Dialysis Patients Research Articles

Pregnancy in patients with chronic kidney disease undergoing dialysis.

Women with chronic kidney disease are less likely to become pregnant and are more susceptible to pregnancy complications when compared to patients with normal kidney function. As a result, these are considered high-risk pregnancies, both maternal and fetal. Over the years, there has been an increase in the incidence of pregnancies in dialysis patients, and an improvement in maternal and fetal outcomes. It is believed that the optimization of obstetric and neonatal care, the adjustment of dialysis treatment (particularly the increase in the number of hours and weekly frequency of dialysis sessions), and the use of erythropoiesis-stimulating agents have provided better metabolic, volume, blood pressure, electrolyte, and anemia control. This review article aims to analyze pregnancy outcomes in chronic kidney disease patients undergoing dialysis and to review nephrological medical management in this scenario. Due to the growing interest in the subject, clinical recommendations for care practice have become more consistent in both drug and dialysis management, aspects that are addressed in this review.

Association between serum intact parathyroid hormone and survival in dialysis patients

Association between serum intact parathyroid hormone and survival in dialysis patients

Phase angle is a useful predicting indicator for protein-energy wasting and cardiovascular risk among maintenance hemodialysis patients.

Protein-energy wasting (PEW) is a major contributor to the high mortality among maintenance hemodialysis (MHD) patients. Cardiovascular disease (CVD) is the leading cause of death in dialysis patients, and PEW can significantly increase cardiovascular mortality in MHD patients. Previous studies have confirmed that PA may be a good objective indicator for determining the nutritional status and prognosis of MHD patients. Our study aimed to determine the predictive value of phase angle (PA) as detected by bioelectrical impedance analysis (BIA) on PEW and cardiovascular (CV) risk among MHD patients. Our retrospective observational study involved 161 adult patients with HD. The Cardiovascular risk score is a risk model based on the Japan Dialysis Outcome and Practice Patterns Study (J-DOPPS). We established LASSO logistic regression analysis model to identify key parameters related to body composition that can predict PEW in MHD patients. The area under the curve (AUC) values for PA, appendicular skeletal muscle mass index (ASMI), body cell mass (BCM), and mid-arm circumference (MAC) in predicting PEW in male MHD patients were relatively large, with 0.708, 0.674, 0.663, and 0.735, respectively. The predicted PEW values of these parameters were slightly lower in female patients than in men. We incorporated PA, ASMI, BCM, and MAC into a model that predicted the incidence of PEW in maintenance hemodialysis patients using LASSO technology. We discovered that the model predicted a greater AUC of PEW occurrence than any single factor, 0.877 for men and 0.76 for women. The results of the univariate logistic regression analysis showed that the low PA tertile array group had a greater incidence of PEW than the high PA group (P < 0.001). Additionally, we also found that lower PA was associated with higher CV risk scores. The PA detected by bioelectrical impedance analysis could predict the risk of PEW and cardiovascular events among patients with MHD. When used in conjunction, PA, ASMI, BCM, and MAC have a high diagnostic efficacy for PEW in patients on maintenance hemodialysis.

Prediction models for ischemic stroke and bleeding in dialysis patients: a systematic review and meta-analysis

Abstract Background Patients with kidney failure on maintenance dialysis have a high stroke and bleeding risk. Multivariable prediction models can be used to estimate the risk of ischemic stroke and bleeding. A systematic review and meta-analysis was performed to determine the performance of the existing models in patients on dialysis. Methods MEDLINE and Embase databases were searched, from inception through January 12, 2024, for studies of prediction models for stroke or bleeding, derived or validated in dialysis cohorts. Discrimination measures for models with c-statistic data from ≥ 3 cohorts were pooled by random effects meta-analysis and a 95% prediction interval (PI) was calculated. Risk of bias was assessed using PROBAST. The review was conducted according to the PRISMA statement and the CHARMS checklist. Results Eight studies were included in this systematic review. All the included studies validated pre-existing models that were derived in cohorts from the general population. None of the identified studies reported the development of a new dialysis specific prediction model for stroke, while dialysis specific risk scores for bleeding were proposed by two studies. In meta-analysis of c-statistics, the CHA2DS2-VASc, CHADS2, ATRIA, HEMORR(2)HAGES and HAS-BLED scores showed very poor discriminative ability in the dialysis population. Six of the eight included studies were at low or unclear risk of bias and certainty of evidence was moderate. Conclusions The existing prediction models for stroke and bleeding have very poor performance in the dialysis population. New dialysis-specific risk scores should be developed to guide clinical decision making in these patients.

Association of inflammatory cytokines with mortality in peritoneal dialysis patients

Association of inflammatory cytokines with mortality in peritoneal dialysis patients

The Donnan equilibrium is still valid in high-volume HDF.

Clinical studies have shown that hemodiafiltration reduces morbidity and mortality of dialysis patients compared to hemodialysis alone. This is attributed to its superior middle molecule clearance compared to standard hemodialysis. However, doubts arose as to whether a high convective flux through the dialyzer membrane has an influence on the equilibrium concentration of small ions, especially that of sodium. Due to the presence of negatively charged impermeable proteins on the blood side, the Gibbs-Donnan effect leads to an asymmetric distribution of membrane permeable ions on both sides of the membrane. In thermodynamic equilibrium, the concentrations of those ions can easily be calculated. However, the convective fluid flow leads to deviations from thermodynamic equilibrium. In this article, the effect of a convective flow on the ion distribution across a semipermeable membrane is analyzed in a theoretical model. Starting from the extended Nernst-Planck equation, including diffusive, convective, and electrostatic effects, a set of differential equations is derived. An approximate solution for flow speeds up to 0.1 ms-1 as well as a numerical solution are given. The results show that in any practical dialysis setting the convective flow has negligible influence on the electrolyte concentrations.

Abstract 4124084: Nitric Oxide Releasing Bionanomatrix Gel For Dialysis Arteriovenous Fistula Maturation

Introduction: About 600,000 patients in the US suffer from end-stage renal disease (ESRD); more than 75% of ESRD patients undergo dialysis. Vascular access dysfunction is a major cause of morbidity and hospitalization in dialysis patients. Arteriovenous fistulas (AVFs) are considered the gold standard of vascular access for dialysis. However, about 60% of AVFs fail to mature because of early venous neointimal development and poor vasodilation and vascular wall remodeling. Therefore, to promote AVF maturation, we propose the application of a nitric oxide (NO) releasing nanomatrix gel, or ‘NO gel’, on the created AVF. The NO gel is composed of peptide amphiphiles (PA), which contain a polylysine (KKKKK) group to form NO-donating residues. In this study, we test our hypothesis that the NO gel applied at AVF can promote AVF maturation by decreasing venous intimal hyperplasia, enhancing vasodilation and vascular outward remodeling in porcine model. Materials and Methods: PA containing with KKKKK was synthesized and charged with NO to produce NO gel. For in vivo studies, AVFs in porcine were created by connecting the jugular vein and carotid artery. The NO gel was applied perivascularly over the AVF anastomosis. And the pigs were sacrifice after 35 days. AVF hemodynamics were evaluated using MRI-based computed fluid dynamics analysis. Results: We found significant decrease in neointimal hyperplasia in porcine AVFs treated with NO gel compared to the control groups. Additionally, the percentage of open lumens was significantly higher in the NO gel-treated group. It is indicated that veins in NO treated group showed less fibrosis as an less type I collagen I produced in the NO treated group than control. Also, the NO gel significantly improved hemodynamics and vascular remodeling of porcine AVFs compared to the control. Conclusion: These results suggest that the NO gel plays a crucial role in AVF maturation by reducing intimal hyperplasia and stenosis following AVF creation in a pig model. When intimal hyperplasia is reduced and the vessel is dilated, less tensile force of blood flow is applied on the arterialized vein, directing the AVF to appropriate maturation.

Health literacy profiles in kidney transplanted patients: A cluster analysis.

Health literacy is important in chronic conditions, such as kidney transplantation. Understanding patients' health literacy profiles can assist tailoring follow-up and educational programmes to the health literacy needs of vulnerable kidney transplant recipients. This approach enabled us to cluster patients according to their profiles of challenges and strengths in different health literacy domains. This study aimed to identify different health literacy profiles within kidney transplant recipients and what characterized the different profiles. Cross-sectional study. One hundred ninety-five kidney transplanted recipients were included. We used the self-reported Health Literacy Questionnaire and analyzed using Ward's method (hierarchical cluster approach). We also collected background characteristics and clinical variables, including psychological distress (Hopkins Symptoms Checklist) and perceived health status (visual analogue scale, EuroQol-5D). The analysis revealed four clusters with substantial differences in health literacy profiles. One cluster's patients had the most challenges in all health literacy domains constituting 24% of the sample. Compared to the other three clusters, this cluster was associated with shorter duration of kidney disease, higher number of patients in dialysis before transplantation, higher percentage of male patients, lower number of kidneys from living donors, higher number of patients not working and higher representation of psychological distress. All four clusters reported the most challenges in the same domain: the ability to critically appraise health information. In kidney transplant recipients, profiling clusters with the Health Literacy Questionnaire and Ward's method aids in identifying health literacy needs in vulnerable groups, enabling transplant professionals to offer tailored health literacy support.

Current status and influencing factors of kinesiophobia in patients with peritoneal dialysis: a multicenter cross-sectional study.

Kinesiophobia, an irrational fear-avoidance behaviour, can significantly impact the quality of life and prognosis of peritoneal dialysis patients. This study aimed to assess the prevalence of kinesiophobia in patients undergoing peritoneal dialysis and to analyse its influencing factors. A total of 291 patients who visited the outpatient and ward of peritoneal dialysis in 7 tertiary hospitals in Jiangsu Province from December 2023 to March 2024 were selected as research subjects via the convenience sampling method. A cross-sectional survey was conducted using a general data questionnaire, the Tampa Kinesiophobia-11 Scale, the Chinese Version of the Multidimensional Fatigue Symptom Scale, and the Simplified Coping Style Questionnaire. The score obtained using the Tampa Scale for kinesiophobia in patients with peritoneal dialysis was 22.44 ± 7.46, with a prevalence rate of 69.1%. Binary logistic regression analysis revealed that no complications, daily exercise before illness, and positive coping styles were protective factors (p < 0.05), whereas fatigue and negative coping styles were risk factors for kinesiophobia in patients receiving peritoneal dialysis (p < 0.05). The prevalence of kinesiophobia in patients receiving peritoneal dialysis was high but at a mild level. Medical staff should combine influencing factors to identify high-risk groups as early as possible, formulate targeted interventions to reduce the occurrence of kinesiophobia and mitigate adverse effects on peritoneal dialysis patients.

Diuretics and mortality reduction in incident dialysis patients: a two-year observational study

Fluid overload predicts morbidity and mortality in dialysis patients. Diuretics can reduce fluid overload, but their effects on morbi-mortality following inception remain ill-defined. To determine whether diuretics reduce mortality and hospitalization rates in incident dialysis patients in the first 2 years after inception. Adult patients starting dialysis between 2009 and 2015 in the REIN registry were matched with the SNDS database and divided into four subgroups according to loop diuretics exposure: < 5%, 5–50%, 50–80% or > 80% over the observation period of each patient. The incidence of hospitalization was described based on the primary diagnoses of the discharge summaries and codes. In this study, which included 67,736 patients, 53,829 (79.5%) who had varying degrees of diuretic exposure exhibited a significantly lower mortality rate at 2 years compared to those without diuretic exposure (24.8% [95% CI 24.4–25.2], vs 37.5% [95% CI 36.7–38.3] respectively). However, the duration of diuretic exposure significantly impacted outcomes. The all-cause mortality rate at two years was highest in the group with ≥ 80% exposure (68.2% [95% CI 67.3–69.1]), followed by those with 50–80% exposure (15.7% [95% CI 15.0–16.4]), and those with 5–50% exposure (6.6% [95% CI 6.3–7.0]). An inverse probability weighting (IPW) propensity score analysis supported these findings. Stratified analyses showed consistent results regardless of a history of congestive heart failure and were similar for both hemodialysis and peritoneal dialysis patients. Additionally, the number of hospitalizations and length of stay were generally higher in the group with the longest exposure to loop diuretics. Diuretic exposure was generally associated with a lower mortality rate in dialysis patients. However, prolonged exposure (≥ 80%) was linked to an increased risk of mortality and hospitalization. This prolonged exposure may indicate residual diuresis at the cost of chronic fluid overload.

Colostomy formation in a peritoneal dialysis patient.

This case report discusses the complex management of a 46-year-old man with poorly controlled type 1 diabetes mellitus, stage 5 chronic kidney disease, and severe neuropathic complications, which led to bilateral leg amputations. The patient experienced persistent diarrhea due to diabetic neuropathy, significantly impairing his daily functioning. Despite transitioning from hemodialysis to peritoneal dialysis, the diarrhea persisted. A colostomy was subsequently performed, which, although it did not completely resolve the diarrhea, allowed for better control, improving the patient's self-care and independence. Notably, the catheter exit site was maintained on the opposite side of the abdomen. Despite initial concerns about the feasibility of peritoneal dialysis (PD) in patients with stomas, including the challenges of creating a stoma in patients with an existing PD catheter, this case demonstrates the successful continuation of PD following a colostomy. Traditionally, intestinal stomas have been viewed as a relative contraindication to PD due to risks such as leakage and infection. However, current guidelines recommend using extended catheters with a presternal exit site to minimize these risks. The patient's quality of life improved significantly after the colostomy, with no major complications observed during follow-up. This report underscores the importance of tailoring treatment to individual patient needs, balancing risks with potential well-being benefits, and highlights the necessity of interdisciplinary collaboration and adherence to best practices. Given the limited literature on PD in patients with intestinal stomas, this case contributes valuable clinical insights for future management.

Comparative analysis of gut microbiota in incident and prevalent peritoneal dialysis patients with peritoneal fibrosis, correlations with peritoneal equilibration test data in the peritoneal fibrosis cohort.

The connection between peritoneal function and gut microbiota in peritoneal fibrosis (PF) patients remains uncertain. Peritoneal equilibration test (PET) was employed to evaluate peritoneal function in patients with peritoneal fibrosis (PF). 16S rRNA sequencing was used to analyze the gut flora in incident peritoneal dialysis (PD) and PF groups, identifying differential microbial communities. Spearman's correlation analysis, conducted using SPSS 26.0, was employed to explore the microbial associations with PF. In the PF group, the PET showed a 4-h dialysate-to-plasma creatinine ratio (D/PCr) ratio of 0.62 ± 1.01 and a 4-h ultrafiltration (UF) volume of 41.73 ± 76.71 mL with a 2.5% glucose dwell. The alpha diversity between the PD and PF groups did not exhibit a significant difference. The PD and PF groups were predominantly composed of Firmicutes, Tenericutes, and Ignavibacteriae. Linear discriminant analysis effect size (LEfse) analysis indicates that the Firmicutes, Lactobacillales, and Bacilli were significantly enriched in the PD group, whereas Lachnospiraceae, Phenylobacterium, and Caulobacteraceae were enriched among the PF group. The functional prediction of gut microbiota genes revealed variations in metabolic pathways related to lipid transport, energy metabolism, and post-translational protein modifications between the two cohorts. In the PF group, Ignavibacteriae and Bdellovibrio correlated positively with the 4-h D/PCr ratio (p <0.05), while Prevotella negatively correlated with the 4-h UF from 2.5% glucose dwell (p <0.05). The intestinal microbiota of patients newly initiated on peritoneal dialysis significantly differs from that of those with long-term peritoneal dialysis complicated by peritoneal fibrosis, with the latter's peritoneal function potentially linked to Prevotella, Ignavibacteriae, and Bdellovibrio.

Sural-to-medial femoral cutaneous amplitude ratio in early diagnosis of uremic neuropathy.

Medial femoral cutaneous (MFC) sensory nerve action potentials (SNAPs) can be easily recorded using distal stimulation. This study aimed to identify a new parameter using MFC SNAPs for the early electrophysiological diagnosis of length-dependent axonal polyneuropathy (LDAP) associated with uremic neuropathy. Patients with chronic renal failure who were referred to the electrodiagnostic laboratory due to symptoms suggesting polyneuropathy were included. Assessments encompassed neurological examination, Michigan Neuropathy Screening Instrument (MNSI), and Semmes-Weinstein monofilament test. Antidromic radial, median, ulnar, MFC, sural, and superficial peroneal sensory; median, ulnar, tibial, and peroneal motor nerve conduction studies were performed. Sural-to-radial amplitude ratio (SRAR) and sural-to-medial femoral cutaneous amplitude ratio (SMFCAR) were calculated, and their diagnostic sensitivities were compared with the age and sex matched healthy controls. Thirty-two chronic renal failure patients (mean age 60.0 ± 9.6 years) and 37 controls (60.6 ± 9 years) were included. MNSI indicated clinical polyneuropathy in 59.4% of patients, while sural SNAP amplitude was diagnostic in 78%. Median SRAR and SMFCAR values were significantly lower in patients than controls (p < .001 for both). The cut-off values for SMFCAR and SRAR were <1.82 and <0.30, respectively, both with a sensitivity of 59% and a specificity of 94%. Sural SNAP is the most sensitive parameter in the diagnosis of LDAP. SMFCAR is not superior to SRAR. If the sural SNAP amplitude is normal, SMFCAR can serve as an alternative to SRAR in dialysis patients with bilateral arteriovenous fistulae or in those unable to undergo radial NCS.

Case report: Peritonitis caused by Pantoea agglomerans from pet dog exposure in peritoneal dialysis.

Peritonitis caused by Pantoea agglomerans is a rare occurrence in patients undergoing peritoneal dialysis. Cases potentially linked to pet dogs are even rarer, and there is limited literature available. A patient undergoing peritoneal dialysis presented with symptoms of peritonitis, including abdominal pain and cloudy dialysis fluid. Microbiological analysis identified P agglomerans as the causative organism. The patient was treated with targeted antibiotic therapy and showed a positive response. During a subsequent medical interview, it was revealed that the patient had close contact with their pet dog, raising the possibility that the infection may have been associated with this exposure. This case highlights the importance of considering zoonotic transmission as a potential source of infection in peritoneal dialysis patients, particularly when there is close contact with pets. Healthcare providers should educate patients about the potential risks posed by pets and implement preventive strategies to mitigate such risks.

The cardiovascular unphysiology of thrice weekly hemodialysis.

This review examines the unphysiological nature of conventional intermittent hemodialysis (IHD) and explores alternative dialysis modalities that more closely mimic natural kidney function. As cardiovascular complications remain a leading cause of morbidity and mortality in dialysis patients, understanding and addressing the limitations of IHD is crucial for improving outcomes. IHD's intermittent nature leads to significant fluctuations in metabolites, electrolytes, and fluid status, contributing to hemodynamic instability and increased cardiovascular risk. More frequent dialysis modalities, such as short daily hemodialysis and nocturnal hemodialysis have numerous benefits including reduced left ventricular hypertrophy, improved blood pressure control, and potentially decreasing mortality. Peritoneal dialysis offers a more continuous approach to treatment, which may provide cardiovascular benefits through gentler fluid removal and residual kidney function preservation. Conventional thrice weekly intermittent hemodialysis offers a fundamentally unphysiologic equilibrium of uremic solutes. Alternate approaches have demonstrated cardiovascular benefits.

Evaluation of LPRDA Pentapeptide for the Prevention and Treatment of Staphylococcus aureus Peritoneal Infection

Targeting virulence determinants is a promising approach to controlling S. aureus infections in the face of the global spread of antibiotic resistance. S. aureus-induced peritonitis often occurs in dialysis, implant and trauma patients. To develop novel prevention and treatment options for peritoneal infection, we investigated the oligopeptide sortase A inhibitor LPRDA as a non-conventional antibacterial that does not affect staphylococcal survival. Administration of LPRDA prior to S. aureus challenge reduced the bacterial load of internal organs and bacterial colonization of the abdominal cavity in animals. In addition, LPRDA inhibited α-hemolysin production in 80% of the 35 reference and clinical S. aureus strains tested. Consequent research of LPRDA interactions with cefazolin and vancomycin has demonstrated the potential for combined application of the antivirulent and antibiotic agents under study.

Association of hypoalbuminemia with hospitalization and mortality in hemodialysis patients with COVID-19.

Hypoalbuminemia is associated with poor nutritional status and inflammatory response in infectious diseases. It is commonly observed in COVID-19 patients. The aim of this study is to assess the association of serum albumin with hospitalization and mortality in dialysis patients with COVID-19. We retrospectively collected 250 dialysis patients, with and without COVID-19. Demographic characteristics, clinical symptoms, and laboratory tests on admission or the confirmation of COVID-19 were collected. Univariate logistic regression model was used to evaluate the association of various factors with hospitalization and death in these patients. A total of 250 patients were included between December 1, 2022, and February 1, 2023, in our dialysis center. Among them, 218 were dialysis patients with COVID-19, and 32 were without COVID-19. Ten patients died due to COVID-19, and 8 patients had clinical data. In dialysis patients with COVID-19, a significant difference in serum albumin levels was observed between outpatients (37.28 ± 4.01 g/L) and hospitalized patients (33.42 ± 3.82 g/L), as well as between survivors (37.12 ± 4.07 g/L) and non-survivors (31.92 ± 2.52 g/L). Univariate logistic regression showed that the reduced albumin levels were associated with an increased risk of hospitalization and mortality in dialysis patients with COVID-19. Our study revealed that reduced serum albumin is associated with an increased risk of hospitalization and mortality in dialysis patients with COVID-19. Low serum albumin levels suggest a poor prognosis and nutritional support may improve clinical outcomes.

The Effect of Fordyce Happiness Training on Life Expectancy and Quality of Life in Hemodialysis Patients: An Intervention Study in Yazd, Iran

Background: Dialysis patients frequently experience issues such as fear, reduced social activity, and hopelessness due to lifestyle changes and treatment requirements. Objectives: This study aimed to determine the effect of Fordyce happiness training on quality of life and life expectancy in hemodialysis patients. Methods: This quasi-experimental intervention study involved 48 hemodialysis patients who were referred to Shahid Rahnemoun Hospital in Yazd, Iran, and selected through simple random sampling. Data collection tools included the Quality-of-Life Questionnaire for Kidney Patients (KDQOL-36) and the Miller Life Examination Questionnaire. Patients participated in ten 60-minute training sessions, held twice weekly. Data were collected at baseline and one month after the intervention and analyzed using SPSS 21 software. Results: Following Fordyce's happiness training, levels of potassium (K), creatinine (Cr), and blood urea nitrogen (BUN) in patients significantly decreased. Before the intervention, the mean scores for quality of life and life expectancy in dialysis patients were 51.9 ±28.27 and 169.75 ±11.95, respectively, which increased to 64.66 ±27.17 and 179.95 ±9.37 after the intervention. Paired t-test results indicated that Fordyce happiness training had a statistically significant positive effect on patients' quality of life (P &lt; 0.05) and life expectancy (P &lt; 0.05). Conclusions: The Fordyce happiness training program can improve quality of life and life expectancy in dialysis patients. In other words, happiness training may serve as a preventive strategy against mental disorders such as depression, anxiety, and life dissatisfaction in dialysis patients.

Multidimensional assessment of physical function for people in dialysis: the Rehabilitation in hEmodialysis Area Centro Toscana (REACT) Study.

BACKGROUNDː Physical performance is poorly addressed in dialysis patients, due to several clinical and organizational barriers. In this study we investigated the physical functional status of a cohort of dialysis patients, using a multidimensional assessment. METHODSː Four hundred and forty-six individuals from 8 hemodialysis centers (176 females), mean age 67.5±14.1 years, and dialysis vintage 62 ± 72.1 months, were assessed by a multidimensional battery including Short Form Health Survey (SF12), Elderly Falls Screening Test (EFST), Short Physical Performance Battery (SPPB), and handgrip strength test (HST). Individuals were stratified into 3 groups (poor, moderate and good performers) according to the SPPB score. Functional assessments were performed by staff nurses, with the support of physiotherapists and nephrologists. RESULTSː According to SPPB 53,4% of dialysis patients showed a severe physical impairment. A significant difference emerged among the 3 SPPB groups for age, HST, EFST and SF12. The main predictors of the SPPB score group were age (p=0,0001) EFST (p=0,028 moderate performers and p=0,0001 poor performers) dominant HST(p=0,04 moderate performers) and SF12 physical (p=0,003 moderate performers and p=0,0001 poor performers) . Each age groups showed physical performance comparable to healthy general population of ten years older. CONCLUSIONSː Our results confirmed the severe impairment of physical function in ESKD population. The multidimensional assessment showed that SPPB test is an effective tool to stratify dialysis population. Moreover, EFST, HST and SF12 may contribute to the definition of a tailored physical activity program based on patient characteristics.

Successful kidney transplantation improves atrophic bladder capacity and function within 3 months in long-term dialysis patients.

Successful kidney transplantation improves atrophic bladder capacity and function within 3 months in long-term dialysis patients.