Insulin-dependent Diabetes Mellitus Patients Research Articles

Effect of apple cider vinegar on delayed gastric emptying in patients with type 1 diabetes mellitus: a pilot study

BackgroundPrevious studies on healthy people show that vinegar delays gastric emptying and lowers postprandial blood glucose and insulin levels. The aim of this study was to investigate the effect of apple cider vinegar on delayed gastric emptying rate on diabetes mellitus patients.MethodsTen patients with type 1 diabetes and diabetic gastroparesis, including one patient who had undergone vagotomy, were included and completed the investigator blinded crossover trial. The gastric emptying rate (GER) was measured using standardized real-time ultrasonography. The GER was calculated as the percentage change in the antral cross-sectional area 15 and 90 minutes after ingestion of 300 g rice pudding and 200 ml water (GER1), or 300 g rice pudding and 200 ml water with 30 ml apple cider vinegar (GER2). The subjects drank 200 ml water daily before breakfast one week before the measurement of GER1. The same subjects drank 200 ml water with 30 ml vinegar daily before breakfast for two weeks before the measurement of GER2.ResultsThe median values of GER1 and GER2 were 27% and 17%, respectively. The effect of vinegar on the rate of gastric emptying was statistically significant (p < 0.05).ConclusionThis study shows that vinegar affects insulin-dependent diabetes mellitus patients with diabetic gastroparesis by reducing the gastric emptying rate even further, and this might be a disadvantage regarding to their glycaemic control.Trial registration numberISRCTN33841495.

Diabetic macular edema and its relationship to renal microangiopathy: a sample of Type I diabetes mellitus patients in a 15-year follow-up study

Purpose In the present study, our objective was to determine the epidemiological risk factors for the development of diabetic macular edema, especially attendant on renal diabetic lesion (microalbuminuria or overt nephropathy) in 112 Type I diabetic patients after 15 years. Methods This is a 15-year follow-up study of a cohort of 112 consecutive Type I (insulin-dependent) diabetes mellitus patients without diabetic retinopathy or nephropathy who were enrolled in 1990. We studied the incidence of diabetic macular edema and its risk factors. The epidemiological risk factors included in the study were as follows: gender, diabetes duration, glycated hemoglobin (HbA 1c) levels, arterial hypertension, macroangiopathy, triglyceride levels, fractions of cholesterol [high-density lipoprotein cholesterol and low-density lipoprotein (LDL) cholesterol], and cigarette smoking. Results The incidence of diabetic macular edema after 15 years was as follows: the focal form of diabetic macular edema was present in 13 (11.6%) patients and the diffuse form of macular edema was present in 10 (8.9%) patients, among 23 (20.5%) patients. The following factors were significant in the development of diabetic macular edema: high levels of LDL-cholesterol ( P=.013), high levels (>7.5%) of HbA 1c ( P=.021), the presence of macroangiopathy ( P=.022), the severity of diabetic retinopathy ( P=.029), the presence of arterial hypertension ( P=.037), and the presence of overt nephropathy ( P=.047). Microalbuminuria was not significant in logistic regression ( P=.587), and cigarette smoking was not significant ( P=.976). The relationship between diabetic macular edema and duration of diabetes presented two peaks of incidence: first in patients with 15–20 years' duration of diabetes mellitus, and second in patients with >35 years' duration. Conclusions In summary, our data suggest that better control of glycemia, LDL-cholesterol levels, and blood pressure in Type I diabetes mellitus patients may be beneficial in reducing the incidence of diabetic macular edema. Finally, our data validate the current guidelines for ophthalmologic care for the detection of diabetic macular edema over the long-term course of diabetes.

Living Donor Islet Transplantation, the Alternative Approach to Overcome the Obstacles Limiting Transplant

We performed the world's first successful living donor islet transplantation for unstable diabetes. A total of 408,114 islet equivalents were isolated from half a living pancreas and transplanted immediately to the recipient who was a 27-year-old female. The donor was a 56-year-old female in good health, mother of the recipient. The islets functioned immediately, and the recipient was weaned completely from insulin on the 22nd posttransplant day, and has maintained excellent glycemic control since. The donor was discharged on the 18th postoperative day with normal oral glucose tolerance test and without complications. Living donor islet transplantation could cure one insulin-dependent diabetes mellitus patients with a single donor. There are some advantages in the living donor islet transplantation: (a) living donor can alleviate the issue of donor shortage; (b) highly potent islets can be isolated from a living donor; and (c) the recipient can be treated with immunosuppressant and controlled blood glucose level tightly prior to the transplantation. These are important factors in overcoming the obstacles limiting islet transplantation. We believe that the living donor islet transplantation may become an additional option in treating insulin-dependent diabetes.

Thiazolidinediones May Not Reduce Diabetes Incidence in Type 1 Diabetes

Thiazolidinediones improve glycemic control by reducing insulin resistance. Some studies have demonstrated that troglitazone had a preventative effect on diabetes in NOD (non-obese diabetic) mice. One of the mechanisms proposed for the prevention of diabetes by thiazolidinediones is an effect on T-helper 1/T-helper 2 (Th1/Th2) balance. In this article, we attempted to clarify whether pioglitazone is also effective in preventing diabetes as compared to metformin, which has no immunological effect. Female NOD mice were administered pioglitazone or metformin orally, and the insulitis score, cytokines secreted from splenocytes, cytokine expression levels in the pancreas, and the incidence of diabetes after acceleration by cyclophosphamide were analyzed. We could not find any advantage of pioglitazone in preventing Th1 skewing and the development of diabetes over metformin. Therefore, further research should take place before the application of thiazolidinediones to human slowly progressive insulin-dependent diabetes mellitus (SPIDDM) patients.

Species diversity of yeast in oral colonization of insulin-treated diabetes mellitus patients

The aim of this study was to investigate oral yeast colonization, antifungal susceptibility and strain diversity in insulin-dependent diabetes mellitus patients (175), as well as to evaluate the influence of dental prostheses. Oral rinse samples were cultured on selective media, in order to isolate, count and identify the yeasts recovered. More than half of the diabetic subjects (53%) carried significant amounts of Candida cells in the buccal cavity and these organisms were recovered at higher densities in diabetics wearing dentures. A total of 93 yeast strains were isolated from these patients, including: Candida spp. (n = 89); Pichia (n = 02); Trichosporon (n = 1), and Geotrichum (n = 1). C. albicans represented 56% of these strains, non-albicans Candida 39.8%, and other genera of yeast 4.3%. C. albicans was prevalent, followed by C. parapsilosis, C. tropicalis, C. glabrata, C. krusei, C. rugosa and C. guilliermondii. Agar disk-diffusion tests of the susceptibility of non-albicans Candida and other genera of yeast to fluconazole showed resistance in 21.9%, mainly in C. rugosa (100%), C. glabrata (57%) and C. krusei (50%). Local oral factors, such as the presence of dentures, in association with diabetes, seemed to have the effect of increasing the amount and variety of Candida species in the oral cavities, mainly those with lower drug susceptibilities.

Serum antioxidant vitamins levels in non-insulin-dependent diabetes mellitus subjects in Sokoto, Nigeria

Evidence is accumulating that most of the degenerative diseases including diabetes mellitus have their origin in deleterious free radical reactions. Humans are well endowed with antioxidant defences primarily by free radical scavengers, such as ascorbic acid, alphatocopherol, betacarotene, and trace elements. Deficiencies of these micronutrients may increase susceptibility to these diseases and the associated complications. Antioxidant vitamins (vitamins A, E and C) were estimated in one hundred and fifty (150) non insulin dependent diabetes mellitus (NIDDM) patients attending the outpatient clinic of the Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria. The results obtained were compared to those of One hundred and fifty (150) apparently healthy non-diabetic subjects. Serum glucose of the diabetic patients (13.59 ± 4.85mM) was significantly higher (P Keywords : antioxidant vitamins, non-insulin dependent diabetes mellitus, Sokoto Biokemistri Vol. 17(2) 2005: 107-114

H. Pylori re-infection in insulin dependent diabetes mellitus patients: A five year follow-up

H. Pylori re-infection in insulin dependent diabetes mellitus patients: A five year follow-up

Serum IL‐1β, IL‐2, and IL‐6 in Insulin‐Dependent Diabetic Children

Insulin-dependent diabetes mellitus (IDDM) is a chronic disease characterized by T-cell-dependent autoimmune destruction of the insulin-producing β cells in the pancreatic islets of Langerhans, resulting in an absolute lack of insulin. T cells are activated in response to islet-dominant autoantigens, the result being the development of IDDM. Insulin is one of the islet autoantigens responsible for the activation of T-lymphocyte functions, inflammatory cytokine production, and development of IDDM. The aim of this study was to investigate serum concentrations of interleukin (IL)-1β, IL-2, IL-6, and tumor necrosis factor (TNF)-α in children IDDM. The study population consisted of 27 children with IDDM and 25 healthy controls. Children with IDDM were divided into three subgroups: (1) previously diagnosed patients (long standing IDDM) (n : 15), (2) newly diagnosed patients with diabetic ketoacidosis (before treatment) (n : 12), and (3) newly diagnosed patients with diabetic ketoacidosis (after treatment for two weeks) (n : 12). In all stages of diabetes higher levels of IL-1β and TNF- α and lower levels of IL-2 and IL-6 were detected. Our data about elevated serum IL-1β, TNF- α and decreased IL-2, IL-6 levels in newly diagnosed IDDM patients in comparison with longer standing cases supports an activation of systemic inflammatory process during early phases of IDDM which may be indicative of an ongoing β-cell destruction. Persistence of significant difference between the cases with IDDM monitored for a long time and controls in terms of IL-1β, IL-2, IL-6, and TNF-α supports continuous activation during the late stages of diabetes.

Infectious Complications After Simultaneous Pancreas–Kidney Transplantation

Simultaneous pancreas-kidney transplantation (SPKT) improves long-term survival of insulin-dependent diabetes mellitus patients with diabetic nephropathy. The increasing success of SPKT is a result of improved surgical technique, better organ preservation, potent antirejection therapy, and effective use of antibiotics to prevent and treat infectious complications. However, morbidity and mortality following SPKT remain high mainly owing to infection. From 1988 to 2004, the 51 patients who underwent SPKT were 32 women and 19 men of mean age 34 ± 4 years old with diabetes and end-stage renal disease. The mean duration of diabetes mellitus was 23 ± 4 years. The incidence of HCV and HBV infections were 19.6% and 13.7%, respectively. Preoperative work-up included identification and elimination prior to surgery of potential sources of infection. All patients prior to SPKTx had been treated by dialysis (26 ± 20 months). The kidneys were always placed into the left retroperitoneal space first; at the same time the pancreatic grafts were prepared on the back table. The reconstruction of the superior mesenteric and the splenic arteries was performed using a Y graft of donor iliac artery to the common or external donor’s iliac artery. The pancreas was transplanted intraperitoneally to the right iliac vessels. The portal vein was sutured to the common or external iliac vein and the arterial conduit of donor iliac artery. In 20 of the patients, bladder drainage and in 31, enteric drainage was used for the pancreatic juice exterioration. Patients received immunosuppression with a calcineurin inhibitor (tacrolimus or cyclosporin), mycophenolic acid or azathioprine, and steroids. Antibody induction (alternatively anti–IL-2 monoclonal antibody or ATG) was used in last 38 patients. Antibacterial (tazobactam) and antifungal (fluconazole) as well as antiviral (gancyclovir) prophylactic treatment was given to all patients for 7 to 10 days after transplantation. Thirty-eight recipients are alive, 26 with function of both grafts; 8 with functioning kidney grafts; and 4 with nonfunctioning grafts on dialysis treatment from 1 to 14 years after transplantation. Thirteen patients (24.5%) died during the first year after transplantation. Infectious complications were the main cause of death. Systemic infections accounted for the death of five patients and CNS infection for death of another five patients. Three patients died with functioning grafts due to cardiopulmonary disorders (myocardial infarction, pulmonary embolus) early in the postoperative period. A total of 102 infections were diagnosed in 51 patients during the posttransplant course. Twenty-one episodes of CMV infection (systemic 20, duodenal site 1), 73 bacterial infections (systemic 13, pulmonary 13, urinary tract 15, intestinal 8, wound 23), and 8 fungal infections (central nervous system 5, gastrointestinal tract 3). Some patients had more than one type of infection. Overall mortality in the investigated group was 24.5%. Infectious complications were the main cause of death (77%), including systemic infection (38.5%) and CNS infection (38.5%). The predominant etiology of the systemic infections was bacterial. The etiology of CNS infections was fungal. In conclusion, infectious complications are the main cause of morbidity and mortality following SPKT. The early diagnosis of infection, particularly fungal complications, is necessary. The administration of broad-spectrum prophylactic antibiotics, antifungal, and antiviral agents is recommended.

Establishment of a Diabetic Mouse Model with Progressive Diabetic Nephropathy

Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER Igamma) in pancreatic beta cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER Igamma transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER Igamma transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.

Prokinetic therapy: What can be measured by gastric scintigraphy?

To evaluate whether gastric scintigraphy with quantitative analysis of gastric peristalsis may be a useful tool for documenting the effects of prokinetic therapy. Gastric emptying was determined in eight patients with insulin dependent diabetes mellitus (IDDM) and nine patients with progressive systemic sclerosis (PSS) after ingestion of a semi-solid test meal. Fourier analysis of condensed images was used to evaluate contraction amplitudes of the entire stomach, as well as frequency and velocity of gastric contractions. Patients were studied twice, first under baseline conditions and then after 4 weeks of continuous oral prokinetic therapy with cisapride (10 mg t.i.d.). Findings were compared with data derived from 15 healthy controls. At baseline conditions IDDM and PSS patients exhibited reduced gastric peristalsis and delayed emptying compared to controls. After 4 weeks of prokinetic treatment, gastric contraction amplitudes increased significantly, especially in the gastric corpus and the proximal stomach, associated with a slight improvement of gastric emptying. Changes in frequency and velocity of gastric contractions during prokinetic treatment correlated with the improvement of gastric motility and emptying. Prokinetic therapy with cisapride stimulates gastric motility, and could be non-invasively monitored by scintigraphy. This radionuclide technique provides a number of relevant parameters of gastric function, such as gastric emptying, contraction amplitudes, frequency and velocity of gastric contractions, which give crucial insights into the mechanisms of action of prokinetic drugs.

Simultaneous Pancreas-Kidney Transplants in Type I and Type II Diabetic Patients With End-Stage Renal Disease: Similar 10-Year Outcomes

Introduction Herein we report 10- to 15-year results of simultaneous pancreas-kidney (SPK) transplants in 135 type I and type II insulin-dependent diabetes mellitus (IDDM) patients. Methods Diabetes type was defined by the absence (type I) or presence (type II) of C-peptide. The freedom from dialysis and need for insulin defined graft survival. Patient survival was verified by record review and the Social Security Death Registry. The mean follow-up exceeded 100 months. Results Type II IDDM present in 28% of the 135 cohort, predominately among African-Americans (AA). The type II group was two-thirds AA (43% of the total AA patients) and 17% of the non–African-American (nAA) group. The difference between the two groups by C-peptide level was significant ( P = .001). Type II patients had a higher body mass index, were slightly older at the onset of DM, but had similar duration of IDDM before ESRD. At 5 and 10 years, pancreas survival for type 1 DM was 71% and 49%; for type II DM it was 67% and 56% ( P = .52). Kidney survival for type I DM was 77% and 50%; for type II it was 72% and 56% ( P = .65). Patient survival for type I DM was 85% and 63%; for type II DM it was 73% and 70% ( P = .98). Conclusions We conclude that the outcomes of SPK transplants are equivalent regardless of diabetes type. Accordingly, the decision whether to perform pancreas transplants in diabetic recipients of kidney allografts should be based on general acceptance criteria not diabetes type.

Advances in the Chemistry of Thiazolidinediones as Antidiabetic Agents

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cytotoxic T lymphocyte antigen 4 heterozygous codon 49 A/G dimorphism is associated to latent autoimmune diabetes in adults (LADA)

Autoimmune diabetes is an organ specific and multifactorial disorder with a classical onset as insulin dependent diabetes mellitus (IDDM) and with another form of onset as latent autoimmune diabetes in adults (LADA), which has a slower onset and a later progress to insulin dependency as a result of the beta cells destruction.The cytotoxic T lymphocyte-antigen 4 (CTLA4) has been identified as a susceptible marker of the disease; it is considered a down regulator of T cell function, playing a key role in autoimmunity.We analyzed CTLA4 codon 49 A/G polymorphism in 123 IDDM patients, 63 LADA patients and 168 healthy non-diabetic control individuals.The frequency of the heterozygous A/G genotype in LADA patients was significantly increased compared to IDDM patients (55.6 vs. 39.8%, p = 0.0415). There was no statistical significant difference in the distribution of the A/G dimorphism between autoimmune diabetes patients (LADA or IDDM) and non-diabetic control individuals.HLA DQ region is responsible for the genetic susceptibility to autoimmune diabetes in IDDM patients in about 50% and it has a lower effect in genetic susceptibility in LADA patients. Several other genetic loci are needed to develop autoimmune diabetes in adult patients. Therefore, LADA may be the result of a combined minor risk loci effect in a major risk haplotype.

Psychosocial aspects of xenotransplantation: Survey in adolescent recipients of porcine islet cells

Introduction Transplantation is a process with several psychosocial challenges. Regarding the case of xenotransplantation, the perceived similarity between humans and pigs may be stressful. Adjustment disorders have been reported among transplantation recipients. We sought to assess the psychosocial aspects of xenotransplantation among porcine islet-cell recipients and their efforts to adapt themselves to this condition. Material and methods Ten insulin-dependent diabetes mellitus patients aged 14.58 ± 7.93 who received porcine islet-cells were included. The bioartificial steel/fibrous tissue chamber method was used. All patients and their relatives were interviewed about their expectations, overall functioning, and experiences. The quality of life, enjoyment, and satisfaction scale and the hospital anxiety and depression scales were used. A 1-year follow-up was done. Results Their motivation was centered on autonomy; there were no troubles regarding the graft origin. Xenotransplantation was perceived with pragmatism, seeing pigs as an unlimited resource. The patients with best outcomes also had the greatest improvements in several quality of life areas (QOL) while the medium responders had fewer QOL improvements. The nonresponders experienced mainly frustration. Parents' concerns were not related to their children's health but to their recently gained autonomy. Conclusions In addition to enthusiasm, the perception of animals as an unlimited source of organs may affect patient compliance; in this group, xenotransplantation was seen as using as a long-lasting drug, with chamber walls considered as a physical, immunologic, and, in certain manner, a psychological barrier.

Exploration des petites fibres dans le dépistage des neuropathies diabétiques

Introduction. – Electrophysiological exploration of neuropathies is a standard method of investigating the dysfunction of myelinated larger fibers (Aα, Aβ). However, this method cannot test dysfunctions in other fibers. To evaluate the smaller (Aδ) and unmyelinated fiber (C-fibers) lesions a quantitative method has been perfected: the study of the sensory thresholds (Quantitative Sensory Testing: QST). It allows the investigation of the sensory symptoms and is a reproducible, non invasive and painless method. It is used above all in patients suffering from diabetic neuropathy (Dyck et al. 1987). Methods. – We used the QST testing in comparison with nerve conduction velocities in 40 non insulin-dependent diabetes mellitus (NIDDM or Type II) patients in their 60’s (±10 years). Depending on the duration of their diabetes (dd), we distinguished three groups: dd <5 years (GI) dd from 5 to 15 years (GII) and dd >15 years (GIII). All the patients underwent a clinical neurological examination which enabled us to establish a gravity score comparable to the NDS (Neuropathy Disability Score: Dyck 1988). Results. – Nerve conduction velocities and QST were studied for each group of patients. Electrophysiological alterations were connected to the gravity clinical score and in some asymptomatic patients a higher QST heat threshold could be observed. Discussion. – These results indicate that QST can detect the early dysfunction of the unmyelinated fibers in this kind of neuropathy. Subclinical detection can reduce severe neurological complications and make possible an early and effective treatment.

Utility of Bran Products in Non Insulin Dependant Diabetes Mellitus (NIDDM) Patients

Bran is the waste material in the preparation of excruded products from millets. To develop a cheapest product for diabetic patients and to assess its impact on them was the major objective. Hence, bran products i.e. wheat, jowar and mixed bran were prepared and evaluated in terms of its effect on the blood glucose response among 40 to 50 years old non obese, non insulin dependent diabetes mellitus (NIDDM) patients. As compared to the different bran products, mixed bran papadi had found significant impact on reducing the blood glucose level among all the grades of diabetic patient.

오소리 지질이 인슐린 비의존형 당뇨환자의 건강상태 당뇨지표 및 혈청지질농도에 미치는 영향

오소리 지질이 인슐린 비의존형 당뇨환자의 건강상태 당뇨지표 및 혈청지질농도에 미치는 영향

PSYCHOSOCIAL ASPECTS OF XENOTRANSPLANTATION. SURVEY IN PORCINE ISLET CELL RECIPIENTS

P868 Aims: Transplantation is a process with several psychosocial challenges that are commonly reflected as adjustment disorders. Regarding xenotransplantation, these issues involve the perceived similarity between humans and animals that may have self-image repercussions; the patient may feel stigmatized by being seen as an hybrid between species. Beside this, the cultural background has its own implications regarding organs, animals and xenografts. The objective of this work was to assess the psychosocial issues of xenotransplantation in porcine islet cell recipients and their efforts to adapt themselves to this condition. Material and methods: 10 insulin-dependent diabetes mellitus patients aged 14.58±1.93 who received porcine islet cells were included. The patients and their parents were interviewed before the procedure about their expectations and overall functioning. The quality of life, enjoyment and satisfaction questionnaire and the hospital anxiety and depression scale were used. A 6-month follow-up was done, statistical analysis was made using Wilcoxon’s test. Results: Motivation was focused mainly in autonomy increase and simplified treatments, there were no misgivings related to the cell source. There was a pragmatic view about xenografts, perceiving them as an unlimited resource. Affective status and QOL had non-significant improvements, except in sex life (p<0.05). Conclusions: Additionally to enthusiasm regarding xenotransplantation, using animals as an endless source of organs may affect patients compliance to treatment because this process can be repeated several times.

Ambulatory surgery adult patient selection criteria - a survey of Canadian anesthesiologists.

An increasing number of patients with complex medical problems are now considered suitable for ambulatory surgery. The purpose of this study was to identify the current clinical practice of ambulatory surgical patient selection. A standardized questionnaire specifying 30 clinical conditions was sent to all practicing anesthesiologists who are members of the Canadian Anesthesiologists' Society. Recipients were asked to indicate if they would provide ambulatory anesthesia (yes/no answers) for an adult patient with each of those isolated conditions. A 75% agreement was considered a majority opinion. One thousand three hundred thirty-seven questionnaires were sent and 774 replies were received (57.8%). Over 75% of anesthesiologists were willing to include in their selection criteria American Society of Anesthesiologists' (ASA) physical status III, patients with low-grade angina pectoris (AP) and congestive heart failure (CHF), prior myocardial infarction, asymptomatic valvular disease, sleep apnea without use of narcotics, morbid obesity (MO) without co-morbidities, insulin dependent diabetes mellitus and malignant hyperthermia (MH) susceptible patients. Over 75% of responders found ASA IV patients, high grade AP and CHF, sleep apnea with postoperative narcotics, MO with co-morbidities and no patient escort to be unsuitable for ambulatory anesthesia. Our survey demonstrated that medical conditions with extreme grades of severity (mild or severe) are associated with majority opinion to proceed or not to proceed with ambulatory surgery. Issues with over 75% agreement reflect the common practice. Similar surveys may form a part of patient selection guidelines development in the future.