Medical Staff Training - Quality Initiative to Reduce Errors in the Pre-Preanalytical Phase.

BACKGROUND: Numerous studies indicate that most error sources in hemostasis laboratories occur during the pre preanalytical phase through biological product sampling. OBJECTIVES: The purpose of this study was documentation, monitoring, and reduction of preanalytical errors through operator training. METHODS: For a period of 4 months in the "St. SpiridonË® Hospital from Iasi, 978 specimens were identified with non-conformities, due to the following causes: insufficiently-collected, hemolyzed- and coagulated samples. Data collection was conducted in two stages: before and after training of medical staff in clinical departments, upon improving the coagulation specimen sampling practices. RESULTS: The study pointed out that subsequent to training, a reduction of the coagulated samples has been registered as follows: in medical departments from 33.33% to 16.78%, in surgery from 27.20% to 17.02%, ICU (intensive care units) from 10.63% to 8.74%, and slightly in EU (emergency) from 10.63% to 8.74%. Moreover, we noticed that the incidence of hemolyzed samples increased in clinical sections, as follows: EU from 4.50% to 14.89%, medical departments from 3.42% to 9.21%, surgery from 1.44% to 6.38%, and 4.50% to 14.89% for ICU. The insufficiently sampled volume persisted during the study in almost all sections: surgery from 1.80% to 4.96%, medical from 2.52% to 4.96%, EU from 1.80% to 3.78% with a slight decrease in ICU from 1.26% to 1.18%. CONCLUSIONS: Nurses traditionally represent the core of quality medical services. Peer education is effective and implementation and compliance of sample collection procedure rules ultimately providing patient safety.

Blood Clot Identification Procedures in Clinical Laboratory Sampling.

BACKGROUND: Monitoring of anticoagulation therapy is based on screening tests: prothrombin time (PT) and activated partial thromboplastin time (APTT). The accidental presence of a clot in the coagulation samples determines a false prolongation of PT by fibrinogen (FI) consumption and the false or delayed prolongation of APTT, depending on FI consumption or activation. The purpose of this study is to document from the present data re-garding procedures used to exclude the accidental presence of clot in the sample. METHODS: For a more efficient approach, we conducted a study based on research from the main databases that included original and peer-reviewed studies. RESULTS: We have reported studies in which pre-analytical procedures have been recommended and studies that have also presented post-analytical protocols. A correlation between the efficiency of the procedures in terms of additional laboratory costs has been performed, as well. CONCLUSIONS: Focusing on patient safety, it remains a continuous challenge for each laboratory to be able to establish its own pre-analytical and post-analytical procedure for highlighting accidental clot presence, thus ensuring provision of results with maximum confidence to the clinicians.

In vitro activity of echinocandins against 562 clinical yeast isolates from a Romanian multicentre study.

The study presents the echinocandin susceptibility profile of a multi-centre collection of pathogenic yeast isolates from Romanian tertiary hospitals. The 562 isolates were identified using ID32C strips, MALDI-TOF MS and DNA sequencing. Minimal inhibitory concentrations (MICs) of caspofungin (CAS), micafungin (MCA), and anidulafungin (ANI) were assessed and interpreted according to EUCAST guidelines. Minimal fungicidal concentrations (MFC) were determined by plating content from the clear MIC wells. The activity was considered fungicidal at MFC/MIC ≤ 4. The three echinocandins had strongly correlated MICs and high percentages of MIC essential agreement. Most often, MCA had the lowest MICs, followed by CAS and ANI. Against C. parapsilosis and C. kefyr, CAS had the lowest MIC values. The MIC50 values were between 0.03 and 0.25 mg/l, except C. parapsilosis. The MIC90 values were usually one dilution higher. MFCs and MICs were weakly correlated. ANI and MCA had the lowest MFC values. The MFC50 values were between 0.06 and 0.5 mg/l, except C. parapsilosis, C. guilliermondii, and C. dubliniensis. The MFC90 values were usually two dilutions higher. Based on EUCAST breakpoints, 47 isolates (8.4%) were resistant to at least one echinocandin, most often ANI. Most resistant isolates were of C. albicans, C. glabrata, and C. krusei. There were 17 isolates (3%) resistant to echinocandins and fluconazole and most belonged to the same three species. MCA and ANI had the highest rates of fungicidal activity. The high rates of echinocandin resistance and significant multidrug resistance make prophylaxis and empiric therapy difficult.

Knowledge and Attitudes towards Medical Emergencies among Dentists in Iași, Romania.

The aim of this study was to evaluate the level of knowledge of resident dentists and new graduates regarding the etiology, clinical diagnosis, and treatment of the main medical emergency conditions. The study included a sample of 152 new graduates and residents in the first, second, and third year of training in Prosthodontics and General Dentistry from the Faculty of Dental Medicine in Iasi, Romania. Their level of knowledge and the attitudes were assessed using a questionnaire with 24 questions, divided into four sections. The differences among groups were identified using the chi-square test (p < 0.05). A high level of knowledge was found among the three groups of subjects for the questions regarding the recognition of clinical signs in hypoglycemic crisis (88-100%), in anaphylactic shock (83.3-94.5%), and the treatment of angina pectoris (76.2-84.2%). In contrast, a low level of knowledge was found for the questions regarding pulse evaluation in the case of an emergency (26.3-35.7%), the parameters of normal breathing (28.9-43%), and the treatment of hypoglycemic crisis (27.8-44.8%). The study indicated that the dentists had a moderate understanding of dental office medical emergencies and preferred practical training over theoretical courses.

Early Detection of Inflammation and Malnutrition and Prediction of Acute Events in Hemodialysis Patients through PINI (Prognostic Inflammatory and Nutritional Index).

Protein-energy wasting and inflammation are major risk factors for complications in hemodialysis patients. As these risk factors are triggered by a pro-inflammatory state, oxidative stress and hemodynamic dysfunction, which overlap in hemodialyzed subjects, we aimed to assess the efficacy of a cost-effective and straightforward screening tool, the Prognostic Inflammatory and Nutritional Index (PINI), in regularly screening maintenance hemodialysis (MHD) patients, to detect early signs of inflammation and malnutrition. A 12-month follow-up was carried out on a cohort of 102 adult patients undergoing maintenance dialysis, during which the Prognostic Inflammatory and Nutritional Index (PINI) was calculated using the formula alpha1-Acid Glycoprotein (AGP) × C-reactive protein (CRP)/albumin (ALB) × transthyretin (TTR). A PINI score < 1 was considered normal. The patients were stratified based on their PINI score: 66 patients (64.70%) had a normal score, below 1, while 36 patients (35.30%) had a PINI score ≥ 1. Despite the absence of clinical evidence of inflammation at enrollment, the latter group exhibited higher levels of CRP. During the follow-up period, all patients with a PINI score ≥ 1 experienced at least one acute event, compared to only 6% of patients with a normal PINI score, which presented COVID-19 infection as an acute event. The evaluation of the PINI can effectively identify the silent malnutrition-inflammation syndrome and predict the risk of acute events. This straightforward test appears to be a rapid tool that is independent of the examiner's experience and subjectivity, thereby potentially reducing hospitalization costs.

Research Regarding Dental Mobility Phenomena in the Clinical Recognition Diagnosis of Temporomandibular Disorders.

The main objective of this study is to quantify the implications of the complications of periodontal pathology and dental mobility on the pathology of dysfunctional algo syndrome, a clinical entity with profound implications for the patient's quality of life. METHODOLOGY: Clinical and laboratory evaluation was conducted in the 2018-2022 period, on a group of 110 women and 130 men, aged between 20-69, selected from our practice venue, Policlinica Stomatologica nr. 1 Iasi, Clinical Base of Dentistry Education "Mihail Kogalniceanu" Iasi, "Grigore T. Popa" University of Medicine and Pharmacy Iasi and "Apollonia" University Iasi. Overall, 125 subjects were diagnosed with periodontal disease with complications and TMJ disorders and followed periodontal therapy in the context of oral complex rehabilitation treatments (study group); the results of their clinical evaluation were compared with the results of the evaluation of the control group, made from the other 115 patients). RESULTS: Dental mobility and gingival recession were identified as more frequent in the study sample compared with the control sample, the differences being statistically significant in both cases. In total, 26.7% of patients had different types of TMJ disorders and 22.9% of patients had occlusal changes; the percentages are slightly increased in the study sample compared with the control one, but the recorded differences are not statistically significant. CONCLUSIONS: Dental mobility, most of the time, is a negative consequence of periodontal disease, leading to the alteration of the mandibular-cranial relations, materializing in an important proportion as an etiopathogenic factor of the dysfunctional syndrome of the stomatognathic system.

Evaluation of cardiovascular events and progression to end-stage renal disease in patients with dyslipidemia and chronic kidney disease from the North-Eastern area of Romania.

PURPOSE: The aim of this prospective cohort study was: to identify the association between different biomarkers [proprotein convertase subtilisin/kexin 9-PCSK9, lipoprotein(a)-Lp(a) and high-sensitivity C-reactive protein-hsCRP] and the cardiovascular events; to evaluate the relationship between the 3 biomarkers mentioned above and the renal outcomes that contributed to end-stage renal disease (ESRD). METHODS: We studied 110 patients with chronic kidney disease (CKD) stages 2 to 4. The identification of the new cardiovascular events and the renal outcomes were performed by clinical and paraclinical explorations. RESULTS: 350 patients were examined and 110 (31.4%) were included in this study. The mean age was 55.6 ± 10.9 years, with a higher number of men compared to women. The CKD patients with de novo cardiovascular events and new renal outcome during the study, had significantly increased values of total cholesterol (TC), low density cholesterol lipoprotein (LDL-C) at 6 and 12 months and higher levels of Lp(a), PCSK9, hsCRP and low ankle-brachial index (ABI) and ejection fraction (EF) values compared to patients without cardiovascular and renal events. In CKD patients, PCSK9 > 220 ng/mL was a predictor of cardiovascular events, while the EF < 50% was a predictor for renal outcomes. For CKD patients with PCSK9 > 220 ng/mL and hsCRP > 3 mg/L levels, the time-interval for the new cardiovascular and renal events occurrence were significantly decreased compared to patients displaying low values of these biomarkers. CONCLUSION: The results of this study show that PCSK9 > 220 ng/mL was predictor for cardiovascular events, while EF < 50% was predictor for CKD progression to ESRD. PCSK9 > 220 ng/mL and hsCRP > 3 mg/L were associated with the occurrence of renal and cardiovascular events earlier.

Evaluation of Oxidative Stress before and after Using Laser and Photoactivation Therapy as Adjuvant of Non-Surgical Periodontal Treatment in Patients with Rheumatoid Arthritis.

(1) Background: The aim of this split-mouth design study was to analyze the clinical periodontal indexes and oxidative stress markers in gingival crevicular fluid modifications after three periodontal disease treatment possibilities (scaling and root planning-SRP; SRP and diode laser-L; SRP and photodynamic therapy-PDT). (2) Methods: The study was conducted on 52 patients: systemically healthy subjects with periodontal disease-non-RA (n = 26); and test group (n = 26) subjects with rheumatoid arthritis and periodontal disease-RA. Clinical periodontal measurements (probing depth-PD; Löe and Silness gingival index-GI; papillary bleeding index-PBI; and periodontal community index of treatment needs-CPITN) and oxidative stress markers (8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4 hydroxynonenal (4-HNE)) were analyzed at baseline (T0), after three sessions of periodontal treatment (T1), and 6 months after treatment (T2). (3) Results: Periodontal therapy improved clinical periodontal measurements and oxidative stress markers in both analyzed groups, with supplementary benefits for laser- and PDT-treated periodontal pockets. (4) Conclusions: The analyzed oxidative stress markers decreased significantly following non-surgical periodontal therapy in both rheumatoid arthritis and systemically healthy patients. All the periodontal disease treatment possibilities analyzed in this study offered clinical and paraclinical improvements; however, the association of laser with SRP and photodisinfection with SRP yielded the best clinical and paraclinical outcomes when compared to SRP alone.

Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania.

This study identifies the genetic background of familial hypercholesterolemia (FH) patients in Romania and evaluates the association between mutations and cardiovascular events. We performed a prospective observational study of 61 patients with a clinical diagnosis of FH selected based on Dutch Lipid Clinic Network (DLCN) and Simon Broome score between 2017 and 2020. Two techniques were used to identify mutations: multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. The mutation rate was 37.7%, i.e., 23 patients with mutations were identified, of which 7 subjects had pathogenic mutations and 16 had polymorphisms. Moreover, 10 variants of the low-density lipoprotein receptor (LDLR) gene were identified in 22 patients, i.e., one variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in six patients, and one variant of the apolipoprotein B (APOB) gene in three patients. Of the LDLR gene variants, four were LDLR pathogenic mutations (c.81C > G, c.502G > A, c.1618G > A mutations in exon 2, exon 4, exon 11, and exon 13-15 duplication). The PCSK9 and APOB gene variants were benign mutations. The pathogenic LDLR mutations were significant predictors of the new cardiovascular events, and the time interval for new cardiovascular events occurrence was significantly decreased, compared to FH patients without mutations. In total, 12 variants were identified, with four pathogenic variants identified in the LDLR gene, whereas 62.3% of the study population displayed no pathological mutations.

Apolipoproteins A and B and PCSK9: Nontraditional Cardiovascular Risk Factors in Chronic Kidney Disease and in End-Stage Renal Disease.

PURPOSE: Nontraditional cardiovascular risk factors as apolipoprotein A (ApoA), apolipoprotein B (ApoB), and the proprotein convertase subtilisin/kexin type 9 (PCSK9) increase the prevalence of cardiovascular mortality in chronic kidney disease (CKD) or in end-stage renal disease (ESRD) through quantitative alterations. This review is aimed at establishing the biomarker (ApoA, ApoB, and PCSK9) level variations in uremic patients, to identify the studies showing the association between these biomarkers and the development of cardiovascular events and to depict the therapeutic options to reduce cardiovascular risk in CKD and ESRD patients. METHODS: We searched the electronic database of PubMed, Scopus, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins and PCSK9 in CKD and ESRD. Randomized controlled trials, observational studies (including case-control, prospective or retrospective cohort), and reviews/meta-analysis were included if reference was made to those keys and cardiovascular outcomes in CKD/ESRD. RESULTS: 18 studies met inclusion criteria. Serum ApoA-I has been significantly associated with the development of new cardiovascular event and with cardiovascular mortality in ESRD patients. ApoA-IV level was independently associated with maximum carotid intima-media thickness (cIMT) and was a predictor for sudden cardiac death. The ApoB/ApoA-I ratio represents a strong predictor for coronary artery calcifications, cardiovascular mortality, and myocardial infarction in CKD/ESRD. Plasma levels of PCSK9 were not associated with cardiovascular events in CKD patients. CONCLUSIONS: Although the "dyslipidemic status" in CKD/ESRD is not clearly depicted, due to different research findings, ApoA-I, ApoA-IV, and ApoB/ApoA-I ratio could be predictors of cardiovascular risk. Serum PCSK9 levels were not associated with the cardiovascular events in patients with CKD/ESRD. Probably in the future, the treatment of dyslipidemia in CKD/ESRD will be aimed at discovering new effective therapies on the action of these biomarkers.

Hepatitis C Infection and Periodontal Disease: Is there a Common Immunological Link?

Hepatitis C virus (HCV) infections could have an important impact on the oral health status of patients, favoring conditions such as periodontal disease and oral cancer. The review of the existing scientific literature written in English was performed, searching for oral and periodontal manifestations of HCV infection and its impact on the oral fluids. HCV infection can determine direct extrahepatic manifestations at the oral and periodontal level including oral lichen planus, Sjögren-like sialadenitis, and oral cancer. The changes caused by the infection in the subjects' immune system, diet, and lifestyle can facilitate the development of oral conditions such as periodontal disease. Important changes also occur in the composition of the infected patients' saliva and gingival fluid. HCV-infected patients need to be carefully monitored in terms of oral health since the infection with the virus can result in oral complications. The cellular and molecular particularities of the gingival fluid of HCV-infected patients can answer some questions regarding its impact upon periodontium impairment and whether this refers to a possible bidirectional relationship, with hepatic biomarker adjustments being induced by the periodontal patients' inflammatory status.

Drug-induced gingival hyperplasia - experimental model.

Several causes of gingival hyperplasia are known, the most widely accepted being the drug-induced gingival augmentation, a side effect associated mainly with three classes of drugs: anticonvulsants (Phenytoin), immunosuppressants (Cyclosporine A), and various calcium channel blockers (Nifedipine, Verapamil, Diltiazem). We studied the effect of Cyclosporine A (CsA) and Nifedipine on gingival fibroblasts extracted from the rat gum. Gingival fibroblasts were isolated from 6-week-old male rats weighing 150-170 g, from gingival explants, and grown in a specific culture medium consisting of Dulbecco's Modified Eagle's Medium (DMEM) supplemented with antibiotic and 10% fetal bovine serum (FBS). The medium was also supplemented with CsA (1 µg÷mL) and Nifedipine (3 mM). We also used a control group that received no treatment. The cells were photographed at 7, 14 and 30 days, with a Nikon Eclipse TE300 phase contrast microscope. For cell viability evidence, we used immunofluorescence (flow cytometry) with a FACS (fluorescence-activated cell sorting) Calibur device and its software. We noticed that the proliferation of these cells increased with the period of drug administration, and the subsequent morphological changes that occurred were related to the presence of drug accumulations in the cell cytoplasm. Modern molecular techniques are needed to shed some light upon the pathogenesis of drug induced gingival overgrowth and, thereby, provide novel information for preventative and effective future therapeutic strategies.

Expression of Pentraxin 3 and Thrombospondin 1 in Gingival Crevicular Fluid during Wound Healing after Gingivectomy in Postorthodontic Patients.

Background. Wound healing is a tissue repair process after an injury, and two of its main components are inflammation and angiogenesis, in which course a cascade of mediators is involved. The aim of this research was to evaluate the involvement of Pentraxin 3 and Thrombospondin 1 in wound healing after periodontal surgery (gingivectomy) for gingival overgrowth during orthodontic treatment with or without magnification devices, by assessing their levels in GCF. Methods. From 19 patients with gingival overgrowth as a result of fixed orthodontic treatment, the overgrown gingiva was removed by gingivectomy, from one half of the mandibular arch without magnification and from the other under magnification. Pentraxin 3 and Thrombospondin 1 were determined from gingival crevicular fluid by ELISA tests. Results. Statistically significant differences (p < 0.05) and correlations between levels of the two biomarkers were analyzed. Statistically significant differences were established between levels of the two biomarkers at different time points, with significant positive correlation at the point of 24 hours. Conclusions. Within the limitations of this study, the results seem to sustain the involvement of Pentraxin 3 and Thrombospondin 1 in the processes of inflammation and angiogenesis in wound healing of patients with postorthodontic gingivectomy. The dynamics of Pentraxin 3 and Thrombospondin 1 levels could suggest a reduced inflammation and a faster angiogenesis using microsurgery.

Value of ICDAS index in a preschool community from Iasi.

UNLABELLED: The International Caries Detection and Assessment System (ICDAS) is a clinical scoring system for use in dental education, clinical practice, research, and epidemiology. The ICDAS is designed to: lead to better quality information to inform decisions about appropriate diagnosis, prognosis, and clinical management at both the individual and public health levels. It provides a framework to support and facilitate personalized management of the caries process and dental decay for improved long-term health outcomes. AIM: This baseline study aims to find out the distribution of the caries lesions in primary teeth and their associations between the socio-economic statuses of families, in an lasi town preschool community (Romania). MATERIAL AND METHODS: The study series included 500 children (276 girls, 224 boys), aged 3-7 years old ( 43 subjects aged 3-3, 9 years, 126 subjects aged 4-4, 9 years, 186 subjects aged 5-5, 9 years, 136 subjects aged 6-6, 9 years and 9 subjects aged 7 years), attending a Iasi town kindergarten, in which the ICDAS index, was applied. RESULTS: The visits to the dentist are statistically correlated only with the average number of healthy teeth from the frontal and the lateral area. In other areas of the dental arch, there is no statistically significant data, but in the frontal area, the children that had visited the dentist present an average number of 3.5 healthy teeth, and the children that had not been to the dentist present an average number of 3.717 healthy teeth. The number of teeth with enamel destruction without dentin visibility is much reduced in children also, statistically significances being present only in lateral mandibular and maxillary areas. Though in lateral mandible area, this value varies from 0 (for children between 6-7 years old), to 0.1176 (for children between 5-6 years old). The frequency of tooth brushing, has a significant influence on the (ICDAS = 4) value in lateral mandibular and maxillary areas, where these values decrease, as the tooth brushing is more often. Though in lateral maxillary area, the value is 0.066 for the children that brush their teeth twice a day, for the children that brush their teeth once a day, the value is 0.0353 and for the children that brush their teeth occasionally the value is 0.018. CONCLUSIONS: This study confirmed the high caries level in this region. The total caries experience indicators are normally higher, in the mixed dentition because the primary teeth have been exposed longer for the risk factors of dental caries for example frequent sugar snacks and drinks. It can be concluded that ICDAS method, gives much more relevant information about caries process than other methods. The distributions of the ICDAS codes are correlated between the primary and the permanent molars of the mixed dentition.

MIDAS intelligent platform for medical services, support for decision optimization in virtual medical communities.

The paper describes the implementation of a open multifunctional platform--MIDAS--for heterogeneous medical data management--support for optimization of clinical decision in virtual medical communities. The objectives of this intelligent environment are: diagnostic easier by access to heterogeneous medical data, a virtual support for medical personal in order to reduce medical errors, fast access to resources for education and improvement of medical education for physicians and students. The structure of the platform is based on a core module and a number of dedicated modules that give an important advantage as re-configurable platform depending on necessities. The core module tries to be as general is possible in order to be used in the future as core model in a platform focused on dentistry cases.

[Evaluation of oral injuries in experimental induced diabetes mellitus by analysis of some gingival fluid markers]. / Evaluarea afectarii teritoriilor orale in diabetul indus experimental prin analiza unor markeri in fluidul gingival.

AIM: The objective of this study was to determine the relationship between the activity of the enzyme aspartate aminotransferase (AST) and IL1-beta in gingival crevicular fluid (GCF) on animal model with experimentally induced diabetes mellitus and periodontal disease. MATERIAL AND METHOD: During our study we used 15 Wistar rats, divided into three groups: I--control, II--with experimental model of periodontal disease, III--with experimental model of periodontal disease and diabetes. The sampling of GCF was realized using Whatman no. 1 paper strips introduced in the gingival sulci from mandibular left and right molars. For the determination of AST in GCF we used a spectrophotometric method while gingival fluid IL-1beta determinations were realized through immune enzymatic methods, using an ELISA kit (rlL-1beta). RESULTS: The results displayed 3.47 times increased gingival fluid AST values in the stimulated experimental model (with periodontal alteration) when compared to control values (without periodontal disease), while in diabetes an increase of 6.139 times higher compared to control (without periodontal disease) were recorded. Moreover, the levels of periodontal disorder-induced IL-1beta were 3.54 times higher compared to control (group II--218.490 pg/mL vs group I--61.691 pg/mL), the most significant increase being recorded for the group with diabetes associated to periodontitis (492.129 pg/mL). CONCLUSION: The present study found a high level of agreement between the presence of AST and IL-1beta in GCF in the experimental model of diabetes associated to periodontal disease, elevated when compared with the periodontal disease only model, and both higher when compared to control group.

[Relationship diabetes mellitus-periodontal disease: etiology and risk factors]. / Binomul diabet zaharat-boala parodontala. Factori etiologici si de risc.

The interrelation between diabetes mellitus and inflammatory periodontal disease has been intensively studied for more than 50 years, a real bidirectional influence existing between patient's glycemic level disorder and periodontal territories alteration. Several studies developed in this direction emerged to the evidences that reveal a general increase of prevalence, extent and severity of gingivitis and periodontitis. Inflammation plays an important role in this interrelation, orchestrating both the periodontal disease and diabetes mellitus pathogeny and complications. Conversely, periodontal disease--infectious disease characterized by a significant inflammatory component--can seriously impair metabolic control of some diabetic patient. Moreover, treatment of periodontal disease and reduction of oral signs of inflammation may have a beneficial result on the diabetic condition (1). Less clear are the mechanisms governing this interrelation (even the literature is abundant in this direction), and, very probably, periodontal diseases serve as initiators of insulin resistance (in a way similar to obesity), thereby aggravating glycemic control. Further research is so imposed in order to clarify this aspect of the relationship between diabetes and periodontal disease.