Dysphagia is one of the major post-stroke complications that can severely damage a patient's quality of life. An increasing number of studies have demonstrated that many kinds of nonpharmacological treatments can be used for post-stroke dysphagia. However, there is not enough evidence evaluating the effectiveness and safety of these interventions. This study will conduct a systematic review, and Bayesian network meta-analysis, of nonpharmacological treatments in order to provide evidence for a future study investigating more options for post-stroke dysphagia.Randomized controlled trials (RCTs) of adult patients aged >18 years old who meet the criteria for a diagnosis of post-stroke dysphagia will be included, regardless of gender, nationality, or education level. Four Chinese databases  and four English databases  will be searched. Two independent reviewers will evaluate the title summary for each RCT. Disagreements will be discussed with a third commentator. Standard pairwise meta-analysis, including heterogeneity analysis, subgroup analysis, and sensitivity analysis, will be performed using the RevMan 5.3 software, and the risk of bias assessment will be conducted based on the methodological quality of the included trials recommended by the Cochrane Handbook 5.1. The Bayesian network meta-analysis will be performed using R-3.3.2 software. The quality evaluation of this study will be completed using the World Health Organization's Grading of Recommendations, Assessment, Development, and Evaluation.This study will summarize all the selected trials aimed at estimating the effectiveness, as well as safety, of applying nonpharmacological treatments to post-stroke dysphagia.This systematic review will provide evidence to assess the validity and safety of applying different types of nonpharmacological treatments for post-stroke dysphagia, which may provide clinicians with more choices in the treatment of this disease.CRD42019119368. Because of dysphagia, food and water are mistakenly inhaled into the lungs, which may cause lung infections and aspiration pneumonia. Dysphagia may also cause an inadequate intake of nutrients and water, which can lead to malnutrition, electrolyte disorders, aspiration pneumonia, and even apnea. Dysphagia also affects the patients’ quality of life and mental health, disrupting their daily lives and causing a social burden.Dysphagia  is 1 of the major poststroke complications. The incidence rate of poststroke swallowing disorders is as high as 37% to 78% , which becomes an independent quality-of-life risk factor that seriously affects the prognosis of stroke patients. for dysphagia include compensation therapy , swallowing function training , physiotherapy , alternative therapy , and drugs. Although drugs improve swallowing speed, pharmacotherapy has only a limited amount to offer patients with more severe complications. At the same time, pharmacotherapy requires a swallowing movement that cooperates with the patient's tongue, which is difficult for patients with a poor swallowing function. Some randomized controlled trials (RCTs) have suggested that nonpharmacological therapy may improve the remaining dysphagia experienced by patients after having a stroke. Noninvasive cortical stimulation–9 , electrical stimulation, exercise, acupuncture, and some other alternative therapies–18 may potentially be viable alternative treatments for patients with poststroke dysphagia. These nonpharmacological therapies have no reported side effects or drug interactions according to the current evidence, so they are more easily accepted by patients than pharmacological treatments are. However, most current meta-analyses have only compared the effectiveness of 2 nonpharmacological therapies.–21 To evaluate the effect of different types of nonpharmacological therapies on patients with poststroke dysphagia, it is necessary to carry out a network meta-analysis to draw a convincing conclusion.The current treatment methodsThis systematic review and network meta-analysis will aim to solve this problem, and evaluate the potential availability and safety of all the different types of nonpharmacological interventions for poststroke dysphagia.1.1The objective of this study will be to compare the effect of different nonpharmacological interventions for poststroke dysphagia using a network meta-analysis of RCTs.22.1A systematic review and network meta-analysis will be carried out in this study, which will only include RCTs and will exclude equivalence trials and clinical inferiority trials.2.2This study is consistent with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statements. We have registered the protocol on the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42019119368).2.32.3.1This study will only include RCTs, and the study design will strictly follow P-Population, I-Intervention, C-Control, O-Outcome, S-Study designs (PICOS) principles. Any RCTs of nonpharmacological treatment for poststroke dysphagia will be included in the study; studies using pharmacological treatment will not be included. In addition, we will not admit non-RCTs, animal experiments, human cell or tissue experiments, or repeated published studies.2.3.2 will be included, regardless of sex, nationality, or education level. Patients with no history of other neurological diseases or with pre-existing oral and maxillofacial surgery that involved the lips and/or tongue will be involved. Participants who do not meet the diagnostic criteria, or who are on medication, will be excluded.Adults aged >18 years who meet the criteria for a diagnosis of poststroke dysphagia according to their National Institutes of Health Stroke Scale score and a Video Fluoroscopic Swallowing Study (VFSS)2.3.3The treatment group will include only nonpharmacological intervention studies, including (but not limited to) complementary and alternative therapies such as acupuncture, massage, cupping, and other methods used to stimulate acupoints; surface neuromuscular electrical stimulation such as tDCS, transcranial magnetic stimulation (rTMS), and surface neuromuscular electrical stimulation (sNMES); rehabilitation training such as tongue to jaw resistance training, tongue training, and swallowing training; and psychological interventions.The control group will use a variety of different conventional treatments such as placebo intervention, no treatment, false stimulation under the same conditions, and usual care.2.3.4Primary outcome indicators will include changes in swallowing function, determined by the following: a VFSS ; and a functional dysphagia scale score .Secondary outcome indicators will include a tongue pressure assessment, a quality of life related to the swallowing questionnaire, a the Rosenbek Penetration-Aspiration Scale (PSA) scale, a Dysphagia Outcome and Severity Scale (DOSS) scale, OTT , PTT , and TTT .2.4We will search electronic databases established before November, 2019, including 4 Chinese databases  and 4 English databases . In addition, gray references such as conference papers and bibliographies will also be included.2.5A comprehensive search strategy will be developed for PubMed or MEDLINE Fig. .2.62.6.1The evaluation staff will be trained, and the literature used will be prescreened, to ensure the standardization of the literature screening process. The selection process requires at least 2 independent evaluators (W.Z.J. and Z.Y.), both of whom are masters of (non)acupuncture and moxibustion. Two reviewers will independently screen the titles and abstracts to select eligible articles, and, after completing the screening phase, articles that are deemed relevant by at least 1 of the reviewers will be subjected to a full-text review. Any disagreements between the 2 reviewers will be resolved by discussion with a third reviewer (J.X.). The study selection process will be detailed in the systematic evaluation plan and the full text. The following steps are included .The extracted information will include study identification , study characteristics , inclusion criteria , intervention type , and other confounding factors may lead to inaccuracy .2.7 in the methodological quality of the RCTs. It includes the following 7 aspects: random sequence generation (selection bias); allocation concealment (selection bias); blinding of participants and personnel (performance bias); blinding of outcome assessment (detection bias); incomplete outcome data (attrition bias); selective reporting (reporting bias); and other biases.We will use the Cochrane Collaboration's tool for assessing the risk of bias (RoB2)The risk of bias will be classified as high, medium, or low. All the differences will be discussed by 2 reviewers, or, if not, will be discussed with the third reviewer.2.82.8.1Q and P values to qualitatively analyze the statistical heterogeneity of the results. The larger the Q value relative to the degree of freedom (d.f.) and the smaller the P value, the greater the possibility of heterogeneity. When the P value is <.05, it will indicate that there is statistical heterogeneity between the groups. We will conduct a quantitative analysis of the heterogeneity of the results through I2. When I2 < 25%, it means the heterogeneity is low. When 25% < I2 < 50%, it indicates a moderate degree of heterogeneity in the study. I2 > 75% means the heterogeneity is large. In general, when I2 > 50%, it indicates that there is substantial heterogeneity. If there is heterogeneity between the results, we will use a subgroup analysis. Meta-regression will be conducted if there are more than 2 variables. A sensitivity analysis will be performed to determine data reliability based on missing data, sample size, and heterogeneity. When the data analysis meets the homogeneity, a fixed-effect model can be used. If there is no homogeneity, a random-effect model will be used to estimate the combined effect. We will use a funnel plot and Nfs to estimate the impact of publication bias on the results of the meta-analysis.Data analysis and pair-wise meta-analysis will be performed using the RevMan 5.3 software through the Cochrane Collaboration. We will determine the effect size based on the form and type of the study. Relative risk and standardized mean difference have been selected as the effect size expressions for dichotomous and continuous variables, with 95% confidence intervals (95% CIs). We will use Cochrane 2.8.2 Parameters such as mean and standard deviation (SD) will use noninformative prior distributions and normal prior distributions. A sensitivity analysis will also be used to evaluate the effect of different prior information on the results. Each Markov chain Monte Carlo will run 100,000 times, and the total number of iterations will be 300,000. The first 50,000 times will be discarded as the number of simulated annealings. The convergence evaluation will use Brooks–Gelman–Rubin plots, and we will calculate the 95% CI. If there is a closed loop, the node analysis method will be used to detect the consistency, calculating the difference and Bayesian P value. A sensitivity analysis will be conducted to judge the stability of the results when any data are missing. This study method will be reported strictly based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocol (PRISMA-P).We will use the “gemtc” V.0.8.1 package of R-3.3.2 software for network meta-analysis based on a Bayesian framework.2.8.3 Because the network meta-analysis is based on RCTs, the basic principles of GRADE's application in network meta-analysis will mainly examine 5 degrading factors: risk of bias, indirectness, inconsistency, imprecision, and publication bias.The quality evaluation of this study will be completed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) established by the the World Health Organization.3 Another systematic review of 6 RCTs, with a total of 163 patients, concluded that repetitive transcranial magnetic stimulation had a positive effect on poststroke dysphagia. In addition, 2 meta-analyses, with a total of 8200 participants, provided new evidence supporting the efficacy and safety of acupuncture therapy for poststroke dysphagia in the short term when compared with medication.,31 However, this literature lacked evidence comparing the benefits of different nonpharmacological interventions for poststroke dysphagia. Our systematic review and network meta-analysis will comprehensively analyze all the evidence available regarding the effects of different nonpharmacological interventions for poststroke dysphagia. This is different to the traditional meta-analysis method in that a Bayesian network meta-analysis will provide comparisons of both direct and indirect interventions.More and more studies are showing that poststroke dysphagia can be improved through some nonpharmacological treatments. During surface neuromuscular electrical treatment, a systematic review of 8 RCTs, with a total of 329 patients, reported tDCS seemed to be more effective than that what without neuromuscular electrical stimulation in the treatment of poststroke dysphagia, in the short term, and considering the limited number of studies available.3.1As this study does not involve raw data collection, no ethical review is required. The results of this study will provide strong evidence for the treatment of poststroke dysphagia using nonpharmacological treatments. This will help clinicians to make treatment decisions for poststroke dysphagia. This systematic review will be published in a peer-reviewed journal and at an international academic conference.3.2This will be the first systematic review and network meta-analysis to synthesize the utility and safety of nonpharmacological treatments for improving poststroke dysphagia. It could provide a basis for clinicians to determine the benefits, and also drawbacks, of the various methods of treatment of poststroke dysphagia and provide evidence for the clinical treatment of dysphagia in the field of nonpharmacological therapy, improving the patients’ quality of life. The methods and quality assessments will follow systematic review guidelines and criteria to minimize the risk of bias. However, a potential limitation of this study could be that different types of nonpharmacological treatment may cause greater heterogeneity, and our conclusions will depend on the quality and quantity of the original studies.Conceptualization: Weixun Qin, Yu Zhang.Data extraction: Xin Jiang, Jing Gao.Investigation: Yue Zhong, Qing Yuan.Methodology: Weixun Qin, Yu Zhang, Zhijie WangProject administration: Qing YuanResources: Zhijie Wang, Jing Gao, Qing YuanSoftware: Yu Zhang, Zhijie WangWriting – original draft: Weixun Qin, Yu Zhang, Zhijie WangWriting – review & editing: Xin Jiang, Qing YuanWeixun Qin orcid: 0000-0001-8512-5686.


Anabolic steroids are commonly used by athletes, body builders, and young adults to improve muscle strength. Deleterious effects of anabolic steroids on physical health are well-established. Psychiatric aspects are of particular importance and include psychosis, delirium, mania, depression, and aggression. We describe the case of a young gentleman who was managed as a case of androgenic steroid induced delirium.A 33-year-old gentleman presented with increased aggression, hostility, and destructive impulses. He was a regular user of testosterone propionate, testosterone cyprionate and trenbolone acetate up to 200 mg daily in injectable form. His mental status examination showed labile effect, flight of ideas and persecutory delusions. Physical examination was positive for atrophic testes. Laboratory results showed a decreased plasma testosterone level of 9.59 nmol/l (10.4–37.4 nmol/l). Sex Hormone Binding Globulin was 23.8 nmol/l (18.3–54.1 nmol/l) and bioavailable testosterone was 5.110 nmol/l (4.36–14.30 nmol/l).He was diagnosed as a case of anabolic steroids induced delirium.Patient was treated with regular haloperidol and quetiapine after which his sensorium, speech and behavior improved. He was discharged on haloperidol 7.5 mg and quetiapine 700 mg daily.The purpose of this case report is to emphasize on the neuropsychiatric effects and management of anabolic steroids manifested by delirium, increased aggression, hostility, and destructive impulses. A variety of formulations of anabolic steroids are available. Oral formulations include methyltestosterone, oxandrolone, and stanozolol. With passage of time, users progress to injectable forms of anabolic steroids like nandrolone decanoate and testosterone propionate. Sometime, these steroids are used in doses much higher than the recommended levels. Deleterious effects of using anabolic steroids on physical health are well-established and include high blood pressure, gynecomastia, atrophic testes, edema, acne, and rapid weight gain. However, psychiatric aspects of the use of these steroids are of particular importance and include psychosis, delirium, mania, depression, and aggression among many others.–5 We report a case highlighting neuropsychiatric effects of AAS use in a young male. This study was approved by the ethics committee and Institutional Review Board of Hamad Medical Corporation (MRC-04-19-475), and the written informed consent was obtained from the patient.Androgen anabolic steroids (AAS) are frequently used by athletes to improve muscle strength and increase endurance due to their effects on testosterone receptors.2A 33-year-old gentleman, working as a school counsellor, with no family history of mental illness, previously diagnosed as bipolar disorder in 2018, was brought to the emergency department of a general hospital after his colleagues called the Emergency Medical Services when they found him in a confused state in his apartment. In the emergency department, he presented with altered level of consciousness and displayed disorganized and agitated behavior in terms of entering a female cubicle and trying to take another patient's mobile phone, damaging an intravenous drip stand, taking a hook from the wall and damaging the tap of an oxygen supply, which was managed by physical and chemical restraints. His manager reported that he was absent from work for three days and that he found anabolic steroids in his apartment. He was then transferred to the psychiatric inpatient unit for further management, with a provisional diagnosis of substance-induced confusion.At the beginning of his admission, his mental state examination was significant for labile affect, irrelevant speech, derailment, flight of ideas, and persecutory delusions. He was on high risk one-to-one observations precautions and nursing team have reported disorganized behavior in terms of eating cigarettes, tried to burn his genitals with cigarettes, jumping over the nursing station, unable to dress himself, tried to use the female nursing staff washroom, talkativeness, and disturbed sleeping pattern, in addition to altered level of sensorium throughout the day. He also mistook the female occupational therapist for his mother and tried to kiss her feet. Otherwise, he did not display hallucinatory behavior, grandiose delusions, or elated mood. He was vitally stable and he had a BMI of 29. Physical examination was unremarkable except for testicular atrophy. He also reported taking tadalafil 20 mg for erectile dysfunction.Past psychiatric history is significant for 1 similar episode in 2018 for which patient was admitted in a psychiatric hospital under the impression of bipolar disorder and was discharged on sodium valproate 2 g daily, olanzapine 20 mg daily, haloperidol 5 mg twice daily, and procyclidine 5 mg BID. He took the medications for 3 months and stopped them because of sedation and weight gain. Collateral history obtained from parents were negative for manic symptoms.Substance use history is positive for anabolic steroids. He took 5 courses of injectable testosterone propionate and cyprionate, and trenbolone acetate from the age of 21 for bodybuilding purposes. Last had the injectable in May 2019. He described 1 course as 100 to 200 mg daily for 90 days. One month prior this admission he used to take metandienone tablets 20 mg daily.Complete blood count, comprehensive metabolic panel, lumbar puncture, computed tomography of the brain were unremarkable. Urine toxicology screen was negative for amphetamines, cannabis, cocaine, and opiate. HIV and syphilis screening were negative. Endocrinology work-up is illustrated in Table 3,7 Initial animal studies have reported that long-term exposure to high doses of testosterone heightened level of aggression in rats. One probable pathophysiology could be that high aggression is associated to decreased serotonin (5-HT) neurotransmission as evidenced by decreased in both 5-HT and 5-HT metabolite, 5-HIAA, in the hippocampus of adult rats exposed to testosterone propionate. In addition, the aggressive behavior was decreased by treatment with selective agonists of 5-HT1A, 5-HT1B, and 5-HT2A / 2C receptors. Likewise, Ambar and Chiavegatto have reported reduced 5-HT1B mRNA levels in the hippocampus, hypothalamus, amygdala, and prefrontal cortex of nandrolone-treated mice suggesting that the serotonergic tone in these brain areas has a key role for AAS-induced aggression.One of the cardinal aspects of this case was the management of the aggressive and disruptive behavior. Numerous studies have linked AAS to aggressive behavior. Cases of delirium following therapeutic use of corticosteroids have been reported as well. The possible mechanisms might be the same as described for AAS-induced aggression and mania.,4Another important, albeit less reported and less studied effect of anabolic steroids use is confusion and delirium. In a double-blind, placebo-controlled crossover trial to study neuropsychiatric effects of anabolic steroids, confusion and increased distractibility was also observed, in addition to violence, aggressive behavior and mood related symptoms, with high-dose methyltestosterone (240 mg/d) administration. There are a few case reports highlighting the occurrence of manic features in context of AAS. For example, Papazisis et al reported the case of a 25-year-old male body builder, with history of depression, who developed mania and psychosis shortly after increasing his AAS dose to >2 g daily, which unfortunately resulted in suicide secondary to AAS discontinuation and ultimately withdrawal-related depression. Of note, the healthy male produces 2.5 to 11 mg of testosterone daily, and the therapeutic dose for treatment for muscle wasting in HIV is approximately 100 to 150 mg daily.,15 On the other hand Weiss et al described a case of a 28-year-old gentleman, known to have bipolar disorder, with acquired immunodeficiency syndrome (AIDS) who developed mania after starting the prescribed testosterone patch therapy (2–6 mg daily) 1 month earlier, thus indicating a lower threshold to AAS-induced mania in certain populations. Franey and Espiridion have highlighted the probable increase in susceptibility to develop mania in context of heavy cannabis usage in their case report of a 30-year-old male, when actually previous randomized clinical trials investigating psychiatric effects of AAS have excluded participants with a history of drug abuse.As regard to the past psychiatric history of bipolar disorder with our patient, we were doubtful that he indeed suffered from bipolar disorder. We were unable to obtain a medical report of his admission in 2018 as he was in another country at that time. However, collateral history from parents were negative for manic symptoms. Besides, the patient presented with delirium-type of clinical picture together with disorganized behavior rather than a manic type. At best we speculate that his past episode was possibly an AAS-induced manic state in light of a review by Pope et al which reports at least 5% of AAS users will experience AAS dose-dependent manic or hypomanic episodes.4Patient improved significantly after receiving treatment in terms of his orientation and behavior. He was fully oriented by the time he was discharged. He was informed about his diagnosis and that anabolic steroids use was the potential causative factor of his condition. He understood and vowed to abstain from using anabolic steroids use in future.5The purpose of this case report is to emphasize on the neuropsychiatric effects and management of anabolic steroids manifested by delirium, increased aggression and hostility, and destructive impulses. Physicians and psychiatrists alike should be aware of the dimensions of use of AAS and the complex connection between neuropsychiatric and behavioral presentation. Further studies that will shed light on AAS-induced delirium, especially in the clinical setting, are necessary.Mohamed Adil Shah Khoodoruth conceived the topic idea, identified and managed the case. He wrote the case presentation, discussion and conducted literature review. Adeel Ahmad Khan conducted literature review, contributed to writing introduction and discussion. In addition, he critically reviewed the manuscript.


Sarcopenia is prevalent in patients with chronic liver disease, and affected patients tend to have worse clinical outcomes and higher mortality. However, relevant analyses are limited by heterogeneity in the definition of sarcopenia and in the methodological approaches in assessing it. We reviewed several radiologic methods for sarcopenia in patients with chronic liver disease. Dual energy X-ray absorptiometry (DXA) can measure muscle mass, but it is difficult to evaluate muscle quality using this technique. Computed tomography, known as the gold standard for diagnosing sarcopenia, enables the objective measurement of muscle quantity and quality. The third lumbar skeletal muscle index (L3 SMI) more accurately predicted the mortality of subjects than the psoas muscle index (PMI). Few studies have evaluated the sarcopenia of chronic liver disease using ultrasonography and magnetic resonance imaging, and more studies are needed. Unification of the measurement method and cut-off value would facilitate a more systematic and universal prognosis evaluation in patients with chronic liver disease. Sarcopenia is defined as reduced skeletal muscle mass and reduced muscle functionality . PrimaryDespite growing research on sarcopenia, progress is hampered by the lack of unified definitions. Several imaging modalities, such as dual energy X-ray absorptiometry (DXA), ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) have made it possible to use body composition assessments for patients with chronic liver disease. Measuring muscle mass with several forms of imaging is less affected by acute illness or cognitive dysfunction compared with measuring strength or physical performance and can be objectively employed in clinical practice . This reMeasurements of skeletal mass are provided by DXA, which allows for the quantification of three body compartments ) based upon the differential tissue attenuation of X-ray photons .Lean mass includes muscle and other components such as skin, tendons, and connective tissues. DXA is biased by the fluid overload that is frequently present in decompensated cirrhosis . Lean map < 0.001), but the correlation between the lean mass index and SMI was weaker  and falsely high in patients with ascites in the image analysis of patients before liver transplantation (LT) [Lindqvist et al. noted that ASMI showed similar results to SMI  based on CT  . To dateion (LT) ,17. The The limitation of DXA is its inability to assess muscle quality in contrast to CT and MRI. DXA cannot quantify intramuscular adipose tissue within and around muscles, and DXA-measured ASMI has shown only moderate correlation with SMI based on CT (γ = 0.41–0.66), which is considered to be the gold standard for estimating muscle mass in research ,18. DespUS has also been applied to measure muscle size and myosteatosis. US is easy, inexpensive, and uses portable equipment, allowing it to be performed at the bedside, with no harm to the patient from radiation. US-based measurements have shown positive correlations with DXA-, CT-, and MRI-based measurements ,20,21. HTandon et al. demonstrated that a nomogram based on body mass index and right thigh muscle thickness can identify male and female patients with sarcopenia defined by cross-sectional CT . Hari etCT imaging is increasingly used as the gold standard to quantify skeletal muscle mass along with MRI and constitutes a good resource for the objective identification of sarcopenia. However, CT suffers from the disadvantage of radiation exposure. Nevertheless, patients with chronic liver disease frequently receive CTs to evaluate hepatocellular carcinoma or the complications of portal hypertension.Generally, the cross-sectional areas of the psoas or abdominal muscle mass of the third (L3) or fourth (L4) lumbar vertebra levels that are not affected by activity are used. Although the cross-sectional area of the level of the umbilicus has previously been used , this arMost of the measured area is corrected with height and sometimes with BMI . Height Occasionally, the psoas muscle is selected from other skeletal muscles of the region because it is located centrally, is easily identified, and is not directly affected by abdominal distension in the presence of ascites. There are several methods for measuring the area of the psoas muscle:(1) Transverse psoas muscle thickness (TPMT), where the greatest transverse diameter of the psoas muscle runs perpendicular to the long axis (anterior–posterior oblique) of the psoas muscle diameter . The res2) The psoas muscle index (PMI), where the estimated or measured psoas muscle area is adjusted by height . The est The psoa2/m2 in males and 3.92 cm2/m2 in females and a cut-off value for the estimated psoas muscle of 6.0 cm2/m2 in males and 3.4 cm2/m2 in females [A consensus definition using PMI was proposed by the Japan Society of Hepatology guidelines for sarcopenia. This definition includes a cut-off value for the measured psoas muscle area of 6.36 cm females ,30,39 or females ,33.However, there is no evidence confirming that the cross-sectional area of the psoas muscles has a good correlation with the whole-lumbar or the whole-body muscle volume. Among 396 patients with end-stage liver disease, PMI was less likely to predict mortality than SMI in male patients. Male patients who died had a lower SMI but not a lower PMI compared to male patients who were alive [The attenuation of muscle was additionally measured to evaluate muscle quality. Low muscle attenuation, referred to as myosteatosis, indicates increased intramuscular fat content, which contributes to muscle weakness independent of the age-associated loss in muscle mass ,48. Wang2/m2 for males and less than 39 cm2/m2 for females at the L3 level [The same cut-off value cannot be uniformly applied because the muscle mass varies according to age, sex, BMI, and ethnicity. There is wide heterogeneity in the cut-off values of SMI used to defined sarcopenia in chronic liver disease: A sex-specific cut-off value derived in patients with solid tumors related to mortality ,35,49,50L3 level . In theiMRI can also be used to evaluate muscle quantity and quality. MRI provides high resolution and permits the separation and quantification of muscle compartments and fat distribution. It can be used to evaluate detailed anatomical changes of muscle, including muscular atrophy, fatty degeneration, and edema. In contrast to CT, MRI carries no risk of ionizing radiation exposure or kidney injury due to iodine contrast media administration. MRI can be performed without the administration of contrast media because of its high soft-tissue contrast and multiparametric characteristics.With advances in MRI techniques, the assessment of the chemical composition of tissue has also become possible. MR spectroscopy (MRS) is a representative MR technique that assesses the chemical composition of tissue ,52. DIXOCompared with CT, which is the gold standard for the evaluation of sarcopenia in several guidelines, MRI has shown similar performance in the evaluation of sarcopenia in healthy subjects ,57. TradThe radiologic evaluation of sarcopenia has the advantage of being able to measure muscle mass objectively and quantitatively. CT and MRI, which are considered to be gold standards for muscle mass measurements, showed high interobserver agreement with Pearson’s correlation coefficient ,63. The 2/(kg/m2) for men and 7.47 cm2/(kg/m2) for women. After the publication of the EWGSOP guidelines, some studies were designed to determine specific cut-off values for sarcopenia assessment using CT for Japanese and Asian adults. Two studies provided PMI cut-off values of 3.74 and 6.36 cm2/m2 for men and 2.29 and 3.92 cm2/m2 for women, respectively, based on Japanese liver donor data. The authors suggested that that the cut-off values in Western studies could be different from the actual values in Asian populations due to differences in body sizes, lifestyles, and ethnicities [In previous studies, different cut-off values were applied according to sex, etiology of the disease, ethnicity, and the modality used. The SMI values of male patients were significantly higher than those of female patients; however, the frequency of sarcopenia among male patients was higher than that in female patients when sex-specific cut-offs were applied ,35,39. Pnicities ,66. FurtThere is a need for standardized CT, as CT parameters such as tube potential, the use of a contrast agent, and slide thickness also affect the assessment of skeletal muscle. A reduction in tube potential from 140 to 80 kV leads to a 5.2% decrease in SMI , and thep < 0.001) in predicting mortality [Moreover, radiological assessment does not always reflect strength or physical performance ,72,73,74ortality . For musortality .The evaluation of sarcopenia is crucial in patients with chronic liver disease, as well as other chronic illness, because sarcopenia is one of the important prognostic factors ,5. Overa


Legionella spp. contamination was also verified. For this purpose, four different monochloramine-treated networks, in terms of the duration of treatment and method of biocide injection, were investigated. Untreated hot water, municipal cold water and, limited to N-nitrosamines analysis, hot water treated with chlorine dioxide were analyzed for comparison. Legionella spp. contamination was successfully controlled without any formation of N-nitrosamines. No nitrification or formation of the regulated DBPs, such as chlorites and trihalomethanes, occurred in monochloramine-treated water networks. However, a stable formulation of hypochlorite, its frequent replacement with a fresh product, and the routine monitoring of free ammonia are recommended to ensure a proper disinfection. Our study confirms that monochloramine may be proposed as an effective and safe strategy for the continuous disinfection of building plumbing systems, preventing vulnerable individuals from being exposed to legionellae and dangerous DBPs.The formation of potentially carcinogenic N-nitrosamines, associated with monochloramine, requires further research due to the growing interest in using this biocide for the secondary disinfection of water in public and private buildings. The aim of our study was to evaluate the possible formation of N-nitrosamines and other toxic disinfection by-products (DBPs) in hospital hot water networks treated with monochloramine. The effectiveness of this biocide in controlling  Legionella contamination in complex water systems is still a critical issue, especially in healthcare settings where Legionella colonization of hot water systems is the primary risk factor for Legionnaires’ disease [Legionella infections, recommend using biocides for contaminated hot water treatment [The control of  disease . Nationareatment ,3. To dareatment . Chlorinreatment . Exposurreatment ,7. Alterreatment ,9. The DLegionella colonization in urban water supply systems, using monochloramine instead of free chlorine for disinfecting municipal drinking water [Monochloramine is a biocide that has long been used in the USA for the primary disinfection of municipal water supplies . Some stng water ,14. On tng water ,16,17,18ng water , even ifng water ,21,22,23Legionella spp. contamination was also verified. For this purpose, four different monochloramine-treated networks, in terms of the duration of treatment and method of biocide injection were investigated. Samples of untreated hot water, municipal cold water and, limited to the N-nitrosamines analysis, hot water treated with chlorine dioxide were analyzed for comparison.The aim of our study was to evaluate the possible formation of N-nitrosamines and other DBPs in hospital hot water networks treated with monochloramine. The effectiveness of this biocide in controlling The study was conducted at the University Hospital Policlinico of Modena , a public 621-bed hospital consisting of a central nine-storey block and four separate buildings built between the 1970s and the 1990s. The same municipal water pipeline delivers water to all of the hospital buildings. A single main cold-water line branches out into several supply lines, each of which enters the water station of each hospital building. Once inside, cold water is heated using heat exchangers in order to produce hot water, which is moved in a water recirculating system. Three different water networks  distribute hot water in parallel in the central block, while the other four buildings of the hospital have their own hot water pipelines A. Three Legionella sampling and management plan. The protocol scheduled sampling at, at least, one remote point every 50 beds, reiterating (every 3 or 6 months) the same sites (sentinel taps), and testing other outlets based on the Legionella risk assessment. Samples were collected, without flaming and after flushing for 1 min, in sterile glass bottles containing sodium thiosulfate, in order to neutralize any residual disinfectant. At sampling, for each sample collected for Legionella testing, the water temperature , pH (using a portable pHmeter), and monochloramine concentrations ; limit of detection (LOD) = 0.04 mg/L as combined chlorine) were measured.Over a 5 year period (January 2015–February 2020), 550 hot water samples (1 L) treated with monochloramine were collected from return loops and showers/taps for microbiological analysis, according to the hospital’s 4+) were measured on a more limited number of samples (about 20 samples/year) following the Legionella sampling program, with an increase in their monitoring for research purposes in the last period of the study, for a total of 136 water samples. The first sampling was performed when the chlorine dioxide devices were still operating in the A and B pipelines, and monochloramine had been working in pipelines C and E since 2009 and 2012, respectively. During each sampling session, a one liter sample was collected from the hot-water return loop of the four monochloramine-treated and one untreated networks, together with the cold water inlet to the hospital.Other chemical parameters such as chlorite, chlorate, total THMs, total organic carbon (TOC), nitrites, nitrates, and ammonia ; water samples were taken from the hot-water return loop and the two distal taps of the four monochloramine-treated networks, for a total of 36 one liter samples (12 samples for session); simultaneously, a total of 24 one liter control samples (8 samples for the session) were collected from the hot-water return circuit and two distal taps of an untreated and a chlorine dioxide-treated network, together with samples of cold water taken from the pipeline at the entrance to the hospital central block and to the Building E.Acid-preserved glass bottles were used for chemical determinations.All water samples were returned to the laboratory immediately after collection and analyzed within 24 h.2 for 10 days and analyzed on Day 4 with a dissecting microscope. Presumptive Legionella colonies were subcultured on BCYE (with cysteine) and CYE (cysteine-free) media (Thermo Fisher Scientific) and then incubated at 36 ± 1 °C for 48 h. Colonies grown on BCYE were subsequently identified to the species and serogroup levels using an agglutination test (Thermo Scientific™ Legionella Latex Test). The results were expressed as the number of colony forming units (cfu) per liter, and the LOD of the procedure was 25 cfu/L. Only viable planktonic bacteria were enumerated.Legionellae were isolated by a culture method in accordance with the ISO 11731:1998, as previously reported . BrieflyChlorites and chlorates were analyzed using ion chromatography , THMs  by gas chromatography , N-nitrosodibutilamine (NDBA), N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), N-nitrosomorpholine (NMOR), N-nitrosopiperidine (NPIP), N-nitrosopyrrolidine (NPYR), N-nitrosodiphenylamine (NDPHA), and N-nitrosomethylethylamine (NMEA)) extracted with dichloromethane were measured using gas chromatography coupled to a mass spectrometer (EPA SW-846 Methods 3510C ). The LOItalian and European legislations set the parametric values for drinking water at 700 μg/L for chlorite, 30 μg/L for the total THMs, 0.50 mg/L for nitrite and ammonium, and 50 mg/L for nitrate ,28. In ICorrective actions were taken to ensure that the proportions of the chlorine and ammonia precursors during the monochloramine formation were correct. These corrective actions included the draining/cleaning of the hypochlorite storage tanks, the frequent replacement with fresh products, use of a more stabilized hypochlorite solution , and monochloramine set point dosage adjustment.Statistical calculations were performed using PASW statistics version 25.0 . Logarithmic transformations were used to normalize the bacteriological data, and the results are presented as geometric mean values. The chi-square test and one-way analysis of variance (ANOVA) with the Bonferroni test were applied, whenever necessary.Legionella spp. at low levels (geometric mean 1.9 × 102 cfu/L), although most isolates  belonged to serogroup 1. Legionella positive samples and their geometric means, together with the mean values of monochloramine, temperature, and pH, according to the four treated pipelines. Water pipework significantly affected the percentage of positive samples  but not their bacterial load . Network C showed the lowest percentage, followed by the A, B, and E pipeworks, but all of them, ranging from 0.8 to 9.1%, were largely below 30%—a value reported as being an indicator of low risk for disease transmission. No significant difference in monochloramine mean concentration was found between water networks, even if 25/136 samples (18.4%) in loop B had a monochloramine content >4 mg/L, compared to 22/172 (12.8%), 12/121 (9.9%), and 8/121 (6.6%) in the A, C and E loops, respectively. Network A had a mean temperature significantly higher than the other networks (p < 0.05 by the Bonferroni test), although still in a range (45–50 °C) that prevents the degradation of the biocide. A neutral pH was always found in all the treated pipelines.Only 22 out of 550 samples (4.0%), collected over 5 years from the monochloramine-treated hot water networks, were culture-positive for N-nitrosamines were all below the LOD in monochloramine and chlorine dioxide-treated and untreated water, as well as in the cold water entering the hospital buildings.Chlorites were only detected in July 2015, in the A and B loops, when the chlorine dioxide devices were still operating before the application of monochloramine .Corrective actions). As a result, since 2017 the chlorates decreased below the WHO provisional value in all the water networks, and free ammonia below 0.50 mg/L, with the exception of pipeline B for the first months of 2017 (Chlorates ranged between LOD (<60) and 352 µg/L in cold water, and between LOD (<60) and 240 µg/L in the untreated hot water loop. In the monochloramine-treated pipelines, chlorate concentrations were always higher than the WHO value of 700 µg/L during the first 2 years of the study, without any significant differences between the four devices A. Within of 2017 A,B.TOC concentrations were below the LOD in 63% of the samples, and at very low levels (0.1–0.3 mg/L) in the remaining. THMs were extremely low as they were <1 μg/L for all systems. In all the sample nitrites and nitrates were below the limits imposed by Italian and European regulations , and they did not increase in the presence of monochloramine.Legionella contamination, as reported in previous studies [Legionella [Our findings confirm the long-term effectiveness of the monochloramine device operating since 2009 in controlling  studies ,17,30,31gionella ,33. As pTo our knowledge, this is the first study that includes nitrosamines in the assessment of the formation of potentially dangerous DBPs during long-term monochloramine treatment in small-scale plants. In our hospital, no formation of the most prevalent N-nitrosamines was observed, even in the hot-water treated with monochloramine for nine years.The low levels of nitrosamine precursors such as TOC, nitrites, and nitrates found in the hospital tap water may explain this satisfactory result. Indeed, it is known that N-nitrosamine formation during water treatment requires the presence of organic nitrogen-containing precursors ,21,22,34The measured THMs concentrations were extremely low in all water networks, which was in line with the results of our previous study where, in addition to THMs, haloacetic acids were also investigated, and were not detected in the network treated with monochloramine . These fCongenital anomalies, the impairment of neurobehavioral and neurological development, the delay in female sexual development, soft tissue anomalies, and altered thyroid function were observed in association with chlorate exposure via drinking water . ChloratWe emphasize that monochloramine does not produce chlorites, which are regulated at national and international level due to their toxicity . This isA limitation of this study is the lack of information on the potential presence of other DBPs, such as haloketones, chloropicrin, aldehydes, etc., previously found in water treated with monochloramine , but notLegionella spp. contamination, with particular reference to healthcare structures. Disinfection procedures are required to prevent or control the risk of Legionella water contamination, and each procedure has different advantages, as well as maybe posing a risk to human health.National and international guidelines recommend controlling Legionella spp. contamination in different water systems of the same hospital, we can affirm that this biocide, if properly produced, continuously dosed, and regularly maintained is extremely effective against Legionella and does not produce any toxic disinfection by-products, such as nitrosamines and chlorites, or nitrification.Thanks to our decades of experience in the use of monochloramine for the control of In conclusion, our study confirms that monochloramine may be proposed as an effective and safe strategy for the continuous disinfection of building plumbing systems, preventing vulnerable individuals from being exposed to legionellae and to dangerous DBPs.


A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) [Linezolid is an antibiotic with activity against mycobacteria and most Gram-positive bacteria, such as staphylococci, streptococci, and enterococci. It has shown activity toward methicillin-resistant ci (VRE) . Linezolci (VRE) ,2.Selecting the optimal antimicrobial posology becomes a challenge when treating infections in critically ill patients. On the one hand, they are commonly subjected to aggressive medical interventions, such as mechanical ventilation or renal replacement techniques. On the other hand, several pathophysiological alterations may contribute to changes in the volume of distribution (V) or in the clearance (CL) . Moreover, drugs administered to these patients are likely to have higher pharmacokinetic (PK) variability, and, therefore, it becomes difficult to select the optimal dose, leading to suboptimal patient outcomes in some cases .EC) on the total body clearance of drugs [Acute kidney injury (AKI) is one of the most common pathological conditions in the ICU, ranging from 30% to 60% of hospitalized subjects. Continuous renal replacement therapies (CRRT) are frequent procedures for AKI treatment, estimating that around 5% of the ICU patients undergo these techniques ,5. CRRT of drugs . Since mof drugs .The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients, including patients undergoing CRRT and patients with preserved renal function. A secondary objective was to know if the pharmacokinetic/pharmacodynamic targets indicative of efficacy are achieved after the administration of the standard dose .An open-label prospective multicenter study was performed in the ICU of three Spanish University hospitals: Araba (Vitoria-Gasteiz), Doce de Octubre (Madrid), and Joan XXIII (Tarragona). The protocol was approved by the Basque Clinical Research Ethics Committee  and the Spanish Agency of Medicinal Products and Medical Devices . All subjects, or their legal representatives, had previously signed a written informed consent. Patients were eligible for inclusion if (i) they were admitted to the ICU; (ii) they suffered from an infection probably caused by a Gram-positive microorganism and, therefore, were treated with linezolid; (iii) they gave informed consent; and (iv) it was possible to obtain plasma and effluent samples from the extracorporeal device when undergoing CRRT. Effluent samples were collected to calculate the fraction of linezolid eliminated through the extracorporeal circuit .The exclusion criteria were age < 18 years, pregnancy, hypersensitivity to linezolid or any of the excipients, and being on any medicinal product which inhibits monoamine oxidase A or B.EC as follows: CLEC = Sc × Qef, where Qef is the effluent flow.The fraction of the drug eliminated across the membrane of the extracorporeal circuit during CRRT, known as sieving coefficient (Sc), was calculated as the ratio of the linezolid area under the effluent concentration curve to the area under the plasma concentration curve over the dosage interval. The Sc was used to estimate the CLEach patient was administered 600 mg of linezolid every 12 h, by intravenous infusion, over 30 min, except one subject, who received an infusion of 60 min. A mean of 8 doses was administered before sample collection, to ensure steady-state concentrations. Blood samples were drawn at pre-dose, at the end of infusion, and at 1, 2, 3, 6, 8 to 10 and 12 h. For patients undergoing CRRT, effluent samples were taken at the same time points.® C8 column (4.6 × 150 mm × 5 µm). The mobile phase consisted of ammonium phosphate 0.5%: acetonitrile . Linearity range was established from 0.5 to 50 µg/mL for plasma samples and from 0.2 to 30 µg/mL for effluent samples. The analytical method was previously validated following the FDA [Concentrations of linezolid in plasma and effluent samples were quantified, using high-performance liquid chromatography (HPLC) assays with ultraviolet detection. Plasma sample preparation consisted of a protein precipitation step with acetonitrile, where internal standard (propyl-4-hydroxybenzoate) had been previously diluted. Afterward, the samples were centrifuged , and the supernatants were injected into the HPLC system. Effluent samples were directly injected into the system and analyzed. Separation was performed on a Simetry the FDA  guidelinNonlinear mixed-effects modeling was implemented by NONMEM 7.3 , to estimate linezolid PK population parameters, using first-order conditional estimation method with interaction. Drug concentrations were logarithmically transformed. The model selection was based on the decrease in objective function value (OFV), the relative standard errors (RSE) of the parameters, and the goodness-of-fit (GOF) plots. Residual error was shaped, and inter-individual variabilities (IIV) and possible covariance were also explored.EC was considered as a fixed value per patient, calculated individually as Qef multiplied by the Sc. The other three dichotomous covariates were created, depending on whether the patients had one, two, or three of the following parameters out of the normal range: bilirubin , GOT , and GPT .Once the base model was selected, and in order to describe the IIV, all variables presented in p < 0.05 and p < 0.01 levels of significance were used, respectively. GOF plots were also used to confirm whether different models performed satisfactorily.Stepwise covariate model building was used (SCM tool in PsN 4.7.0) to identify covariate candidates. During the forward inclusion and backward deletion, GOF plots assessed were the individual and population predictions versus observations, the conditional weighted residuals (CWRES) against time after dose, and the individual weighted residuals (IWRES) versus individual predictions. Moreover, a VPC was built to explore the performance of the selected model (VPC tool in PsN 4.7.0). Thus, the 2.5th, 50th, and 97.5th percentiles for observed data were plotted. Afterward, a 1000-sample dataset was simulated from the final model parameter estimates, and the 95% confidence intervals for the simulated 2.5th, 50th, and 97.5th percentiles were represented for visual inspection, using the xpose4 package in R 3.4.0. Additionally, parameter precision was evaluated by performing a 2000-dataset bootstrap (Bootstrap tool in PsN 4.7.0).n = 11) was used for external validation, which was also used to elucidate if the administration of linezolid as a continuous infusion would lead to an improvement of the pharmacodynamic target attainment. Forty-four plasma samples from these patients were analyzed. 2) was applied. IBM SPSS statistic® software (version 21) was used.A new group of patients , and the ratio of area under the concentration–time curve over 24 h to the MIC (AUC24/MIC) are the PK/PD indexes that best predict clinical efficacy [24/MIC > 80 and 100% T>MIC were selected as targets indicative of efficacy [24/MIC > 80 and 100% T>MIC for MIC values of 1, 2, and 4 mg/L (probability of target attainment or PTA). The selected PK/PD target when linezolid was administered as continuous infusion was the ratio of the drug concentration at steady state to the MIC . Statistical analyses were performed by using IBM® SPSS® Statistics for Windows, Version 25. A p-value < 0.05 was considered statistically significant.Linezolid presents concentration and time-dependent activity . For theefficacy . AUC24/Mefficacy . Based oA total of 40 critically ill patients were included to develop the pharmacokinetic model, and a total of 311 plasma samples were analyzed. The source of infection was pulmonary in 14 cases, abdominal in 10, neurological in nine, and biliary in two, with other sources in the other five cases.n = 23), eight effluent samples per individual were collected. Eighteen patients underwent continuous venovenous hemodiafiltration (CVVHDF), and five subjects received venovenous hemodialysis (CVVHD). The effluent flow was set at a range from 1.1 to 3.3 L/h. Fluid balance was prescribed according to clinical status.When subjected to CRRT (1) was included, and no correlation between these two parameters was detected. Variability was modeled by using an exponential model for IIV, and a combined error model for the residual variability was found to be the most suitable.Linezolid plasma concentrations were best described by a two-compartment model. A statistically significant drop of the OFV was obtained with respect to the one-compartment fit (ΔOFV = −113.167). IIV of the CL and the central compartment volume of distribution (VNR), a renal component (CLR) conditioned by the Clcr, and the CLEC if the patient underwent CRRT. The inclusion of Clcr in the model led to a reduction of the IIV of the CL, from 98.7% to 61.5% (ΔOFV = −30.451). CLEC was considered as a fixed value per patient. Bilirubin, GOT, and GPT were grouped and studied as potential covariates; however, they were excluded from the final model, since a better fit was not obtained. Although patients with Clcr > 130 mL/min showed a higher apparent volume of distribution of the peripheral compartment (V2), in the final model, the Clcr was not included as a covariate of this PK parameter, since no improvement in the predicted concentrations was observed, and higher estimation errors were obtained. No other covariate resulted in a relevant reduction in the OFV.The linezolid CL was estimated as the sum of a non-renal component (CL24/MIC ≥ 80 and 100% T>MIC) or continuous (Css ≥ MIC) infusion. After the standard dose was administered (600 mg/12 h), the PK/PD targets were not reached in many patients, especially for MICs of 2 and 4 mg/L. No differences between patients treated or not with CRRT were detected. When linezolid was administered by continuous infusion, the target (Css > MIC) was achieved in 100% of the patients for MIC of 1 mg/L, and in more than 85% for the MIC of 2 mg/L.In this study, we developed a population pharmacokinetic model for linezolid in critically ill patients. Data were best supported by a two-compartment model, in accordance with previously published manuscripts ,14. The Regarding linezolid elimination, both non-renal and renal clearance were included in the model, the latter being influenced by patients’ Clcr. The inclusion of this covariate in the PK model is controversial. Thus, while some authors found a correlation between Clcr and total clearance ,17, otheEC was also included in the equation of the total body clearance. The estimation of drug elimination in critically ill patients undergoing CRRT may become complex, since it is influenced by antibiotic-related and CRRT-related characteristics, such as surface area, composition and pore diameter of the membrane, the effluent flow, or the CRRT modality [Since linezolid is partially eliminated by CRRT , the CLEmodality . In thismodality , and didmodality . Howevermodality ,23, as cmodality , where hIt is well-known that, at least in healthy volunteers, linezolid clearance occurs by both renal and hepatic mechanisms . Liver metabolism occurs by oxidation of the morpholine ring of the drug, without involvement of the cytochrome P450 system . Taking In around one-third of the patients, a peak in the concentration–time curve between 2 and 4 h after dose was detected, which could not be explained with the two-compartment model. As previous studies had demonstrated that linezolid presents biliary excretion , we testCE, it is still quite high, as discussed above. Although several demographic and biochemical data were evaluated, unfortunately, we were not able to identify any other variable that could explain the IIV in the PK parameters. The heterogeneity and the limited number of patients may explain that some of the studied covariates resulted in being nonsignificant. However, our study was useful to detect the limitation of the standard dose of linezolid to achieve the PK/PD targets for the clinical breakpoints and to show the advantage of the continuous infusion. In fact, adjustment of linezolid dosing in critically ill patients has been suggested, since recent studies have shown a substantial percentage of subtherapeutic levels [In spite of the fact that the IIV estimated with the base model can be explained in part by the Clcr and by the CLc levels ,6,7,14. c levels ) and 4 mc levels . In a reDifferent authors have suggested that the administration of a continuous infusion of linezolid could be an alternative option to avoid toxicity problems that could occur when increasing the dose ,30. In oTherapeutic drug monitoring has been suggested by some authors to optimize linezolid therapy in critically ill patients ,34. Our NR, CLR (affected by CLcr), and in patients treated with CRRT, the CLEC. Our study confirmed that the standard regimen of linezolid may be insufficient to reach the PK/PD target to cover infections caused by pathogens with MICs ≥ 2 mg/L. The administration of linezolid as continuous, instead of intermittent, infusion notably increases the achievement of PK/PD target.A population pharmacokinetic model for linezolid was developed for critically ill patients. A two-compartment model best described the data. Total body CL was the sum of CL


Polypharmacy is a growing and major public health issue, particularly in the geriatric population. This study aimed to examine the association between polypharmacy and the risk of hospitalization and mortality. We included 3,007,620 elderly individuals aged ≥ 65 years who had at least one routinely-prescribed medication but had no prior hospitalization within a year. The primary exposures of interest were number of daily prescribed medications  and presence of polypharmacy (≥ 5 prescription drugs per day). The corresponding comparators were the lowest number of medications (1–2) and absence of polypharmacy. The study outcomes were hospitalization and all-cause death. The median age of participants was 72 years and 39.5% were men. Approximately, 46.6% of participants experienced polypharmacy. Over a median follow-up of 5.0 years, 2,028,062 (67.4%) hospitalizations and 459,076 (15.3%) all-cause deaths were observed. An incrementally higher number of daily prescribed medications was found to be associated with increasingly higher risk for hospitalization and mortality. These associations were consistent across subgroups of age, sex, residential area, and comorbidities. Furthermore, polypharmacy was associated with greater risk of hospitalization and death: adjusted HRs (95% CIs) were 1.18 (1.18–1.19) and 1.25 (1.24–1.25) in the overall and 1.16 (1.16–1.17) and 1.25 (1.24–1.25) in the matched cohorts, respectively. Hence, polypharmacy was associated with a higher risk of hospitalization and all-cause death among elderly individuals. Some studies have described polypharmacy as the use of a higher number of drugs than clinically indicated2. However, this definition is based on a clinical judgement that is difficult to operationalize in large studies5. By contrast, the numeric definition can vary according to practice setting or research protocol, and it is often used in most epidemiologic studies due to its simplicity 5. Although there is no universal definition of polypharmacy to date, it is considered a growing and major public health problem worldwide, particularly among the geriatric population in whom there is a high burden chronic comorbidities5.Polypharmacy refers to the prescription of multiple medications to a single individual, and it can be defined either numerically or qualitatively5. In fact, several symptoms related to the central nervous system and gastrointestinal tract are caused by adverse drug events, and additional drugs are often prescribed to control these symptoms7. Such multiple drug combinations may lead to drug-drug interactions and heighten the risk of adverse effects7. Furthermore, the use of multiple drugs can increase pill burden and medical costs3. Concurrently, the prescription of multiple medications may negatively affect patient adherence and health-related quality of life (HRQOL)8. Older individuals are particularly vulnerable to unexpected drug-related problems because of the multiple drug regimens, higher number of comorbid conditions, and age-associated physiological changes in pharmacokinetics and pharmacodynamics with respect to certain drugs9.Some patients with multiple comorbidities require the simultaneous prescription of pharmaceutical products. However, a growing body of evidence suggests that drugs are oftentimes prescribed inappropriately. Moreover, polypharmacy may be associated with adverse outcomes particularly in the elderly population12. Predictably, the number of prescribed medications increases concomitantly with age and number of comorbidities13. To date, several epidemiologic studies reported possible detrimental associations of polypharmacy with falls14, renal failure15, frailty16, poor physical function17, and cognitive impairment19. In addition, patients consuming multiple medications are more likely to experience poor HRQOL21 and frequent hospitalizations24. More importantly, in a recent meta-analysis that pooled data across 47 studies, polypharmacy, defined as ≥ 5 prescribed drugs, was associated with a 31% higher risk for mortality25. However, not all studies have confirmed this association27. Nevertheless, interpretation of these aforementioned studies are limited by potential residual confounders and confounding by indication , medication ascertainment by self-report , and examination of drug exposure within a short period  . Thus, to better inform the field, we sought to examine the association of polypharmacy with the risk of hospitalization and death in a large longitudinal cohort of elderly community-indwelling individuals from the Korean National Health Insurance Service (NHIS) database linked to the nationwide pharmacy claims data.There have been a number of studies that examined the relationship between polypharmacy and adverse events. The prevalence of polypharmacy has consistently increased, which is particularly evident among elderly individualsThe flow chart of study cohort construction and the baseline characteristics of 3,007,620 participants who met the eligibility criteria of the study are shown in Supplementary Fig. During a median follow-up period of 5.0 years, 2,028,062  hospitalizations and 459,076  deaths from any cause were observed, with corresponding crude incidence rates of 228.5  and 32.5  per 1000 person-years, respectively. An incrementally higher number of daily prescribed medications was associated with a stepwise increase in outcome event rates . In the overall cohort, individuals with polypharmacy were older and had a higher comorbidity burden compared to those without polypharmacy  adjustment of comorbidity index, 2) subgroup analysis stratified by CCI score, and 3) propensity-score matching analyses. In the conventional Cox models adjusted for disease burden, a higher number of daily prescribed medications was associated with a greater risk of hospitalization and death. Moreover, graded associations were largely similar across all subgroups stratified by CCI score. Furthermore, in the propensity-score matched analyses, individuals with polypharmacy had a 1.2- and 1.3-fold higher risk of hospitalization and mortality. In summary, all three approaches demonstrated a consistent association between polypharmacy and a higher risk of hospitalization and death. To the best of our knowledge, to date, this is the largest study that examined over three million elderly adults in Korea, thereby providing a strong statistical power. While the underlying mechanisms responsible for polypharmacy-related adverse outcomes should be further investigated, our findings highlight the need to identify strategies that can reduce polypharmacy in clinical practice and motivate more judicious prescription of multiple medications, particularly in the geriatric population.36. One of these studies included the D-PRESCRIBE (Developing Pharmacist-Led Research to Educate and Sensitize Community Residents to the Inappropriate Prescriptions Burden in the Elderly), which is a recent randomized controlled trial involving older adults in Quebec36. This study showed that a pharmacist-led educational intervention resulted in greater discontinuation of inappropriately prescribed medications after six months36. However, at present, most studies have only examined the short-term effects of interventions on prescribing patterns. Hence, further long-term studies are required to investigate whether strategies for reducing polypharmacy can significantly improve “hard” clinical endpoints such as hospitalization and mortality.In relation to this, there have been efforts to reduce polypharmacy and inappropriate prescribing practices through educational interventions or alert systems33. However, this threshold may not be applicable to all patients. Therefore, future studies are needed to ascertain inappropriate prescriptions using more sophisticated approaches such as the Beers37 or the STOPP (Screening Tool of Older Peoples Prescriptions)38 criteria. In a recent study by Nam et al.39, the prevalence of potentially inappropriate prescribing (PIP) was remarkably high among Korean elderly individuals based on the 2012 Beers criteria. Currently, we are collecting relevant data to analyze the association between PIP and clinical consequences in corollary studies. Third, although a series of sensitivity analyses were conducted to try to account for potential confounding by indication and reverse causation, residual confounding could not be excluded. In fact, the number of individuals without any CCI comorbidity had at least one prescribed medication. Thus, they are likely to have other comorbid conditions that might not be captured by CCI score, thereby causing confounding effects. Finally, this study was conducted on non-institutionalized elderly individuals; thus, our findings might only be generalizable to community-dwelling elderly individuals not to those living in nursing homes or younger populations.Several limitations of our study bear mention. First, given that the Korean NHIS database only captures information on prescribed medication, data on the use of over-the-counter, complementary, and alternative drugs were not obtained. In addition, drugs prescribed for short-term intervals were not considered and detailed information on the duration of drug use and the number of medications before study entry was not collected. Furthermore, there was no information on long-acting drugs prescribed once a week or month and other types of medications such as injections, inhalers, eye drops, and topical agents. These drugs might also result in adverse reactions. Hence, the current study might have underestimated the actual prevalence of polypharmacy in this population. Moreover, we determined the number of medications consumed based on prescription data. However, they do not convey information on adherence to the prescribed medications nor the actual number of pills taken by the patients. Second, our definition of polypharmacy was based on a cutoff of ≥ 5 prescriptions, which has been used in prior studiesIn conclusion, polypharmacy was associated with a higher risk of hospitalization and all-cause mortality in a large national cohort of Korean elderly individuals. These findings underscore the risk of prescribing multiple pharmaceutical products and highlight the urgent need for judicious and appropriate prescription practices and identification of strategies that avoid polypharmacy in the geriatric population.41. The pharmacy claims database provides details on all prescription medications for each individual, which include drug names (generic and brand names), start and end dates of prescription, number of days for drug supply, and prescribed doses.We obtained data from the Korean NHIS database, which is linked to nationwide pharmacy claims data. Since NHIS, which is a single-payer national health system, covers compulsory health insurance for all citizens in Korea, all medical records of covered inpatient and outpatient visits are centralized in the NHIS database. These include diagnostic codes, procedures, prescriptions, medical costs, and personal information The source population comprised 6,100,982 elderly individuals aged ≥ 65 years who were captured in the 2012 NHIS database. We first excluded 1,876,821 individuals who were hospitalized or who died during the exposure period from January 1, 2012, to December 31, 2012. To determine the association between the number of routinely prescribed medications and adverse outcomes, we further excluded 1,216,541 individuals who were not prescribed any medications or who received a prescription for ≤ 270 days in 2012. Therefore, the final study population comprised 3,007,620 individuals  were assessed using 43. Drugs which had the same fifth level of ATC code were considered as one drug. In the case of combined products containing two or more active components, the number of drugs was calculated as the sum of the number of each active ingredient. Only drugs of oral formulations were included, and other types of drugs such as injections, inhalers, eye drops, and topical agents were excluded. Moreover, long-acting drugs prescribed once a week or month were excluded.Data on outpatient prescription medications were identified from the pharmacy claims database and were extracted using specific drug-class codes or names. To determine the risk associated with longer periods of drug exposure, we only selected “routinely-prescribed” medications, which was defined as medications prescribed for ≥ 270 days from January 1, 2012, to December 31, 2012. The number of drugs was counted according to the fifth level of the Anatomical Therapeutic Chemical (ATC) Classification SystemThe co-primary exposures of interest were the (1) number of daily prescribed medications and (2) presence vs. absence of polypharmacy. The number of daily prescribed drugs was categorized into six groups , and polypharmacy was defined as the use of ≥ 5 prescription drugs per day.The study outcomes of interest were hospitalization and all-cause mortality, which were assessed via a time-to-first-event analysis. Follow-up started on January 1, 2013 (index date) and ended during the occurrence of any event or until December 31, 2017 (study end date), which ever came first.Data from the descriptive analyses were summarized using means (SD), medians (IQR), or proportions according to data type. To determine potential dose–response relationships, we first examined the associations between the number of medications and study outcomes using the Cox proportional hazard regression models with three incremental levels of adjustment. These levels were as follows: (1) Model 1: unadjusted; (2) Model 2: adjusted for age, sex, and residential area; and (3) Model 3 (fully-adjusted model): adjusted for all covariates in model 2 plus the CCI score. To test the robustness of our findings, we also performed subgroup analyses across the following of clinically relevant subgroups: age , sex (men and women), residential area , and comorbidity burden .Next, to assess the associations between polypharmacy and the risk of hospitalization and death, we converted the number of medications into a binary exposure of polypharmacy (≥ 5 vs. 1–4 medications prescribed daily). This was then examined using the Cox models adjusted for age, sex, residential area, and CCI score in the overall and propensity-score matched cohorts. In establishing the propensity-score matched cohort, we matched individuals with and without polypharmacy (1:1 ratio) based on age, sex, residential area, and CCI scores. Further, time to the first occurrence of any hospitalization or death was also evaluated and compared between the two groups based on the number of medications or presence of polypharmacy using the Kaplan–Meier method and the log-rank test. There were no missing data in our study. All analyses were conducted using Stata version 15.1 .The current study was approved by the Institutional Review Board of the National Health Insurance Service Ilsan Hospital (NHIMC 2019-06-014).The Institutional Review Board of the National Health Insurance Service Ilsan Hospital waived the need for informed consent as only deidentified data were examined.Supplementary Information.


Also, in serum at rest, creatinine (mg/dL) concentration was measured. Results: After the study, significantly better results in TT, AP and MP were observed in the SG. No significant changes in the RAST results were observed in the PG. After the study, significant changes in the first 35 m sprint, as well as the sixth 35 m sprint results were registered in the SG, while insignificant changes occurred in the PG. A significantly higher creatinine concentration was observed. Also, a higher post-RAST concentration of LA, HCO3− and lower values of pH were observed in April, May and June compared with baseline values. Conclusions: The long timeframe, i.e., 16 weeks, of the low dose of magnesium creatine chelate supplementation improved the RAST results in the SG. Despite the long period of MgCr-C supplementation, in the end of the study, the creatinine level in the SG reached higher but still reference values.Aim: The aim of the study was to evaluate the effects of 16 weeks of a low dose of magnesium creatine chelate supplementation on repeated sprint ability test (RAST) results in elite soccer players. Materials: Twenty well-trained soccer players participated in the study. The players were divided randomly into two groups: the supplemented group (SG = 10) and placebo group (PG = 10). Out of the 20 subjects selected for the study, 16  completed the entire experiment. The SG ingested a single dose of 5500 mg of magnesium creatine chelate (MgCr-C), in 4 capsules per day, which was 0.07 g/kg/d. The PG received an identical 4 capsules containing corn starch. Before and after the study, the RAST was performed. In the RAST, total time (TT), first and sixth 35 m sprint length (s), average power (AP) and max power (MP) were measured. Additionally, before and after the test, lactate LA (mmol/L) and acid–base equilibrium pH (-log(H Numhate ATP . Cr supphate ATP ,10.There are many sport disciplines which involve a combination of high-intensity actions, in isolation or repeatedly, where optimal anaerobic and aerobic metabolism are required . Soccer Over the last decades, there have been numerous studies evaluating the effects of Cr supplementation on physical performance in soccer, which give conflicting results ,10,12,17To date, there have been no studies on the impact of long-term creatine supplementation on speed endurance performance in male soccer players. Only one study has examined the effects of 13 weeks of creatine supplementation on anaerobic capacity, however the participants were female soccer players . It thusThe main objective of this study was to evaluate the long-term effects of Cr supplementation on repeated sprint abilities, crucial for soccer without the classical loading phase, which often causes gastrointestinal problems or muscle cramping. We incorporated the intervention period into the 16 week second round soccer competition to obtain information about fitness variables, especially speed endurance, speed as well as changes in body mass and chosen biochemical variables related to buffering capacity.n = 8) received creatine chelate magnesium and the placebo group (n = 8) received identical capsules filled with starch. The experiment took place during the second part of the season, from the beginning of March until the end of June and lasted 16 weeks. The athletes constituted a homogenous group in regard to age. The participants’ somatic characteristics are presented in Twenty well-trained elite soccer players participated in the study. The players were divided randomly into two groups: the supplemented group (SG = 10) and the placebo group (PG = 10). From the 20 subjects selected for the study, 16  completed the entire experiment. Two athletes dropped out of the research due to injury while one resolved his contract and one did not finish the study due to illness. The SG , 2 weeks before the study was initiated . The parThe subjects underwent medical examinations and somatic measurements in the morning, between 08:00 and 08:30. Body composition was evaluated by the electrical impedance method . The day before these evaluations, the participants had their last meal at 20:00 and were allowed to drink 1.5 L of water between 21:00 and 23:00 to fully hydrate the body. They reported to the laboratory after an overnight fast, refraining from exercise for 24 h. The measurements of body mass were performed on a medical scale with a precision of 0.1 kg. The experiment lasted 16 weeks, during which the Repeated-Anaerobic Sprint Test was performed 5 times, which included baseline evaluations and four post-intervention trials following creatine supplementation or placebo intake. The participants refrained from exercise for one day before testing to minimize the effects of fatigue.During the study period, which included the second part of the competitive season, the athletes trained on an everyday basis (approximately 2 h/d) with an official soccer game on Saturday/Sunday. Additionally, twice a week, the players performed a strength and conditioning training session.Anaerobic performance was evaluated by the Running Anaerobic Sprint Test (RAST) protocol which involved 6 × 35 m maximal sprint efforts, separated by 10 s of active recovery . Infrare+)) and bicarbonates (HCO3− std mmol/L). The evaluations were performed from fingertip capillary blood samples, at rest and after 3 min of post-exercise recovery. Determination of LA was based on an enzymatic method . The remaining acid–base variables were assessed using a Blood Gas Analyzer GEM 3500 . For creatinine analysis, 4.5 mL of venous blood from the antecubital vein was collected and a MAK079  kit test was used.To determine lactate concentration (LA), and acid–base equilibrium, the following variables were evaluated: LA (mmol/L), blood pH (-log(H2) was established as follows: 0.01—small, 0.06—medium and 0.14—large [p < 0.05. All statistical analyses were performed using Statistica 9.1  and Microsoft Office , and are presented as means with standard deviations (SD).The Shapiro–Wilk, Levene and Mauchly’s tests were used to verify the normality, homogeneity and sphericity of the samples’ data variances, respectively. Verifications of the differences between the considered values before and after creatine supplementation, between baseline conditions and the 4 time points in the SG and PG groups were verified using analysis of variance (ANOVA) with repeated measures. Effect sizes (Cohen’s d) were reported where appropriate. According to Hopkins guidelines, the effect size , May  and June  compared to baseline values. Simultaneously, higher values of HCO3− at rest and pH at rest in March , April , May  and June  were observed compared to baseline values. There were no statistically significant intra-group differences between baseline conditions and the four time points of LA concentration at rest in the SG , May  and June  compared to baseline values. Higher values of LA concentration post-exercise in March , April , May  and June  were observed compared to baseline values in the PG. Serum creatinine levels did not change significantly throughout the 16-week intervention in the PG, and ranged from 0.92 mmol/L at baseline to 0.85 mmol/L during the last evaluation in June. In the SG, the creatinine concentration rose from 0.83 mmol/L at baseline in February to 1.87 mmol/L (p = 0.01) in March and decreased in the following time points, reaching 1.38 mmol/L (p = 0.05) during the last evaluation in June after 16 weeks of continuous supplementation , and a significant increase of the AP  and the MP  were observed in the SG. No significant changes in these variables were observed in the PG , as well as the sixth 35 m  sprint was registered in the SG, while insignificant changes occurred in the PG.A significant effect of the interventions on the TT, the AP and the MP in the intragroup measures was revealed. A significant decrease of the TT  as well as higher values of MP  and AP  in the SG compared to the PG , followed by a maintenance dose of 4–5 g/d for a few weeks ,35. In o3− levels observed in the SG, as well as the lower blood pH compared with better RAST results, show that despite the high rate of ATP re-synthesis both from the breakdown of PCr stores and from glycolysis, which promotes cellular acidosis, the soccer players were buffered against acidosis. Despite the low blood pH (3− and pH and also in the results of the first and last sprint. Beside Cr, LA is essential in removing pyruvate, regenerating nicotinamide adenine dinucleotide NAD+ to sustain a high rate of ATP regeneration from glycolysis and contributes to metabolic proton buffering [In soccer, it is known that there is a strong positive correlation between game performance and the number of repeated sprints during a game ,18,36. Tblood pH , which ablood pH  were prouffering .In most of the studies conducted so far, the impact of Cr supplementation on anaerobic performance in soccer players has brought positive results ,42,43. O+ absorption, the SG consumed it with a high-carbohydrate fruit juice [Other factors which influence the results of Cr supplementation include the daily dosing and the exercise and supplementation protocol implemented in the study . The majit juice . So far,it juice ,28,39. Cit juice , after aCreatine is known to cause mild water retention and to decrease urinary volume due to its osmotic effect . The absThe long-term, 16-week, low-dose magnesium creatine chelate supplementation improved RAST results in elite soccer players during the second part of the competitive season. Compared to the placebo group, speed as well as power increased over the intervention period, with small increases in body mass and fat-free mass over the first 4 weeks of supplementation. Despite the 16-week period of MgCr-C supplementation, blood creatinine levels remained within reference values at the end of the season.Given the effect of creatine on the anaerobic capacity of athletes, research into its various forms over an extended period of time seems justified and may be of great practical significance for team sport athletes, where the competitive season lasts for several months.