Diabetic Foot Research Articles

Impact of Drugs Effective for Neuropathic Pain on the Frequency of Hospitalization, Debridement and Amputation Need in Patients with Diabetic Foot Infection

Impact of Drugs Effective for Neuropathic Pain on the Frequency of Hospitalization, Debridement and Amputation Need in Patients with Diabetic Foot Infection

Computer-aided drug design to generate a unique antibiotic family.

The World Health Organization has identified antibiotic resistance as one of the three greatest threats to human health. The need for antibiotics is a pressing matter that requires immediate attention. Here, computer-aided drug design is used to develop a structurally unique antibiotic family targeting holo-acyl carrier protein synthase (AcpS). AcpS is a highly conserved enzyme essential for bacterial survival that catalyzes the first step in lipid synthesis. To the best of our knowledge, there are no current antibiotics targeting AcpS making this drug development program of high interest. We synthesize a library of > 700 novel compounds targeting AcpS, from which 33 inhibit bacterial growth in vitro at ≤ 2 μg/mL. We demonstrate that compounds from this class have stand-alone activity against a broad spectrum of Gram-positive organisms and synergize with colistin to enable coverage of Gram-negative species. We demonstrate efficacy against clinically relevant multi-drug resistant strains in vitro and in animal models of infection in vivo including a difficult-to-treat ischemic infection exemplified by diabetic foot ulcer infections in humans. This antibiotic family could form the basis for several multi-drug-resistant antimicrobial programs.

Mortality rates in people presenting with a new diabetes-related foot ulcer: a cohort study with implications for management.

People with diabetes-related foot ulcers (DFUs) have high mortality rates. This analysis assesses the impact of selected risk factors on short-term mortality using a population registered in the National Diabetes Foot Care Audit (NDFA). Mortality rates at 12, 26 and 52 weeks was assessed in people with a new DFU registered by a specialist diabetes footcare service in the NDFA in England and Wales between April 2017 and March 2022. Poisson regression models were created to explore risk factors for mortality. In 71,000 people registered with a new DFU, mortality rates at 12, 26 and 52 weeks was 4.2%, 8.2% and 14.4%, respectively. At 26 weeks, higher mortality rates was associated with older age (rate ratio 2.15; 95% CI 2.03, 2.28, for age ≥80 years vs age 65-79 years), certain ulcer characteristics (area ≥1 cm2 [1.50; 95% CI 1.42, 1.59], deep ulcers [1.26; 95% CI 1.18, 1.35] or hindfoot location [1.53; 95% CI 1.44, 1.62]) and recorded evidence of ischaemia in the lower limb (1.78; 95% CI 1.69, 1.88) and various comorbidities (heart failure [2.13; 95% CI 2.00, 2.26], myocardial infarction [1.45; 95% CI 1.29, 1.63], stroke [1.37; 95% CI 1.22, 1.53], renal replacement therapy [2.34; 95% CI 2.09, 2.61] and chronic kidney disease stage 3 or greater [1.20; 95% CI 1.12, 1.29]). The 26-week mortality rate exceeded 25% for 7.3% of all individuals, rising to 11.5% of those aged 65 years and older, and 22.1% of those aged 80 years and over. Short-term mortality rates in people with a DFU is high. Teams managing people with DFUs should consider modifying the burdensome interventions and care required to heal such ulcers so maximising the quality of residual life, rather than focusing exclusively on healing.

Tibial transverse transport combined with platelet-rich plasma sustained-release microspheres activates the VEGFA/VEGFR2 pathway to promote microcirculatory reconstruction in diabetic foot ulcer

This study proposes to investigate the therapeutic efficacy and mechanism of combining tibial transverse transport (TTT) with platelet-rich plasma (PRP) for diabetic foot ulcer (DFU). The diabetic rabbit model was constructed with Streptozotocin, which was intervened with TTT and PRP. PRP injection combined with TTT significantly promoted vascularisation and enhanced CD31, VEGFA, and VEGFR2 expressions compared to traditional TTT. However, the VEGFR2 inhibitor suppressed these phenomena. In the in vitro injury model, PRP reversed the diminished human umbilical vein endothelial cells (HUVECs) function and vascularisation caused by high-glucose damage. Additionally, PRP reduced inflammation and oxidative stress (approximately 47% ROS level) and enhanced VEGFA and VEGFR2 expression in HUVECs. However, the knockdown of VEGFR2 reversed the effect of PRP. In conclusion, TTT combined with intraosseous flap injection of PRP sustained-release microspheres activated the VEGFA/VEGFR2 pathway to promote microcirculatory reconstruction in DFU. These findings may provide new potential therapeutic strategies for DFU.

Impact of ZnO nanoparticles on MagA gene expression in Klebsiella pneumoniae isolated from diabetic foot ulcers

Impact of ZnO nanoparticles on MagA gene expression in Klebsiella pneumoniae isolated from diabetic foot ulcers

Potential Benefits of Moringa oleifera for Diabetic Foot Ulcers - Future Research and Applications

Diabetic foot ulcers are permanent scars in people with diabetes that result from nerve damage, inadequate blood flow, and infection. The ulcers not only cause significant financial burdens but also remain poorly controlled, necessitating the need for new therapeutic approaches. Moringa oleifera, or Moringa, has the potential to be more valuable in the treatment of diabetic foot ulcers due to its long-standing and traditional use. Several civilizations, especially in Africa and Asia, have administered the Moringa plant for quite a long period of time, due to its medicinal values in curing wounds and infections through traditional medicine. It is precisely the extensive composition of phytochemicals, including vitamins, minerals, flavonoids, and phenolic compounds, that shapes this herb's medicinal potential. Ultimately, these are elements that relate to meaningfully striking antibacterial, anti-inflammatory, and antioxidant impacts. The extracts of Moringa are known to carry a pharmacological potential that, importantly, contributes to wound healing. Research indicates that the herb can accelerate wound healing, lower the number of microorganisms, and promote the regeneration of damaged tissue. Some of the basic mechanisms include oxidative stress regulation, promotion of collagen formation, and mitigation of inflammatory reactions, all of which play a crucial role in the improvement of ulcer healing. In the near future, the incorporation of Moringa into treatment against diabetic foot ulcers presents substantial hope. Future studies should focus on formulation procedures to improve and understand the long-term consequences of combined applications with traditional therapies. Applying Moringa's natural healing abilities to ulcer treatment could potentially transform diabetic foot ulcers treatment into long-lasting plant-based solutions, improving patient outcomes.

Vitabiotic: An alternative approach to diabetic foot.

Diabetic foot ulcers and infections are complications that can result in significant morbidity such as the need for amputations, especially in uncontrolled diabetes, thereby profoundly impacting quality of life. While traditional treatments like wound care and antibiotics are effective, there is growing interest in the role of micronutrients (such as vitamins C, D, E, zinc and magnesium) in improving outcomes. This study aims to evaluate how these micronutrients affect diabetic foot infections and the need for amputation, offering insights to enhance overall prognosis. Patients who were hospitalised with a diagnosis of diabetic foot infection in the Infectious Diseases Department of Ege University Faculty of Medicine Hospital between 1 April 2022, and 31 January 2023 were included in the study. The patients' socio-demographic information, characteristics of diabetic wounds, operation history, as well as their levels of micronutrients recorded on the case report form. A total of 202 patients were included in the study. The most common micronutrient deficiencies were vitamin D (69%), vitamin C (64%) and zinc (49%). The amputation rates were significantly higher in patients with deficiencies vitamin C, vitamin A and vitamin D (p < 0.005). Our research revealed a significant prevalence of vitamin deficiencies among the participants, and we observed a noteworthy correlation between amputation rates and these deficiencies. Although these findings show promise, it is essential to emphasise that micronutrient supplements should not replace traditional treatments but should rather be considered as a warning sign for preventing complications, particularly amputation or extremity loss.

Study on the mechanism of activating SIRT1/Nrf2/p62 pathway to mediate autophagy-dependent ferroptosis to promote healing of diabetic foot ulcers.

Diabetic foot (DF), a prevalent and grave diabetes sequela, is considered as a notable clinical concern, with SIRT1 downregulation observed in DF patients' blood specimens. Nonetheless, the regulatory mechanisms of SIRT1 in diabetic foot ulcer (DFU) remain unclear. Thus, in the current study, we investigated the role and mechanisms of SIRT1 in alleviating DFU. Western blotting was used to detect the expression of autophagy and ferroptosis-related proteins, CCK8 assay was used to measure cell proliferation. Plate colony method was used to measure bacterial growth, and the inhibitory effect on intracellular and extracellular Staphylococcus aureus was observed after drug intervention. ELISA was used to detect inflammatory cytokines and oxidative stress markers levels. ROS, total iron, and Fe2+ levels were detected using corresponding assays. Additionally, HE staining detected the thickness of the epidermis and dermis of the rat wound tissue while the collagen deposition in the wound tissue was detected using Masson staining. In addition, Prussian blue staining was used to detect iron deposition, and C11 BODIPY 581/591 lipid peroxidation probe was used to detect lipid ROS. Our results suggested that the activation of SIRT1/Nrf2/p62 signaling affects cell proliferation, colony formation, ferroptosis, and the production of lipid ROS in DFU-infected cell model through autophagy. In vivo experiments indicated that activating SIRT1/Nrf2/p62 signaling affects oxidative stress, inflammation, and autophagy in wound tissue and promotes wound healing in DFU rats through mediating autophagy-dependent ferroptosis. Taken together, the activation of SIRT1/Nrf2/p62 pathway can promote DFU healing, which might be mediated by autophagy-dependent ferroptosis.

Effectiveness Of 3% Citric Acid Dressing Verses Normal Saline Dressing On Diabetic Foot Ulcer Among Patients Admitted In Selected Tertiary Care Hospitals, Belagavi

Effectiveness Of 3% Citric Acid Dressing Verses Normal Saline Dressing On Diabetic Foot Ulcer Among Patients Admitted In Selected Tertiary Care Hospitals, Belagavi

Assessment of Microvascular Function Based on Flowmotion Monitored by the Flow-Mediated Skin Fluorescence Technique.

This review summarizes studies dedicated to the assessment of microvascular function based on microcirculatory oscillations monitored by the Flow-Mediated Skin Fluorescence (FMSF) technique. Two approaches are presented. The first approach uses oscillatory parameters measured under normoxic conditions, expressed as flowmotion (FM), vasomotion (VM), and the normoxia oscillatory index (NOI). These parameters have been used for the identification of impaired microcirculatory oscillations associated with intense physical exercise, post-COVID syndrome, psychological stress, and erectile dysfunction. The second approach involves characterization of the microcirculatory response to hypoxia based on the measurement of hypoxia sensitivity (HS). The HS parameter is used to characterize microvascular complications in diabetes, such as diabetic kidney disease and diabetic foot ulcers. Based on research conducted by the authors of this review, the FMSF parameter ranges characterizing microvascular function are presented. The diagnostic approach to assessing microvascular function based on flowmotion monitored by the FMSF technique has a wide range of applications and the potential to be integrated into widespread medical practice.

Fierce Fusarium solani infection in diabetic foot – A double-barrel rifle

Fierce Fusarium solani infection in diabetic foot – A double-barrel rifle

Health care impact of lower extremity amputations in diabetes mellitus derived from Dutch insurance claims; design of the retrospective cohort study; Dutch diabetes estimate—amputation initiative (DUDE-8)

Introduction: Many individuals with diabetes mellitus (DM) experience complications that significantly impact their quality of life and life expectancy. Foot complications, arising from neuropathy, macroangiopathy, and metabolic derangements, or a combination of these factors, are a major concern. The combination of these disorders increases the risk of developing diabetic foot ulcers (DFUs), which in turn can lead to lower extremity amputations (LEAs) if not promptly and adequately treated. Globally, 80% of all nontraumatic LEAs are due to DM, and most of these were preceded by a nonhealing DFU. Studies in the Netherlands have explored the incidence of LEA in the diabetic population, reporting a range from 78 to 704 per 100 000 person-years. The current design focuses on utilizing the available all-claims data to gain valuable insights into amputation rates among individuals with DM in the Netherlands during the years 2013–2019 and develop a more comprehensive understanding of the current Dutch situation. Methods and analyses: In the Netherlands, all amputations are performed in hospitals, allowing for comprehensive financial claims data. The current project focuses on utilizing the available all-claims data to gain insights into yearly LEA rates among individuals with and without DM in the Netherlands. Over the period 2013–2019, various predefined analyses will be performed, including costs and outcomes. Individuals will be matched based on age, gender, and, where applicable, socioeconomic status. Depending on the research questions, additional analyses will take place on epidemiology, healthcare use, costs, and mortality rates.

Healthcare workers' perspectives on diabetic foot complications among type 2 diabetes mellitus patients in Fiji.

Diabetic Foot Complications (DFCs) are a growing cause of morbidity and mortality with less than one third of physicians able to discern the signs of diabetes related peripheral neuropathy. DFCs and resultant amputations account for a considerable proportion of surgeries in Fiji, with very limited literature available to verify the factors that influence these alarming figures. This study aimed to explore Health Care Workers' (HCWs) perspectives on diabetic foot complications and challenges of foot care management in Fiji. An exploratory descriptive qualitative design was used among HCWs at the Sigatoka Sub Divisional Hospital (SDH), Fiji in 2021. HCWs at the SDH were required to have a minimum work experience of at least six months in public health. All participants who met the inclusion criteria were selected through purposive sampling. Data was collected using a focus group discussion guide composed of semi-structured open-ended questions to guide the Focus Group Discussions (FGDs). Focus discussions were audio recorded and transcribed with thematic analysis applied to derive the themes and sub-themes outlined in the study. Twenty HCWs participated in four FGDs with four major themes identified. The first theme was HCWs' perceptions and practice of foot care which revealed that all participants had adequate diabetic foot care knowledge. The second theme was factors affecting foot care which was mainly focused on identified barriers such as inadequate patient foot care knowledge, the lack of resources such as manpower, and health system challenges like the COVID-19 pandemic. The third theme is creating awareness among patients and HCWs to improve foot care practices. The fourth theme is strengthening foot care practices at the different levels of health care that is aimed at optimizing diabetic foot outcomes. Various foot care barriers namely patient factors and the lack of resources is a concern depicted in this study. There is a need to address health system barriers and enforce diabetic foot education, screening and care for patients and the community.

A Network Meta-Analysis of Randomized Controlled Trials on the Comparative Efficacy of Stem Cells Therapy for Diabetic Foot Ulcer Healing

Stem cell therapy in diabetic foot ulcer has emerged as a promising treatment option to promote ulcer healing. This network meta-analysis was undertaken to evaluate how they compete with each other and their ranking with respect to chances of ulcer healing. A systematic search strategy to retrieve data from five databases, were used to identify potential studies. Randomized controlled trial or clinical controlled trial, published in English, using any type of stem cells as intervention in individuals aged over 18 years diagnosed with diabetic foot ulcers were included. This network meta-analysis was performed using frequentist method using R version 4.2.1. Eighteen clinical trials were included in the study which included 13 interventions. The study found that most of the stem cells were significantly promoting ulcer healing chances with human viable wound matrix (hVWM) [RR 2.91; CI: 1.28, 6.64], peripheral blood mononuclear cells (PBMNC) [RR 2.35; CI: 1.21, 4.55], bone marrow mesenchymal stem cells (BMMSCs) [RR 2.20; CI: 1.34, 3.60], were top three stem cell options among all. P score also suggested the same. Risk of bias study suggested that there was “some concern or “high risk’’ among majority of studies. It is evident from this study that bone marrow mononuclear cells were found to be most effective in wound healing in cases of diabetic foot ulcer in that order. Though there was no significant difference between these and more studies were required to ascertain whether they differ in term of efficacy for the clinical outcome of ulcer healing.

DFUCare: deep learning platform for diabetic foot ulcer detection, analysis, and monitoring.

Diabetic foot ulcers (DFUs) are a severe complication among diabetic patients, often leading to amputation or even death. Early detection of infection and ischemia is essential for improving healing outcomes, but current diagnostic methods are invasive, time-consuming, and costly. There is a need for non-invasive, efficient, and affordable solutions in diabetic foot care. We developed DFUCare, a platform that leverages computer vision and deep learning (DL) algorithms to localize, classify, and analyze DFUs non-invasively. The platform combines CIELAB and YCbCr color space segmentation with a pre-trained YOLOv5s algorithm for wound localization. Additionally, deep-learning models were implemented to classify infection and ischemia in DFUs. The preliminary performance of the platform was tested on wound images acquired using a cell phone. DFUCare achieved an F1-score of 0.80 and a mean Average Precision (mAP) of 0.861 for wound localization. For infection classification, we obtained a binary accuracy of 79.76%, while ischemic classification reached 94.81% on the validation set. The system successfully measured wound size and performed tissue color and textural analysis for a comparative assessment of macroscopic wound features. In clinical testing, DFUCare localized wounds and predicted infected and ischemic with an error rate of less than 10%, underscoring the strong performance of the platform. DFUCare presents an innovative approach to wound care, offering a cost-effective, remote, and convenient healthcare solution. By enabling non-invasive and accurate analysis of wounds using mobile devices, this platform has the potential to revolutionize diabetic foot care and improve clinical outcomes through early detection of infection and ischemia.

Effects of different treatment measures on the efficacy of diabetic foot ulcers: a network meta-analysis.

Through a network meta-analysis, we compared different treatment measures for patients with diabetic foot ulcers (DFU), assessing their impact on the healing of DFU and ranking them accordingly. We searched the PubMed, the China National Knowledge Infrastructure (CNKI), Embase, the WanFang and the WeiPu database. The retrieval time was from database establishment to January 2024, and retrieval entailed subject and free words. Randomized controlled trials (RCTs) with different treatment measures for DFU were included. Data extraction and evaluation were based on the PRISMA guidelines. Meta-analyses using pairwise and network methods were employed to compare and rank the effectiveness of different treatments for DFU. Ultimately, we included 57 RCTs involving a total of 4,826 patients with DFU. When it comes to ulcer healing rates, compared to standard of care(SOC),platelet-rich plasma(PRP), hyperbaric oxygen therapy(HBOT), topical oxygen therapy(TOT), acellular dermal matrix(ADM), and stem cells(SCs) in both direct meta-analysis(DMA) and network meta-analysis(NMA) can effectively increase the complete healing rate. For Scs+PRP, a statistically significant improvement was only observed in the NMA. Moreover, when compared to the negative pressure wound therapy(NPWT) group, the PRP+NPWT group was more effective in promoting the complete healing of ulcers. In terms of promoting the reduction of ulcer area, no statistical differences were observed among various treatment measures. When it comes to ulcer healing time, both PRP and NPWT can effectively shorten the healing time compared to SOC. Furthermore, when compared to the NPWT group, the combined treatment of PRP and ultrasonic debridement(UD) with NPWT is more effective in reducing healing time. In terms of amputation rates and adverse reactions, the PRP group effectively reduced the amputation rate and adverse reactions for patients with DFU. Additionally, compared to the NPWT group, the combined treatment of PRP and UD with NPWT reduced the incidence of adverse reactions. However, no significant differences were observed among other treatment measures in terms of amputation rates and adverse reactions. The ranking results showed that the efficacy of PRP+NPWT and UD+NPWT in promoting ulcer healing, reducing ulcer area, shortening healing time, decreasing amputation rates and adverse reactions is superior to that of the alone PRP group, NPWT group, and UD group. Conversely, the SOC group demonstrates the least effective performance in all aspects. Due to the particularity of the wound of DFU, the standard of care is not effective, but the new treatment scheme has a remarkable effect in many aspects. And the treatment of DFU is not a single choice, combined with a variety of methods often achieve better efficacy, and will not bring more adverse reactions.

Diabetic Patients’ Perception of Diabetic Foot Ulcers: A Qualitative Study

Background: Diabetic foot ulcer (DFU) is one of the serious and debilitating challenges faced by patients with diabetes, which imposes a financial burden on both patients and healthcare systems. Although this problem can be prevented and treated by proper foot care techniques, many patients do not follow the recommendations. Accordingly, this study aimed to rely on deep insight and knowledge to explain diabetic patients’ perception of DFU and identify appropriate care and support practices to prevent and manage it. Methods: This descriptive study was conducted using qualitative content analysis. The participants were 15 patients with diabetes, who visited the healthcare centers in Shahrekord, Iran selected using purposive sampling. Data were collected through face-to-face and semi-structured interviews with the participants until data saturation. Data were analyzed simultaneously with data collection using the method proposed by Graneheim and Lundman. Results: Data analysis led to the identification of four main categories including being destined to a doomed fate, self-treatment, indifference to obsessive care, and care-inhibiting beliefs. Conclusion: To gain a deeper understanding of standard foot care, the causes of foot ulcers, preventive care services, and existing treatments, different strategies can be adopted such as peer education or using the experiences of other patients with ulcers.

Minimally Invasive Distal Metatarsal Diaphyseal Osteotomy (MIS-DMDO) for the Prevention and Treatment of Chronic Plantar Diabetic Foot Ulcers.

Diabetic foot is one of the major complications of diabetes, affecting 15% of patients with diabetes. This study aims to evaluate and compare the clinical and radiographic outcomes of patients with diabetes affected by forefoot plantar preulcerative or ulcerative lesions who have undergone minimally invasive distal metatarsal diaphyseal osteotomy (MIS-DMDO) to assess its efficacy in the prevention and treatment of chronic plantar diabetic foot ulcers (CPDFUs). The study included 60 patients, 38 with preulcers and 22 with ulcers, with at least 2 years of clinical and radiologic follow-up. Clinical outcomes were assessed using the European Foot and Ankle Society (EFAS) score, the Foot Function Index (FFI), and the Manchester-Oxford Foot Questionnaire (MOXFQ). The radiographic evaluation was performed according to the Maestro criteria. Both groups improved in clinical and radiologic outcomes when comparing baseline measurements to those at the final follow-up. There were no statistical differences between preulcer and ulcer groups in terms of both clinical and radiologic outcomes, with the only exception being FFI, which was lower in the preulcerative group. In multivariate analysis, gender and glycated hemoglobin (HbA1c) were predictors of better outcomes. Specifically, FFI and MOXFQ (P < .05) exhibited larger improvements in females, while Maestro 1 and 2 were better in patients with lower HbA1c (P < .05). All patients were considered healed at the final follow-up. Carefully performed minimally invasive distal metatarsal diaphyseal osteotomy can be an effective approach to the care of impending or chronically present plantar diabetic foot ulcers.

Effect of swimming exercise program on quality of life in patients with diabetic foot ulcer

This research aimed to examine the effect of a swimming exercise program on the quality of life in patients with diabetic foot ulcers (DFUs). DFUs are a common complication of diabetes that significantly impact patients' physical and psychological well-being and impose a substantial burden on healthcare systems. Physical activity, including swimming, has been shown to improve various aspects of health and well-being. However, its specific effects on the quality of life in patients with DFUs have not been extensively studied. The study included twenty patients diagnosed with DFUs who volunteered to participate in a 12-week swimming exercise program. The program consisted of three one-hour sessions per week, with exercises performed in an indoor swimming pool. Participants' quality of life was assessed using the Diabetic Foot Ulcer Scale Short Form (DFS-SF) before the program and at 4, 8, and 12 weeks into the program. The results demonstrated significant improvements in various domains of quality of life among participants. The leisure, physical health, dependence/daily life, negative emotions, worry about ulcers/feet, and bothered by ulcer care domains all showed positive changes, with reduced scores on negative items and increased scores on positive items over time. These findings highlight the potential benefits of swimming as a therapeutic intervention for improving the quality of life in patients with DFUs. Swimming, as a low-impact aerobic exercise, offers physiological and psychological advantages, including fat burning, mood improvement, stress reduction, and enhanced cognitive function. The study suggests that incorporating swimming exercise programs into the management and treatment of DFUs may lead to improved overall well-being and quality of life for these patients. Further research and larger-scale studies are necessary to validate these findings and explore the long-term effects of swimming exercise programs on the quality of life in patients with DFUs. Nevertheless, this research provides valuable insights for healthcare professionals in developing comprehensive treatment approaches for individuals with DFUs.

Translation and validation of the Arabic Jordanian version of the diabetic foot ulcer scale-short form (DFS-SF)

The Diabetic Foot Ulcer Scale-Short Form (DFS-SF) is an important tool for assessing the quality of life of diabetic foot patients. This study aims to translate and validate the DFS-SF into Arabic and evaluate its validity and reliability. The translation process followed WHO guidelines, including forward translation, expert panel review, back translation, pre-testing, and final version development. The translated questionnaire was then administered to a sample of Arab Jordanian patients with diabetic foot ulcers. Validity was assessed by examining the correlation coefficients between each item and its corresponding dimension, as well as its correlation with the DFS-SF scale as a whole. Reliability was evaluated using Cronbach's alpha coefficient. The results demonstrated high validity and reliability of the Arabic Jordanian version of the DFS-SF, making it a valuable tool for assessing the impact of diabetic foot ulcers on patients' quality of life.