Bezmiâlem Vakıf Üniversitesi

There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .

Hypertension is an important factor in cardiovascular diseases. Angiotensin-I-converting enzyme (ACE) inhibitors like synthetic drugs are widely used to control hypertension. ACE-inhibitory peptides from food origins could be a good alternative to synthetic drugs. A number of plant-based peptides have been investigated for their potential ACE inhibitor activities by using in vitro and in vivo assays. These plant-based peptides can be obtained by solvent extraction, enzymatic hydrolysis with or without novel food processing methods, and fermentation. ACE-inhibitory activities of peptides can be affected by their structural characteristics such as chain length, composition and sequence. ACE-inhibitory peptides should have gastrointestinal stability and reach the cardiovascular system to show their bioactivity. This paper reviews the current literature on plant-derived ACE-inhibitory peptides including their sources, production and structure, as well as their activity by in vitro and in vivo studies and their bioavailability.

AIMS: Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion therapy in ST-elevation myocardial infarction (STEMI). We conducted this study to evaluate the contemporary status on the use and type of reperfusion therapy in patients admitted with STEMI in the European Society of Cardiology (ESC) member countries. METHODS AND RESULTS: A cross-sectional descriptive study based on aggregated country-level data on the use of reperfusion therapy in patients admitted with STEMI during 2010 or 2011. Thirty-seven ESC countries were able to provide data from existing national or regional registries. In countries where no such registries exist, data were based on best expert estimates. Data were collected on the use of STEMI reperfusion treatment and mortality, the numbers of cardiologists, and the availability of PPCI facilities in each country. Our survey provides a brief data summary of the degree of variation in reperfusion therapy across Europe. The number of PPCI procedures varied between countries, ranging from 23 to 884 per million inhabitants. Primary percutaneous coronary intervention and thrombolysis were the dominant reperfusion strategy in 33 and 4 countries, respectively. The mean population served by a single PPCI centre with a 24-h service 7 days a week ranged from 31 300 inhabitants per centre to 6 533 000 inhabitants per centre. Twenty-seven of the total 37 countries participated in a former survey from 2007, and major increases in PPCI utilization were observed in 13 of these countries. CONCLUSION: Large variations in reperfusion treatment are still present across Europe. Countries in Eastern and Southern Europe reported that a substantial number of STEMI patients are not receiving any reperfusion therapy. Implementation of the best reperfusion therapy as recommended in the guidelines should be encouraged.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) updates the KDIGO 2012 guideline and has been developed with patient partners, clinicians, and researchers around the world, using robust methodology. This update, based on a substantially broader base of evidence than has previously been available, reflects an exciting time in nephrology. New therapies and strategies have been tested in large and diverse populations that help to inform care; however, this guideline is not intended for people receiving dialysis nor those who have a kidney transplant. The document is sensitive to international considerations, CKD across the lifespan, and discusses special considerations in implementation. The scope includes chapters dedicated to the evaluation and risk assessment of people with CKD, management to delay CKD progression and its complications, medication management and drug stewardship in CKD, and optimal models of CKD care. Treatment approaches and actionable guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence and the strength of recommendations which followed the “Grading of Recommendations Assessment, Development, and Evaluation” (GRADE) approach. The limitations of the evidence are discussed. The guideline also provides practice points, which serve to direct clinical care or activities for which a systematic review was not conducted, and it includes useful infographics and describes an important research agenda for the future. It targets a broad audience of people with CKD and their healthcare, while being mindful of implications for policy and payment. The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) updates the KDIGO 2012 guideline and has been developed with patient partners, clinicians, and researchers around the world, using robust methodology. This update, based on a substantially broader base of evidence than has previously been available, reflects an exciting time in nephrology. New therapies and strategies have been tested in large and diverse populations that help to inform care; however, this guideline is not intended for people receiving dialysis nor those who have a kidney transplant. The document is sensitive to international considerations, CKD across the lifespan, and discusses special considerations in implementation. The scope includes chapters dedicated to the evaluation and risk assessment of people with CKD, management to delay CKD progression and its complications, medication management and drug stewardship in CKD, and optimal models of CKD care. Treatment approaches and actionable guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence and the strength of recommendations which followed the “Grading of Recommendations Assessment, Development, and Evaluation” (GRADE) approach. The limitations of the evidence are discussed. The guideline also provides practice points, which serve to direct clinical care or activities for which a systematic review was not conducted, and it includes useful infographics and describes an important research agenda for the future. It targets a broad audience of people with CKD and their healthcare, while being mindful of implications for policy and payment. This 2024 update of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) heralds a new era in the care of people with kidney diseases. The majority of statements from the 2012 guideline have been updated based on current knowledge and practice. Only 6 statements were retained in their original form in 2012. There is clear and increasing recognition of CKD as a global public health problem. The inclusion of people with CKD in clinical trials has improved substantially, thus generating an evidence base upon which to recommend care and treatments that have not previously existed. There are increasing efforts to improve diagnostic evaluation of cause, with increased sophistication of imaging methods, biopsy interrogation, and genetic evaluation, as well as methods to optimize blood and urine testing. With advances in technology, such as molecular diagnostics for tissue samples, integrated omics platforms, and the use of machine learning/artificial intelligence to explore large databases of both clinical and biological data, we are truly at the beginning of a new era in nephrology. This guideline integrates existing and new knowledge to guide the care of people with CKD. It has been developed by an international Work Group that included patient partners, clinicians, and researchers with diverse experience across the spectrum of populations, a dedicated Evidence Review Team, and professional KDIGO staff. This clinical practice guideline includes 2 different types of statements: graded recommendations, which are supported by systematic reviews (i.e., de novo reviews conducted by the independent Evidence Review Team or existing high-quality reviews that have been systematically identified), and ungraded practice points, which serve to direct clinical care or activities for which a systematic review was not conducted for various reasons (e.g., lack of a sufficient evidence base or randomized controlled trials that would be impractical/unethical). Both recommendations and practice points are intended to help guide clinical practice and aid in decision-making; thus, collectively are the guideline statements. They are clearly articulated, actionable, and presented together so that all guideline statements can be implemented. The distinction between them is based on the process by which they are derived, and that process is based on the framework methodology from the KDIGO Methods Committee and aligns with other international guideline groups using the “Grading of Recommendations Assessment, Development, and Evaluation” (GRADE) methodology. New developments in the refinement of evaluation of glomerular filtration rate (GFR), population and individual risk prediction, and novel treatments have all positively influenced the prognosis for people with CKD and are presented here. The Work Group has aimed to generate a guideline that is both rigorously devoted to new and existing evidence, and that is clinically useful. Research recommendations are presented in a separate section of the document and are intended to guide the next set of important research questions to inform and improve the outcomes of people living with CKD. We specifically urge the community to be inclusive of people across the lifecycle and include sex (referring to biological factors including genetics, sex steroids, physiology, and anatomy), gender (referring to sociocultural factors such as identity, roles, and relations), and etiology of CKD as important variables in all studies. We offer recommendations to clinicians and clinical laboratories to understand and promote the standardization and accuracy of testing tools including assays and equipment. The effective use of clinical practice guidelines and, therefore, effective patient care, including accurate diagnosis and referral prioritization, clinical research, and public health prioritization, requires comparability of laboratory results independent of time, place, and measurement procedure. Key to this is establishing precision of testing and between-laboratory agreement with traceability to accepted international reference standards wherever available. Therefore, this guidance document includes standards for laboratory tests. Specifically, we focus on creatinine and cystatin C, with the goal of normalizing access to both tests for increased accuracy of GFR assessment, and the assessment of urine albumin which is also critical to risk assessment and care plans. The guideline is organized into 6 chapters (Tables 1, 4, and 5 cover Chapters 1–5). In this summary, we outline the key evidence-based recommendations together with selected practice points by chapter. Readers are referred to the full guideline for a comprehensive description of benefits and harms, certainty of evidence, values and preferences, resource use and costs, factors affecting implementation, special considerations, and both general and specific research recommendations.Table 1Recommendations and practice points from Chapters 1 and 2 of the KDIGO 2024 Clinical Practice Guideline for Evaluation and Management of CKDChapter 1. Evaluation of CKD1.1 Detection and evaluation of CKD1.1.1 Detection of CKDPractice people at risk for and with kidney (CKD) using both urine albumin measurement and assessment of glomerular filtration rate of or GFR tests to of Methods for of In at risk for CKD, we recommend using glomerular filtration rate cystatin is available, the GFR be from the of creatinine and cystatin and cystatin glomerular filtration rate Evaluation of of of a of can be of of of of or and urine such as kidney and in such as and to or to and the not based upon a for and as the be the of a kidney or kidney of treatments for CKD at of GFR or CKD is to of other clinical Evaluation of the of CKD using clinical and and laboratory and genetic and diagnosis in full tests to a based on 6 in full We a kidney biopsy as an diagnostic to and guide clinically Evaluation of of the to the specific kidney of glomerular the general with the of of the to and other creatinine and an for assessment of GFR in full We recommend using in clinical is accurate and GFR clinical in full accurate of GFR GFR using or of an filtration in full the and limitations in both and glomerular filtration rate as well as the and factors that and cystatin of requires of the for in a in GFR the use of cystatin glomerular filtration rate in specific the implications of between and as be in both and of those urine for creatinine is not and is to be to clinical the laboratory standards of care in in full to accuracy and GFR using creatinine and cystatin clinical laboratories the of measurement of both creatinine and cystatin as an or as a referred creatinine in or their quality process include the of the of values for the of the use of creatinine assays in the of to creatinine in using the and the of and in the can be as in and the of 2 of GFR We recommend using a GFR to GFR from filtration than on the filtration the and and as large as such for and of in the of be GFR in using that have been developed or in Evaluation of for and other the for testing of of In all a in the is in and for albumin and with urine use the for with for with accurate methods is using accurate by laboratory measurement and as a to urine creatinine wherever (i.e., the or tests are on a urine with a in the urine factors that of of urine albumin and urine creatinine and tests as in full In a urine for testing of and of urine and urine for and for albumin with for and for albumin with to clinical the laboratory and standards in in full to accuracy and of the urine of an quality assessment for urine albumin and including of the is a practice for We that testing be for creatinine and urine albumin measurement access to a laboratory is or a at the the clinical a is for creatinine and urine albumin that the and quality to the and of the including quality assessment, and the of the is a for creatinine testing is being generate an of the with that the a is being for the of also creatinine and an is the of the to a in of people with or as of the evaluation and of using the assessment in people with on for progression of CKD based upon GFR and in or in and GFR at in people with and GFR for at risk of CKD progression measurement people with CKD, a in of on a the and people with CKD who GFR of on testing the and of people with CKD, a of the on a laboratory and in people with In people with CKD we recommend using an risk to the risk of kidney kidney risk of can be to for referral in to based on or urine and other clinical kidney risk of can be to the of care in to and other clinical kidney risk of can be to the of for kidney including access or referral for in to and other clinical that risk developed for use in people with CKD not be for use in those with CKD in people with and kidney of risk in people with CKDPractice risk to guide therapies in people with CKD, use models that are developed CKD populations or that and risk to guide of care, use models that specifically developed in the CKD kidney Kidney Disease: Improving Global in full 6 in full in full in full in full in full in full in full in a new and practice points from of the KDIGO 2024 Clinical Practice Guideline for Evaluation and Management of CKDChapter CKD progression and its CKD and risk people with CKD with a comprehensive to of progression of CKD and its in full people with CKD to with and of an optimal and not to use to and (e.g., or and and be and use specific recommendations or practice and We recommend that people with CKD be to for a of at or to a with their and Recommendations for of other and access to with CKD be to people at risk of on the of or and the of or people with and CKD to with CKD to for (i.e., and to a people with CKD to and diverse with a of to and a of or to people with CKD and to their individual and of CKD and other We a of in with CKD in with CKD at risk of In with CKD who are and and who are at risk of kidney a with or to not or in people with not in with CKD to the risk of The and in with CKD be at the of the for to promote optimal In with such as and and We that be of of or of in people with CKD is not for with for with CKD who have blood for and We that with and CKD be with a blood of using measurement in people with risk of and or We that in with CKD, by blood be to for and a with and with in with In with CKD, is not available, it is to in a of for and this is by or of to the KDIGO Clinical Practice Guideline for Management in Chronic Kidney Disease: Improving Global Outcomes Work Clinical Practice Guideline for Management in Chronic Kidney for specific recommendations, practice points, and research We recommend or for people with CKD and increased We or for people with CKD and increased We recommend or for people with CKD and increased and with We recommend of and direct in people with CKD, with or or be using the that is to the benefits the benefits were in trials using in and be of or in the of a on the current GFR and with use of can be by to the than the or or creatinine by than of or an in the or or in the of or or to while kidney glomerular filtration rate people with CKD with to increased on or for specific (e.g., to or with or in people with CKD the We recommend with 2 CKD, and an with an an is it is to an the it is not or is It is to of or critical people be at risk for We recommend with CKD with an for the with urine of of or use not of of CKD and the in on is not an to We with to with urine with an We a with kidney or for with an and of are for with who are at risk of CKD progression and as by other be to a and an for of and CKD in risk of people with and of a in full The of a with kidney or be for of or or a in glomerular people with a In with and CKD who have not targets use of and or who are to use those we recommend a The of with In people with CKD, use of with or to of with clinical implications (e.g., in for to it not in the of and not or in of factors on of the of laboratory as well as factors and that measurement including and samples, and the of of or with to the management of to and in specific recommendations or practice specific recommendations or practice an in people with CKD and that includes and and into and quality of and a or an are to the of in (e.g., for people with CKD who have a of or as a in which risk be a to the KDIGO Clinical Practice Guideline for in Chronic Kidney Disease for specific recommendations, and of specific and research to the KDIGO Clinical Practice Guideline for the and Treatment of Chronic Kidney and for specific recommendations, of specific and research We recommend people with CKD and be for people with CKD their of is or is in to in people with CKD and of in CKD, or are to which help include and We not using to in people with CKD and to delay CKD progression and specific to In with not with dialysis or kidney we recommend with a or In with CKD and we recommend with a In with CKD not with dialysis or kidney we in people with or of the or of or risk using a risk In people with CKD, to the in to the 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clinical using are for drug accuracy is for (e.g., to or drug or clinical be use of that both creatinine and cystatin C, or GFR be In people with of for be for with a or a to be and drug in people of the filtration or of are not in a and drug medication review and at of care to and drug people with CKD have medication and are by are an a clear of to the to the and and in the of as and in the to or the management of as a to that to the or to Practice to promote drug and inform people with CKD the benefits and of so that they can and that can be with other and use tools to and improve drug stewardship in people with CKD to management of their medication the for imaging studies in with general population and benefits of imaging studies be on an individual in the of their and the risk for in people with CKD receiving for using The of can be in with statements from the in people with or GFR people with GFR who offer them of and models of to kidney care with CKD to kidney care in the in in 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Importance: Recanalization of intracranial thrombus is associated with improved clinical outcome in patients with acute ischemic stroke. The association of intravenous alteplase treatment and thrombus characteristics with recanalization over time is important for stroke triage and future trial design. Objective: To examine recanalization over time across a range of intracranial thrombus occlusion sites and clinical and imaging characteristics in patients with ischemic stroke treated with intravenous alteplase or not treated with alteplase. Design, Setting, and Participants: Multicenter prospective cohort study of 575 patients from 12 centers (in Canada, Spain, South Korea, the Czech Republic, and Turkey) with acute ischemic stroke and intracranial arterial occlusion demonstrated on computed tomographic angiography (CTA). Exposures: Demographics, clinical characteristics, time from alteplase to recanalization, and intracranial thrombus characteristics (location and permeability) defined on CTA. Main Outcomes and Measures: Recanalization on repeat CTA or on first angiographic acquisition of affected intracranial circulation obtained within 6 hours of baseline CTA, defined using the revised arterial occlusion scale (rAOL) (scores from 0 [primary occlusive lesion remains the same] to 3 [complete revascularization of primary occlusion]). Results: Among 575 patients (median age, 72 years [IQR, 63-80]; 51.5% men; median time from patient last known well to baseline CTA of 114 minutes [IQR, 74-180]), 275 patients (47.8%) received intravenous alteplase only, 195 (33.9%) received intravenous alteplase plus endovascular thrombectomy, 48 (8.3%) received endovascular thrombectomy alone, and 57 (9.9%) received conservative treatment. Median time from baseline CTA to recanalization assessment was 158 minutes (IQR, 79-268); median time from intravenous alteplase start to recanalization assessment was 132.5 minutes (IQR, 62-238). Successful recanalization occurred at an unadjusted rate of 27.3% (157/575) overall, including in 30.4% (143/470) of patients who received intravenous alteplase and 13.3% (14/105) who did not (difference, 17.1% [95% CI, 10.2%-25.8%]). Among patients receiving alteplase, the following factors were associated with recanalization: time from treatment start to recanalization assessment (OR, 1.28 for every 30-minute increase in time [95% CI, 1.18-1.38]), more distal thrombus location, eg, distal M1 middle cerebral artery (39/84 [46.4%]) vs internal carotid artery (10/92 [10.9%]) (OR, 5.61 [95% CI, 2.38-13.26]), and higher residual flow (thrombus permeability) grade, eg, hairline streak (30/45 [66.7%]) vs none (91/377 [24.1%]) (OR, 7.03 [95% CI, 3.32-14.87]). Conclusions and Relevance: In patients with acute ischemic stroke, more distal thrombus location, greater thrombus permeability, and longer time to recanalization assessment were associated with recanalization of arterial occlusion after administration of intravenous alteplase; among patients who did not receive alteplase, rates of arterial recanalization were low. These findings may help inform treatment and triage decisions in patients with acute ischemic stroke.

OBJECTIVE: To determine the global capacity (availability, accessibility, quality, and affordability) to deliver kidney replacement therapy (dialysis and transplantation) and conservative kidney management. DESIGN: International cross sectional survey. SETTING: International Society of Nephrology (ISN) survey of 182 countries from July to September 2018. PARTICIPANTS: Key stakeholders identified by ISN's national and regional leaders. MAIN OUTCOME MEASURES: Markers of national capacity to deliver core components of kidney replacement therapy and conservative kidney management. RESULTS: Responses were received from 160 (87.9%) of 182 countries, comprising 97.8% (7338.5 million of 7501.3 million) of the world's population. A wide variation was found in capacity and structures for kidney replacement therapy and conservative kidney management-namely, funding mechanisms, health workforce, service delivery, and available technologies. Information on the prevalence of treated end stage kidney disease was available in 91 (42%) of 218 countries worldwide. Estimates varied more than 800-fold from 4 to 3392 per million population. Rwanda was the only low income country to report data on the prevalence of treated disease; 5 (<10%) of 53 African countries reported these data. Of 159 countries, 102 (64%) provided public funding for kidney replacement therapy. Sixty eight (43%) of 159 countries charged no fees at the point of care delivery and 34 (21%) made some charge. Haemodialysis was reported as available in 156 (100%) of 156 countries, peritoneal dialysis in 119 (76%) of 156 countries, and kidney transplantation in 114 (74%) of 155 countries. Dialysis and kidney transplantation were available to more than 50% of patients in only 108 (70%) and 45 (29%) of 154 countries that offered these services, respectively. Conservative kidney management was available in 124 (81%) of 154 countries. Worldwide, the median number of nephrologists was 9.96 per million population, which varied with income level. CONCLUSIONS: These comprehensive data show the capacity of countries (including low income countries) to provide optimal care for patients with end stage kidney disease. They demonstrate substantial variability in the burden of such disease and capacity for kidney replacement therapy and conservative kidney management, which have implications for policy.

Kamari, G., Blanche, C. & Siljak-Yakovlev, S. (eds): Mediterranean chromosome number reports – 22. — Fl. Medit. 22: 211-232. 2012. — ISSN: 1120-4052 printed, 2240-4538 online. This is the twenty-two of a series of reports of chromosomes numbers from Mediterranean area, peri-Alpine communities and the Atlantic Islands, in English or French language. It comprises contributions on 15 taxa: Cakile, Chrithmum, Dorycnium, Inula, Reichardia and Pancratium from Greece by E. Liveri, P. Bareka & G. Kamari (Nos 1753-1758); Pimpinella from Turkey by

PURPOSE: The aim of the present study was to assess both the credibility and strength of evidence arising from systematic reviews with meta-analyses of observational studies on handgrip strength and health outcomes. METHODS: An umbrella review of systematic reviews with meta-analyses of observational studies was conducted. We assessed meta-analyses of observational studies based on random-effect summary effect sizes and their p values, 95% prediction intervals, heterogeneity, small-study effects, and excess significance. We graded the evidence from convincing (Class I) to weak (Class IV). RESULTS: ). No outcome presented convincing evidence. Three associations showed Class II evidence (i.e., highly suggestive): (1) higher handgrip values at baseline were associated with a minor reduction in mortality risk in the general population (n = 34 studies; sample size = 1,855,817; relative risk = 0.72, 95% confidence interval (95%CI): 0.67-0.78), (2) cardiovascular death risk in mixed populations (n = 15 studies; relative risk = 0.84, 95%CI: 0.78-0.91), and (3) incidence of disability (n = 7 studies; relative risk = 0.76, 95%CI: 0.66-0.87). CONCLUSION: The present results show that handgrip strength is a useful indicator for general health status and specifically for early all-cause and cardiovascular mortality, as well as disability. To further inform intervention strategies, future research is now required to fully understand mechanisms linking handgrip strength scores to these health outcomes.

BACKGROUND: Relationships among sexual activity, problems and concerns, and well-being among older adults have not been fully explored. AIM: To investigate associations among sexual activity, problems and concerns, and experienced well-being in a representative sample of older adults. METHODS: In this cross-sectional analysis from the English Longitudinal Study of Ageing, sexual behavior, problems, and concerns were assessed via a self-completed questionnaire. Covariates included age, partnership status, socioeconomic status, smoking status, alcohol intake, limiting long-standing illness, and depressive symptoms. Data were analyzed using 1-way independent analysis of variance. MAIN OUTCOME MEASURE: Enjoyment of life was assessed with the pleasure subscale of the CASP-19 (Control, Autonomy, Self-realization, and Pleasure), a validated measure of quality of life specific to older age. RESULTS: Data on sexual activity and enjoyment of life were available for a total of 3,045 men and 3,834 women (mean age 64.4 years in men and 65.3 years in women). Men and women who reported any sexual activity in the past year had significantly higher mean enjoyment of life scores compared with those who were not sexually active (men, 9.75 vs 9.44 [P < .001]; women, 9.86 vs 9.67 [P = .003]). Among sexually active men, frequent (≥2 times a month) sexual intercourse (P < .001) and frequent kissing, petting, or fondling (P < .001) were associated with greater enjoyment of life. Among sexually active women, frequent kissing, petting, or fondling was also associated with greater enjoyment of life (P < .001), but there was no significant association with frequent intercourse (P = .101). Concerns about one's sex life and problems with sexual function were strongly associated with lower levels of enjoyment of life in men and to a lesser extent in women. CONCLUSION: This is among the first studies to show that well-being is higher among older adults when they are sexually active. Preferences regarding the expression of sexual activity differed between the sexes. Further longitudinal research is needed to confirm a causal association between sexual activity and well-being. Smith L, Yang L, Veronese N, et al. Sexual Activity is Associated with Greater Enjoyment of Life in Older Adults. Sex Med 2019;7:11-18.

OBJECTIVES: The aim of this umbrella review was to determine the effect of physical activity/exercise on improving cognitive and noncognitive outcomes in people with MCI (mild cognitive impairment) and dementia. DESIGN: Umbrella review of systematic reviews (SR), with or without meta-analyses (MAs), of randomized controlled trials (RCTs) and observational studies. SETTINGS AND PARTICIPANTS: People with MCI or dementia, confirmed through validated assessment measures. Any form of physical activity/exercise was included. As controls, we included participants not following any prespecified physical activity/exercise intervention or following the same standard protocol with the intervention group. METHODS: The protocol was registered in PROSPERO (CDR 164197). Major databases were searched until December 31, 2019. The certainty of evidence of statistically significant outcomes was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. SRs' findings, without a formal MA, were reported descriptively. RESULTS: Among 1160 articles initially evaluated, 27 SRs (all of RCTs, 9 without MA) for a total of 28,205 participants with MCI/dementia were included. In patients with MCI, mind-body intervention (standardized mean difference [SMD] = 0.36; 95% confidence intervals [CI] 0.20-0.52; low certainty) and mixed physical activity interventions (SMD = 0.30; 95% CI 0.11-0.49; moderate certainty) had a small effect on global cognition, whereas resistance training (SMD = 0.80; 95% CI 0.29-1.31; very low certainty) had a large effect on global cognition. In people affected by dementia, physical activity/exercise was effective in improving global cognition in Alzheimer disease (SMD = 1.10; 95% CI 0.65-1.64; very low certainty) and in all types of dementia (SMD = 0.48; 95% CI 0.22-0.74; low certainty). Finally, physical activity/exercise improved noncognitive outcomes in people with dementia including falls, and neuropsychiatric symptoms. CONCLUSIONS AND IMPLICATIONS: Supported by very low-to-moderate certainty of evidence, physical activity/exercise has a positive effect on several cognitive and noncognitive outcomes in people with MCI and dementia, but RCTs, with low risk of bias/confounding, are still needed to confirm these relationships.

We aimed to investigate whether increased consumption of fructose is linked to the increased prevalence of fatty liver. The prevalence of nonalcoholic steatohepatitis (NASH) is 3% and 20% in nonobese and obese subjects, respectively. Obesity is a low-grade chronic inflammatory condition and obesity-related cytokines such as interleukin-6, adiponectin, leptin, and tumor necrosis factor-α may play important roles in the development of nonalcoholic fatty liver disease (NAFLD). Additionally, the prevalence of NASH associated with both cirrhosis and hepatocellular carcinoma was reported to be high among patients with type 2 diabetes with or without obesity. Our research group previously showed that consumption of fructose is associated with adverse alterations of plasma lipid profiles and metabolic changes in mice, the American Lifestyle-Induced Obesity Syndrome model, which included consumption of a high-fructose corn syrup in amounts relevant to that consumed by some Americans. The observation reinforces the concerns about the role of fructose in the obesity epidemic. Increased availability of fructose (e.g., high-fructose corn syrup) increases not only abnormal glucose flux but also fructose metabolism in the hepatocyte. Thus, the anatomic position of the liver places it in a strategic buffering position for absorbed carbohydrates and amino acids. Fructose was previously accepted as a beneficial dietary component because it does not stimulate insulin secretion. However, since insulin signaling plays an important role in central mechanisms of NAFLD, this property of fructose may be undesirable. Fructose has a selective hepatic metabolism, and provokes a hepatic stress response involving activation of c-Jun N-terminal kinases and subsequent reduced hepatic insulin signaling. As high fat diet alone produces obesity, insulin resistance, and some degree of fatty liver with minimal inflammation and no fibrosis, the fast food diet which includes fructose and fats produces a gene expression signature of increased hepatic fibrosis, inflammation, endoplasmic reticulum stress and lipoapoptosis. Hepatic de novo lipogenesis (fatty acid and triglyceride synthesis) is increased in patients with NAFLD. Stable-isotope studies showed that increased de novo lipogenesis (DNL) in patients with NAFLD contributed to fat accumulation in the liver and the development of NAFLD. Specifically, DNL was responsible for 26% of accumulated hepatic triglycerides and 15%-23% of secreted very low-density lipoprotein triglycerides in patients with NAFLD compared to an estimated less than 5% DNL in healthy subjects and 10% DNL in obese people with hyperinsulinemia. In conclusion, understanding the underlying causes of NAFLD forms the basis for rational preventive and treatment strategies of this major form of chronic liver disease.

BACKGROUND: Chronic kidney disease (CKD) and immunosuppression, such as in renal transplantation (RT), stand as one of the established potential risk factors for severe coronavirus disease 2019 (COVID-19). Case morbidity and mortality rates for any type of infection have always been much higher in CKD, haemodialysis (HD) and RT patients than in the general population. A large study comparing COVID-19 outcome in moderate to advanced CKD (Stages 3-5), HD and RT patients with a control group of patients is still lacking. METHODS: We conducted a multicentre, retrospective, observational study, involving hospitalized adult patients with COVID-19 from 47 centres in Turkey. Patients with CKD Stages 3-5, chronic HD and RT were compared with patients who had COVID-19 but no kidney disease. Demographics, comorbidities, medications, laboratory tests, COVID-19 treatments and outcome [in-hospital mortality and combined in-hospital outcome mortality or admission to the intensive care unit (ICU)] were compared. RESULTS: A total of 1210 patients were included [median age, 61 (quartile 1-quartile 3 48-71) years, female 551 (45.5%)] composed of four groups: control (n = 450), HD (n = 390), RT (n = 81) and CKD (n = 289). The ICU admission rate was 266/1210 (22.0%). A total of 172/1210 (14.2%) patients died. The ICU admission and in-hospital mortality rates in the CKD group [114/289 (39.4%); 95% confidence interval (CI) 33.9-45.2; and 82/289 (28.4%); 95% CI 23.9-34.5)] were significantly higher than the other groups: HD = 99/390 (25.4%; 95% CI 21.3-29.9; P < 0.001) and 63/390 (16.2%; 95% CI 13.0-20.4; P < 0.001); RT = 17/81 (21.0%; 95% CI 13.2-30.8; P = 0.002) and 9/81 (11.1%; 95% CI 5.7-19.5; P = 0.001); and control = 36/450 (8.0%; 95% CI 5.8-10.8; P < 0.001) and 18/450 (4%; 95% CI 2.5-6.2; P < 0.001). Adjusted mortality and adjusted combined outcomes in CKD group and HD groups were significantly higher than the control group [hazard ratio (HR) (95% CI) CKD: 2.88 (1.52-5.44); P = 0.001; 2.44 (1.35-4.40); P = 0.003; HD: 2.32 (1.21-4.46); P = 0.011; 2.25 (1.23-4.12); P = 0.008), respectively], but these were not significantly different in the RT from in the control group [HR (95% CI) 1.89 (0.76-4.72); P = 0.169; 1.87 (0.81-4.28); P = 0.138, respectively]. CONCLUSIONS: Hospitalized COVID-19 patients with CKDs, including Stages 3-5 CKD, HD and RT, have significantly higher mortality than patients without kidney disease. Stages 3-5 CKD patients have an in-hospital mortality rate as much as HD patients, which may be in part because of similar age and comorbidity burden. We were unable to assess if RT patients were or were not at increased risk for in-hospital mortality because of the relatively small sample size of the RT patients in this study.

Systematic reviews and meta-analyses pool data from individual studies to generate a higher level of evidence to be evaluated by guidelines. These reviews ultimately guide clinicians and stakeholders in health-related decisions. However, the informativeness and quality of evidence synthesis inherently depend on the quality of what has been pooled into meta-research projects. Moreover, beyond the quality of included individual studies, only a methodologically correct process, in relation to systematic reviews and meta-analyses themselves, can produce a reliable and valid evidence synthesis. Hence, quality of meta-research projects also affects evidence synthesis reliability. In this overview, the authors provide a synthesis of advantages and disadvantages and main characteristics of some of the most frequently used tools to assess quality of individual studies, systematic reviews, and meta-analyses. Specifically, the tools considered in this work are the Newcastle-Ottawa scale (NOS) and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) for observational studies, the Consolidated Standards of Reporting Trials (CONSORT), the Jadad scale, the Cochrane risk of bias tool 2 (RoB2) for randomized controlled trials, the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) and the Assessment of Multiple Systematic Reviews 2 (AMSTAR2), and AMSTAR-PLUS for meta-analyses. WHAT IS ALREADY KNOWN?: The informativeness and quality of evidence synthesis inherently depend on the quality of what has been pooled into meta-research projects. Beyond the quality of included individual studies, only a methodologically correct process, in relation to systematic reviews and meta-analyses themselves, can produce a reliable and valid evidence synthesis. WHAT IS NEW?: In this overview, the authors provide a synthesis of advantages and disadvantages and main characteristics of some of the most frequently used tools to assess quality of individual studies, systematic reviews, and meta-analyses. POTENTIAL IMPACT: This overview serves as a starting point and a brief guide to identify and understand the main and most frequently used tools for assessing the quality of studies included in meta-research. The authors here share their experience in publishing several meta-research-related articles covering different areas of medical sciences.

Intraoperative use of opioids may be associated with postoperative hyperalgesia and increased analgesic consumption. Side effects due to perioperative use of opioids, such as postoperative nausea and vomiting may delay discharge. We hypothesized that total intravenous anesthesia consisting of lidocaine and dexmedetomidine as an opioid substitute may be an alternative technique for laparoscopic cholecystectomy and would be associated with lower fentanyl requirements in the postoperative period and less incidence of postoperative nausea and vomiting. 80 Anesthesiologists I–II adults were scheduled for elective laparoscopic cholecystectomy. Patients were randomly allocated into two groups to have either opioid-free anesthesia with dexmedetomidine, lidocaine, and propofol infusions (Group DL) or opioid-based anesthesia with remifentanil, and propofol infusions (Group RF). All patients received a standard multimodal analgesia regimen. A patient controlled analgesia device was set to deliver IV fentanyl for 6 h after surgery. The primary outcome variable was postoperative fentanyl consumption. Fentanyl consumption at postoperative 2nd hour was statistically significantly less in Group DL, compared with Group RF, which were 75 ± 59 μg and 120 ± 94 μg respectively, while it was comparable at postoperative 6th hour. During anesthesia, there were more hypotensive events in Group RF, while there were more hypertensive events in Group DL, which were both statistically significant. Despite higher recovery times, Group DL had significantly lower pain scores, rescue analgesic and ondansetron need. Opioid-free anesthesia with dexmedetomidine, lidocaine and propofol infusions may be an alternative technique for laparoscopic cholecystectomy especially in patients with high risk for postoperative nausea and vomiting. O uso de opioides no período intraoperatório pode estar associado à hiperalgesia e ao aumento do consumo de analgésicos no período pós-operatório. Efeitos colaterais como náusea e vômito no período pós-operatório, por causa do uso perioperatório de opioides, podem prolongar a alta. Nossa hipótese foi que a anestesia venosa total com o uso de lidocaína e dexmedetomidina em substituição a opioides pode ser uma técnica opcional para a colecistectomia laparoscópica e estaria associada a uma menor solicitação de fentanil e incidência de náusea e vômito no período pós-operatório. Foram programados para colecistectomia laparoscópica eletiva 80 pacientes adultos, estado físico ASA I-II. Os pacientes foram randomicamente alocados em dois grupos para receber anestesia livre de opioides com infusões intravenosas (IV) de dexmedetomidina, lidocaína e propofol (Grupo DL) ou anestesia baseada em opioides com infusões de remifentanil e propofol (Grupo RF). Todos os pacientes receberam um regime padrão de analgesia multimodal. Um dispositivo de analgesia controlada pelo paciente foi ajustado para liberar fentanil IV por seis horas após a cirurgia. O desfecho primário foi o consumo de fentanil no pós-operatório. O consumo de fentanil na segunda hora de pós-operatório foi significativamente menor no grupo DL do que no Grupo RF, 75 ± 59 μg e 120 ± 94 μg, respectivamente, mas foi comparável na sexta hora de pós-operatório. Durante a anestesia, houve mais eventos hipotensivos no Grupo RF e mais eventos hipertensivos no grupo DL, ambos estatisticamente significativos. Apesar de apresentar um tempo de recuperação mais prolongado, o Grupo DL apresentou escores de dor e consumo de analgésicos de resgate e de ondansetrona significativamente mais baixos. A anestesia livre de opioides com infusões de dexmedetomidina, lidocaína e propofol pode ser uma técnica opcional para a colecistectomia laparoscópica, especialmente em pacientes com alto risco de náusea e vômito no pós-operatório.

CONTEXT: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. OBJECTIVE: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. DESIGN: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. SETTING: The study was conducted in 19 tertiary pediatric endocrinology clinics. PATIENTS: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study. RESULTS: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. CONCLUSION: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Microbial resistance has progressed rapidly and is becoming the leading cause of death globally. The spread of antibiotic-resistant microorganisms has been a significant threat to the successful therapy against microbial infections. Scientists have become more concerned about the possibility of a return to the pre-antibiotic era. Thus, searching for alternatives to fight microorganisms has become a necessity. Some bacteria are naturally resistant to antibiotics, while others acquire resistance mainly by the misuse of antibiotics and the emergence of new resistant variants through mutation. Since ancient times, plants represent the leading source of drugs and alternative medicine for fighting against diseases. Plants are rich sources of valuable secondary metabolites, such as alkaloids, quinones, tannins, terpenoids, flavonoids, and polyphenols. Many studies focus on plant secondary metabolites as a potential source for antibiotic discovery. They have the required structural properties and can act by different mechanisms. This review analyses the antibiotic resistance strategies produced by multidrug-resistant bacteria and explores the phytochemicals from different classes with documented antimicrobial action against resistant bacteria, either alone or in combination with traditional antibiotics.

OBJECTIVE: The aim of this review is to make a state of the art of the potential influence of neuropsychiatric symptoms (NPs) on caregiver stress and vice versa. METHODS: We searched PubMed and Google Scholar for potential eligible articles. RESULTS: Patients with Alzheimer's disease (AD) usually need high levels of care in all activities of daily living, most of them provided by family members, friends, or informal caregivers. Caregivers have to cope with both age-related conditions and dementia-related factors. Therefore, caregiving in dementia is more difficult and stressful than caregiving for older adults, affected by other conditions. Neuropsychiatric symptoms, such as anxiety, agitation, disinhibition, aggressive behavior, and sleep disturbances are more closely related to caregiver burden, and associated with more negative outcomes such as decline in their general health, quality of life, and social isolation. Caregiver burden worsens relationship between caregiver and patients with AD. Thus, this relationship may increase the frequency and severity of NPs. Predictors of burden were being a woman, a spouse, and old person with immature coping mechanisms, social isolation, with insufficient knowledge about dementia, poor premorbid relationship with patient, and high levels of negative expressed emotions. CONCLUSION: Because of the bidirectional relationship between caregiver burden and NPs, the active management strategies of dementia care should include early identification and treatment risk factors for both caregiver stress and NPs in patients with AD. Therefore, to improve one of them can be exert beneficial for the other.

BACKGROUND: Diabetes is characterized by chronic hyperglycemia and disturbances of carbohydrate, lipid and protein metabolism. We aimed to research association between serum lipid profile and blood glucose, hypothesizing that early detection and treatment of lipid abnormalities can minimize the risk for atherogenic cardiovascular disorder and cerebrovascular accident in patients with type 2 diabetes mellitus. METHODS: Fasting blood glucose (FBG), total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), triglyceride (TG) and glycated haemoglobin (HbA1c) levels were evaluated. A hepatic ultrasound was performed for every diabetic to evaluate hepatosteatosis. The study was done from January 2014 to June 2014 among 132 patients with T2DM who were admitted to outpatient clinic of Family Medicine department in a university hospital. The patients whose taking multi-vitamin supplementation or having hepatic, renal or metabolic bone disorders (including parathyroid related problems) were excluded from the study for the reason that those conditions might affect the carbohydrate and lipid metabolism in diabetes. Test of significance was calculated by unpaired student's t test between cases and controls. Correlation studies (Pearson's correlation) were performed between the variables of blood glucose and serum lipid profile. Significance was set at p<0.05. RESULTS: Results of serum lipid profile showed that the mean values for TC, TG, HDL and LDL in female patients were 227.6 ± 57.7 mg/dl, 221.6 ± 101.1 mg/dl, 31.5 ± 6.7 mg/dl and 136.5 ± 43.7 mg/dl, respectively. The mean values for TC, TG, HDL and LDL in male patients were 219.1 ± 34.7 mg/dl, 250.0 ± 100.7 mg/dl, 30.2 ± 7.4 mg/dl and 125.7 ± 21.4 mg/dl, respectively. Significantly higher mean serum levels of TC, TG and LDL and significantly lower mean serum levels of HDL were noted in patients with diabetes (p<0.001). FBG showed significant positive correlation with TC (p<0.05) and TG (p<0.05). Significant correlations were observed between serum levels of TC, TG, LDL and hepatosteatosis and HbA1c (p<0.05). CONCLUSIONS: The study showed widespread lipid abnormalities in the course of diabetes triggered dyslipidemia as hypercholesterolemia, hypertriglyceridemia, elevated LDL and decreased HDL. This study proposes the predominance of hyperlipidemia over increased prevalence of diabetic dyslipidemia.

INTRODUCTION: Hyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome (MODS), and critical illness. The International Histiocyte Society has recommended that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) should be treated with the same immunosuppressant/cytotoxic therapies used to treat primary HLH. We hypothesized that patients with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH. METHODS: We conducted a multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS treated with less immunosuppression (plasma exchange and intravenous immunoglobulin or methyl prednisolone) or with the primary HLH protocol (plasma exchange and dexamethasone or cyclosporine A and/or etoposide). The primary outcome assessed was hospital survival. RESULTS: Twenty-three children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS were enrolled (median ferritin = 6341 μg/dL, median number of organ failures = 5). Univariate and multivariate analyses demonstrated that use of plasma exchange and methyl prednisolone or intravenous immunoglobulin (n = 17, survival 100%) was associated with improved survival compared to plasma exchange and dexamethasone and/or cyclosporine and/or etoposide (n = 6, survival 50%) (P = 0.002). CONCLUSIONS: Children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone. Randomized trials are required to evaluate if the HLH-94 protocol is helpful or harmful compared to this less immune suppressive and cytotoxic approach in this specific population.