Exploring potential correlations between HLA class II and the risk of microvascular complications in Japanese patients with type 1 diabetes.

Managing complications in Type 1 diabetes (T1D) remains challenging. HLA genes, particularly DR and DQ, are linked to T1D susceptibility. We studied 48 Japanese T1D inpatients and revealed associations between DRB1*04:05-DQB1*04:01 and DRB1*09:01-DQB1*03:03 haplotypes and complications, offering a new perspective for future research.

Mixed-Lineage Leukaemia Gene Regulates Glucose-Sensitive Gene Expression and Insulin Secretion in Pancreatic Beta Cells.

The escalating prevalence of diabetes mellitus underscores the need for a comprehensive understanding of pancreatic beta cell function. Interest in glucose effectiveness has prompted the exploration of novel regulatory factors. The myeloid/lymphoid or mixed-lineage leukaemia gene (MLL) is widely recognised for its role in leukemogenesis and nuclear regulatory mechanisms through its histone methyltransferase activity in active chromatin. However, its function within pancreatic endocrine tissues remains elusive. Herein, we unveil a novel role of MLL in glucose metabolism and insulin secretion. MLL knockdown in ßHC-9 pancreatic beta cells diminished insulin secretion in response to glucose loading, paralleled by the downregulation of the glucose-sensitive genes SLC2a1 and SLC2a2. Similar observations were made in MLL heterozygous knockout mice (MLL+/-), which exhibited impaired glucose tolerance and reduced insulin secretion without morphological anomalies in pancreatic endocrine cells. The reduction in insulin secretion was independent of changes in beta cell mass or insulin granule morphology, suggesting the regulatory role of MLL in glucose-sensitive gene expression. The current results suggest that MLL interacts with circadian-related complexes to modulate the expression of glucose transporter genes, thereby regulating glucose sensing and insulin secretion. Our findings shed light on insulin secretion control, providing potential avenues for therapeutics against diabetes.

Calorie Restriction Using High-Fat/Low-Carbohydrate Diet Suppresses Liver Fat Accumulation and Pancreatic Beta-Cell Dedifferentiation in Obese Diabetic Mice.

In diabetes, pancreatic ß-cells gradually lose their ability to secrete insulin with disease progression. ß-cell dysfunction is a contributing factor to diabetes severity. Recently, islet cell heterogeneity, exemplified by ß-cell dedifferentiation and identified in diabetic animals, has attracted attention as an underlying molecular mechanism of ß-cell dysfunction. Previously, we reported ß-cell dedifferentiation suppression by calorie restriction, not by reducing hyperglycemia using hypoglycemic agents (including sodium-glucose cotransporter inhibitors), in an obese diabetic mice model (db/db). Here, to explore further mechanisms of the effects of food intake on ß-cell function, db/db mice were fed either a high-carbohydrate/low-fat diet (db-HC) or a low-carbohydrate/high-fat diet (db-HF) using similar calorie restriction regimens. After one month of intervention, body weight reduced, and glucose intolerance improved to a similar extent in the db-HC and db-HF groups. However, ß-cell dedifferentiation did not improve in the db-HC group, and ß-cell mass compensatory increase occurred in this group. More prominent fat accumulation occurred in the db-HC group livers. The expression levels of genes related to lipid metabolism, mainly regulated by peroxisome proliferator-activated receptor α and γ, differed significantly between groups. In conclusion, the fat/carbohydrate ratio in food during calorie restriction in obese mice affected both liver lipid metabolism and ß-cell dedifferentiation.

Influence of diet and body weight in treatment-resistant acquired partial lipodystrophy after hematopoietic stem cell transplantation and its potential for metabolic improvement.

Lipodystrophy is a rare disease characterized by various metabolic complications resulting from the complete or partial loss of adipose tissues and abnormal fat accumulation. Acquired lipodystrophy may occur due to certain drugs, autoimmunity or for unknown reasons. Recently, cases of acquired lipodystrophy after hematopoietic stem cell transplantation (HSCT) have been reported. Leptin administration, used recently to treat generalized lipodystrophy, effectively controlled metabolic complications; however, few reports demonstrated the effectiveness of leptin for acquired partial lipodystrophy. In this report, we present the case of a 17-year-old woman who developed insulin resistance, hypertriglyceridemia, and fatty liver after HSCT. Due to her thin gluteal fat and low blood adiponectin levels, her metabolic abnormalities were attributed to partial lipodystrophy. While both leptin and pemafibrate administration partially attenuated metabolic abnormalities, its effects were relatively limited, probably because the serum leptin levels were maintained, which is not likely in generalized lipodystrophy. Nevertheless, after she developed adjustment disorder and experienced weight loss, along with decreased food intake, her metabolic markers significantly improved. This case suggests the modest effect of leptin and permafibrate in partial lipodystrophy after HSCT, highlighting the importance of diet therapy in metreleptin treatment for acquired partial lipodystrophy.

A case of insulinoma-induced hypoglycemia managed by Dexcom G4 Platinum.

This report details the case of a 41-year-old woman who was diagnosed with insulinoma. As the patient developed severe life-threatening hypoglycemia, we introduced Dexcom G4 Platinum (DG4P), a modern continuous glucose-monitoring system (CGM). The algorithm of the sensor glucose (SG) values of CGM is based on patients with diabThis report details the case of a 41-year-old woman who was diagnosed with insulinoma. As the patient developed severe life-threatening hypoglycemia, we introduced Dexcom G4 Platinum (DG4P), a modern continuous glucose-monitoring system (CGM). The algorithm of the sensor glucose (SG) values of CGM is based on patients with diabetes; therefore, we evaluated the accuracy of DG4P in this patient. The mean absolute relative differences and absolute differences between SG of DG4P and self-monitoring of blood sugar values were 10.8%±8.3% and 6.8±5.7 mg/dL, respectively, in the hypoglycemic region, which verifies DG4P's accuracy. DG4P was found to be useful for monitoring hypoglycemia not only in patients with diabetes but also in those with insulinoma.etes; therefore, we evaluated the accuracy of DG4P in this patient. The mean absolute relative differences and absolute differences between SG of DG4P and self-monitoring of blood sugar values were 10.8%±8.3% and 6.8±5.7 mg/dL, respectively, in the hypoglycemic region, which verifies DG4P's accuracy. DG4P was found to be useful for monitoring hypoglycemia not only in patients with diabetes but also in those with insulinoma.

Maternal hypothyroidism is associated with M-opsin developmental delay.

Thyroid hormones are critical for the development of opsins involved in color vision. Hypothyroid mice show delayed M-opsin development and expanded distribution of S-opsin on the retina. However, the effects of maternal hypothyroidism on opsin development remain unknown. This study investigates the effects of congenital central hypothyroidism and maternal hypothyroidism on opsin development in thyrotropin-releasing hormone knockout (TRH-/-) mice. We examined the mRNA expression and protein distribution of S/M-opsin on postnatal days (P)12 and 17, as well as mRNA expression of type 2 and 3 iodothyronine deiodinase (DIO2 and DIO3, respectively) in the retina and type 1 iodothyronine deiodinase (DIO1) in the liver at P12 in TRH+/- mice born to TRH+/- or TRH-/- dams, and conducted S/M-opsin analysis in TRH+/+ or TRH-/- mice born to TRH+/- dams at P12, P17, and P30. M-opsin expression was lower in TRH+/- mice born to TRH-/- dams than in those born to TRH+/- dams, whereas S-opsin expression did not significantly differ between them. DIO1, DIO2, and DIO3 mRNA expression levels were not significantly different between the two groups; therefore, thyroid function in peripheral tissues in the pups was similar. S/M-opsin expression did not significantly differ between the TRH+/+ and TRH-/- mice born to TRH+/- dams on any postnatal day. These results demonstrate that maternal hypothyroidism causes M-opsin developmental delay during the early developmental stages of neonatal mice, and TRH-/- mice, a model of congenital central hypothyroidism, born to a euthyroid dam do not have delayed opsin development.

Superior Mesenteric Artery Syndrome Accompanied by Acute-onset Type 1 Diabetes Complicated with Graves' Disease.

A 35-year-old man experienced general fatigue and could not eat solid food because of nausea and vomiting. His weight abruptly decreased from 49 to 45 kg after 2 weeks. A detailed examination indicated superior mesenteric artery syndrome (SMAS) accompanied by acute-onset type 1 diabetes complicated by Graves' disease, referred to as autoimmune polyglandular syndrome type 3A (APS3A). Although SMAS has a good prognosis, some cases require emergency surgery, especially when complicated by gastric perforation. In our case, APS3A and SMAS developed rapidly and at approximately the same time, resulting in a cycle of mutual exacerbation.

The Optimal "Time in Range" and "Time below Range" are Difficult to Coordinate in Patients with Type 1 Diabetes.

Achieving the optimal glucose level time in range (TIR), as recently proposed by the "International Consensus on Time in Range," is challenging. We retrospectively analyzed data from 192 patients, including 58 with type 1 diabetes, using the FreeStyle Libre Pro system. This device was used by physicians for continuous glucose monitoring (CGM) and for making therapeutic decisions based on unbiased data, as the patients were blinded to their blood glucose levels during monitoring. The desired 70% TIR among patients with type 2 diabetes corresponded to an HbA1c of 7.7%. Importantly, however, a 70% TIR for patients with type 1 diabetes corresponded to an HbA1c of 6.9%, which diverged markedly from the HbA1c of 7.9% that corresponded to the desired 4% time below range (TBR). Moreover, these dissociations were observed more in patients with type 1 diabetes with a higher % coefficient of variation (> 36%). Hence, while the TIR is strongly correlated with HbA1c, it is difficult to coordinate with the TBR in Japanese patients with type 1 diabetes. As these metrics (which are critical indicators in clinical practice) are rapidly gaining popularity globally, including in Japan, our data strongly support the cautious use of new CGM metrics such as TIR and TBR/time above range, and emphasize the importance of individualized treatment in achieving the optimal TIR and TBR, especially in patients with type 1 diabetes.

Overexpressed exocyst complex component 3-like 1 spontaneously induces apoptosis.

Exocyst complex component 3-like 1 (EXOC3L1), which regulates insulin secretion, is ubiquitously present in heart, lung, liver, spleen, kidney, muscle, cerebellum, pituitary, adrenal grand, and pancreatic islets. Its deduced amino acid sequence has 31% identity and 53% similarity with Sec6, so they are considered isoforms. Since Sec6 suppresses apoptosis via HSP27, we investigated the involvement of EXOC3L1 expression in apoptosis. We found that overexpressed EXOC3L1 in Chinese hamster ovary cells significantly reduced cultured cell numbers. It also significantly increased apoptotic DNA ladder, caspase 3 activity, and cleavage of caspase 3 compared with the control. Thus, although Sec6 reduces apoptosis by increasing HSP27 phosphorylation, overexpressed EXOC3L1 alone can spontaneously induce apoptosis without apoptotic stimulators or inducers.

TBC1D8B, a GTPase-activating protein, is a novel apoptosis inducer.

Overexpressed TBC1D8B, a GTPase-activating protein, significantly reduced cultured HCT116 human colon cancer cell number. We tested N-terminal TBC1D8B, which is identical to wild type TBC1D8B from amino acid positions 1 to 427 and possesses a modified sequence from position 428 to 435 (ECGGLFLL) because of the introduction of a premature stop codon at position 436 to narrow down the minimum requirement element. The N-terminal TBC1D8B contains two GRAM domains but not the TBC domain essential for Rab-GTPase activity. The N-terminal TBC1D8B overexpression significantly reduced the cultured HCT116 cell number. When we tested C-terminal TBC1D8B, containing the portion of TBC1D8B absent in the N-terminal TBC1D8B, the cell number reduction was not observed. The N-terminal TBC1D8B overexpression significantly increased the coronin 1B expression and reduced the phosphorylation of serine 51 in eIF2α, respective markers of apoptosis and cell death/survival. Also, caspase 3 and poly ADP-ribose polymerase increased cleavage in suspended cells overexpressing the N-terminal TBC1D8B. Taken together, it is not the TBC domain for Rab-GTPase activity, but amino acids 1 to 435, including the two GRAM domains, that is enough for TBC1D8B to cause spontaneous apoptosis. TBC1D8B could be a potential anticancer therapeutic molecule.

Late-onset non-islet cell tumor hypoglycemia: A case report.

BACKGROUND: Hypoglycemia due to non-insulin-producing tumors is referred to as non-islet cell tumor hypoglycemia (NICTH). As NICTH is a rare lesion, the natural course of NICTH is not well understood. We report a case of NICTH that was observed 30 years before the onset of hypoglycemia. CASE SUMMARY: A 50-year-old man was diagnosed with an abnormal right chest shadow during a routine X-ray examination, but no further examination was undertaken because the lesion appeared benign. Thirty years after the tumor discovery, the patient was admitted to the hospital with symptoms of severe hypoglycemia, which was diagnosed as NICTH based on a complete examination. The tumor was resected and found to be a solitary fibrous mass (15.6 cm × 13.7 cm × 10.4 cm); thereafter, the patient's blood glucose levels normalized and he completely recovered. CONCLUSION: NICTH can have an acute onset, even if the tumor has been present and asymptomatic over a long time period.

In patients with type 2 diabetes the presence of Hashimoto's thyroiditis reduces the beneficial effect of dipeptidyl peptidase-4 inhibitor on plasma glucose control.

In this study, we compared the efficacy of a dipeptidyl peptidase-4 inhibitor (DPP4i) to improve glucose control in patients with type 2 diabetes mellitus (T2DM) with or without Hashimoto's thyroiditis (HT). First, we compared the change in glycated hemoglobin (HbA1c) between the hypothyroid condition (before levothyroxine sodium hydrate [LT4] treatment) and euthyroid condition (after LT4 treatment when patients had achieved euthyroidism for at least six months) in patients with T2DM and HT. Next, we compared the change in HbA1c levels before and six months of DPP4i treatment in patients with T2DM with and without HT. In hypothyroid condition the change in HbA1c after six months of DPP4i treatment was 0.13% ± 0.86%. The change in HbA1c levels from when patients first achieved euthyroidism to after six months in the euthyroid condition was 0.26% ± 0.90%. DPP4i efficacy in patients with T2DM and HT was reduced compared to patients with T2DM but without HT (-0.40 ± 0.90 vs. -0.99 ± 0.5, p = 0.0032). These data suggest that hypothyroidism does not impact on DPP4i efficacy. However, the effect of DPP4i in patients with T2DM and HT was reduced compared to that in T2DM patients without HT. An estimation of thyroid function before prescribing DPP4i may be useful tool for predicting the efficacy of DPP4i, allowing the ruling out complications from HT.

Administration of small-molecule guanabenz acetate attenuates fatty liver and hyperglycemia associated with obesity.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid ß-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.

Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver.

Brief refeeding times (~60 min) enhanced hepatic Angptl8 expression in fasted mice. We cloned the mouse Angptl8 promoter region to characterise this rapid refeeding-induced increase in hepatic Angptl8 expression. Deletion of the -309/-60 promoter region significantly attenuated basal promoter activity in hepatocytes. A computational motif search revealed a potential binding motif for hepatocyte nuclear factor 1α/1ß (HNF-1α/ß) at -84/-68 bp of the promoter. Mutation of the HNF-1 binding site significantly decreased the promoter activity in hepatocytes, and the promoter carrying the mutated HNF-1 site was not transactivated by co-transfection of HNF-1 in a non-hepatic cell line. Silencing Hnf-1 in hepatoma cells and mouse primary hepatocytes reduced Angptl8 protein levels. Electrophoretic mobility-shift assays confirmed direct binding of Hnf-1 to its Angptl8 promoter binding motif. Hnf-1α expression levels increased after short-term refeeding, paralleling the enhanced in vivo expression of the Angptl8 protein. Chromatin immunoprecipitation (ChIP) confirmed the recruitment of endogenous Hnf-1 to the Angptl8 promoter region. Insulin-treated primary hepatocytes showed increased expression of Angptl8 protein, but knockdown of Hnf-1 completely abolished this enhancement. HNF-1 appears to play essential roles in the rapid refeeding-induced increases in Angptl8 expression. HNF-1α may therefore represent a primary medical target for ANGPTL8-related metabolic abnormalities. The study revealed the transcriptional regulation of the mouse hepatic Angptl8 gene by HNF-1.

Assessment of factors that determine the mean absolute relative difference in flash glucose monitoring with reference to plasma glucose levels in Japanese subjects without diabetes.

The Abbott FreeStyle Libre flash glucose monitoring system (FGM) is a recently introduced, but widespread continuous glucose monitoring system. While its mean absolute relative difference (MARD) value indicating its accuracy is acceptable with reference to the self-monitoring of blood glucose (SMBG) levels, few reports have examined the MARD in sensor glucose values of FGM (FGM-SG) with reference to plasma glucose (PG) levels and the factors determining it. We performed oral glucose tolerance tests (OGTTs) in 25 Japanese subjects without diabetes. Parkes error grid analyses showed that FGM-SG with either SMBG or PG levels as a reference met International Organization for Standardization criteria. The MARD in FGM-SG with reference to SMBG levels was 10.9 ± 4.1% during OGTTs. Surprisingly, the MARD in FGM-SG with reference to PG levels was 20.3 ± 10.3% during OGTTs, revealing a discrepancy in the accuracy of FGM-SG compared with that of PG levels; moreover, the MARD showed negative correlations with fasting blood sugar level, homeostasis model assessment insulin resistance index, and body mass index (BMI). Multiple regression analyses revealed that BMI contributed the most to the MARD when FGM-SG and PG level were compared, as lean individuals have a greater MARD regardless of glucose levels. Inaccurate FGM data could potentially increase the risk of inappropriate treatment; consideration of such factors is critical to ensure reliable FGM values.

Regulation of the KCNJ5 gene by SF-1 in the adrenal cortex: Complete genomic organization and promoter function.

Activating mutations in the KCNJ5 gene are responsible for the significant number of aldosterone-producing adenomas. To elucidate the molecular mechanisms underlying KCNJ5 expression, we characterized the entire human KCNJ5 gene. The gene spanned approximately 29.8 kb and contained three exons and two introns. The strongest expression of KCNJ5 mRNA was observed in the adrenal gland. The promoter region contained a putative binding site for SF-1 at -1782 bp. A construct containing -2444 bp of the promoter region exhibited the strongest promoter activity in adrenal H295R cells, and the introduction of a mutation in the SF-1 binding site almost completely abolished promoter activity. Furthermore, deletion mutation, EMSA, and knockdown analyses revealed that SF-1 bound to this element and was functional. Immunochemistry showed that KCNJ5 was predominantly expressed in the zona glomerulosa, while SF-1 was ubiquitously expressed in the adrenal cortex. These results demonstrated that SF-1 mediates the expression of human KCNJ5 in the adrenal cortex.

Central Hypothyroidism Related to Pituitary Adenomas: Low Incidence of Central Hypothyroidism in Patients With Acromegaly.

CONTEXT: The most frequent cause of central hypothyroidism (CeH) is pituitary adenomas, but the mechanisms remain unclear. OBJECTIVE: We investigated serum thyroid levels and GH/IGF-1 in central hypothyroidism in untreated patients with pituitary nonfunctioning and GH-secreting adenomas. DESIGN: This was a retrospective cross-sectional study of cases collected from Gunma University and Toranomon Hospitals between 2007 and 2016. PATIENTS: One-hundred thirty-nine cases of nonfunctioning pituitary adenoma (NFPA) and 150 cases of GH-secreting pituitary adenoma (GHPA) were analyzed. MAIN OUTCOME MEASURES: The correlations between thyroid levels, several clinicopathological parameters, and GH/IGF-1 were examined. RESULTS: Twenty-four percent of NFPA patients had CeH. The severity did not correlate with tumor size, age, or sex, and all cases had normal TSH levels. In contrast, only 8.7% of GHPA patients had CeH; approximately half had normal TSH levels and approximately half had low TSH levels. Serum TSH levels in GHPA patients were significantly lower and free T4 (FT4) and free T3 levels were higher than those in patients with NFPA. Furthermore, approximately one-fourth of GHPA patients had normal FT4 and low TSH levels. In addition, serum FT4 levels and serum TSH levels were positively and negatively correlated, respectively, with serum IGF-1 levels. Furthermore, IGF-1 levels in patients with GHPA decreased with age. CONCLUSIONS: (i) NFPA patients with CeH had TSH levels within a normal range. (ii) GHPA patients had a low incidence of CeH, which may be a result of stimulated thyroid function by GH/IGF-1. (iii) We found an age-dependent decrease in serum IGF-1 levels in patients with GHPA.

Carotid artery stenting with proximal embolic protection via the transbrachial approach: sheathless navigation of a 9-F balloon-guiding catheter.

PURPOSE: Transbrachial carotid artery stenting (TB-CAS) is performed as an alternative procedure for patients with hostile vascular anatomy of the aortic arch and aortic or peripheral artery disease. Proximal protection during TB-CAS is not generally feasible because a small size of the brachial artery may preclude using a large-diameter sheath introducer. We, herein present a novel method that enables proximal protection during TB-CAS by sheathless navigation of a 9-F balloon-guiding catheter equivalent to a 7-F sheath. METHODS: We analyzed eight consecutive patients who underwent TB-CAS with proximal protection using the sheathless method from April 2016 to June 2017. Relevant demographic, radiographic, and procedural features were retrospectively reviewed. RESULTS: We performed TB-CAS using our method for five patients with a bovine or type 3 aortic arch, for one patient with combined peripheral artery disease, and for two patients with a type 1 or 2 aortic arch. We successfully navigated the balloon-guiding catheter via the brachial artery and performed CAS under proximal flow control in all patients. However, we experienced kinking and exchange of the balloon-guiding catheter in one patient and a periprocedural thromboembolic event occurred. A pseudoaneurysm at the access site developed in one patient. CONCLUSION: TB-CAS with proximal embolic protection using the sheathless method is feasible and may provide an alternative approach in carefully selected patients who have difficult anatomy in the transfemoral approach and plaques with a high risk of distal embolization.

Usage of continuous glucose monitoring (CGM) for detecting an unrecognized hypoglycemia and management of glucocorticoid replacement therapy in adult patients with central hypoadrenalism.

Patients with adrenal insufficiency require appropriate glucocorticoid replacement therapy; however, reliable biological parameters for optimizing glucocorticoid supplementation are limited. The physician has to rely primarily on clinical judgment, carefully taking into account signs and symptoms potentially suggestive of over- or under-replacement. We have found that some patients who are viewed as receiving sufficient doses of glucocorticoids occasionally exhibit morning headache or morning discomfort, which may be caused by unrecognized nocturnal hypoglycemia. Our aim in this study was to evaluate the usefulness of continuous glucose monitoring (CGM) for detecting unrecognized hypoglycemia and optimizing glucocorticoid replacement therapy in adult patients with central hypoadrenalism. Six patients with central hypoadrenalism of various etiologies were included in this study. All patients exhibited occasional morning headache or discomfort. We performed CGM to measure plasma glucose levels in all patients, and CGM identified unrecognized hypoglycemia episodes at midnight and early in the morning in five patients (83%). The CGM findings were used to fine-tune the dosing and regimens of glucocorticoid replacement and to re-evaluate glucose levels to avoid further unrecognized hypoglycemic events. This optimization of hydrocortisone supplementation prevented additional nocturnal hypoglycemia incidences in all cases. The addition of L-thyroxine with hydrocortisone continued to provide favorable glycemic control. Occasional symptoms also improved after maintenance in all patients. These findings demonstrated that CGM may represent a powerful tool for identifying unrecognized hypoglycemia and for optimizing supplementary hormones in patients with central hypoadrenalism, thereby improving their quality of life.