A platelet count increase was associated with a Lyso-Gb1 decrease in both treatment groups . The association of Lyso-Gb1 with evaluated markers was stronger in the SRT cohort. Our results indicate that ERT and SRT in combination or in a switch manner could offer the potential of individual drug effectiveness for particular GD symptoms. Combination of the key biomarker of GD, Lyso-Gb1, with other biomarkers can offer improved response assessment to long-term therapy.A personalized treatment decision for Gaucher disease (GD) patients should be based on relevant markers that are specific to GD, play a direct role in GD pathophysiology, exhibit low genetic variation, reflect the therapy, and can be used for all patients. Thirty-four GD patients treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) were analyzed for platelet count, chitotriosidase, and tartrate-resistant acid phosphatase activity in plasma samples, and quantitative measurement of Lyso-Gb1 was performed in dried blood spots. In our ERT and SRT study cohorts, plasma lyso-GL1 correlated significantly with chito-triosidase (ERT: r = 0.55,  GBA gene. This autosomal recessive disorder due to an enzymatic deficiency of β-glucocerebrosidase (EC 3.2. 1.45) results in an intra-lysosomal accumulation of glucosylceramide . Glucosylceramide accumulates primarily within cells of mononuclear phagocyte origin in the spleen, liver, and bone marrow. During its deacylation by acid ceramidase, glucosylceramide transforms into a sensitive biomarker for GD, lyso-glucosylsphingosine (lyso-Gb1). The accumulation of deacylated lysolipids leads to a progressive disease hallmarked by immune dysregulation and multi-system involvement [Gaucher disease , one of the most common lysosomal storage disorders, is caused by biallelic pathogenic variants in the  EC 3.2. .45 resulGBA gene mutations associated with GD have been identified .The clinical manifestation of GD varies broadly from a perinatal-lethal form to an asymptomatic form. The classification of GD by clinical subtype is useful for prognosis and disease management. Three major clinical types are distinguished by the absence (GD type 1) or presence (GD types 2 and 3) of neurologic signs and symptoms. Perinatal-lethal and cardiovascular forms represent fewer common phenotypes. Symptoms of the most prevalent type 1 GD may include hepatosplenomegaly, anemia, thrombocytopenia, growth delay, and bone or pulmonary involvement. Most heterozygous mutations in the GBA1 gene elevate the risk of Parkinson’s disease and dementia with Lewy bodies. Even though type 1 GD patients classically do not have CNS involvement, they are at increased risk for developing parkinsonism and Parkinson’s disease (PD). Heterozygous mutations in the GBA1 gene cause a more severe PD phenotype and are associated with synucleinopathies in general . HoweveGuidelines for the evaluation of the disease burden and management of patients with GD can be challenging due to a high degree of phenotypic heterogeneity. The clinical picture can vary from patients remaining asymptomatic for decades to children with severe clinical manifestations . TraditiCHIT1 SNP and thus present with half-normal serum levels [The first and most widely used biomarker is chitotriosidase (CHITO), an orthologue of the chitinase family. While CHITO has been used as an established biomarker since 1994 , some com levels . TherefoThe other alternative biomarkers are also used, irrespective of the chitotriosidase genotype. Lyso-Gb1 concentration from a dried blood spot has been the most specific and sensitive diagnostic GD biomarker . The eleThe concentrations of another plasma biomarker, tartrate-resistant acid phosphatase (TRAP), rise with GD progression and decrease in response to ERT. The TRAP isoenzyme 5b is a specific marker of bone resorption. It plays a key role in the degradation of type I collagen by the osteoclast. Like CCL18/PARC, elevation of TRAP activity also appears in other diseases  .Appropriate candidate biomarker selection is complicated due to the vast clinical and biochemical heterogeneity in GD. Some plasma biomarkers for disease monitoring and response-to-treatment evaluation were or are used, such as ferritin and hemoglobin levels, angiotensin-converting enzyme (ACE), and alkaline phosphatase activity (ALP). However, they were also shown to be affected by other factors, and their lack of specificity was reported ,21.The aim of our present study was to test the utility of relevant plasma biomarkers for disease trend evaluation in patients receiving ERT or substrate reduction therapy (SRT) in the Czech cohort of patients with GD.®, Sanofi Genzyme, Cambridge, MA, USA) (n = 21) or velaglucerase alfa  (n = 9) during their first study visit. On visit 2, one patient was switched from VPRIV® to Cerdelga® . The remaining 29 patients continued ERT during subsequent visits. Three patients started the study period with Cerdelga® and one with Zavesca®   . Due to The effect of ERT and SRT was assessed with changes in Lyso-Gb1 levels, CHITO and TRAP activities, and platelet count in a mostly female study cohort of 34 patients. At Visit 0, 30 of the included patients were treated with ERT and four with SRT . On visiA genotype–phenotype correlation was clearly observed. In thirty-three patients exhibiting phenotype I GD, the presence of at least one p.Asn409Ser allele was detected . Patient no. 19, homoallelic for p.Leu483Pro, presented with phenotype III GD . OverallCHIT1 gene. In the remaining 20 patients, the dup24 allele was not detected. Three other known single nucleotide variants, c.304G>A , c.1325C>G , c.1351C>T , and one unpublished variant, c.922_923delinsAT (p.Ser308Ile), were detected within the cohort  in the e cohort .At every scheduled visit, a peripheral blood sample was drawn for CHITO and TRAP activity, Lyso-Gb1 levels, and platelet count assessment. The results of biomarker changes at the beginning and end of the study period are summarized in p = 0.123, p = 0.045, p < 0.001). The isotonic regression curve was estimated using the pool adjacent violators algorithm and fitted to minimize the mean squared error . The isotonic regression curves for both treatments are shown in To compare Lyso-Gb1 responses to long-term therapy, we estimated Lyso-Gb1 levels over 30 months of treatment. The median Lyso-Gb1 level dropped comparably, irrespective of treatment. By 30 months of ERT treatment, there was a significant decrease in plasma Lyso-Gb1 level from a median of 81.5 ± 12.4 ng/mL to 60.9 ± 8.6 ng/mL . Our data suggests that long-term SRT could affect bone resorption in GD I patients more effectively than ERT. The isotonic regression curves for both treatments are depicted in To analyze whether ERT resulted in significant differences in serum TRAP activity compared to SRT, we evaluated median TRAP activities. At month 30, an overall increase in median TRAP activity values was observed within the ERT cohort, whereas median TRAP activity dropped in the subjects treated with SRT. Both trends were significant for the particular group. The median Lyso-Gb1 level dropped irrespective of treatment. In the ERT patients, we observed a significant increase in plasma TRAP activity from a median of 60.9 ± 3.5 nkat/L to 73.5 ± 3.1 nkat/L . The isotonic regression curve revealed a continuously increasing trend  and TRAP  irrespective of treatment method (p = 0.92) (p = 0.0249)  C. On the 0.0249) F. The asThe system-wide involvement of Gaucher disease requires regular monitoring of all GD patients. Appropriate biomarkers correlating with the disease burden are important for monitoring disease progression and response-to-treatment evaluation. However, the choice of the optimal biomarker has its limitations, reflecting their lack of specificity, different sensitivity and specificity, or the fact that they can be affected by other factors ,21. ReceGBA gene mutation heterogeneity was not equal between our study cohorts  in the subjects treated with SRT in our study. The isotonic regression curve depicted reached a plateau in TRAP activity decrease in patients with SRT treatment, whereas an increasing trend was evident in the ERT group.It was documented that the TRAP level could differ as a function of age ; howeverThe platelet count recovered steadily and significantly over 30 months, regardless of the method of treatment. The trends of platelet count recovery were comparable for both therapies, and our observation confirms literary evidence ,48,50. MIn our ERT and SRT study cohorts, we observed a significant correlation of Lyso-Gb1 with CHITO and TRAP markers. A platelet count increase was associated with a Lyso-Gb1 decrease in both treatment groups; however, the correlation was insignificant in ERT patients. The association of Lyso-Gb1 with all evaluated markers was markedly stronger in the SRT cohort. Correlations between Lyso-Gb1 levels and other established biomarkers of GD were summarized in several studies ,54,55,56With respect to correlations, there is evidence of a moderate pairing between decreasing plasma Lyso-Gb1 levels and increasing platelet counts in patients with ERT ,52. In tGBA1 mutation. Regardless, our data confirmed the effectiveness of ERT and SRT long-term treatment in patients with GD. We proved the non-inferiority of SRT. Our results indicate that ERT and SRT show the potential of individual drug effectiveness in treating particular symptoms, either as a combination or in a switch manner.The present study has several limitations, and the results should be interpreted with caution. First, our study sample is of a very limited size. Moreover, the ERT to SRT patient ratio is highly inequal (6 to 1) and differs in the duration of treatment before entering the study. One of the further limitations of the study was the inclusion of a higher ratio of females to males (24F/11M), reflecting our center’s patient population. Another limitation of the study was the heterogeneity of patients in treatment dosage and the wide variation in the GD has possibly the widest range of thoroughly studied biomarkers among lysosomal storage disorders. Combining the key biomarker of GD and the evaluation of the treatment, Lyso-Gb1, with other biomarkers, can offer an improved assessment of response to long-term therapy. Nevertheless, new therapeutic options and reliable biomarkers for GD monitoring are crucial to tailoring therapies to a patient’s specific clinical needs.N-N′-N″-triacetylchitotriose . The assay was performed according to the Hollak method. Fluorescence of 4-methylumbelliferone released from the substrate was detected at excitation 365 nm and emission 448 nm by a luminescence spectrometer .Chitotriosidase activity in plasma samples stored at −20 °C was determined using the fluorogenic substrate 4-methylumbelliferyl-β-D-Genomic DNA was isolated from peripheral blood leukocytes using the QIAamp DNA Blood Mini Kit . Purified DNA of the entire coding region of the 12-exon human CHIT1 gene, including intron/exon junctions , was used for PCR amplification. Each amplicon was sequenced by Sanger sequencing or by high-throughput sequencing using the NexteraXT kit and the MiSeq platform .Tandem mass spectrometry from dried blood spots was used to quantitatively measure Lyso-Gb1. Blood samples were collected as dried blood spots on filter cards. Lyso-Gb1 levels were performed using liquid chromatography-mass spectrometry at ARCHIMEDlife Laboratories .Serum TRAP activity was measured by a spectrophotometric assay in the presence of 0.1 M L(+) sodium tartrate at pH 5.6 using 10 mM 4-nitro-phenyl phosphate as substrate.t-test was used to assess differences in plasma markers over time. Two sample T-tests were performed to test differences between therapies for statistical significance. To describe the relationships between the effects of the treatment and time, a linear regression analysis was performed and a regression equation was calculated. Each point of the regression curve corresponded to the mean of values measured at regular 6-month visits, giving a sample size of 6. Slopes of linear regression curves were compared to determine whether the slopes of the two treatments were significantly different from each other, given the slope, standard error, and sample size for each line  and OriginPro 8.5.0 SR1 .Descriptive analysis and a test for the characteristics of a normal distribution  were performed for sample background characteristics. Continuous variables were presented as a range of values as minimum and maximum, mean and standard error of the mean (SEM), or median and standard deviation (SD), depending on the distribution. A paired sample ne (c.f. ). The is


To evaluate the effect of Ajwa dates pit powder (ADP) on lipid profile, body composition and blood pressure in patients with hyperlipidemia. This randomized controlled clinical study was carried out on 40 patients with total cholesterol >200 mg/dl, triglycerides >150 mg/dl and BMI >25, of either sex, aged 30-50 years, who were recruited through written consent. The patients were divided into two groups (n=20 each): the ADP and the control group (CG). All patients received the doctor’s prescribed class A statin (Rosuvastatin/ Atorvastatin) 10 mg/day, while 2.7 g ADP was given on daily basis before breakfast with lukewarm water for 40 days and the control group received the same amount of wheat flour. Body composition, blood pressure and lipid profile were determined at baseline, and after 20 and 40 days. Data were analyzed by using SPSS and GraphPad Prism. ADP significantly reduced body weight (p<0.001), BMI (p<0.001), fat mass, body fat percentage, visceral fat area and waist circumference compared to the control group. Similarly, ADP significantly (p=0.000) decreased the serum level of total cholesterol and low-density lipoprotein. ADP may have the potential to improve dyslipidemia and obesity. Globally, cardiovascular diseases (CVDs) are the most prevalent of all non-communicable diseases (NCDs) which account for an estimated 50% of deaths, out of which 31% are caused by CVDs. In Pakistan, CVDs are 19% prevalent with a 21% probability for each adult citizen to develop CVDs with the present diet and life style factors . Moreover, in 2013, 23.6% adults were having ischemic heart disease . Hyperlipidemia is a chief foundation of heart diseases. It comprises a heterogeneous group of disorders and reflects dyslipidemia characterized by an elevation in the serum total cholesterol, triglyceride , and low-density lipoprotein cholesterol (LDL-C), and a noticeable decline in high-density lipoprotein cholesterol (HDL-C) concentration . Evidence shows that the initiation and progression of cardiovascular dysfunction including hyperlipidemia, hypercholesterolemia, and hypertension are closely related to oxidative stress .Phoenix dactylifera L.) holds an amazing prominence being the invincible provider of nutrition as well as a healing therapy . Nevertheless, the present era scientists and researchers become concerned with the anti-oxidative properties, phenolic and flavonoid contents of date. These compounds have been found to counterbalance the reactive oxidative species (ROS) inside the body which prevents from metabolic processes . Researches have attributed antioxidant property of date seed extract majorly due to phenolic and oleic acid contents . Previous studies have also stated that some phytocomponents, mainly saponins, bring out anti-hyperlipidemic action by hindering the absorption of lipids in the intestine through a resin-like action, furthermore, holding back the activity of lipase . There is some compelling evidence suggesting that flavonoids in Ajwa date seed powder have cardio-protective effects . Flavonoids along with hydroxycinnamates, due to their ability of metal ion chelation and hydroxyl hydrogen ion donation prevent the LDL peroxidation in in-vitro and become the radical scavengers of ROS, and flavonoids intake is significantly and inversely connected with coronary heart disease mortality .Date (Oleic acid (omega-9), linoleic acid (co-6), and linolenic acid (co-3) in the date seed are beneficial dietary interventions to treat hyperlipidemia by lowering LDL, and at the same time increasing HDL content in blood . Saponins in the date pits extract and showed the antihyperlipidemic effects through the suppression of pancreatic lipase , adipogenesis inhibition , and affecting the expression of appetite peptides . The high potassium and low sodium contents of date pits , are suitable for people with hypertension . Additionally, the resistant starch found in the Ajwa date pit , results in propionic acid production which in diet alone is responsible for inhibition of hydroxy-methylglutaryl-CoA reductase (HMG- CoA) .On the foundation of numerous animal research studies, as well as, considering the extraordinary nutritional worth of Ajwa date pits powder (ADP), this study possesses the manifesto of finding out the influence of the powder of Ajwa date pits upon the lipid profile, body composition and blood pressure of patients with hyperlipidemia to be considered a therapeutic remedy against heart diseases.Study design and locationA single-blind randomized controlled trial was carried out to conduct this interventional study in the Cardiac Rehabilitation Center (CRC) of Hayatabad Medical Complex, Peshawar, Khyber Pakhtunkhwa. The study was briefed to and ethical approval (IRB-23231) was granted by the Institutional Research and Ethics Board (IREB) of Postgraduate Medical Institute, Hayatabad, before the initiation of the study.Subjects recruitmentA total of 40 patients visiting outpatient department (OPD) with hyperlipidemia aged 30-50 years, of either sex, were recruited. OpenEPI software was used for calculation of sample size considering alpha being 95%. A written consent form was taken from each patient prior to the enrolment. The subjects were selected randomly from Cardiology department within the Cardiac Rehabilitation Center (CRC) and they were kept blind throughout the study. Inclusion and exclusion criteria2 were included. Pregnant and lactating women, patients with other problems such as liver, kidney or psychological diseases, physically active or athletic individuals or those having BMI below normal were excluded from the study.Patients on doctor’s medication of Class-A statins (either Rosuvastatin or Atorvastatin), having hyperlipidemia with risk of CVDs, a total cholesterol >200 mg/dl , total triglycerides >150 mg/dl  and BMI >25 kg/mPreparation of dosesºC in drying oven for two hours and put in an air tight plastic bag inside a desiccator after which 2.7 g per dose per sachet was measured using an analytical balance. Food grade foil was used to make the sachets and was packed using a heat belt sealer.Locally available Ajwa date pit powder (ADP) was purchased from Madinah market Saudi Arabia. The Ajwa pit powder in its bottles was stored in a dry place at room temperature. The product was then tested and packed in Pakistan Council of Scientific and Industrial Research (PCSIR) Laboratory Peshawar, after confirming the quality and taking authorization. The powder was treated with hot air at 45-50Study protocolst group was kept as control group (CG) receiving the prescribed statin (Rosuvastatin or Atorvastatin) 10 mg/day, while the 2nd group was given 2.70 grams (2.70 g = an ample 1 teaspoon full of Ajwa date pits powder) ADP before breakfast in the morning (fasting) with 1 cup lukewarm water along with the same prescribed statin (Rosuvastatin or Atorvastatin) 10 mg/day. Assessment of body composition, blood pressure was done and blood samples were collected at baseline (day 0), and on day 20 and 40 for lipid profile analysis.The patients with hyperlipidemia (n=40) were divided into 2 groups, each group comprising 20 patients. The 1Experiment methodAs the total study period was 40 days, the doses were started at the day of registration with the initial assessment in accordance with the inclusion criteria. For every 20 days, the patients were given a box of prepared product containing a total of 20 ADP sachets and directed to return the remaining sachets at the upcoming visit. The prescribed dose (i.e. 1 sachet) was taken by the ADP group every morning for 20 days along with the regular medication. Method for blood collectionFasting blood was strained from the incubated vein by hospital nurse. The upper arm was wrapped with a tourniquet band to decrease the flow of blood though the veins and the puncture point was wiped with an alcohol swab. The needle was injected to draw 3-4 ml blood which was collected in tubes containing ethylenediamine tetraacetic acid (EDTA), and then shaken. These blood samples were taken to the Laboratory of Hayatabad Medical Complex for analysis. Later on, these samples were centrifuged 3000 rpm for 3-4 min at 20°C and serum was kept frozen at -80°C until analysis in polypropylene serum tubes. Determination of serum lipid profileSerum lipid profile was determined by using enzymatic calorimetric method. Reagents were purchased from DIALAB Company, Austria and were analyzed by Microlab-300 following previous protocol . The value of triglyceride was used to estimate the VLDL-c through Wilson Rule . VLDL = Triglycerides (TGL)/5 (mg/dl)Assessment of body composition and nutritional status 2 accordingly. Waist and hip circumferences were measured to the nearest 0.01 m using a non-stretchable measuring tape , and waist to hip ratio (WHR) was calculated according to the WHO criteria (2005).Anthropometric measurements were taken at the two time points (baseline and after 40 days) except BMI as it was measured at baseline, and on day 20 and 40. Body weight, fat mass and percent, fat-free mass, and total body water were measured using direct segmental multi-frequency bioelectrical impedance analysis . The visceral fat rating was measured by DSM-BIA machine, and the value (from 0 to 100) was converted into a visceral fat surface area by multiplying the obtained value by 10, as per the instructions of the manufacturer. Height was measured using a fixed stadiometer to the nearest 0.1 cm. BMI was calculated as Kg/mBlood pressureUsing sphygmomanometer, blood pressure was noted during consultation for each patient in a relaxed seated position with their right arm entirely bare and lying upon any assistive plane. Diastolic and systolic readings were recorded twice with a time interval of 6 to 12 minutes whose mean was documented as the blood pressure (BP) of the patient.Statistical analysisStatistical Analysis was carried out using SPSS software (version 21.0) and Graphpad Prism 5. Once the data for BMI, blood pressure, cholesterol, triglyceride, HDL, LDL and VLDL was put, the results are expressed as mean±standard deviation (SD).  Repeated measure analysis was done by using ANCOVA to check within group changes, followed by Bonferroni post test. Independent T-test was applied to find out the net difference between the control and Ajwa Date pits powder-treated group and means for both tests were compared through Least Significance Difference Test at 5% level of significance.In the present study, the impact of Ajwa date pits powder (ADP) was observed on body composition, blood pressure, and lipid profile among patients with hyperlipidemia. Our results demonstrated that ADP supplementation improved the nutritional status and lipid profile of the patients. A total of 126 patients were recruited. After screening, 80 patients were excluded due to not meeting the criteria and other reasons. Further 6 patients were excluded out of 46 due to travel and unspecified personnel reasons .Baseline anthropometric characteristicsAt baseline, the patients were screened and body composition and nutritional status of both groups were assessed. There was no significant difference in the body composition between the groups at baseline .Effect of ADP on body compositionFurther to investigate the effect of ADP consumption on body composition, we again assessed the anthropometric parameters of the patients after 40 days of ithntervention and identified that weight (p<0.001), fat mass , body fat percentage , visceral fat area  and waist circumference  were reduced significantly in the ADP compared to control group . Effect of ADP consumption on lipid profileMoreover, we tested the serum lipid profile of the patients by using calorimetric method at three time points , to identify the effect of ADP on total cholesterol (TC), TG, LDL, and VLDL) and HDL . IntriguEffect of ADP consumption on blood pressure and body mass indexFurther, we assessed the blood pressure and BMI of the patients, whether ADP has any effect on these parameters. There was a non-significant change observed in the mean level of systolic blood pressure (SBP) and diastolic blood pressure (DBP) while BMI was changed significantly (p=0.001) after 40 days of ADP consumption compared to the control group . in-vitro and in rodents. Ajwa dates (Phoenix dactylifera L.) fruit contains high percentage of carbohydrates, dietary fiber, fats and various types of amino acids and vitamins . They possess free-radical scavenging, antioxidant , antimutagenic, antimicrobial , hepatoprotective, nephroprotective, anticancer , and immunostimulant activities . The antioxidant and antihyperlipidemic activities are attributed to the extensive range of phenolic compounds, alkaloids, volatile oils, sterols and flavonoids being present in date pits . Ajwa dates and pits are previously known to scientists and researchers as a functional food, associated with numerous cellular mechanisms in lowering the elevated lipid levels, hyperglycemia, and disturbed hepatic and renal conditions Presently, no clinical study has been conducted to assess the effect of ADP on body composition of humans. Therefore, for the first time, we identified that 40 days of ADP supplementation with antihyperlipidemic drugs significantly decreased the body weight, fat mass, body fat percentage, visceral fat area and waist circumference of patients with hyperlipidemia. These are the first line factors associated with progression of metabolic related diseases such as hyperlipidemia, obesity, coronary artery diseases and diabetes. This significant effect on body composition and nutritional status of the patients may be due to ADP, containing nutritious and therapeutic elements. Ajwa dates are rich source of dietary fiber , polyphenols , iron, calcium, potassium, phosphorous, copper, magnesium and sulfur , that aid in weight loss, fat burning, decrease in level of cholesterol and glucose and beneficial effect on lipid metabolism which in turn reduces the development of cardiovascular related symptoms .In this study, ADP supplementation significantly reduced the serum level of TC and LDL while HDL increases non-significantly after 40 days. These findings indicated that ADP helps prevent the metabolic dyslipidemia by improving the risk factors in terms of body composition. However, this is the first study that investigated the effect of Ajwa dates pits powder on lipid profile of human, so we only justify our results by comparing other dates varieties. Similarly, our findings in respect of LDL, TG and HDL are supported by a previous study that used two varieties of raw dates in healthy individuals . The non-significant decrease and increase in serum level of TG and HDL respectively, while significant decrease in LDL supported by population based human study . Consistent with our results, a study reported that Medjool date consumption by healthy subjects changed their BMI, TC, VLDL, LDL and HDL non-significantly .The findings demonstrated that the blood pressure either SBP or DBP was changed non-significantly. Although previous literature showed that Ajwa dates have the potential to improve the blood pressure, our study results fail to achieve this objective probably due to low sample size and low dose of ADP. Some studies suggested that dietary intake of high potassium and low sodium has beneficial in lowering of hypertension while Ajwa dates are rich source of potassium and magnesium that play a vital role in reducing of hypertension .The strength of the study is that we have addressed the effect of Ajwa dates pits powder on lipid profile and blood pressure of patients with hyperlipidemia. Limitation that this study performed was not a part of any project or funded by any institution rather self-financed by the researcher. This includes the product , anthropometry equipment, lab tests and logistics. In addition, due to lack of sponsorship, we were unable to provide RCT code and the human subjects were mostly reluctant to enroll, thus, a small number of subjects were included and the study was single centered.In conclusion, the study explored the effect of Ajwa date pits powder (ADP) on body composition, lipid profile and blood pressure of patients with hyperlipidemia. The consumption of 2.7 g of ADP improved the lipid profile and body composition of the patients after 40 days. This could be a safe remedy in powder form along with other medication for the prevention of hyperlipidemia and weight loss. Therefore, researchers should conduct more studies on this valuable functional food in different domains for the prevention of metabolic diseases. The authors have declared that there is no conflict of interest.


P = 0.011), and that those with sarcopenia were twice as likely to develop end‐stage kidney disease . Future studies on cachexia and sarcopenia in patients with CKD are needed to report rigorously defined cachexia concerning kidney function. Moreover, in studies on sarcopenia with CKD, it is desirable to accumulate studies using cystatin C to accurately estimate kidney function.Cachexia, in the form of unintentional weight loss >5% in 12 months or less, and secondary sarcopenia in the form of muscle wasting are serious conditions that affect clinical outcomes. A chronic disease state such as chronic kidney disease (CKD) often contributes to these wasting disorders. The purpose of this review is to summarize the prevalence of cachexia and sarcopenia, their relationship with kidney function, and indicators for evaluating kidney function in patients with CKD. It is estimated that approximately half of all persons with CKD will develop cachexia with an estimated annual mortality rate of 20%, but few studies have been conducted on cachexia in CKD. Hence, the true prevalence of cachexia in CKD and its effects on kidney function and patient outcomes remain unclear. Some studies have highlighted the concept of protein‐energy wasting (PEW) which usually include sarcopenia and cachexia. Several studies have examined kidney function and CKD progression in patients with sarcopenia. Most studies use serum creatinine levels to estimate kidney function. However, creatinine may be influenced by muscle mass, and creatinine‐based glomerular filtration rate may overestimate kidney function in patients with reduced muscle mass or muscle wasting. Cystatin C, which is least affected by muscle mass, has been used in some studies, and creatinine‐to‐cystatin‐C ratio has emerged as an important prognostic marker. A previous study incorporating 428 320 participants reported that participants with CKD and sarcopenia had a 33% higher hazard of mortality compared with those without (7% to 66%,  Cachexia and sarcopenia are serious conditions that affect the long‐term prognosis of patients, with weight loss and loss of muscle mass/strength as the main symptoms, respectively. Cachexia was defined at a consensus conference in Washington, USA, in 2006 as ‘a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass’.There is surprisingly little research on the prevalence of cachexia in patients with chronic kidney disease (CKD) and its impact on kidney function Table . The preP < 0.0001).On the other hand, there are some reports of CKD and protein‐energy wasting (PEW), a condition similar to cachexia. PEW is a concept proposed by the International Society of Renal Nutrition and Metabolism and the International Society of Nephrology in 2008 and is defined as the state of decreased body stores of protein and energy fuels .Patients with CKD often suffer from cachexia and PEW as a result of disease‐related factors. The aetiology of PEW encompasses anorexia, reduced energy and protein consumption, hypermetabolism, uraemia, metabolic acidosis, decreased physical activity, decreased anabolism, comorbidities , and dialysis.CKD is considered to be an important cause of cachexia, but few studies have reported on cachexia and CKD, and most studies have been on PEW and CKD. In patients with CKD, PEW prevalence increases as the severity of CKD progresses, and can have a negative impact on kidney function. More researches are needed in the future on the prevalence of strictly defined cachexia and its impact on kidney function in patients with CKD.P = 0.011), and that those with sarcopenia were twice as likely to develop end‐stage kidney disease .More studies on sarcopenia and kidney function in patients with CKD have been reported than on cachexia and PEW Table . IsoyamaFuture studies on sarcopenia in patients with CKD will need to use cystatin C to accurately estimate kidney function. Although there have been several studies on sarcopenia and kidney function, most studies used creatinine to estimate eGFR. Creatinine is known to be influenced by muscle mass and the use of creatinine‐based eGFR in sarcopenia patients with reduced muscle mass may overestimate kidney function. There are, in fact, some studies that show the opposite trend to what might be expected, such as a decline in kidney function accompanied by a decline in the prevalence of sarcopenia. In contrast, cystatin C is known to be less affected by muscle mass and more accurate in estimating GFR than creatinine.The presence of cachexia and sarcopenia can adversely affect patients' prognosis, so they should be evaluated for CKD and other chronic diseases. However, although there are some studies about PEW and CKD, surprisingly little research has been conducted on cachexia and kidney function in CKD, and new studies are warranted. The use of creatinine in sarcopenia patients with reduced muscle mass or muscle wasting may overestimate kidney function and further studies using cystatin C will be required to accurately assess kidney function in patients with CKD.Masatsugu Okamura and Masaaki Konishi have no conflict of interest to disclose. Javed Butler reports consulting fees from Abbott, Adrenomed, Amgen, Array, Astra‐Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo‐Nordisk, Roche, and Vifor. Kamyar Kalantar‐Zadeh has received honoraria and/or support from Abbott, Ardelyx, Astra‐Zeneca, Cara, Daiichi, DaVita, Fresenius, GSK, Haymarket Media, Kabi, Novartis, Novo‐Nordisk, Pfizer, Sanofi, Shire, Travere, and Vifor. Stephan von Haehling has been a paid consultant for and/or received honoraria payments from Astra‐Zeneca, Bayer, Boehringer Ingelheim, BRAHMS, Chugai, Grünenthal, Helsinn, Hexal, Novartis, Pharmacosmos, Respicardia, Roche, Servier, Sorin, and Vifor. Stephan von Haehling reports research support from Amgen, Boehringer Ingelheim, IMI, and the German Center for Cardiovascular Research (DZHK). Stefan D. Anker has received grants from Abbott Vascular and Vifor International; and has received personal fees from Abbott Vascular, Actimed, Vifor, Bayer, Boehringer Ingelheim, Brahms, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions, and Thermo Fisher Scientific; all outside the submitted work.


Hematoma expansion is a common manifestation of acute intracranial hemorrhage (ICH) which is associated with poor outcomes and functional status.We determined the prevalence of expansive intracranial hematomas (EIH) and assessed the predictive model for EIH occurrence and surgical evacuation outcomes in patients with traumatic brain injury (TBI) in Uganda.We recruited adult patients with TBI with intracranial hematomas in a prospective cohort study. Data analysis using logistic regression to identify relevant risk factors, assess the interactions between variables, and developing a predictive model for EIH occurrence and surgical evacuation outcomes in TBI patients was performed. The predictive accuracies of these algorithms were compared using the area under the receiver operating characteristic curve (AUC). A p-values of < 0.05 at a 95% Confidence interval (CI) was considered significant.A total of 324 study participants with intracranial hemorrhage were followed up for 6 months after surgery. About 59.3% (192/324) had expansive intracranial hemorrhage. The study participants with expansive intracranial hemorrhage had poor quality of life at both 3 and 6-months with p < 0.010 respectively. Among the 5 machine learning algorithms, the random forest performed the best in predicting EIH in both the training cohort (AUC = 0.833) and the validation cohort (AUC = 0.734). The top five features in the random forest algorithm-based model were subdural hematoma, diffuse axonal injury, systolic and diastolic blood pressure, association between depressed fracture and subdural hematoma. Other models demonstrated good discrimination with AUC for intraoperative complication (0.675) and poor discrimination for mortality (0.366) after neurosurgical evacuation in TBI patients.Expansive intracranial hemorrhage is common among patients with traumatic brain injury in Uganda. Early identification of patients with subdural hematoma, diffuse axonal injury, systolic and diastolic blood pressure, association between depressed fracture and subdural hematoma, were crucial in predicting EIH and intraoperative complications. Globally, TBI affects at least 69 million individuals and accounts for 5 million deaths annually2. Of these, 93% occur in low- and middle-income countries (LMICs) 5. The highest cases of TBI result from road traffic accidents (RTA) 4. In Uganda, mortality among TBI patients is 4.2 times higher than in the US7. TBI is a major cause of prolonged sequelae, death in the young population, and a social burden as well 11. TBI encompasses numerous types of insults to the brain, including scalp injury, skull fractures, surface contusions, diffuse axonal injury (DAI), hypoxic-ischemic damage, meningitis, and intracranial hemorrhage 12. Among the most serious consequences is expansive intracranial hematoma (EIH). EIH refers to evidence of increased hematoma volume of over 33% within the intracranial vault or absolute hematoma growth over 6mL from an initial scan with varying consequences 13. Intracranial hemorrhages can be classified in three ways: (1) based on time, classified as hyperacute, acute, subacute, and chronic; (2) based on size, including small, big, and massive; and (3) based on location, classified as epidural, subdural, intracerebral, intraventricular and subarachnoid 14.Traumatic brain injury (TBI) is common around the world, burdening economies with substantial healthcare costs in treatment and long-term neuropsychological disability 19. There is no clear effective therapy for EIH, thus also affecting the time of interventions making them experience varying prognoses, which at times can be poor 21. Although there have been advances in quick and accurate diagnostic imaging procedures, the related morbidity and mortality following EIH are persistently high 13. EIH is a critical predictor of poor prognosis in TBI patients, with varying incidences of progression of hematoma between 13 to 38% 22. It is necessary to assess the risk of EIH in patients with intracranial hematoma (IH) as early as possible during hospitalization to avoid unnecessary morbidity and poor prognosis. The subdural hematoma (SDH), skull fracture, subarachnoid hemorrage (SAH) have been identified as risk factors for EIH among IH patients using logistic regression 26.Currently, there is no effective treatment strategy to prevent EIH development in patients with TBI 14.Some studies propose different prognostic models, for example, the ICH score, to assess which patients would benefit from surgical treatment and which from a conservative one. A problem they present is that they do not take into account the evolutionary nature of intracranial hematomasThe prospect of modeling has gained attention and excitement because of its advantages in processing large and high-dimensional medical data. It might offer a practical tool to enhance resource allocation in remote settings with limited resources. Accurate predictive models for EIH occurrence and unfavorable surgical evacuation outcomes could be derived from early biological markers of injury severity. Currently, no studies have investigated the accuracy of modeling algorithms in predicting EIH and surgical evacuation outcomes in patients with IH in Uganda. Therefore, this study was conducted to identify relevant risk factors, assess the interactions between variables, and establish a predictive model for EIH occurrence and neurosurgical outcomes in TBI patients at MNRH.A prospective cohort study conducted between the June 2021 and June 2023 to predict EIH occurrence and surgical evacuation outcomes in TBI patients.27. The Accident and Emergency department attends to approximately 64 urgent surgical evacuations of intracerebral hemorrhage in patients with acute TBI at MNRH every month 28. TBI patients were recruited on admission at the Accident and Emergency Department, then followed up in the operative theatres and the neurosurgery department.The study was conducted at Mulago National Referral Hospital (MNRH), Kampala, Uganda. MNRH, the largest public hospital in Uganda located around 5 kilometers from the city center. It serves about 75% of injured victims in Kampala and surrounding districts All TBI patients aged 18 years or older with a radiologically confirmed brain computerized tomography scan that showed an intracranial bleed were eligible to participate in the study. Purposive sampling was used to recruit participants.Participants were TBI patients aged 18 years and above, post resuscitation GCS of 4 to14, with evidence of EIH on two CT scans  exclusively, eligible for cranial surgery and enrolled in the study within 24 hours of initial presentation to hospital. A written signed informed consent from the patient or their next of kin was obtained. Patients with (1) known pre-thrombocytopenia, (2) a history of coagulation disorders, and (3) used anticoagulants, (4) pregnancy, (5) and those with the inability to consent before surgical intervention were excluded from the study.29EIH was defined by an increase in acute intracranial traumatic hematoma volume > 33% or absolute hematoma growth > 6ml from the initial scan within 72 hours of injury during the study period30. Late surgical evacuation occurs when the expansive mass lesion is removed later (within 25 to 72 hours) after an acute TBI 31. Delayed surgical evacuation occurs when an expansive mass lesion is removed 72 hours after an acute TBI.Patients were recruited from their admission at the Accident and Emergency Department, followed up in the operative theatres, postoperatively in the neurosurgery ward, and neurosurgical outpatient clinics for up to 6 months for the occurrence of complications. Trained research assistants, using a Research Electronic Data Capture (REDCap) system, collected pertinent demographic, clinical, laboratory, and radiological information. Patient demographic characteristics recorded included age, gender, occupation, residence type, geographic regions, and matrimonial state. Outcome’s data were obtained at enrollment (baseline) and then at 1 day, 30-, 90-, and 180-days post-discharge. Clinical outcomes were recorded during these outpatient visits. The principal outcomes included death from any cause and complications . Other parameters of concern included type of cranial surgery , evolution of intracranial hematomas over time , timing to surgery , and site of surgery . Early surgical evacuation occurs when an expansive mass lesion is removed early (within 24 hours) after an acute TBINon-parametric continuous data were summarized using the median and interquartile range, whereas continuous parametric data were shown using the mean and standard deviation. Categorical variables were expressed as frequencies and percentages. To assess for the risk factors of expansive hematoma, the chi-square test was used at bivariate to assess for variables that had an independent association with the outcome.We used logistic regression model and selected variables and those of clinical significance by a stepwise backwards selection based on model AICs. The explanatory variables were categorized into demographical features, neurological assessment, baseline laboratory characteristics, baseline blood pressure characteristics, and neuroimaging patterns. Only the first orders of the variables were included at this step. Then, implemented the model selection again by including all the interaction terms of the selected variables in the previous step. The model selection procedure is the same and based on model AICs. Eventually, we pooled all the selected variables together and manually picked the most relevant variables. All the variables and their interaction terms were included in this model which was later under the same screening process as previous models. The study evaluated the model performance using AUC, accuracy, and five-fold cross-validation.The study adapted this metric-based and manual mixed screening procedure, because of the large number of candidate variables collected in the data. The metric-based screening was to eliminate statistically irrelevant factors from the data, while the manual screening was based on neurological knowledge and the purpose of having an interpretable model. It was likely that some variables were missed, but we believe that this procedure was both feasible and suitable.The data were analyzed using regression models that fit the response type: logistic for binary, ordinal logistic for ordinal variable, and linear for continuous. Variables with p-values < 0.05 remained in the model and were considered to be significant risk factors for intra and post-operative complications, including death among adult patients with expansive hematomas following traumatic brain injury. Then, variables that “best” fit the outcome  were selected by choosing the model with the lowest AIC during a backward stepwise selection. Finally, all selected variables were pooled from each category to fit the final logistic regression model. The final model was selected based on the same criteria, but the predictive performance on the validation dataset was undesirable. Therefore, the model was manually tweaked to achieve better accuracy, AUC in both validation dataset and five-fold cross-validation. Levels of p < 0.05 were considered statistically significant.During the study period, a total of 1500 patients were screened . Out of In this study, a majority of the participants with EIH were significantly older than the no EIH group (42.3 ± 17.9 vs. 30.5 ± 14.0), most of the patients were male 261 (80.6%) and majority 152 (46.9%) were motorcyclists known as boda riders. The results show that most of the patients 184 (56.8%) were from rural residence .Of the 324 patients with intracranial hematomas, 59.3% (n = 192) had expansive hematomas identified on CT scan.In the final model, age, systolic blood pressure, diastolic blood pressure, subdural hematoma (SDH), diffuse axonal injury (DAI), skull fracture, and an interactive term of skull fracture and SDH were selected. Odds of having EIH increased to 1.045 times for one increment in systolic blood pressure. Odds decreased to 0.942 times for one increment in diastolic blood pressure. Having SDH increased the odds of EIH to 6.286 times, while diffuse axonal injury increased it to 4.024 times. Given a patient has skull fracture, SDH decreased the odds of EIH to 0.0676 times .The respective inpatient postoperative risks were 10.2% for death, 58.0% for intraoperative complications, 15.7% for early posttraumatic seizures (PTS), 11.7% for coma, 11.7% for brain oedema, 4.9% for wound infection, 4% for nutrition deficit, 3.4% for pneumonia, 2.8% for CSF leakage, 1.2% for subdural hygroma . HoweverIn this study, 324 TBI patients with intracranial hematomas after surgery were followed up for a total of 15.9 months and the overall survival was 46.6%, 95% CI= (17.0 to 71.9) based on Kaplan–Meier curve. The median survival time was 12.8 months, 95% CI= (11.1 to 13.0). The estimated cumulative survival was 97.38% (95% CI: 94.83–98.68) within the first month of follow-up, 94.35% (95% CI: 90.92–96.50) after 2 months of follow-up, 93.95% (95% CI:90.43–96.20) after 3months of follow-up,90.81% (95% CI: 86.32–93.87%) after 6 months of follow-up, 62.07% (95% CI: 40.35–77.83) after 12 months of follow-up, and 46.55 (95% CI: 16.96–71.93) after 15.9 months of follow-up. The probability of survival decreased as the follow-up time increased, especially within the first months of follow-up according to the Kaplan–Meier survival curve for time to death for TBI patients with intracranial hematomas after surgery .Holding the rest of variables constant, undergoing craniectomy would make the odds of getting intraoperative complication become 8.5317969 times (p = 0.03578). Holding the rest of variables constant, undergoing craniotomy would make the odds of getting intraoperative complications become 1.5244901 times (p = 0.56229). Holding the rest of variables constant, having delay surgery (over 72 hours from the accident) would make the odds of getting intraoperative complications become 2.8757974 times (p = 0.00229). Holding the rest of variables constant, having early surgery (within 24 from the accident) would make the odds of getting intraoperative complications become 1.6229086 times (p = 0.27600). Holding the rest of variables constant, undergoing frontoparietal decompression would make the odds of getting intraoperative complications become 3.6784446 times (p = 0.00531).Holding the rest of variables constant, undergoing fronto-parieto-temporal decompression would make the odds of getting intraoperative complications become 13.329105 times (p = 0.00027). Holding the rest of variables constant, undergoing parieto-temporal decompression would make the odds of getting intraoperative complications become 2.3774298 times (p = 0.04745). Holding the rest of variables constant, undergoing occipito-parietal decompression would make the odds of getting intraoperative complications become 5.2172998 times (p = 0.06236)  and Fig.Holding the rest of variables constant, undergoing craniotomy would make the odds of dying become 10.094291 times (p = 0.000623). Holding the rest of variables constant, undergoing craniotomy would make the odds of dying become 10.094291 times (p = 0.000623). Holding the rest of variables constant, undergoing decompressive craniectomy would make the odds of dying become 1.9833354 times (p = 0.421221)  and Fig.Health related quality of life of intracranial hematomas after TBI who undergoing surgical evacuation increases overtime. Health-related quality of life of intracranial hematomas after TBI, assessed 6 months post-surgical evacuation, was higher for patients with no EIH  vs 85.0(9.5), P = 0.010)  and Fig.Holding the rest of variables constant, undergoing craniotomy would make the odds of having unfavorable quality of life become 94.632408 times (p = 0.000642). Holding the rest of variables constant, undergoing decompressive craniectomy would make the odds of having unfavorable quality of life become 2.2630195 times (p = 0.639813)  and Fig.Holding the rest of variables constant, undergoing decompressive craniectomy would make the odds of having unfavorable functional outcomes become 2.2412587 times (p = 0.023181). Holding the rest of variables constant, undergoing craniotomy would make the odds of having unfavorable functional outcome become 1.0187434 times (p = 0.000824) .32. The evolutionary character of cerebral bleeding and effect of timing from injury (as observed in practice and time of presentation at the unit) to cranial surgery on outcomes are not taken into account by the majority of models 33. Furthermore, the models were established on small samples, many were methodologically flawed, and few were validated in external populations 33. Few others were neither presented in a clinically practical way, nor were they established in populations in LMIC, where 93% of TBI occur 34. Furthermore, patients and surgeons frequently are faced with difficult decisions making in regard to the management of EIH. Weighing in patient characteristics when several options  are available is currently done in an arbitrary way. The development of EIH-specific models would be the cornerstone of defining quality in surgical health care delivery32.This study assessed the burden, identify relevant risk factors, the interactions between variables, and establish a predictive model for EIH occurrence and surgical evacuation outcomes among TBI patients at Mulago National Referral Hospital. The application of these models can assist in decision-making for individual TBI patients with risk of EIH. Several predictive models for intracranial hematomas have been described by regulatory bodies, most of which focus on the quality of hospitalization 26. Some studies have linked the evolution of intracranial hematomas with factors such as age greater than 61 37 and elevated admission systolic blood pressure 39. This study did not find subarachnoid hemorrage(SAH) among risk factors as reported by Allison et al.24. The average area under the receiver curve (AUC) from a five-fold cross-validation was 0.833, while the average accuracy was 73.4%. The AUC of the current study seven-point models disagree with models developed by Cepata et al (0.72) 40, but higher than a simple four-point predictive score reported by Allison et al.(0.77) 24.Considering the feature importance in our developed random forest algorithm-based model, the top five features were age, systolic blood pressure, diastolic blood pressure, subdural hematoma (SDH), diffuse axonal injury (DAI), skull fracture, and an interaction between skull fracture and SDH and were found to be indepently associated with EIH in the final model . These f41. The Monro Kellie doctrine’s space restrictions are intended to be circumvented through decompressive craniectomy (DC), which disturbs the cerebral blood and CSF flow dynamics. The timing of the resulting difficulties, which occur days to months following the operation, can be predicted to help in managing them41. This finding is in line with a study conducted by Hawryluk et al which confirmed that DC remains a controversy 30. Choosing to perform a DC is still challenging and the overall benefits should be balanced against the outcomes and complications on a case by-case basis. DC causes serious complications including meningitis, subdural hygroma, hydrocephalus and increased reoperation rate. Morbidity related to the surgical evacuation was also examined. Intraoperative complications occurred in 58.0% of our patients; the high intraoperative complications confirmed substantial challenges in surgical intervention in LMIC which may impact on the long-term survival and outcomes. Early posttraumatic seizures (PTS) were the most common complication and was observed in 15.7% of patients. PTS are a serious consequence among TBI patients with EIH globally and most especially in low developed countries like Uganda. PTS are commonly associated with severe TBI and the reported incidences vary greatly42. In the present study, coma and brain oedema were observed in 11.7% among patients. Furthermore, wound infection (4.9%) and pneumonia (3.4%), CSF leakage (0.3%) were reported in the analysis of 324 patients 6. Undergoing craniotomy was found to be independently associated with intraoperative mortality in the final model  is recommended over a small frontotemporoparietal DC for reduced mortality and improved neurologic outcomes in patients with severe TBI49.The overall mortality rate in this study was 10.2%, which is lower than the 20% overall mortality rate seen in a prospective research in China on patients who underwent early versus late craniectomy after a traumatic brain injury al model . Holdingal model . Even if50. In addition, EIH appears to be associated with a high rate of neurological deterioration in patients with TBI21. What is not contested is that EIH patients face the risk of a large number of complications after the operation and that can further compromise their quality of life.Undergoing craniotomy and having delayed EIH progression were found to be independently associated with 18 months unfavorable quality of life after neurosurgical evacuation in the final model . Holding51. Undergoing craniotomy, craniectomy and having delayed EIH progression were found to be independently associated with 18 months unfavorable functional outcomes after neurosurgical evacuation in the final model  patients survived from intracranial hematoma following TBI. Among these patients, 73.8% (208) were discharged with favourable condition (defined by GOS of > 3) while 26.2% (74) were discharged with unfavourable condition (defined by GOS of < 3). These findings are better when compared with a study conducted at MNRH which reported 71.7% patients were alive at the end of the study al model . Holdingal model . This reThe present study had limitations including, small sample size, more variables of 824 than the sample size of the study participants and missing values. This was expected and the research team increased 10% of possible dropout or missing data. Thus, the model selection was done to achieve better interpretability of the findings. The model used a 70% and 30% split for the train and test data. A seed was set so that the findings were reproducible. However, the findings show that the selected models were subject to changes when the seed changes, meaning a person who uses a different configuration for the 70%, 30% is likely to get different models in the positive direction. And these findings could be due to the small sample size used in the study. In addition, there were not enough samples to fit a large model with all these factors and their interaction and then do model selection.We developed 5 proposed models including (1) model with 8 coefficients for EIH occurrence; (2) model for intraoperative complications; (3) model for death occurrence; (4) model for unfavorable quality of life and (5) model for unfavorable functional outcomes which have 15 coefficients each to predict earlier individualized estimates of EIH occurrence and surgical evacuation outcomes based on preoperative conditions at MNRH and similar settings across the region. These proposed models have demonstrated good discrimination with AUC for EIH occurrence (0.833) while the average accuracy was 73.4%, intraoperative complications (0.67), mortality (0.36), and 18 months unfavorable quality of life after neurosurgical evacuation in TBI patients (0.61).


Fluid overload secondary to loss of functional nephron mass can elevate blood pressure, which is characteristic of hypertension shown in chronic kidney disease (CKD). Therefore, it is logical to use diuretics at appropriate dose to lower blood pressure in patients with CKD and hypertension. Despite the theoretical background on the use of diuretics in CKD, there have been no definitive data on the effectiveness or safety of diuretics as first-line therapy for the management of hypertension in patients with CKD. Results from some clinical trials have demonstrated that diuretics would not lower blood pressure. They could even worsen electrolyte imbalance and kidney function when they are administered in patients with CKD. Major clinical practice guidelines on management of blood pressure or CKD have stated that evidence for benefits of thiazide diuretics is not conclusive yet in patients with advanced CKD, although loop diuretics are often effective for volume control at lower glomerular filtration rate. Recently, evidence for diuretics as effective blood pressure lowering agents in patients with advanced CKD is increasing. Renoprotective effect of thiazide or loop diuretics might represent a consequence of their influence on blood pressure or their ability to potentiate the effect of renin-angiotensin system blockade by making intraglomerular pressure more renin-angiotensin system-dependent, although their direct benefit on renal function remains controversial. This review summarizes recent data on the possible role of diuretics in lowering blood pressure, slowing the progression of kidney disease, and reducing cardiovascular risk in CKD patients. Hypertension is a well-known risk factor for chronic kidney disease (CKD) and cardiovascular disease , 2. A re2; serum potassium level, 4.6 mmol/L; hemoglobin A1c, 7.1%; and 24-hour urine protein level, 5,481 mg/day. In addition to maintaining current medications, what drug should be provided to this patient?A 68-year-old woman with a long duration of type 2 diabetes and hypertension was referred to the Division of Nephrology with worsening renal function and proteinuria. She was taking azilsartan 80 mg, amlodipine 5 mg, rosuvastatin/ezetimibe 10/10 mg, nebivolol 5 mg, sitagliptin 50 mg, and extended-release metformin 1,000 mg with insulin injection. She had a blood pressure of 153/72 mmHg, a heart rate of 73 beats/min, and a respiratory rate of 16 breaths/min. Physical examination revealed regular heart beats without murmur, clear lung fields, and mild pitting edema. At presentation, she had the following results: serum creatinine, 1.61 mg/dL; estimated glomerular filtration (eGFR), 31.7 mL/min/1.73 mCurrent evidence has shown that controlling blood pressure to be lower than the previous one could reduce cardiovascular events and all-cause mortality in patients with CKD –12. AccoTo find what combinations work the best for treating blood pressure in CKD, it is necessary to look again at the pathophysiology of hypertension in CKD. Numerous factors including genetics, pressure natriuresis, salt sensitivity, renin-angiotensin-aldosterone system, sympathetic nervous system, obesity, natriuretic peptides, endothelial dysfunction, arterial stiffness, and immune system have been thought to be mainly involved in the pathogenesis of hypertension . Among tOddly enough, diuretics for treating high blood pressure has been undervalued against other classes of antihypertensive agents for years. Although diuretics might have an advantage as an initial therapy for reducing cardiovascular events in certain racial or ethnic groups, there is a reluctance to reassess the “passé” drug in the era when RAS inhibitors such as angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) are undoubtedly thought to be better than other agents –27. When2 [The term “thiazide diuretic” currently incorporates all diuretics believed to have a primary action on the Na-Cl cotransporter (NCC) in the distal tubule despite chemical structural variation among the heterogeneous group of agents including the thiazide-type diuretic hydrochlorothiazide as well as thiazide‐like diuretics such as metolazone and chlorthalidone , 32. The2 , 34. How2 and poorly controlled blood pressure, which was defined as systolic blood pressure ≥ 135 mmHg or diastolic blood pressure ≥ 85 mmHg by 24-hour ambulatory blood pressure monitoring despite taking ACEi or ARB and other classes of antihypertensive agents [Although evidence against the use of thiazide diuretics in advanced CKD is still weak , 34, a f2 and uncontrolled hypertension as confirmed by 24-hour ambulatory blood pressure monitoring were included while receiving at least one antihypertensive drug [In the CLICK trial, patients with stage 4 CKD defined as eGFR 15 to < 30 mL/min/1.73 mive drug . The majive drug . It was ive drug .2 [These small but influential results have made the recent KDIGO guideline to mention that several thiazide diuretics including chlorthalidone, metolazone, and indapamide appear to remain effective at GFR < 30 mL/min/1.73 m2 . It is e2 , 38. Bas2 . However2 . On the 2 , 40. In 2 . Since tAlthough thiazide diuretics have been proven to be effective even in patients with CKD than previously thought, the mechanisms responsible for the blood pressure lowering effect observed for thiazide diuretics are incompletely understood , 38. AftGoing back to case 1 presented in the beginning of this paper, hydrochlorothiazide 12.5 mg was added to antihypertensive regimens of the patient. Three months later, she experienced a 9 mmHg decrease in her systolic blood pressure with a decrease in urine protein level down to 3,530 mg/day and an increase in serum creatinine level up to 1.91 mg/dL. It is unclear if the lower blood pressure by adding the diuretic could affect the long-term cardiovascular or renal outcome. However, if blood pressure is not controlled with initial antihypertensive agents, the addition of a thiazide diuretic would be a reasonable and effective step .Compared with thiazide diuretics, loop diuretics are known to have relatively short acting duration, limiting their widespread adoption for generally treating hypertension , 38. As When using diuretics in CKD, it may be preferable to choose torsemide over furosemide because torsemide has a longer duration of action . Torsemi2, a tradition at one time, turned out to be unnecessary as noted above, one might wonder which of thiazide diuretics and loop diuretics could be a better choice for treating hypertension in CKD. A randomized, double-blind, crossover trial has compared fractional excretion of sodium and chloride after chronic administration of furosemide and hydrochlorothiazide [Since the change in diuretic therapy from thiazides to loop diuretics when GFR declined below 30 ml/min/1.73 mthiazide . In thatthiazide . These aIn the case of “kidney failure”, a more appropriate term than previously used term of “end-stage renal disease” or “end-stage kidney disease” , loop diOutpatient visit-to-visit blood pressure variability (BPV) has been reported to be independently associated with poor cardiovascular outcomes in the general population , 57. Alt2, and a spot urine protein to creatinine ratio of 9,190 mg/g. Kidney biopsy showed typical diabetic nephropathy with 90% glomerular sclerosis, grade 3 of tubular atrophy, grade 3 of interstitial fibrosis, and grade 3 of fibrous wall thickening of vessels. ARB was started but immediately discontinued due to a fast increase in serum creatinine by more than 40%. He was put on cilnidipine, carvedilol, furosemide, and hydrochlorothiazide. On visit after 8 months, pitting edema of lower extremities was not observed. He had a blood pressure of 125/83 mmHg and a serum creatinine level of 4.07 mg/dL. His doctor was worried about if long-term use of diuretics could wreak havoc on this patient’s renal function and asked an expert opinion. How should you as an expert respond to this issue?A 64-year-old man with an unknown duration of diabetes visited a clinic with uncontrolled blood pressure, decreased visual acuity, and generalized edema. His blood pressure was 159/86 mmHg and his heart rate was 88 beats/min. He was noted to have decreased kidney function with a serum creatinine level of 3.70 mg/dL, an eGFR of 18.0 mL/min/1.73 mSince RAS inhibitors are superior to other classes of antihypertensive agents in patients with high blood pressure and CKD for kidney and cardiovascular outcomes with or without diabetes and albuminuria, renoprotective potentials of diuretics have had quite a low profile. The only diuretics that have been investigated in large clinical trials with hard end points for antiproteinuric and renoprotective effects have been mineralocorticoid receptor antagonists such as spironolactone, eplerenone, and finerenone . HoweverRenoprotective effects of thiazide-like diuretics have also been reported. Based on data from the CLICK trial and its pilot trial targeting patients with advanced CKD, the administration of chlorthalidone could lead to a reduction in urine albumin excretion , 35. AdvUnlike thiazide diuretics, loop diuretics have little evidence to support its antiproteinuric effects Table . IncreasThe precise mechanisms by which thiazide or loop diuretics have antiproteinuric effects have not been clarified yet. The effect of a sodium load that can inhibit the antiproteinuric effect of RAS blockades could be restored by diuretics . In addiIt also remains that the effect of loop diuretics on proteinuria is independent of its diuretic property. Like thiazide diuretics, chronic use loop diuretics in CKD might contribute to a reduction of proteinuria by lowering blood pressure with subsequent volume regulation , 69. TheOne of the reasons why physicians hesitate to use diuretics acutely or chronically is because whether diuretics could result in direct kidney injury or just benign hemoconcentration of serum creatinine by volume depletion remains controversial . Especia2 without previous receipt of loop or thiazide diuretics using database of Kaiser Permanente Northern California, neither initiation of diuretics nor type of diuretic was significantly associated with CKD progression or kidney failure after accounting for receipt of other medications and time-dependent confounders using marginal structural model with inverse probability weighting [In order to overcome such difficult challenges, a recent study has employed causal inference statistical methods to estimate the effect of using loop and thiazide diuretics on CKD progression, finally reporting no adverse effect of diuretic use in CKD patients . Among 4eighting . In realeighting . Possibleighting , 75.For the answer to question raised at case 2 presentation, an extensive literature review suggests maintaining existing diuretic therapy if prescribed doses of diuretic combination are currently appropriate for volume homeostasis and optimal blood pressure. Certainly, such decision should be individualized according to each patient profile considering age, comorbid conditions, concurrent medications, and potential long-term effects of diuretic exposure. Already advanced renal dysfunction at presentation as described in case 2, will ultimately precipitate the patient into a status of kidney failure requiring kidney replacement therapy in the near future. At least diuretic therapy might bridge CKD patients to dialysis or kidney transplantation. During that time, a process of shared decision-making with the patient about the type of kidney replacement therapy to use could be used .Considering that the overall prevalence of comorbid cardiovascular disease is high in patients with CKD , better Physicians tend to be always interested in developing first-in-class drugs and testing experimental medications. However, we should not lose our “old friends” or miss a chance to reconsider their forgotten talent. Although further long-term trials are needed to prove more favorable clinical outcomes with diuretics in patients with CKD, it becomes more evident that diuretics are useful for managing high blood pressure in both early and advanced CKD.


Asthma is a heterogeneous disease characterized by chronic airway inflammation. The pathophysiologic processes of asthma can disrupt iron homeostasis, resulting in anemia. However, the association between asthma and anemia among adult asthma patients remains limited. Therefore, the main aim of this study was to determine the prevalence and factors associated with anemia among adult asthmatic patients from May to August 2021.An institution-based, cross-sectional study was conducted among 291 asthmatic patients in Northwest Ethiopia. A pre-tested structured questionnaire and checklist were used to collect sociodemographic and clinical data. A blood specimen was collected from asthmatic patients for a complete blood count analysis and morphology assessment. The data were entered into the Epi data software and exported to the statistical package for social science version 20 software for analysis. Non-parametric Mann-Whitney U test was used to compare red blood cell parameters among groups with acute and chronic exacerbations. Binary logistic regression models were used to determine the factors associated with anemia. A p-value less than 0.05 was considered statistically significant.The overall prevalence of anemia in this study was 11% (95% CI: 7.2–14.8%). Acutely exacerbated asthmatic patients had significantly lower median values of red blood cell parameters such as red blood cell count, hemoglobin, and mean cell hemoglobin when compared to chronic exacerbations. In addition, using systemic corticosteroids  and being hospitalized in the emergency department  were found to be significantly associated with anemia.This study demonstrated that anemia was predominant in adult asthma patients. Red blood cell number, hemoglobin level, and mean corpuscular hemoglobin were significantly lower in acute asthma exacerbations. Therefore, appropriate intervention strategies should be undertaken to reduce the prevalence of anemia among adult asthma patients to reduce further complications and provide better monitoring of asthma patients. Asthma is a heterogeneous disease characterized by chronic airway inflammation. It is an inflammatory condition associated with airway hyperresponsiveness. Coughing, wheezing, shortness of breath, and chest tightness are common symptoms, along with variable expiratory airflow limitation. These symptoms are intermittent and frequently worse at night or after exercise .Asthma is a significant public health issue . It affeAnemia occurs when the number of red blood cells (RBC), hemoglobin (Hb), or hematocrit value is lower than the normal range . Accordi2+) and activates various pathways that coordinate inflammation [Asthma is known to affect iron homeostasis, resulting in anemia. The pathophysiologic mechanisms of asthma, such as inflammation, bronchoconstriction, and bronchial obstruction disrupt iron homeostasis . Chronicammation .Evidence suggests that anemia is common in asthmatic patients, mainly due to iron deficiency . Lack ofOn the other hand, hemoglobin can stabilize the oxygen pressure in the blood and tissues. Hence, a lack of iron lowers Hb synthesis. As a result, anemia and reduced Hb levels may be associated with the global rise in asthma and allergic disorders. Anemia is considered a risk factor for asthma exacerbations , 17. FurEven though studies reported that hypoxia induces erythropoiesis, different studies have shown that RBC parameters like hemoglobin level, hematocrit, and RBC indices were lower among asthmatic patients. This might be due to the effect of corticosteroids. Use of interferes erythrocyte maturation and erythropoiesis. That predisposes the development of anemia among adult asthma patients , 19.Only a few studies have found highest prevalence of anemia among asthma patients. However, the magnitude of anemia among adult asthmatic patients remains limited. Also, the magnitude of anemia among adult asthma patients in our country including our study area is not studied well. Therefore, our study was an effort to fill this gap and provide information on the burden of anemia among adult asthmatic patients. Furthermore, this study also gives knowledge on variations of RBC parameters with respect to chronic and acute asthma exacerbation states.The institution-based cross-sectional study was conducted from May to August 2021 in Northwest Ethiopia at Tibebe-Ghion Comprehensive Specialized Hospital (TGCSH) and the University of Gondar Comprehensive Specialized Hospital (UGCSH). TGSH is a teaching hospital located in Northwest Ethiopia, 560 km away from the capital city (Addis Ababa), in the Amhara regional state, Bahirdar city. This hospital provides inpatient and outpatient care for up to 2,000 patients per day. It also serves more than five million people in the catchment area. On the other hand, UGCSH is found in Northwest Ethiopia, in the Amhara Regional State, Gondar town. The hospital serves more than 7 million people in the catchment area. There are over 400 regular follow-ups of asthmatic patients in the outpatient department of this hospital.This study comprised a total of 291 asthmatic patients confirmed by a specialist  via clinical history and lung function tests. Patients had either an acute exacerbation or chronic, stable asthma. On the other hand, asthma patients diagnosed with chronic conditions such as HIV/AIDS, chronic kidney disease, hematological malignancies, blood loss, bleeding disorders, pregnancy, bronchiectasis, and tuberculosis were excluded from this study.The required sample size was determined by using the single population proportion formula. By considering the proportion of 50%, 5% margin error, and 95% confidence interval.From the previous annual report, the total number of asthmatic patients in two hospitals per year was 1,200 . Thus, a reduction formula was used. As a result, the final sample size was 291 (n = 291). The study participants were then proportionally allocated between two hospitals  2019 guideline [uideline .Stages of asthma were classified as intermittent, mild persistent, moderate persistent, and severe persistent based on GINA 2019 guidelines [idelines .A habit of doing physical exercise: study subjects who had the habit of doing physical activity for at least 20–30 min per day as a continuous activity [activity .Acute exacerbation: asthma patients with decreased expiratory airflow, which can range from mild to a life-threatening state.A structured, pre-tested questionnaire was used to collect socio-demographic and behavioral data from study participants. A checklist was used to collect clinical data from patients’ medical records, such as duration of patients living with asthma, family history of asthma, history of asthmatic drug intake before 3 months, types of asthmatic drugs, chronic disease, severity and stages of asthma, symptoms of asthma, and history of taking other drugs before 3 months. Clinical nurses collected the data through face-to-face interviews and chart reviews .A venous blood specimen (4 mL) was collected from asthmatic patients by the trained laboratory technician using the syringe method. Complete blood counts (CBC) of the study participants were analyzed using a five-differential Unicel DxH 800 Coulter cellular analysis system . This automated analyzer uses Coulter counting, spectrophotometry, and VCS technology principles.Peripheral blood morphology examination was performed to confirm flags generated by the automated hematology analyzer, to check the performance of the automated hematology analyzer, and to examine RBC morphology (to classify anemia). A thin blood smear was prepared from leftover blood from the CBC. The smear was air-dried and stained with Wright stain. Then the stained smear was carefully examined with a 100X oil immersion objective by laboratory technologists. All laboratory tests were performed in the UGCSH and TGSH laboratories. The results of each study participant were carefully recorded in a form designed for laboratory result registration.The English-version questionnaire was prepared and then translated into the local language (Amharic). To check for consistency and correctness, the questionnaire was retranslated back into the English version. A pretest was done on 5% of asthmatic patients at the Felege Hiwot Comprehensive Specialized Hospital (FHCSH). FHCSH is located in Northwest Ethiopia in Amhara regional state, Bahirdar city. Based on the findings of the pretest, the questionnaire was modified. In addition, data collectors were trained before starting data collection to minimize technical and observer bias.Pre-analytical, analytical, and post-analytical phases of quality assurance were maintained in the overall laboratory procedures. Quality control for working equipment and reagents was ensured by using standard controls. Standard operating procedures and manufacturer’s instructions were strictly followed during sample collection and laboratory procedures. The questionnaire was checked for clarity, consistency, and completeness by the principal investigator. The result of every test was properly recorded, reviewed, and transcribed.Data was entered into the Epi-data software (version 3.0.4). The data were then cleaned and exported into the Statistical Package for Social Science version 20 software  for analysis. Descriptive statistics, such as frequencies and percentages, were used to summarize the data. The Shapiro-Wilk test and histogram were used to assess normal distribution for continuous variables. Tables and figures were used to present the data.Since the continuous variables were not normally distributed the non-parametric Mann Whitney U test was used to compare RBC parameters among groups. A bivariable and multivariable binary logistic regression analysis was carried out to determine the association between predictors and outcome variables. The strength of the association was determined by using the crude odds ratio (COR) and adjusted odds ratio (AOR) with a 95% confidence interval (CI). Variables with a p-value of less than 0.2 were fitted into the multivariable logistic regression analysis. Hosmer and Lemeshow’s goodness-of-fit statistic was used to check the model’s fitness. In all cases, a p-value of less than 0.05 was considered statistically significant.Ethical clearance was gained from the ethical review committee of the School of Biomedical and Laboratory Science, College of Medicine and Health Sciences, University of Gondar, with letter reference number SBMLS-2748/2021. The department of Hematology and Immunohematology provided a support letter, which was forwarded to the directors of UGCSH and TGCSH. In addition, a permission letter to conduct research was obtained from the UGCSH and TGCSH directors.Written informed consent was obtained from each study participant after the objective of the study was explained. Study participants were identified by using codes rather than individual identifiers. The results and information of the study participants were kept confidential. Study participants who had anemia were linked to the UGCSH and TGSH chronic outpatient departments for proper management. All methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsinki).A total of 291 adult asthma patients were enrolled in this study. The age range was from 18 to 65 years, with a median and interquartile range (IQR) of 50 (38–60) years. Females comprise 164 (56.4%). About 186 (63.9%) of the study participants were urban residents. Regarding educational status, 126 (43.3%) were unable to read and write  were current cigarette smokers, and 52 (17.9%) had a habit of doing physical exercise. About 64 (22%) had an alcohol-drinking habit. In terms of BMI, 51 (17.5%) were overweight . Around 176 (60.5%) and 186 63.9%) had moderate severity and moderately persistent stages of asthma, respectively. About 241 (82.8%) were used asthma medication in the past three months. Asthma-related emergency admissions account for 86 (29.6%) (Table .9% had mThe median (IQR) values of RBC, Hb, HCT, and MCV were 4.9 (4.44–5.41), 14.7 (13.4–14.7), 43.4 (40–43.4), and 88.8 (85.1–92.5), respectively  of RBC parameters between acute and chronic asthma exacerbations. Based on this analysis, RBC, Hb, and MCH showed a statistically significant median difference between acute and chronic asthma exacerbations Table .A bivariable and multivariable logistic regression analysis was done to determine factors associated with anemia. In a bivariable logistic regression analysis, variables like monthly income, asthma severity, asthma-related emergency admissions, and SC use showed an association with anemia. While in multivariable logistic regression analysis, taking SC  and being admitted to the emergency department  only showed a statistically significant association . This finding was in line with a study conducted in Egypt (11.2%)  and a stOn the other hand, the findings of this study were lower than a study conducted in Iraq . The disThere are different ways to explain the existence of anemia in asthma patients. Chronic inflammation, which is a characteristic feature of asthma, may be associated with anemia. It can cause anemia of inflammation by impairing hepcidin regulation. The involvement of cytokines and inflammatory mediators plays an important role in the development of anemia by altering iron availability and ferritin accumulation. Several cytokines, which are essential for iron homeostasis, accelerate the turnover of red blood cells (RBC) and reduce Hb and iron levels –32. CytoIn particular, anemia of inflammation can be related to aging. Studies have shown that older age might be a risk factor for inflammatory anemia , 39. In 2+) necessary for hemoglobin synthesis [Based on the non-parametric Mann-Whitney U test, patients with acute exacerbations had significantly lower median (IQR) values of RBC, Hb, and MCH when compared to patients with chronic asthma exacerbations. This might be due to the fact that asthma disrupts iron hemostasis. Thus, disruption of iron hemostasis leads to a decrease in the amount of metal . This might be due to the fact that anemic patients may have a higher risk of developing more asthma attacks, which cause emergency admissions. In asthma patients, the presence of anemia can be associated with more severe clinical patterns (poorly controlled asthma) . MoreoveStudy participants who were using SC had four times higher odds of developing anemia than those who had not taken SC . The possible explanation might be due to the effects of drugs. A study by Saidu H et al. reported the decreased HCT, Hb, and RBC values of asthmatic patients on corticosteroids compared with healthy controls . It has This study has many limitations. Firstly, the cross-sectional nature of the study does not employ cause-and-effect relationships . Another limitation is due to the lack of testing materials, we were unable to assess iron parameters like serum iron level and ferritin level (we have not investigated iron deficiency anemia) and inflammatory cytokines like IL-6 and TNFα.In conclusion, our study indicated the predominant existence of anemia among adult asthmatic patients. Asthma-related emergency department admissions and SC use were associated with anemia among adult asthma patients. Therefore, appropriate intervention strategies should be implemented to lower the prevalence of anemia among adult asthma patients to reduce further complications, hospitalization, and provide better follow-up of asthma patients. Furthermore, the effect of asthmatic drugs such as ICS and SC on erythropoiesis should be independently assessed with an appropriate control group in the future.


Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxicity that markedly limits the use of oxaliplatin and affects quality of life. Statins have been shown to exert neuroprotective effects in preclinical settings. The aim of the present study was to clarify whether statins prevented OIPN in patients with colorectal cancer (CRC) receiving adjuvant CAPOX therapy.We examined 224 patients who received adjuvant CAPOX therapy for CRC between July 2010 and December 2021 at our hospital. Patients were divided into “Statin” and “Non-statin” groups based on statin use. Details on and the adverse events of adjuvant CAPOX therapy were examined in association with statin use.p=0.67). The severity of OIPN was similar between the two groups (p=0.89). The frequency of treatment delays in CAPOX did not significantly differ between the Statin and Non-statin groups .Thirty-one patients (14%) were treated with statins. There were no intergroup differences in the relative dose intensity or number of CAPOX cycles between the Statin and Non-statin groups. In total, 94% of patients in the Statin group and 95% of those in the Non-statin group developed OIPN (The efficacy of statins to attenuate OIPN during adjuvant CAPOX therapy was not apparent in the current study. Further studies are needed to confirm the present results. Colorectal cancer (CRC) is the third most deadly and fourth most commonly diagnosed cancer worldwide , 2. PrevMajor adverse events of oxaliplatin include peripheral neuropathy, myelosuppression, and gastrointestinal reactions, such as diarrhea and stomatitis , 13. TheAnimal studies previously demonstrated that statins, HMG-CoA reductase inhibitors, exerted neuroprotective effects by attenuating oxidative stress , 18. HowRegarding the relationship between statins and OIPN, only one retrospective study reported that the incidence of OIPN decreased with statin use in patients with several cancer types . TherefoWe investigated consecutive Japanese patients who underwent radical surgery for primary CRC and received adjuvant CAPOX therapy between July 2010 and December 2021 at the University of Tokyo Hospital. Patients who received preoperative chemoradiotherapy without oxaliplatin were included. We excluded patients who had previously received duloxetine, a medication recommended for the treatment of OIPN , 10.The present retrospective study was approved by the Ethics Committee of the University of Tokyo (No. 3252-).2 oxaliplatin and the oral administration of capecitabine at a dose of 1,000 mg/m2 twice daily for two weeks. The treatment course was repeated every three weeks [At our hospital, we recommend adjuvant chemotherapy to CRC patients based on the latest guidelines of the Japanese Society for Cancer of the Colon and Rectum . Howeveree weeks .We retrieved the following data from our prospective database and patient medical charts: age, sex, body mass index, Eastern Cooperative Oncology Group PS, comorbidities, such as diabetes mellitus, cardiac, pulmonary, renal, and hepatic diseases, statin use, the primary location, the pathological classification of tumors according to the American Joint Committee on Cancer staging manual , the relWe divided patients into two groups according to statin use: the ‘Statin’ and “Non-statin” groups.U test. Qualitative variables were compared using Fisher’s exact test or the chi-squared test with Yates’ correction where appropriate. All reported p-values were two-sided, and results were considered to be significant when p-values were <0.05.Statistical analyses were performed using JMP Pro 16.2.0 . All variables were summarized as medians (ranges), means ± standard deviations, or numbers (percentages). Quantitative variables were compared using the Mann-Whitney A total of 224 patients who received CAPOX therapy were included in the present study. Thirty-one patients 14%) received statins during adjuvant CAPOX therapy . Body mass index was higher in the Statin group than in the Non-statin group (p=0.023). In addition, the Statin group included more patients with diabetes mellitus, hypertension, cardiovascular disease, and dyslipidemia than the Non-statin group . No significant differences were observed in other parameters between the two groups.Table The treatment details of adjuvant CAPOX therapy are reviewed in Table p=0.67); both groups showed a similar distribution of the severity of OIPN (p=0.89). Moreover, grade ≥2 OIPN often occurred as early as at the end of the second cycle of CAPOX regardless of statin use (p=0.99). The incidence of dose reductions or treatment delays in CAPOX due to OIPN did not significantly differ between the Statin and Non-statin groups . The overall incidence of grade 3/4 adverse events other than OIPN was 23% in the Statin group and 30% in the Non-statin group (p=0.43).Table Although OIPN is a major dose-limiting adverse event of oxaliplatin, there are currently few preventive or treatment measures. Animal models of chemotherapy-induced peripheral neuropathy, including OIPN, have been established since the late 2000s –28, and Gstm1 mRNA, which promotes the detoxification of reactive oxygen species [Regarding the mechanisms of OIPN, previous studies suggested that OIPN is caused by ion channel dysfunction, glial activation, nuclear DNA damage, mitochondrial damage, neuroinflammation, and oxidative stress , 32. Amo species .Despite promising findings from preclinical studies, clinical evidence suggested that the administration of statins to patients was associated with the development of neuropathy , 34. ThePrevious studies reported that OIPN occurred in 80–95% patients after treatment with oxaliplatin –38. SimiThe relationship between OIPN and diabetes mellitus currently remains unclear; however, a few previous studies suggested that patients with diabetes mellitus were more likely to develop early-onset and persistent OIPN than non-diabetic patients –41. In tThere are several limitations that need to be addressed. This was a retrospective study conducted at a single hospital. In addition, the number of patients receiving statins was relatively small, which may have caused type II errors. Besides diabetes mellitus, the intergroup disparities in age, body mass index, hypertension, cardiovascular disease and dyslipidemia may have contributed to the similar incidence and severity of OIPN between the two groups, even if statins protect against neuropathy. Moreover, the present study may have included a selection bias; adjuvant chemotherapy may not have been selected for patients who already had neuropathy and patients with dyslipidemia who were likely to have severe concurrent comorbidities. We also included some patients with a short follow-up, which may hamper the evaluation of long-term changes in chronic OIPN. Furthermore, the duration of and adherence to statin therapy were not examined.In CAPOX therapy for CRC patients, the effectiveness of statins for reducing the incidence or severity of OIPN was not observed in our cohort. The frequency of dose reductions or treatment delays was also independent of statin use. Further studies with a larger patient cohort are needed to confirm the present results.