Tunneled catheter-related bacteremia in hemodialysis patients: incidence, risk factors and outcomes. A 14-year observational study.

BACKGROUND: Tunneled catheter-related bacteremia represents one of the major complications in patients on hemodialysis, and is associated with increased morbidity and mortality. This study aimed to evaluate the incidence of tunneled catheter-related bacteremia and, secondly, to identify possible factors involved in the first episode of bacteremia. METHODS: This is a retrospective study of all tunneled catheters inserted between 1 January, 2005 and 31 December, 2019. Data on patients with a tunneled catheter were analyzed for comorbidities, catheter characteristics, microbiological culture results and variables related to the first episode of bacteremia. Patient outcomes were also assessed. RESULTS: In the 14-year period under study, 406 tunneled catheters were implanted in 325 patients. A total of 85 cases of tunneled catheter-related bacteremia were diagnosed, resulting in an incidence of 0.40 per 1000 catheter days (81.1% after 6 months of implantation). The predominant microorganisms isolated were Gram-positive organisms: Staphylococcus epidermidis (48.4%); Staphylococcus aureus (28.0%). We found no significant differences in time to catheter removal for infections or non-infection-related reasons. The jugular vein, the Palindrome® catheter, and being the first vascular access were protective factors for the first episode of bacteremia. The 30-day mortality rate from the first tunneled catheter-related bacteremia was 8.7%. CONCLUSIONS: The incidence of bacteremia in our study was low and did not seem to have a relevant impact on catheter survival. S. epidermidis was the most frequently isolated microorganism, followed by S. aureus. We identified Palindrome® catheter, jugular vein, and being the first vascular access as significant protective factors against tunneled catheter-related bacteremia.

Consensus document for lipid profile testing and reporting in Spanish clinical laboratories.

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports.

Consensus document for lipid profile testing and reporting in Spanish clinical laboratories: What parameters should a basic lipid profile include?

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports.

Consensus document for lipid profile determination and reporting in Spanish clinical laboratories. What parameters should be included in a basic lipid profile? / Documento de consenso para la determinación e informe del perfil lipídico en laboratorios clínicos españoles: ¿Qué parámetros debe incluir un perfil lipídico básico?

Cardiovascular diseases (CVD) continue to be the main cause of death in our country. Adequate control of lipid metabolism disorders is a key challenge in cardiovascular prevention that is far from being achieved in real clinical practice. There is a great heterogeneity in the reports of lipid metabolism from Spanish clinical laboratories, which may contribute to its poor control. For this reason, a working group of the main scientific societies involved in the care of patients at vascular risk, has prepared this document with a consensus proposal on the determination of the basic lipid profile in cardiovascular prevention, recommendations for its realization and unification of criteria to incorporate the lipid control goals appropriate to the vascular risk of the patients in the laboratory reports.

Blockade of interleukin-6 as a possible therapeutic target for AA amyloidosis.

INTRODUCTION: AA (secondary) amyloidosis is a severe complication of chronic inflammatory disorders. It is characterized by the systemic deposition of an abnormal protein called amyloid, affecting mainly renal function. IL-6 is a cytokine with a relevant role in this disease development. Interleukin-receptor antagonists, like Tocilizumab (TCZ), have become possible treatment choice for AA amyloidosis. In published reports, TCZ has shown good efficacy for AA amyloidosis, being associated with regression of renal amyloid deposits. METHODS: Retrospective review that included patients with histological diagnosis of AA renal amyloidosis under treatment with TCZ during the years 2018-2019 in our center. We have registered clinical and demographic variables. Renal function was measured by means of CKD-EPI equation to estimate the glomerular filtration rate (FG) and protein/creatinine ratio (IPC) at 3, 6 and 12 months. We define renal response as a decrease by at least 30% of proteinuria and/or stabilization or improvement of FG. We consider that an anti-inflammatory response is a decrease of more than 50% in serum amyloid protein (PSA) and/or C-reactive protein (CRP). RESULTS: We collected 3 cases of patients with histologically proven AA amyloidosis treated with TCZ (2 men; 1 woman; aged 55, 74 and 75 years). The follow-up was 13, 14 and 75 months. FG was stabilized in two patients. The third patient remained on hemodialysis during follow-up, although with excellent control of her underlying inflammatory disease. In all three cases, reduced PSA and CRP were observed. There have been no adverse events. CONCLUSIONS: The TCZ may be an effective and safe option in treatment of AA amyloidosis with renal involvement. Our results position it as an interesting therapeutic option to consider in these cases, although prospective studies would be necessary to evaluate the global role of TCZ in AA amyloidosis.

Predictive performance and clinical application of COV50, a urinary proteomic biomarker in early COVID-19 infection: a prospective multicentre cohort study.

BACKGROUND: The SARS-CoV-2 pandemic is a worldwide challenge. The CRIT-CoV-U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression from SARS-CoV-2. After the interim analysis presented for the German Government, here, we aimed to analyse the full dataset to consolidate the findings and propose potential clinical applications of this biomarker. METHODS: CRIT-CoV-U was a prospective multicentre cohort study. In eight European countries (Austria, France, Germany, Greece, North Macedonia, Poland, Spain, and Sweden), 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8-point WHO scale. Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling. Statistical methods included logistic regression and receiver operating characteristic curve analysis with a comparison of the area under curve (AUC) between nested models. Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalisation costs adjusted for the gross per capita domestic product of each country. FINDINGS: From June 30 to Nov 19, 2020, 228 participants were recruited, and from April 30, 2020, to April 14, 2021, 784 participants were recruited, resulting in a total of 1012 participants. The entry WHO scores were 1-3 in 445 (44%) participants, 4-5 in 529 (52%) participants, and 6 in 38 (4%) participants; and of all participants, 119 died and 271 had disease progression. The odds ratio (OR) associated with COV50 in all 1012 participants for death was 2·44 (95% CI 2·05-2·92) unadjusted and 1·67 (1·34-2·07) when adjusted for sex, age, BMI, comorbidities, and baseline WHO score; and for disease progression, the OR was 1·79 (1·60-2·01) when unadjusted and 1·63 (1·41-1·91) when adjusted (p<0·0001 for all). The predictive accuracy of the optimised COV50 thresholds was 74·4% (71·6-77·1%) for mortality (threshold 0·47) and 67·4% (64·4-70·3%) for disease progression (threshold 0·04). When adjusted for covariables and the baseline WHO score, these thresholds improved AUCs from 0·835 to 0·853 (p=0·033) for death and from 0·697 to 0·730 (p=0·0008) for progression. Of 196 participants who received ambulatory care, 194 (99%) did not reach the 0·04 threshold. The cost reductions associated with 1 day less hospitalisation per 1000 participants were million Euro (M€) 0·887 (5-95% percentile interval 0·730-1·039) in participants at a low risk (COV50 <0·04) and M€2·098 (1·839-2·365) in participants at a high risk (COV50 ≥0·04). INTERPRETATION: The urinary proteomic COV50 marker might be predictive of adverse COVID-19 outcomes. Even in people with mild-to-moderate PCR-confirmed infections (WHO scores 1-4), the 0·04 COV50 threshold justifies earlier drug treatment, thereby potentially reducing the number of days in hospital and associated costs. FUNDING: German Federal Ministry of Health.

Blockade of interleukin-6 as a possible therapeutic target for AA amyloidosis. / La inhibición de la interleucina-6 como posible diana terapéutica en la amiloidosis AA.

INTRODUCTION: AA (secondary) amyloidosis is a severe complication of chronic inflammatory disorders. It is characterized by the systemic deposition of an abnormal protein called amyloid, affecting mainly renal function. IL-6 is a cytokine with a relevant role in this disease development. Interleukin-receptor antagonists, like Tocilizumab (TCZ), have become possible treatment choice for AA amyloidosis. In published reports, TCZ has shown good efficacy for AA amyloidosis, being associated with regression of renal amyloid deposits. METHODS: Retrospective review that included patients with histological diagnosis of AA renal amyloidosis under treatment with TCZ during the years 2018-2019 in our center. We have registered clinical and demographic variables. Renal function was measured by means of CKD-EPI equation to estimate the glomerular filtration rate (FG) and protein/creatinine ratio (IPC) at 3, 6 and 12 months. We define renal response as a decrease by at least 30% of proteinuria and/or stabilization or improvement of FG. We consider that an anti-inflammatory response is a decrease of more than 50% in serum amyloid protein (PSA) and/or C-reactive protein (CRP). RESULTS: We collected 3 cases of patients with histologically proven AA amyloidosis treated with TCZ (2 men; 1 woman; aged 55, 74 and 75 years). The follow-up was 13, 14 and 75 months. FG was stabilized in two patients. The third patient remained on hemodialysis during follow-up, although with excellent control of her underlying inflammatory disease. In all three cases, reduced PSA and CRP were observed. There have been no adverse events. CONCLUSIONS: The TCZ may be an effective and safe option in treatment of AA amyloidosis with renal involvement. Our results position it as an interesting therapeutic option to consider in these cases, although prospective studies would be necessary to evaluate the global role of TCZ in AA amyloidosis.

[Impact of the COVID-19 pandemic on Spanish Nephrology Services]. / Impacto de la pandemia COVID-19 en los servicios de Nefrología españoles.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has required a rapid and drastic transformation of hospitals, and consequently also of Spanish Nephrology Units, to respond to the critical situation. The Spanish Society of Nephrology conducted a survey directed to the Heads of Nephrology Departments in Spain that addressed the reorganisation of Nephrology departments and activity during the peak of COVID-19 pandemic. The survey has been focused on the integration of nephrologists in COVID-19 teams, nephrology inpatient care activities (elective admissions, kidney biopsies), the performance of elective surgeries such as vascular accesses or implantation of peritoneal catheters, the suspension of kidney transplantation programmes and the transformation of nephrology outpatient clinics. This work details the adaptation and transformation of nephrology services during the COVID-19 pandemic in Spain. During this period, elective admissions to Nephrology Services, elective surgeries and biopsies were suspended, and the kidney transplant programme was scaled back by more than 75%. It is worth noting that outpatient nephrology consultations were carried out largely by telephone. In conclusion, the pandemic has clearly impacted clinical activity in Spanish Nephrology departments, reducing elective activity and kidney transplants, and modifying activity in outpatient clinics. A restructuring and implementation plan in Nephrology focused on telemedicine and/or virtual medicine would seem to be both necessary and very useful in the near future.

Taurolidine as adjuvant treatment of relapsing peritonitis in peritoneal dialysis patients. / Taurolidina como tratamiento adyuvante en casos de peritonitis recidivante en pacientes en diálisis peritoneal.

Relapsing peritonitis in peritoneal dialysis patients is one of the complications that jeopardizes the continuity of the technique. It is often associated with the formation of biofilm in the lumen of the catheter. To date, its removal remains the only recommended attitude. Due to its antimicrobial and antifungal properties, taurolidine has been previously used for the sealing of central line catheters and hemodialysis. Despite the good results obtained, there is no evidence available regarding its utility in peritoneal dialysis. This case report describes the use of taurolidine (TauroLock™HEP500) in 5 patients with relapsing peritonitis after antibiotic treatment completion. Mean follow-up for the detection of recurrences was 13.4 months. In 4 patients with infections caused by Staphylococcus epidermidis, eradication was achieved. In the remaining case, caused by Staphylococcus aureus, the taurolidine seal was ineffective and the removal of the catheter was required.

Advanced Chronic Kidney Disease Units in Spain: a national survey on standards of structure, resources, results and patient safety. / Unidades de Enfermedad Renal Crónica Avanzada en España: una encuesta nacional sobre los estándares de estructura, recursos, resultados y seguridad del paciente.

BACKGROUND AND OBJECTIVE: Recently, the Advanced Chronic Kidney Disease Units (UERCA, in Spanish) have been developed in Spain to offer a better quality of life to patients with advanced chronic kidney disease (ACKD), improving their survival and reducing morbidity in this phase of the disease. Nowadays, there is not much evidence in the Spanish and international literature regarding the structure and how to achieve these objectives in the UERCA. From the ERCA working group of the Spanish Society of Nephrology (SEN), this project is promoted to improve care for ERCA patients through the definition of quality standards for the operation of the UERCA. MATERIAL AND METHODS: An initial proposal for quality standards concerning the operation of the UERCA was configured through consultation with the main sources of references and the advice of an expert working group through face-to-face and telematic meetings. Base on this initial proposal of standards, a survey was conducted and sent it via email to 121 nephrology specialist and nursing professionals with experience in Spanish UERCA to find out, among others, the suitability of each standards, that is, its mandatory nature or recommendation as standards. The access to the survey was allowed between July 16th, 2018, until September 26th, 2018. RESULTS: A total of 95 (78.5%) professionals participated out of the 121 who were invited to participate. Of these, 80 of the participants were nephrology specialists and 15 nursing professionals, obtaining a varied representation of professionals from the Spanish geography. After analyzing the opinions of these participants, the standards were defined to a total of 68, 37 of them (54.4%) mandatory and 31 of them (45.5%) recommended. Besides, it was observed that the volume of patients attended in the UERCA is usually above 100 patients, and the referral criteria is generally below 25-29 mL/min/1.73 m2 of glomerular filtration. CONCLUSIONS: This work constitutes a first proposal of quality standards for the operation of UERCA in Spain. The definition of these standards has made it possible to establish the bases for the standardization of the organization of UERCA, and to subsequently work on the configuration of a standards manual for the accreditation of ERCA Units.

Consensus document for ultrasound training in the specialty of Nephrology. / Documento de consenso para la formación en ecografía en la especialidad de Nefrología.

Ultrasound is an essential tool in the management of the nephrological patient allowing the diagnosis, monitoring and performance of kidney intervention. However, the usefulness of ultrasound in the hands of the nephrologist is not limited exclusively to the ultrasound study of the kidney. By ultrasound, the nephrologist can also optimize the management of arteriovenous fistula for hemodialysis, measure cardiovascular risk (mean intimate thickness), implant central catheters for ultrasound-guided HD, as well as the patient's volemia using basic cardiac ultrasound, ultrasound of the cava inferior vein and lungs. From the Working Group on Interventional Nephrology (GNDI) of the Spanish Society of Nephrology (SEN) we have prepared this consensus document that summarizes the main applications of ultrasound to Nephrology, including the necessary basic technical requirements, the framework normative and the level of training of nephrologists in this area. The objective of this work is to promote the inclusion of ultrasound, both diagnostic and interventional, in the usual clinical practice of the nephrologist and in the Nephrology Services portfolio with the final objective of offering diligent, efficient and comprehensive management to the nephrological patient.

User-centred design for developing e-Health system for renal patients at home (AppNephro).

BACKGROUND: Despite the promising benefits of the e-Health approaches (including provide technology-based healthcare services to anyone, anytime, and anywhere), few solutions are adopted in daily practice. User acceptance is one of the major obstacles that hinder the success of technology approaches. End-users often stress misalignments among their problems and the solutions that technology systems aim to solve. In other cases, systems developed are unfriendly or unadjusted to the daily practice of clinicians or patient's life. To maximize user acceptance, the relevance of adopting user-centred design and development techniques is well-known. However, users are often assumed to be a homogeneous group with the same set of requirements, what leads to an ineffective identification and addressment of user requirements. Furthermore, usability and accessibility issues must be carefully addressed to guarantee also the right alignment of solutions with user needs. OBJECTIVE: to develop an e-Health system for renal patients at home by adopting user-centred design practices, usability and accessibility standards. MATERIAL AND METHODS: users were categorized in four different groups (i.e., digital patients/caregivers, non-digital patients/caregivers, clinicians and nurses) and a sample was included in the design and development team. Questionnaires and interviews were used to identify user requirements and assess prototypes. RESULTS: Requirements were considered for every kind of user, what resulted on a multi-faceted e-Health system implying different technologies and functionalities regarding to each target user. CONCLUSION: Identification and continuous involvement of all kind of users allow their needs to be properly understood and addressed by technology, raising user acceptance of the final product.

The Spanish Society of Nephrology (SENEFRO) commentary to the Spain GBD 2016 report: Keeping chronic kidney disease out of sight of health authorities will only magnify the problem.

The Global Burden of Disease (GBD) study measures the health of populations worldwide and by country on an annual basis and aims at helping guide public policy on health issues. The GBD estimates for Spain in 2016 and recent trends in mortality and morbidity from 2006 to 2016 were recently published. According to these estimates, chronic kidney disease was the 8th cause of death in Spain in 2016. Among the top ten causes of death, chronic kidney disease was the fastest growing from 2006 to 2016, after Alzheimer disease. At the current pace of growth, chronic kidney disease is set to become the second cause of death in Spain, after Alzheimer disease, by 2100. Additionally, among major causes of death, chronic kidney disease also ranked second only to Alzheimer as the fastest growing cause of Years Lived with Disability (YLDs) and Disability Adjusted Life Years (DALYs). Public resources devoted to prevention, care and research on kidney disease should be in line with both its current and future burden.

Thermal disinfection in hemodialysis using the A0 concept as dispenser. / Desinfección térmica en hemodiálisis usando el concepto A0 como dosificador.

Patients with chronic kidney disease in the hemodialysis program are exposed to large amounts of water, as this constitutes about 96% of the dialysis fluid. It is known that the use of better quality water decreases the state of chronic inflammation in dialysis patients. Disinfection as part of water treatment plays an important role in meeting the established quality standards; currently, heat disinfection is highly recommended, however its dose is not clearly established in the literature. The objective of this review is to know what is available in the literature on the dose of heat disinfection that should be used in hemodialysis and to present our experience with this method at a set dose of 12.000 A0.

Advanced chronic renal failure (ACRF) study. Baseline characteristics, evaluation of the application of the structured information for the election of renal replacement therapy and one-year evolution of the incident patients in the ACRF medical office. / Estudio ERCA. Características basales, evaluación de la aplicación de la información estructurada para la elección de tratamiento renal sustitutivo y evolución a un año de los pacientes incidentes en la consulta ERCA.

BACKGROUND AND OBJECTIVES: Analyze evolution Renal Chronic Failure stage 4-5 (ACRF) patients and influence information they receive (educational process, EP) in modality Renal Replacement Therapy (RRT) or conservative treatment (CT) in multidisciplinar ACRF Office. MATERIAL AND METHODS: Prospective, multicenter study (3 centers). Inclusion: from June-01-2014 to October-01-2015; observation: 12 months or until start RRT or death if they occur before 12 months; ends October-01-2016. RESULTS: 336 patients were included (60% males), median and intercuartile rank 71.5 (17), 55% ≥ 70 years; Follow up initiation eGFR CKD-EPI: 21 (9) ml / min / 1.73m2; Charlson Index (ChI) with / without age 8 (3) / 4 (2); Diabetic patients: 52,4%. The EP was carried out in 168, eGFR 15 (10) ml / min / 1.73m2. The initial treatment election: 26% peritoneal dialysis (PD), 45% hemodyalisis (HD), 26% CT, kidney trasplant 3%; 60 patients started RRT: 3.3% kidney traspant; 30% PD, 66% HD; 104 admissions in 73 patients, the most frequent cause: cardiovascular disease (42%). Fallecimiento: 23 patients (6.8%). Age was higher (78.4 (6) vs. 67.8 (13.4), P<.001), higher ChI 9.8 (2.1) vs. 7.4 (2.5), P<.001). All deceased who received EP had chosen CT; 61% of deceased had at least one hospital admission vs. 39% alive (P<0.001). Cox regression: age and Charlson index were the predictive mortality variables. CONCLUSIONS: The population of ACRF patients is elder, comorbid, with high rate hospitalizations rate. The PD election is higher than usual. The EP has been very useful tool and has favored the PD choice.

'Real-life' experience with direct-acting antiviral agents for hepatitis C virus in end-stage renal disease.

BACKGROUND AND AIMS: The advent of direct-acting antiviral agents promises to change the management of hepatitis C in patients with end-stage renal disease, a patient group where the treatment of hepatitis C was historically challenging. We investigated the safety and efficacy of all-oral, interferon-free direct-acting antiviral agents for the treatment of hepatitis C in a 'real-world' group of patients with end-stage renal disease. METHODS: We performed a single-arm, multi-centre study in a cohort (n=30) of patients with advanced chronic kidney disease (mostly on dialysis) who underwent antiviral therapy with direct-acting antiviral agents. The primary end-point was sustained virologic response (serum hepatitis C virus RNA < 15 mIU/mL, 12 weeks after treatment ended). We collected data on on-treatment adverse events, serious adverse events and laboratory abnormalities. RESULTS: In total, 23 (77%) and 7 (23%) patients underwent regular dialysis and had chronic kidney disease at pre-dialysis stage, respectively. Six regimens were adopted: elbasvir/grazoprevir ( n = 6), ledipasvir/sofosbuvir ± ribavirin ( n = 4), PrOD regimens ± ribavirin ( n = 10), simeprevir + daclatasvir ( n = 3), sofosbuvir + daclatasvir ± ribavirin ( n = 3), sofosbuvir + ribavirin ( n = 4). The SVR12 rate was 90% (95% confidence interval, 74%; 96%). A total of 27 (90%) patients achieved SVR12; there were three virologic failures - two were non-responders and one had a viral breakthrough while on therapy. Adverse events occurred in 53% (16/30) (95% confidence interval, 0.39; 0.73) of patients and were managed clinically without discontinuation of therapy or hospitalization. The most common adverse event was anaemia ( n = 12) that required blood transfusions in seven individuals; deterioration of kidney function occurred in one (14%). CONCLUSION: All-oral, interferon-free therapy with direct-acting antiviral agents for chronic hepatitis C virus in advanced chronic kidney disease was effective and well tolerated in a 'real-life' clinical setting. Careful monitoring of haemoglobin and serum creatinine during therapy with direct-acting antiviral agents is suggested. Studies are under way to address whether sustained viral response translates into better survival in this population.

Does the Kidney Donor Profile Index (KDPI) predict graft and patient survival in a Spanish population? / ¿Predice el Kidney Donor Profile Index (KDPI) la supervivencia del injerto y del paciente en una población española?

BACKGROUND AND OBJECTIVE: The Kidney Donor Profile Index (KDPI), together with other donor and recipient variables, can optimise the organ allocation process. This study aims to check the feasibility of the KDPI for a Spanish population and its predictive ability of graft and patient survival. MATERIALS AND METHODS: Data from 2,734 kidney transplants carried out in Andalusia between January 2006 and December 2015 were studied. Cases were grouped by recipient age, categorised by KDPI quartile and both graft and patient survival were compared among groups. RESULTS: The KDPI accurately discriminated optimal organs from suboptimal or marginal ones. For adult recipients (aged: 18-59years) it presents a hazard ratio of 1.013 (P<.001) for death-censored graft survival and of 1.013 (P=.007) for patient survival. For elderly recipients (aged: 60+years), KDPI presented a hazard ratio of 1.016 (P=.001) for death-censored graft survival and of 1.011 (P=.007) for patient survival. A multivariate analysis identified the KDPI, donor age, donation after circulatory death, recipient age and gender as predictive factors of graft survival. CONCLUSIONS: The results obtained show that the KDPI makes it possible to relate the donor's characteristics with the greater or lesser survival of the graft and the patient in the Spanish population. However, due to certain limitations, a new index for Spain based on Spanish or European data should be created. In this study, some predictive factors of graft survival are identified that may serve as a first step in this path.