33million cases worldwide with mortality of 275,000 cases annually by the global burden of disease in 2013.4Percutaneous Transvenous Mitral Commissurotomy (PTMC) started as a new technique that enabled the mitral valve commissurotomy without the need for thoracotomy in 1984 by a Japanese cardiologist Kanji Inoue. It is being used as an alternative to thoracotomy in the treatment of mitral stenosis throughout the world.8An increase in the passion for minimally invasive procedures has aided in broadening the spectrum of PTMC where the procedure has now been tried in patients who were not the usual candidates for PTMC and with otherwise a higher risk of surgical intervention, including patients with mitral stenosis secondary to calcified mitral valves and elderly patients.10The candidates are selected for PTMC via echocardiography as an assessment tool for the mitral valve and its various dimensions. The immediate outcomes of this study show, along with the clinical examination, the Echocardiographic score was important in selecting patients for a successful outcome.A total of 229 patients with mitral stenosis who went through Percutaneous trans-venous mitral commissurotomy (PTMC) in the Department of cardiology in Lady Reading hospital, Pakistan, from 2006-2016 were included in this retrospective cross-sectional study. Patients with rheumatic heart disease, both genders and mitral stenosis were included while all those were excluded who had mitral stenosis other that rheumatic heart disease. Data was reclaimed from the electronic medical record, including demographic characteristics, symptoms, medications, comorbidities, echocardiographic data, cardiac catheterization data, and subsequent clinical outcomes after PTMC.All the patients had a thorough clinical and echocardiographic  evaluation to gauge the severity of mitral stenosis, the morphology of the valve, and mitral regurgitation (MR). Wilkin’s echocardiographic scoring system2D-echocardiography estimated the Mitral valve area with polarimetry in the parasternal short-axis view utilizing the standard technique. Trans-esophageal echocardiography (TEE) was routinely performed before Balloon Mitral Valvuloplasty (BMV) in all patients included in the study. Transthoracic echocardiogram was performed multiple times, firstly during BMV, then 24 hours after the procedure, and then at follow-up visits. The contraindications were Mitral Regurgitation of Seller’s grade more than 2. A thrombus in the left atrium detected on the transthoracic echocardiography performed before PTMC and having extensive commissural calcification. All patients had been administered antibiotic cover before the procedure, and all had been heparinized after septal dilatation. Instantly before and after PTMC, the right and left heart pressures along with the mean trans-mitral pressure gradient (TMG) were measured. Left ventricular (LV) angiogram in the 30° right anterior oblique view was completed before the procedure in all patients suspected to have more than mild mitral regurgitation. The Institutional Review Boards and Ethical Committees of the hospital approved the study protocol and related materials (Ref: 05/IRB/PGMI/LRH-2019)Statistical analysis was performed via SPSS software version 22. The continuous variables were measured as mean ± standard deviation (SD). The comparison of means between the two groups was made using the independent student t-test was used. P-value < 0.05 was considered significant.Out of 229 patients, males were 96(41.9%), and females were 133(58.1%). The mean [SD] age of the patients was 25 ± 11years. A female predominance was observed in this study with a female to male ratio of 1.38:1. Total Wilkin score [SD] was 7 ±1.5. About 151(65.9%) were in NYHA functional class III, and 78(34.1%) were in NYHA class IV. The patient’s baseline characteristic is shown in 2 to 1.78 ± 0.44 cm2 (P<0.001). A dangerous descent in the systolic pulmonary artery pressure was observed after PTMC from 61.47 ± 8.97 mm Hg to 46.94 ± 11.22 mm Hg (p<0.001). Left Atrium diameter was 5.16 ± 0.75 mm prior to PTMC, and significantly decreased to 4.7± 0.7 mm (p=0.005) after PTMC. Ejection fraction (LVEF) changed from 60.45± 8.25 mm Hg to 62.76±10 mm Hg (p=0.001). All the changes that occurred after PTMC are shown in In the follow-up, on two-dimensional echocardiography, the mitral value area considerably increased from 0.98±0.94 cmThere was no significant change in the myocardial acceleration during isovolumic contraction (IVA) and myocardial velocity during isovolumic contraction . There was no immediate change after PTMC in systolic myocardial velocities (SV) measured at the lateral tricuspid annulus. One patient had a successful replacement of the mitral valve due to mitral regurgitation after PTMC. two of the patients developed ischemic cerebrovascular accidents secondary to systemic embolization.In the developing world, the most common cause of mitral valve stenosis is rheumatic heart disease.In this study the procedural success was achieved in all the patients’ almost similar findings by Liaqat Ali et al. 52 44 cm2, almost similar finding by Nawaz T & Noor A et al.  from 27.20 to 12.88. A study from Punjab Institute of cardiology by Ahmad A et al.2 in patients with Echo-Sc<8. In agreement with the available data.24This study shows that PTMC creates significant morphological and hemodynamic changes in the mitral valve. Our study established the positive instant results of PTMC in terms of a significant increase in Mitral Valve Area 0.98 ± 0.94 to 1.78 ± 0.44 cmA statistically significant increase in the mitral valve area and decrease in mean left atrium pressure after the procedure was achieved which was again comparable to other studies.Although PTMC is a minimally invasive procedure, there is a number factor, which affects a successful outcome, including valve morphology, the Wilkin score. PTMC is a reasonably safe procedure with a very low rate of complication, albeit, it comprises a daunting list including stroke, cardiac tamponade, procedure-related death, and regurgitation of the mitral valve (MR> 2+).24Being a retrospective study, it is mostly based on the hospital database; a follow-up study could not be included in the study. Hence, further studies regarding prospective study and follow up are recommended.PTMC is associated with significant changes in mitral valve morphology in terms of splitting of the fused mitral commissures, increased MVA, improved leaflet excursion, and splitting of the subvalvular structures. The improvement in leaflet excursion after PTMC is determined by several morphologic and hemodynamic changes produced in the valve. The increase in MVA improves leaflet mobility within the limit.Adnan Khan and he also did the data analysis.The topic was conceived by MJ, ZH, IS: did the manuscript writing and the data entry.AK: did the final approval of the article and accountable for the accuracy or integrity of the work.


Stroke contributes to a significant proportion of deaths and disability worldwide, with a high fatality rate within 30 days following a first ever stroke. We describe the outcomes within one year among patients who succumbed a first ever stroke and survived the first 30 days.Participants were patients who survived after 30 days from succumbing a first ever stroke admitted at the Muhimbili University of Health and Allied Sciences Academic Medical Center. Stroke survivors or their next of kin were contacted at one year after succumbing a first stroke to determine the outcomes. We assessed participants’ vital status and level of disability using the modified Rankin scale. Assessment on utilization of stroke secondary preventive measures among survivors was done by an interviewer-based questionnaire that assessed the number of times participants attended follow up clinics, medication refill and adherence. Participants were examined for waist-hip ratio, body mass index and blood pressure. Cholesterol levels were assessed at one year post first stroke for survivors. Outcomes were summarized as proportions, survival at one year was estimated by using the Kaplan Meier analysis and Cox regression analysis was performed to determine for predictors of mortality.We recruited 130 first stroke survivors. Mortality within one year was 53/130 (40.8%) and disability rate measured by Modified Rankin Scale with scores of 3–5 was 29/77 (37.7%) among survivors. Factors associated with mortality were residual disability HR = 8.60, {95% CI (1.16–63.96)}, severe stroke, HR = 2.67 {95% CI (1.44–4.95)} and residing in Dar-es-Salaam HR = 2.15 {95% (CI 1.06–4.36)}. Non-adherence rates to antihypertensives, antiplatelets and statins was 11/73 (15.1%), 9/23 (39.1%) and 18/22 (81.8%) respectively. Attendance rates of follow-up clinics among all survivors and physiotherapy among survivors with disability are 45/77 (58.4%) and 16/29 (55.2%) respectively.The mortality and disability rates within a year following a first ever stroke among 30 days stroke survivors is high. Secondary stroke preventive measures should be enhanced to mitigate stroke adverse outcomes. Community outreach programs could be useful interventions in preventing the adverse outcomes of stroke. Globally there were 13.7 million new stroke cases for the year 2016 . HospitaModifiable risk factors such as hypertension, diabetes mellitus, obesity, dyslipidemia, cigarette smoking, alcohol consumption, psychosocial stress and rheumatic mitral stenosis  have conThe outcomes of stroke are either death or survival , 7. SurvStroke accounted for 5.5 million deaths and was the second leading cause of death globally in 2016  and 50% Globally stroke led to 116.4 million disability adjusted life years (DALYs) in the year 2016  whereas This cohort study enrolled patients who survived after 30 days from succumbing a first ever stroke admitted at Muhimbili University of Health and Allied Sciences Academic Medical Center (MAMC) between June 2018 to January 2019 at a year post stroke. MAMC is a specialized hospital that receives walk in and referral patients from all over the country. The hospital offers medical care in several disciplines including neurology and neurosurgery.2, normal 18.5–24.9Kg/m 2, overweight 25–29.9Kg/m2 or obese ≥ 30Kg/m2. Blood pressure was measured in sitting position using an automated sphygmomanometer MICROLIFE™. Hypertension was defined as systolic blood pressure ≥ 140mmHg and/ or diastolic blood pressure of ≥ 90mmHg [The investigator (KM) and co-investigator (SM) identified 136 patients out of the 369 patients who survived after 30 days post first ever stroke who were admitted at MAMC between June 2018 and January 2019. There were 233 patients who died within 30 days from first ever stroke  leaving ≥ 90mmHg , 18 thatEach participant’s baseline information including: the first ever stroke subtype, severity, disability status, clinical and laboratory findings during the first stroke were obtained from a study specific data set .First stroke subtype was confirmed using brain imaging by either a non-contrast Computerized Tomography (CT) scan model GE Healthcare Optima CT660 SE, or Magnetic Resonance Imaging (MRI) model GE SIGNA CREATOR 1.5 TESLA . Stroke Disability at one year was assessed using the Modified Rankin Scale (mRS) . We haveEthical clearance was obtained from Muhimbili University of Health and Allied Science institutional review board approval reference number DA.287/298/01A/. Written informed consent was obtained from all study participants or their next of kin prior to enrollment, including consent to HIV testing. Participants who were found to have uncontrolled cardiovascular risk factors were counselled and treated according to standard treatment guidelines.Data analysis was performed using SPSS version 23.0. The outcomes of stroke were summarized as proportions. Survival at one year for stroke participants was estimated using Kaplan Meir analysis. Comparison in differences in survival at one year by age groups, stroke subtype and severity was computed by Log rank test. Cox regression method was performed to assess for predictors of mortality at one year, variables with a p value <0.2 in univariate analysis were entered in to the multivariate analysis model and a p value <0.05 was considered as statistically significant.A total of 136 patients survived for 30 days following a first ever stroke. At one year of follow up, we were able to contact 130 (95.6%) survivors or their next of kin, six (4.4%) patients and their next of kin were not reachable by phone and were excluded. Of the 130 evaluable participants, males and females were 47(36.2%) and 83(63.8%) respectively. There were 53/130 (40.8%) who died within one year of succumbing a stroke, as shown in The mean age and standard deviation of the 130 first ever stroke survivors was 54 ± 16 years. The mean age for the 53 participants who died within one year was 57 ± 17 years while mean age for the 77 participants who survived up to one year was 51 ± 14 years. A significant proportion of participants who died within a year of succumbing a stroke were aged > 45 years 37/74 (50%) vs 16/56 (28.6%) p = 0.014 and had informal employment 44/92(41.1%) vs 1/15(6.7%), p = 0.01 as summarized in Majority of participants had moderate to severe disability at baseline, 112/130 (86.2%). Among 53 participants who died, 48 participants could perform brain CT scan during admission for the first ever stroke and there were 34(70.8%) who had ischemic stroke while 9(18.8%) had hemorrhagic stroke. A higher proportion of participants with severe stroke at baseline died within one year as compared to those who survived , p value < 0.001. Other clinical characteristics are presented in Participants who were 45 years or below were more likely to survive at 1 year following a stroke, {HR: 1.8, (95% CI 1.06–3.22)} compared to participants above 45 years, {HR: 0.54, (95% CI 0.31–0.95)}, p = 0.031, as illustrated in Predictors of mortality included: severe stroke, {HR: 2.67, }, presence of disability at 30 days after first stroke, {HR: 8.60, (95% CI: 1.16–63.96)} and residing in Dar-es-Salaam region, {HR: 2.15, (95% CI: 1.06–4.36)} .At one year, 29/77(37.7%) participants who survived had moderate to severe disability with mRS scores of 3–5 while 48/77(62.3%) survived with mild disability with mRS score of less than 3. Among participants with moderate to severe disability, 14/29 (48.3%) had moderate disability (mRS = 3) and 15/29 (52.7%) had severe disability (mRS = 4–5). There were 28/29 (97%) of participants with moderate to severe disability who were unable to resume to work.Among one year first stroke survivors, non-adherence rates to antihypertensive, antiplatelet and statins medications were 11/73 (15.1%), 9/23 (39.1%) and 18/22 (81.8%) respectively. Among 29 patients who recovered with moderate and severe disability at one year, 13 (44.8%) had not undergone any physiotherapy .Of the 77 stroke survivors at one year, 32 (41.6%) lacked knowledge that stroke could recur and 75 (97.4%) were hypertensive. Blood pressure measurements were obtained in 73/75(97.3%) participants, two participants could not get to MAMC and nearby health centers did not have functioning blood pressure machines. Among the 73 participants, 47(64.4%) had uncontrolled hypertension, with mean and standard deviation of 159.1 ± 19.6mmHg for systolic blood pressure and 102 ± 12.2mmHg for diastolic blood pressure.A total of 56/70 (80%) had higher than normal waist hip ratio with a mean waist hip ratio and standard deviation of 0.97 ± 0.14. Among the 70 participants who had waist hip ratio measured, 22 were male and 48 were female, 17/22 and 39/48 had abdominal obesity with waist hip ratios and standard deviations of 0.94 ± 0.09 and 0.94 ± 0.15 for males and females respectively.BMI was computed for 44 participants others could not have this measurement as they were disabled or were from upcountry and could not get to nearby centers where weight and height could be measured. Out of the 44 participants 18(40.9%) were obese and 17(38.6%) were overweight.Total cholesterol levels were above normal in 22/56 (39.3%) We followed up first ever stroke patients who survived the first thirty days of succumbing a stroke and observed a high mortality rate of 40.8% within a year. Mortality was linked with a severe stroke, presence of moderate to severe disability at 30 days, and residing in Dar-es-Salaam.In this study we observed that, patients with baseline moderate to severe disability had a nine fold increased risk of dying within a year of first ever stroke compared to patients with mild disability. Patients with severe stroke experience worse disability that results in loss of function with risk of complications such as aspiration, deep vein thrombosis, pressure sores and depression that increase the mortality risk , 22.Patients with disability may have further neurological worsening, comorbidities or complications that may not be easily noticed by their caregivers that could contribute to death as a result of delayed health care seeking.Severe disability is linked to depression and reduced motivation that may result into reduced adherence of post stroke management plans eventually predisposing patients with disability to death . Stroke We observed a relatively lower prevalence of disability from stroke compared to what was observed more than a decade ago in northern Tanzania, (37.7% vs 46.5%) . This coIn this study 97% of the patients with disability were unable to return to work out of which a third would be considered to be in the prime time of building the economy as they were aged 45 years or less.In this study patients with disability were unable to attend for physiotherapy sessions due to lack of finances to pay for transportation and consultation for the services and lack of care takers to assist the patient. Stroke and its associated disability management depend on a multidisciplinary team approach. Outreach services and home-based care could be important approaches in reducing patient costs, improving function for patients with disability, assessment and management of comorbidities and overall reduction in mortality.Mortality within a year of stroke was twice as high for participants residing in Dar-es-Salaam, an urban city in Tanzania compared to residents from upcountry. This is surprising based on the fact that Dar-es-Salaam has a relatively higher number of health care facilities that are better equipped with staff, equipment and services compared to the rest of the country. The low socio-economic status among the study participants could have contributed to delayed access to health care and observed mortality based on the fact that; 83% of our participants were informally employed, were more likely to be the income generators for the family and therefore lacked financial sustainability, and two thirds did not have health insurance. Out of pocket payment for health services hinders timely health seeking behavior for stroke survivors . InteresAge above 45 years and severe stroke inversely correlated with one year survival following a first ever stroke as was observed in both low, middle and high countries , 31. PatMore than a half of our study participants had uncontrolled hypertension, were overweight or obese or had abnormal waist hip ratio measurements. This could be due to lack of adherence for medications for hypertension, lipid abnormalities and antiplatelets. More than a third of participants were not attending follow up clinics regularly and this led to high levels of uncontrolled blood pressure levels due to lack of proper monitoring and dose adjustments for antihypertensive medications. In low and middle income countries similar challenges are experienced in controlling stroke risk factors where in South Africa only 8% of stroke survivors were adhering to antihypertensive medications and only about half were taking antiplatelets at 3 months follow up after stroke. Reasons for non-adherence in these studies are lack of knowledge about hypertension being a chronic condition, costs for medications and lack of physical assistance to reach health care facilities and alcohol abuse , 34.More than a third of the study participants or their care takers were unaware that stroke could recur, lack of knowledge could contribute towards delay in timely health seeking behavior and adherence to medications. The barriers to utilization of secondary stroke prophylaxis and adherence to statins, antiplatelets, antihypertensives and attendance to follow up clinics and physiotherapy services among the participants were financial constraints and long distance to health care services. There should be proper counselling to stroke patients and their caretakers on adverse outcomes of stroke like recurrence and death. Proper adherence to the measures for control of cardiovascular risk factors to eliminate the outcomes should be emphasized by health care workers through health education.The cost and long distance incurred by the patients can be mitigated if tertiary hospitals provide outreach services and build capacity of primary health centers to provide rehabilitation services and long term management of stroke patients. Caretakers could also be trained on how to provide physiotherapy especially for patients who have disability and are unable to obtain transportation to a health care facility.The estimate of disability could be underestimated due to the fact that we could not obtain data from participants who died as a result of severe disability. Likewise, we were unable to obtain information on utilization of secondary preventive measures for patients who died therefore limiting the ability to ascertain if these factors were associated with mortality.Mortality and disability rates within a year after sustaining first ever stroke is high. Severe stroke and presence of disability contributed to the high mortality. Financial constraints were a reason for patients’ limitation for follow up clinics and rehabilitation services. Availability of outreach and home based care services are alternative measures for monitoring and managing patients with disability and ultimate reduction in mortality.


Backgroundp16 is a tumor suppressor gene, over expression of which is considered as a surrogate marker of oncogenic human papillomavirus (HPV) infection. Moreover, p16 over expression correlates with good prognosis in head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to evaluate the frequency of p16 overexpression in HNSCC in our setup and its association with clinicopathologic parameters.MethodsWe performed p16 immunohistochemistry (IHC) on 144 cases of HNSCC. Association of p16 overexpression with various clinicopathologic parameters including T-stage, N-stage, grade, recurrence status, and risk factors was evaluated.Resultsp16 over expression was noted in 22.9% (33 cases), while 21.5% (31 cases) were focal positive and 55.6% (80 cases) were negative for p16 over expression. On the basis of percentage of expression; > 70% p16 expression was noted in 4.9% (7 cases), 9% (13 cases) showed 51% - 70% p16 expression, 9% (13 cases) revealed 11%-50% p16 expression, while 77.1% cases revealed no expression or < 10% p16 expression. Significant association of p16 expression was noted with nodal metastasis and extranodal spread while no significant association of p16 was noted with other prognostic parameters and risk factors.ConclusionOur data revealed that high expression (> 50%) of p16 is low in oropharyngeal squamous cell carcinoma in our setup. These finding suggest a low prevalence of HPV as a cause of HNSCC in our population. Moreover, p16 expression was found to be associated with some good prognostic parameters like lack of nodal metastasis, however, no significant association was noted with overall disease-free survival.  Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is the significant cause of morbidity and mortality -3. Tradip16 is a tumor suppression gene, inactivation of which is considered as the major oncogenic event in the carcinogenesis of OSCC. Over expression of p16 is strongly associated with HPV infection and therefore immunohistochemical expression of p16 is considered as a surrogate marker of oncogenic HPV infection -11. MoreThe study was carried out at the Liaquat National Hospital, Karachi from January 2008 till December 2013. During this period of seven years, 144 patients who had surgeries for HNSCC were included in the study. An approval for conducting this study was taken from institutional ethical review and research committee. Informed written consent was taken from the patients prior to surgery. Hematoxylin and eosin stained slides of these cases were retrieved and independently re-evaluated by two surgical pathologists and pathological findings like tumor type and grade, tumor and nodal stage, perineural and lymphovascular invasion. History of addiction was recorded from hospital archives and last follow up was recorded. These clinical records were only available in 57 cases. Moreover, p16 immunohistochemistry (IHC) was performed on the representative tissue blocks of all cases.p16 antibody was purchased from Roche Ventana  and IHC was performed using antibody CINtec R p16INK4a, clone E6H4TM according to the manufacturers protocol. Tonsils and carcinoma cervix was taken as positive controls. Both nuclear and cytoplasmic staining was considered. Intensity of staining was divided into no staining (0), weak (1+), intermediate (2+), and strong (3+). On the other hand, the percentage of positively stained cancer cells was calculated as continuous variable. Intermediate to strong staining in >10% cancer cells was taken as positive while weak to intermediate staining in <10% cancer cells was considered focal positive  was used for data entry and analysis. Mean and standard deviation were calculated for categorical variables. Frequency and percentage were evaluated for qualitative variables. Chi-square was applied to determine association. Survival curves were plotted using Kaplan- Meier method and the significance of difference between survival curves were determined using log-rank ratio. P-value of ≤0.05 was taken as significant.Patients mean age was 51.28+12.14 with 45.8% patients above 50 years. History of addiction especially pan/gutka was noted in 59.6% cases. Most common site of tumor was oral cavity (66.7%). 24.3% cases were at T1 stage, while 52.8% cases were found to be at N0 stage; 59% cases were keratinizing and 27% cases were of grade I. Lymphovascular and perineural invasion was noted in 1.4% and 13.9% cases, respectively and 56.9% of cases recurred after primary surgery as shown in Table p16 over expression was noted in 22.9% (33 cases), while 21.5% (31 cases) were focal positive and 55.6% (80 cases) were negative for p16 over expression. On the basis of percentage of expression; > 70% p16 expression was noted in 4.9% (7 cases), 9% (13 cases) showed 51% - 70% p16 expression, 9% (13 cases) revealed 11%- 50% p16 expression, while 77.1% cases revealed no expression or < 10% p16 expression. Significant association of p16 expression was noted with nodal metastasis and extranodal spread while no significant association of p16 was noted with other prognostic parameters and risk factors as shown in Table Similarly, no significant association was noted with recurrence status of the patients as presented in Figure In the present study, we evaluated p16 expression in HNSCC, as it is considered as the marker of HPV infection. Overall, p16 expression was 22.9% while high p16 expression i.e. 51% -70% and >70% expression was noted in only 9% and 4.9% cases, respectively.Literature review revealed that p16 over expression strongly correlates with HPV infection. In a recent study, the authors compared the results of HPV-16 in situ hybridization and p16 IHC in 256 cases of HNSCC; 71.2% cases were HPV-16 positive and all cases showed p16 staining. They reported sensitivity, specificity, positive predictive value, and negative predictive value of p16 in relation to HPV infection as 100%, 74%, 9%, and 100%, respectively . It is nVarious studies evaluated impact of p16 expression in HNSCC along with its association with prognostic and pathological parameters. A meta-analysis found that p16 expression was associated with better clinical outcome and good prognostic factors including low risk of nodal metastasis . Among oThe major limitation of the study was that molecular studies were not performed to correlate IHC expression with the presence of HPV strains in cases of HNSCC; therefore, we recommend molecular testing of HPV in cases of HNCC especially in those with high p16 expression.Our data revealed that high expression (> 50%) of p16 is low in OSCC in our setup. These finding suggest a low prevalence of HPV as a cause of OSCC in our population. Moreover, p16 expression was found to be associated with some good prognostic parameters like lack of nodal metastasis; however, no significant association was noted with overall disease-free survival.


Patients with BMI lower than 25 had an ORR of 28.5% (p = 0.003), whereas patients with BMI higher than 25 had an ORR of 42.3% (p = 0.002). Patients who gained weight during treatment had a lower probability of having progressive disease , as did patients with creatinine higher than 0.9 (OR = 0.39 [95% CI: 0.13–1.14]). No superiority was found in progression-free survival (PFS) when patients were dichotomized for BMI = 25 or BMI = 18.5. Mean PFS in the BMI under 18.5 group was 10.2 months [95% CI: 5.8–23.1], versus 11.2 for BMI over 18.5 [95% CI: 5.3–25.3], p < 0.03. Mean PFS for the BMI under 25 was 11.2 months [95% CI: 7.2–20.1], vs. 13.3 months [95% CI: 6.4–22] for the BMI over 25, p < 0.001. There were also differences in PFS in the patients with baseline creatinine over 0.9 when compared with under 0.9 values. Mean PFS in the first group was 19.78 months [95% CI: 16.23–22.9] vs. 16.1 [95% CI: 12.2–20.3], p < 0.001. Patients treated with nivolumab who have weight gain during treatment have a better PFS than the ones who do not. Creatinine levels of over 0.9 at treatment initiation also have positive predictive value.Literature suggests that high body mass index can be correlated with better response to immune checkpoint inhibitors. On the other hand, sarcopenia seems to be a negative predictive marker. The present analysis is a retrospective, multicenter trial that included patients with metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma treated with nivolumab between 2018 and 2020. Patients were stratified by creatinine levels both at treatment initiation and at first follow-up (at three months) and by BMI for the same intervals, as recorded in the patients’ charts. Creatinine was considered a surrogate marker for sarcopenia. IBM SPSS version 20 was used for statistical analysis. A total of 57 (n = 57) patients were included in the trial. Overall response rate (ORR) for the entire population was 38.59% ( Nivolumab, an anti-Programmed-Death-1 (PD-1) antibody has brought considerable benefit in the treatment of melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma. Selecting patients for this treatment is still a challenge. The most studied predictive biomarkers for response to checkpoint inhibitors include tumor mutational load, PD-1 expression, CD4/CD8 lymphocyte ratio, the percentage of tumor-infiltrating lymphocytes, and several methods of establishing immune scores ,3.However, selecting patients by basic characteristics remains an acceptable alternative, but the efficacy of such a selection still must be demonstrated. The obesity paradox, for example, is an interesting concept recently described for immunotherapy. It seems that overweight and obese patients have a better response to nivolumab when compared to normal-weight patients ,5. CacheThe central idea of the present paper is to establish whether sarcopenia, indirectly measured through creatinine levels or nutritional status may serve as predictive factors for nivolumab efficacy. All in all, it seems that response to immunotherapy is more feasible before neoplastic disease consumes most of the system resources.A total of 57 (n = 57) patients were included in the trial. The characteristics of the patients were described in p = 0.02). Patients with BMI lower than 25 had an ORR of 28.5% (p = 0.003), whereas patients with BMI higher than 25 had an ORR of 42.3% (p = 0.002). Normal BMI patients were the most prone to weight gain, 8 out of 26 patients (30.7%). Patients with weight gain between the first and the follow-up assessment had the best ORR of 51.2% (p = 0.0042), closely followed by the patients with creatinine values higher than 0.9 mg/dL, where the ORR was 48.9% (p = 0.001). Progression-free survival was also superior in these two groups, so patients who gained weight had a lower probability of progressive disease , as did patients with creatinine higher than 0.9 (OR = 0.39 [95% CI: 0.13–1.14]).The overall response rate (ORR) for the entire population was 38.59%  have default lower creatinine levels was also taken into consideration when choosing the creatinine cut-off value ,9.Creatinine values indirectly related to sarcopenia are subject to debate. The literature proposes both 0.7 mg/dL and 0.9 mg/dL values . The autIt was demonstrated that patients with lower muscle mass had weaker immune responses. This is mainly due to the relationship between muscle proteins and leucocyte function . GlutamiIn the present analysis, no superiority in PFS was found when stratifying either for BMI = 18.5 or BMI = 25, but the largest proportion of patients were overweight or obese. The capacity of the analysis to evaluate the PFS differences was also lower due to the uneven number of female vs. male patients.Inequity in weight groups was reported in other studies, too. The predominance of overweight and obese patients in patients with melanoma or NSCLC was usually described in the literature, with around 60% being reported in this category.The hypothesis that weight gain is a positive prognostic and predictive factor is not new either, with the same concept demonstrated in relation to chemotherapy. This was demonstrated for some other tumors as well ,15,16.A linear correlation was found in a retrospective trial between BMI rise and outcome  in melanoma patients treated with either checkpoint inhibitors or targeted therapy. This benefit was maintained even in morbidly obese patients .The fact that all the patients were treated with fixed doses of nivolumab excludes the possibility that the different outcomes were explained by dosage per kg; the authors consider this a positive aspect of the present analysis.The connection between adipose tissue and immune processes was described in recent literature, and it is well known that fatty tissue can help maintain immune response. Some of the processes that explain this link are the activation of T regulatory cells through adiponectin, maintaining the balance between Th1 and Th2 cells, and the implication of the adipose cell in the CD20 pathway ,18.Some argue that adipose tissue can serve as a pool of memory T cells by offering them a useful microenvironment after an infectious process, for example. Even if these cells can accumulate, there is no certainty that they remain efficient after a period of inactivity .One trial that included obese mice demonstrated that exhausted T reg cells were present in large numbers in these populations. Paradoxically, these T reg cells can be brought back to activity by stimulating the pathway that includes the PD-1 receptor, the exact target of nivolumab . This isThe present trial is an observational, retrospective one that included patients who received nivolumab for metastatic melanoma, renal carcinoma or NSCLC between 2018 and 2020 in 3 centers in Romania: Elias University Emergency Hospital in Bucharest, County Clinical Emergency Hospital of Constanta, and Al. Trestioreanu Institute of Oncology in Bucharest. The present paper gained approval of the Ethics Committee of Elias University Emergency Hospital, reference no. 1/26th May 2020.Prior kidney disease was an exclusion criterion. The trial focused on creatinine levels both at treatment initiation and at first follow-up (at three months) and on the BMI (body mass index) of the patients for the same intervals, as recorded in the patients’ charts. BMI was calculated with the following dedicated formula:p-value was calculated using log-rank test.Patients who had a BMI lower than 18.5 were classified as underweight, between 18.5 and 24.9 as normal and over 25 as overweight and obese. Then, they were dichotomized into BMI under/over 18.5 and under/over 25. A cut-off for the levels of creatinine was established at 0.9 mg/dL and the levels were recorded at the same intervals as for BMI. Progression-free survival was the primary endpoint of the trial, and this was defined as time to lack of clinical benefit or death, whichever came first. BMI and creatinine were the primary variables by which progression-free survival (PFS) was assessed and compared. The Kaplan–Meier method was used for this purpose; the Other used variables included age, gender, ECOG performance status, treatment line, and best response  on first follow-up imaging, partial response, or progressive disease). All patients were radiologically evaluated after 3 or 4 months of nivolumab treatment. ORRs  were established after consulting these imagistic reports. ORR was defined as the percentage of patients who had any reduction in tumor volume during the follow-up time. To establish whether the patient had progressive disease or not, the treating physician gathered and analyzed all the information . Progressive disease was decided in a multidisciplinary board. Data regarding these variables were collected from the patients’ individual reports. All patients received fixed doses of treatment, either nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks (in the case of some melanoma patients). Statistical analysis was done using IMB SPSS version 20.This trial demonstrated that patients treated with nivolumab who have weight gain during treatment have better PFS than those who do not. Creatinine levels of over 0.9 at treatment initiation can also have positive predictive value. These findings would be very easy to follow in daily clinical activity, but they need validation in larger, prospective trials.


MTNR1A) SNP (rs13140012) in end-stage renal disease patients (ESRD) in Alexandria, Egypt on maintenance hemodialysis with or without atherosclerosis.To study the relationship between melatonin levels and Melatonin membrane receptor 1A (MTNR1A) SNP (rs13140012) genotyping was done using 5'nuclease Allelic discrimination.40 end-stage renal disease patients on regular hemodialysis were divided into 2 subgroups, one with (n = 20) and one without atherosclerosis (n = 20) and normal subjects (n = 40). Serum melatonin, carotid intimal medial thickness (CIMT) were measured. Melatonin membrane receptor 1A (MTNR1A) SNP (rs13140012) (p = 0.633).Serum melatonin was significantly lower in ESRD patients [1.6 to 11.30 (pg/mL) with a median of 2.5] than the control group [20.50 to 56.40 (pg/mL) with a median of 35.20]. Serum melatonin was significantly lower in atherosclerotic patients subgroup [1.6–2.50 (pg/mL) with a median value of 2.30] than non-atherosclerotic patients subgroup [2.0–11.30 (pg/mL) with a median of 4.9]. No significant association was found between serum melatonin and (These results lead us to suggest that melatonin production is impaired in ESRD patients (included in this pilot study), and this impairment is more evident in atherosclerotic ESRD patients. Health sciences; Renal system; Internal medicine; Endocrinology; Clinical research; Diagnostics; Melatonin; Single nucleotide polymorphism (SNP); rs13140012; Atherosclerosis; End-stage renal disease (ESRD); Hemodialysis (HD); Carotid intima-media thickness (CIMT) The pinMelatonin has antioxidant and scavenging effects independent of its receptors . MelatonMelatonin receptors are G protein coupler receptors and are expressed in different parts of the CNS besides peripheral organs, including blood vessels, mammary glands, GIT, liver, kidney, and the immune system , 7.The chronic state of kidney disease can be defined as an abnormality in either structure or function that has persisted for over three months, with an impact on the patient's general condition .Progression from CKD to ESRD is an important clinical event that affects over 1500 people per million population in countries like Japan, Taiwan, and the US, with approximately two-thirds of them requiring hemodialysis, a quarter undergoes kidney transplantation, and only one-tenth go through peritoneal dialysis . ESRD isCardiovascular disease is a principal cause of mortality and morbidity in patients on hemodialysis, with up to 30–40% of all deaths attributed to it in the US renal data system . AtherosAtherosclerotic lesions occur early in renal dysfunction with peripheral arteries intense vascular wall thickening. The heightened cardiovascular disease risk in renal disease is probably the reason for high morbidity and mortality. The risk of death from CAD is in direct relationship to renal function deterioration in CKD patients that even a modest decrease in glomerular filtration rate in CKD stage two could lead to a significant increase in the risk of CAD. In HD patients, this increases from up to 100 times when compared with the general population , 13.MTNR1A and MTNR1B SNPs have been linked to autoimmune diseases, including Graves' disease in a study on 83 Hashimoto's thyroiditis showing variations of rs2119882 of MTNR1A supporting melatonin pathway involvement in Graves' disease pathogenesis [Melatonin receptors ogenesis .MTNR1B rs10830963 GG genotype is linked to increased fasting blood sugar levels, suggesting a significant relationship between melatonin, MTNR1B, and fasting blood sugar in type 2 diabetes [diabetes .In a recent study, evidence has been provided showing the relationship between rs2119882 and rs10830963 melatonin receptor polymorphism and lipid metabolism disorder in PCOS patients, highlighting the importance of the therapeutic and protective effects of melatonin and its metabolites .MTNR1A gene, located on the chromosomal region 4q35.2, spans a genomic region of 21 913 bases and is split into two exons [MTNR1A gene can hinder the binding affinity of transcription factors and might help in predicting aggressive phenotypes of UCC [The human wo exons . SNP rs1s of UCC . It has s of UCC .Calcium nephrolithiasis was significantly associated with rs13140012. This common condition where calcium oxalate and calcium phosphate salts are predominant in the crystalline formation of kidney stones. The formation of these stones is dependent on an interplay between hormonal, genetic, and environmental factors as melatonin has been hypothesized to have a role in regulating tubular renal functions through the specific melatonin receptors in the renal cortex .MTNR1A) SNP (rs13140012) in ESRD patients in Alexandria, Egypt, on maintenance hemodialysis with or without atherosclerosis.Aim: To study the relationship between melatonin levels and melatonin membrane receptor 1A (22.1Group I (patients group): It included 40 ESRD patients on regular hemodialysis. Their mean age was 47.25 ± 11.56 years, 22/40 (55%) were males. The patients' group was subdivided into two subgroups according to their CIMT into atherosclerotic and non-atherosclerotic subgroups. Subgroup I A: This Included 20 ESRD patients with atherosclerosis. Subgroup I B: This included 20 ESRD patients with no atherosclerosis. ESRD patients were enrolled from the Dialysis Unit at the Department of Internal Medicine, Nephrology Unit, Faculty of Medicine, Alexandria University, Egypt. Enrolment began in January 2019 and concluded in June 2019.This case-control study was carried out on 80 subjects divided into 2 two groups: Exclusion criteria: Patients with Diabetes, Dyslipidemia, Malignancy, Active infection/inflammation, Patients on Beta-blockers, Patients using Melatonin supplements were excluded.Group II (Control group): It included 40 normal healthy volunteer subjects. Their mean age was 46.35 ± 9.48 years. They were matched for age and sex with group I.2.22.2.1a.MTNR1A gene SNP (rs13140012). Samples were transferred to the laboratory immediately.Two mL in BD vacutainer® blood collection tubes containing K2EDTA for molecular analysis to detect b.Two mL in another BD vacutainer® blood collection tubes containing K2EDTA used for complete blood count (CBC).c.Five mL in BD Vacutainer® plain blood collection tubes for melatonin assay, and chemical analysis. Blood was left to clot at room temperature for 15 min, followed by centrifugation at 4000 rpm for 10 min to separate serum. The serum used for melatonin analysis was stored at -80 °C for further use.Nine milliliters of whole blood was collected by venipuncture from an antecubital vein under complete aseptic technique into three vacutainer tubes:Samples were collected between 8 am, and 9 am. Patients' samples were withdrawn before their first dialysis session of the week. Neither patients or controls received treatments during sample collection.2.2.2All subjects included in the study were subjected to laboratory investigations including serum calcium., PTH, blood urea, serum creatinine, serum albumin, serum K, serum phosphorous, C reactive protein, total cholesterol, triglycerides, complete blood picture .2.2.3μL of melatonin biotin and 50 μL of rabbit-antiserum were added into each well, shaken carefully, and incubated overnight (20 h) at 2–8 °C. After washing, 150 μL of freshly prepared enzyme conjugate was added into each well and incubated for two hours at room temperature on an orbital shaker (500 rpm). The reaction was developed using 200μL p-nitrophenyl phosphate Substrate Solution. Optical densities were measured at 405 nm in an automatic microplate reader .Melatonin was analyzed in serum samples using the melatonin ELISA kit  according to the manufacturer's protocol. First, (0.5 ml) of samples, Standards , and Controls were passed through a C18 reversed-phase column and extracted with methanol. Evaporation was then done, followed by the reconstitution of the extract with water. Each extracted standard extracted control, and extracted sample (50 μL) was added to the respective wells of the Microtiter Plate, which was coated with anti-rabbit IgG . Then, 50 Two quality controls were included in each run; Control 1 ranging from 5.7-14.9 pg/mL and Control 2 ranging from 58.2 - 99.1. According to the manufacturer's protocol, the intra-assay coefficients of variation for serum was 3.0–11.4% in the range of 8.8–151.7 pg/mL, while the inter-assay coefficients of variation were 6.4–19.3% in the range of 5.6–134.3 pg/mL. The lower detection limit of the assay was 1.6 pg/ml.2.2.4Genomic DNA was extracted from whole blood samples using GeneJET whole blood Genomic DNA Mini Kit  according to the manufacturer's instructions. DNA's purity and concentration were measured using Nanodrop 2000/2000c spectrophotometer .MTNR1A polymorphism (rs13140012) was performed using the 5'nuclease allelic discrimination assay. The PCR reaction mix included 10 μLTaqMan® Universal PCR Master Mix , 1 μL of TaqMan® SNP Genotyping Assay 20x (Assay ID: C__31861431_10), 20 ng DNA/reaction and DNAase free water to a final volume of 20 μL. Thermal cycling was done using Stratagene Mx3000P  as follows; 95 °C for 10 min for initial AmpliTaq Gold enzyme activation and 45 cycles of denaturation for 15 s at 95 °C and annealing/extension for 1 min at 60 °C. No template control (NTC) containing nuclease-free water was included in each run as a negative control. The fluorescence profile of each well was detected at the end of each cycle, and a graphic presentation of the fluorescence against the number of cycles was plotted. Data processing was performed using Stratagene Mx3000PTM Software (MX.PRO software).Genotyping for 2.2.5CIMT is known as a low-level echo grey band which does not project into the artery lumen and was measured at the diastolic phase as the distance between the leading edge of the first and second echogenic lines of the far walls of the distal segment of the common carotid artery, the carotid bifurcation, and the internal carotid artery on both sides. The doppler was done with a duplex ultrasound system with a 7.5 MHz scanning frequency in the B-mode, pulsed Doppler mode, and color mode.The B-mode scanning included the scanning of the left and right common carotid arteries (3 cm before the carotid bifurcation), carotid bifurcation, and the internal carotid artery 2 cm distally from the carotid bifurcation. CAIMT measurements were done in arterial segments without plaques. All examinations and measurements were completed by the same examiner to have examiner bias excluded.2.2.6Data were fed to the computer and analyzed using IBM SPSS software package version 20.0.  Qualitative data were described using number and percent. The Kolmogorov-Smirnov test was used to verify the normality of distribution Quantitative data were described using range (minimum and maximum), mean, standard deviation, median, and interquartile range (IQR). Obtained results significance was judged at the 5% level.The used tests were Chi-square test, Monte Carlo correction, Student t-test, Mann Whitney test, Kruskal Wallis test, Spearman coefficient, Odd ratio (OR), and Hardy-Weinberg.2.3All procedures performed in studies involving human participants were per the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.2.4Informed consent was obtained from all individual participants included in the study.33.1No statistically significant differences were observed between ESRD patients and controls as regards age (P = 0.704) or gender (P = 0.116). ESRD patients included 22 (55%) males and 18 (45%) females, whereas the control group consisted of 15 (37.5%) males and 25 (62.5%) females. The age of ESRD patients had a mean of 47.25 ± 11.56, while in the control group, it was 46.35 ± 9.48.ESRD had significantly higher parathormone hormone, urea, creatinine, potassium, phosphorous, c-reactive protein, triglycerides and total cholesterol than the control group. ESRD had significantly lower hemoglobin, and white blood cells than the control group. There was no significant difference between the two groups as regards albumin and platelets. Laboratory findings are summarized in 3.2Serum melatonin levels in the patients' group ranged from 1.6 to 11.30 (pg/mL) with a median of 2.5. While it ranged from 20.50 to 56.40 (pg/mL) in the control group with a median of 35.20. There was a statistically significant decrease in the patients' group in comparison to the control group (p < 0.001), 3.3MTNR1A SNP (rs13140012) genotypes and alleles in the two studied groups. There was no statistically significant difference between the two groups for SNP rs13140012 and its alleles.3.43.5MTNR1A) SNP (rs13140012) with serum melatonin levels in the patients' group.3.63.7CIMT in the non-atherosclerotic subgroup ranged from 0.4 – 0.8mm with a median value of 0.60. While in the atherosclerotic subgroup, it ranged from 1.0 – 2.2 with a median value of 1.0. There was a statistically significant difference between subgroups (p < 0.001).3.8Melatonin levels in non-atherosclerotic patients ranged from 2.0 – 11.30, with a median of 4.9. While in the atherosclerotic subgroup, it ranged from 1.6 – 2.50, with a median value of 2.30. There was a significant statistical difference (p < 0.001).3.9MTNR1A SNP (rs13140012) and its alleles frequency in the patients' subgroups according to whether patients were atherosclerotic or not. There was no statistically significant difference between the two subgroups for SNP rs13140012 and its alleles.3.10There was a significant negative correlation between CIMT and serum melatonin levels , 3.11MTNR1A SNP (rs13140012) as demonstrated in There was no association between CIMT and 4Daytime melatonin levels in renal disease patients are contradictory as both increased and decreased melatonin levels have been noted in daytime hemodialysis patients , 25, 26.In the present study, the serum melatonin levels in ESRD patients' group were statistically significantly decreased than their levels in the control group (P < 0.001).The result of the present study was in agreement with Kock et al.  He and hKarasek et al. also found decreased melatonin levels  in theirKarasek et al.  stated iVarizi et al.  measuredContrary to the result of the present study, Viljoen et al.  tested tAlso, in Ludemann et al.  study wiTo further support the hypothesis of elevated melatonin levels in ESRD patients, Ludemann et al. claim the disturbed hypothalamus-pituitary-gonadal axis disturbance often encountered in ESRD patients could be caused by elevated levels of melatonin linked to hypogonadism and amenorrhea , 38.Several mechanisms could explain the circadian melatonin rhythm abnormalities in renal disease patients. As previously mentioned, daytime dialysis can lead to daytime sleepiness and nocturnal insomnia , 39. ThiDecreased melatonin levels in renal impairment patients have been linked to a derangement in β-adrenoreceptor-mediated responsiveness , 39. TheThe present study also found that the level of serum melatonin was significantly lower in ESRD patients with atherosclerosis compared to ESRD patients without atherosclerosis .In a study by Bozkart et al. , 62 patiLow levels of melatonin were noticed in type 2 diabetes patients  and hypeJavanmard et al.  reportedIn another study by Jeong et al.  12 healtMTNR1A gene is expressed in the kidney and supports the idea that the biological melatonin system may be involved in renal physiology and the pathogenesis of nephrolithiasis. It is worth noting a circadian variation in the urinary excretion of different solutes has been documented in healthy individuals: notably, the nocturnal excretion rates of potassium, sodium, chloride, and urate are only 50% of the rates observed during the light period [The present study did not find a significant association between SNP rs13140012 and atherosclerotic ESRD patients  despite the significant association between the same melatonin receptor SNP with recurrent and idiopathic nephrolithiasis in the study by Esposito et al. in 2011 . Their st period , whereast period  In patiet period , 55, 56.t period .5These results lead us to suggest that melatonin production is impaired in ESRD patients (included in this pilot study), and this impairment is even more evident in atherosclerotic ESRD patients.6Melatonin research on ESRD patients is an area that still requires further research to study its correlation with kidney disease and its complications.MTNR1A) SNP (rs13140012) in renal diseases.Further studies on larger patient groups should be conducted on melatonin membrane receptor 1A (E. Elsayed: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.T. Salem: Conceived and designed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.M. El Nashar: Performed the experiments; Wrote the paper.N. El Kholy and A. El Aghoury: Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.10.13039/501100002353Alexandria Faculty of Medicine, Alexandria University.This work was supported by The authors declare no conflict of interest.No additional information is available for this paper.