Improving diagnosis and treatment of hypomagnesemia.

Magnesium is one of the most abundant cations in the body and acts as a cofactor in more than 600 biochemical reactions. Hypomagnesemia is a highly prevalent condition, especially in subjects with comorbid conditions, but has received less attention than other electrolyte disturbances. This review will discuss magnesium physiology, absorption, storage, distribution across the body, and kidney excretion. After reviewing the regulation of magnesium homeostasis, we will focus on the etiology and clinical presentation of hypomagnesemia. The role of laboratory medicine in hypomagnesemia will be the main purpose of this review, and we will discuss the laboratory tests and different samples and methods for its measurement. Although free magnesium is physiologically active, total serum magnesium is the most commonly used measurement in laboratory medicine and is apt for clinical purposes; however, it is not appropriately used, and many patients with hypomagnesemia remain undiagnosed and not treated. Using information technologies, laboratory medicine can largely improve the diagnosis and treatment of hypomagnesemia through the design and establishment of automatic demand management and result management interventions by acting in the first and last steps of the laboratory cycle, test requests, and actions taken after test results, to unmask patients with hypomagnesemia and improve the number of patients undergoing treatment.

Clinical Decision Support System in laboratory medicine.

Clinical Decision Support Systems (CDSS) have been implemented in almost all healthcare settings. Laboratory medicine (LM), is one of the most important structured health data stores, but efforts are still needed to clarify the use and scope of these tools, especially in the laboratory setting. The aim is to clarify CDSS concept in LM, in the last decade. There is no consensus on the definition of CDSS in LM. A theoretical definition of CDSS in LM should capture the aim of driving significant improvements in LM mission, prevention, diagnosis, monitoring, and disease treatment. We identified the types, workflow and data sources of CDSS. The main applications of CDSS in LM were diagnostic support and clinical management, patient safety, workflow improvements, and cost containment. Laboratory professionals, with their expertise in quality improvement and quality assurance, have a chance to be leaders in CDSS.

HDL Function and Size in Patients with On-Target LDL Plasma Levels and a First-Onset ACS.

Patients admitted for acute coronary syndrome (ACS) usually have high cardiovascular risk scores with low levels of high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels. Here, we investigated the role of lipoprotein functionality as well as particle number and size in patients with a first-onset ACS with on-target LDL-C levels. Ninety-seven patients with chest pain and first-onset ACS with LDL-C levels of 100 ± 4 mg/dL and non-HDL-C levels of 128 ± 4.0 mg/dL were included in the study. Patients were categorized as ACS and non-ACS after all diagnostic tests were performed (electrocardiogram, echocardiogram, troponin levels and angiography) on admission. HDL-C and LDL-C functionality and particle number/size by nuclear magnetic resonance (NMR) were blindly investigated. A group of matched healthy volunteers (n = 31) was included as a reference for these novel laboratory variables. LDL susceptibility to oxidation was higher and HDL-antioxidant capacity lower in the ACS patients than in the non-ACS individuals. ACS patients had lower HDL-C and Apolipoprotein A-I levels than non-ACS patients despite the same prevalence of classical cardiovascular risk factors. Cholesterol efflux potential was impaired only in the ACS patients. ACS-STEMI (Acute Coronary Syndrome-ST-segment-elevation myocardial infarction) patients, had a larger HDL particle diameter than non-ACS individuals (8.4 ± 0.02 vs. 8.3 ± 0.02 and, ANOVA test, p = 0.004). In conclusion, patients admitted for chest pain with a first-onset ACS and on-target lipid levels had impaired lipoprotein functionality and NMR measured larger HDL particles. This study shows the relevance of HDL functionality rather than HDL-C concentration in ACS patients.

The clinical laboratory: a decision maker hub.

OBJECTIVES: We aimed to share a new laboratory model based on laboratory knowledge, meaningful use of information technology, and partnership with clinicians, to lead the appropriate use of laboratory testing and clinical decision making in the diagnosis of as-yet-undiagnosed disease. More specifically, we evaluate the role of eight different opportunistic interventions to diagnose certain asymptomatic disorders, by means of the automatic registration of appropriate laboratory testing according to different scenarios. METHODS: This is a retrospective longitudinal study to evaluate the impact of laboratory interventions on the diagnosis of different diseases and on patient care, including data from January 2012 to September 2020. RESULTS: Overall, the above strategies have so far identified 2063 patients with clinically relevant as-yet-undiagnosed disorders who would have otherwise remained occult, such as for instance, primary hyperparathyroidism, diabetes, and hypomagnesemia. CONCLUSIONS: We are facing a new laboratory model, a leading laboratory rather than a passive traditional laboratory, not just to intervene in clinical decision-making, but to make the clinical decision, through the identification of patients with occult disease.

Treatment of Locally Advanced Cervical Cancer With Kidney Failure and Comorbidities.

A woman aged 63 years presented at the gynecological oncology outpatient clinic with the following medical history: smoking history (smoking index of 10); systemic arterial hypertension diagnosed 6 years ago; menarche at 16 years; menopause at 52 years; 4 pregnancies, 4 deliveries; beginning of active sexual life at 18 years; 3 sexual partners; and no early cancer detection method in her life. Her performance status per ECOG criteria was 1. The patient presented with transvaginal bleeding with 5 months of evolution. Upon physical exploration, a 5 x 5 cm tumor in the cervix was detected, with the following characteristics: exophytic, friable, bleeding, with invasion to the lower third of the vagina, affection to the cul-de-sac and parametria, and bilaterally fixed to the pelvic wall. A biopsy of the cervix showed moderately differentiated invasive squamous cell carcinoma.

Sjögren Syndrome Induced by Immune Checkpoint Inhibitors in a Patient with Advanced Renal Cell Carcinoma.

This clinical quandary details a Mexican man, aged 77 years, who presented to the oncology clinic with a sternal mass. Based on the results, the patient fulfilled the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for Sjögren syndrome, thus the diagnosis triggered by immune checkpoint inhibitors was definitively established.

High frequency of anti-parietal cell antibody (APCA) and intrinsic factor blocking antibody (IFBA) in individuals with severe vitamin B12 deficiency - an observational study in primary care patients.

Background Vitamin B12 deficiency is common worldwide and is also linked to several diseases including autoimmune atrophic gastritis (AAG). The presence of anti-parietal cell antibodies (APCA) and/or intrinsic factor blocking antibodies (IFBA) is indicative of AAG that may develop into pernicious anemia. Both conditions are known to be associated with an increased risk of gastric carcinoma. The aim of this study was to estimate the frequency of individuals positive for APCA and IFBA antibodies in primary care patients with severe vitamin B12 deficiency. Methods An observational study was designed and 5468 consecutive patients from primary care with a request for vitamin B12 status were included and add-on testing for APCA and IFBA that were automatically registered if severe vitamin B12 deficiency was identified (<73.8 pmol/L). For patients included in the intervention, study demographic data, mean corpuscular volume (MCV) and hemoglobin values were collected. Results Seventy-seven patients with severe vitamin B12 deficiency were identified and out of these 44 (57%) presented with antibodies to APCA and 11 (14%) to IFBA, 25 (32.5%) had anemia, and 25 (32.5%) had macrocytosis. The majority of APCA and/or IFBA positive patients were found in the age group >70 years. Both anemia and macrocytosis were more common among APCA positive patients but the association was not statistically significant, neither was the correlation between IFBA status and anemia and/or macrocytosis. Among the patients with anemia, 10 (39%) had macrocytosis, although the rate of macrocytosis among patients with or without anemia did not differ significantly. Conclusions The automated analysis strategy of measuring antibodies to APCA and IFBA in patients with severe vitamin B12 deficiency, efficiently detected positivity in more than 60% the patients. The result point to the presence of a high rate of otherwise undetected AAG and the potential clinical utility of APCA and IFBA as markers in primary care.

Urinary albumin strip assay as a screening test to replace quantitative technology in certain conditions.

Background The clinical laboratory plays a crucial role in the diagnosis and monitoring of chronic kidney disease. The quantitative measurement of urine albumin in a spot sample, expressed as ratio per creatinine (ACR) is the most frequently used biomarker for such a purpose. Our aim was to evaluate the diagnostic performances of a strip for measuring ACR for differentiating patients who are candidates for subsequent albumin quantification, and to evaluate the economic effects of its implementation. Methods We systematically measured strip analysis when quantitative urinary albumin was requested. Semiquantitative urinary albumin was measured using a UC-3500 (Sysmex, Kobe, Japan), based on the protein error of a pH indicator. We collected and reviewed all the values of quantified urinary albumin and their corresponding results in ACR strip tests. We calculated the diagnostic indicators for ACR at different albumin and creatinine values using the quantitative ACR measurement as a "gold standard". We also studied the economic effects based on both tests prices (€1.31 for quantitative albumin plus creatinine, and €0.04 for an albumin strip). Results The study included 9148 patients (mean age 63, 46.3% men). The results at different albumin and creatinine cutoffs showed the best performance when 10 mg/L and above 50 mg/dL, respectively. Based on our results, we would have saved 3506 urine albumin and creatinine tests in the study period, corresponding to €4226.94. Conclusions The present study supports the use of the ACR strip test to identify pathological albuminuria values to be measured through quantitative methods. Considerable economic savings are possible.

Computer-assisted interventions in the clinical laboratory process improve the diagnosis and treatment of severe vitamin B12 deficiency.

BACKGROUND: Severe vitamin B12 deficiency can result in serious complications if undiagnosed or untreated. Our aim was to test the efficacy of interventions in the laboratory process to improve the detection and the treatment of severe vitamin B12 deficiency. METHODS: Quasi-experimental investigation with a retrospective 7-year pre-intervention period and 29-month post-intervention follow-up in a university hospital. Two interventions were designed to improve the detection and treatment of subjects with vitamin B12 deficiency: the laboratory information system (LIS) automatically added seru vitamin B12 (s-vitamin B12) based on certain conditions; and created a comment in the report and scheduled an appointment with the general practitioner (GP). We calculated the number of new diagnoses of severe vitamin deficiency (s-vitamin B12 <73.8 pmol/L) and the proportion of identified patients that were correctly treated in the pre- and post-intervention periods. We compared the number of tests needed to detect a new case when ordered by GPs vs. added by the strategy. Finally, we investigated the economic cost of each new case. RESULTS: The strategy added 699 s-vitamin B12 and detected 66 new cases of severe vitamin deficiency. The number of tests needed to identify a new case when s-vitamin B12 was ordered by GPs was 187, as opposed to 10 when added through the intervention (p<0.001). The intervention reagent cost was €26.7 per new case. In the post-intervention cohort, 88% of patients were correctly treated, as opposed to 52% in the pre-intervention (p<0.001). CONCLUSIONS: Interventions in the clinical laboratory process improved the diagnosis and treatment of severe vitamin B12 deficiency.

Request Pattern, Pre-Analytical and Analytical Conditions of Urinalysis in Primary Care: Lessons from a One-Year Large-Scale Multicenter Study.

BACKGROUND: To study the urinalysis request, pre-analytical sample conditions, and analytical procedures. METHODS: Laboratories were asked to provide the number of primary care urinalyses requested, and to fill out a questionnaire regarding pre-analytical conditions and analytical procedures. RESULTS: 110 laboratories participated in the study. 232.5 urinalyses/1,000 inhabitants were reported. 75.4% used the first morning urine. The sample reached the laboratory in less than 2 hours in 18.8%, between 2 - 4 hours in 78.3%, and between 4 - 6 hours in the remaining 2.9%. 92.5% combined the use of test strip and particle analysis, and only 7.5% used the strip exclusively. All participants except one performed automated particle analysis depending on strip results; in 16.2% the procedure was only manual. CONCLUSIONS: Urinalysis was highly requested. There was a lack of compliance with guidelines regarding time between micturition and analysis that usually involved the combination of strip followed by particle analysis.

Glycated hemoglobin: A powerful tool not used enough in primary care.

BACKGROUND: Glycated haemoglobin (HbA1c) is one of the most useful and relevant laboratory tests currently available. The aim of the actual research was to study the variability and appropriateness in the request of HbA1c in primary care, and differences between regions, to assess if there would be an opportunity to improve the request. METHODS: A cross-sectional study was conducted enrolling clinical Spanish laboratories. The number of HbA1c requested in 2014 by all general practitioners was reported by each participant. Test-utilization rate was expressed as tests per 1000 inhabitants. The index of variability was calculated, as the top decile divided by the bottom decile. HbA1c per 1000 inhabitants was compared between the different regions. To investigate whether HbA1c was appropriately requested to manage patients with diabetes, the real request was compared to the theoretically ideal number, according to prevalence of known diabetes mellitus in Spain and guideline recommendations. RESULTS: A total of 110 laboratories participated in the study, corresponding to a catchment area of 27 798 262 inhabitants (59.8% of the Spanish population) from 15 different autonomous communities (AACCs). 2 655 547 HbA1c were requested, a median of 93.9 (interquartile range (IQR): 33.4) per 1000 inhabitants. The variability index was 1.97. The HbA1c/1000 inhabitants was significantly different among the AACCs, ranging from 73.4 to 126.3. A total of 4 336 529 additional HbA1c would have been necessary to manage patients with diabetes according to guidelines, and 3 861 769 for diagnosis in asymptomatic patients. CONCLUSIONS: There was a high variability and significant differences between Spanish AACCs. Also a significant under-request of HbA1c was observed in Primary Care in Spain.

Temporal and regional variability in the request of vitamin D from general practitioners in Spain.

BACKGROUND: Our main goal is to study the inter-practice regional variability and the temporal evolution in the request of 25-hydroxyvitamin D (25[OH]D) by general practitioners (GPs) in Spain. METHODS: Clinical laboratories in different autonomic communities (AACCs) were invited to report the number of 25(OH)D test requested by GPs during 2012 and 2014. The number of 25(OH)D requested per 1000 inhabitants and the index of variability were calculated, and compared between regions and time periods. We calculated the number of tests that could have been potentially saved in regions where 25(OH)D could be requested from primary care without restrictions taking into account the request in those where it is restricted, and the potential economical savings. RESULTS: Seventy-six laboratories participated in the 2012 edition, and 110 in 2014, corresponding to 17,679,195 and 27,798,262 inhabitants (59.8% Spanish population). The number of 25(OH)D requested per 1000 inhabitants increased from 1.1 in 2012 to 3.4 in 2014 (p<0.001). The variability index also increased from 51.7 to 68. There was a significantly variability among the different AACCs, ranging from 0.94 to 21.24 (p=0.002). 173,885 tests could have been not measured from primary care in regions without ordering restrictions, resulting in potential 886,813.5€ savings. CONCLUSIONS: There was a high variability in the request of 25(OH)D by GPs in Spain, which significantly increased in a 2 year period. The demand was higher in areas where the request of 25(OH)D was not restricted in primary care, with potential savings if the request would approach to regions with ordering restrictions.

Uncritical Request of Thyroid Laboratory Tests May Result in a Major Societal Economic Burden: Results from a Large Population Study in Spain.

BACKGROUND: Our aim is to study the regional variability in the request of thyroid laboratory tests from primary care facilities in Spain and to investigate a potential inappropriate request and its economic societal impact. METHODS: Spain is divided into 17 autonomous communities (AACCs) which are in turn divided in Health Departments that cover a geographic area and its population and a laboratory that attends the needs of every inhabitant. Each participating laboratory was required to report the number of thyroid tests requested from primary care during year 2014 and to provide organizational data. The request of every test per 1000 inhabitants and ratio of related tests (free thyroxine (FT4)/thyrotropin (TSH), triiodothironine (FT3)/TSH, antithyroglobulin antibody (ATG)/antiperoxidase antibody (TPO)) were calculated and compared in different AACCs with more than 4 participants. The economic costs taking into account reagent cost were calculated. RESULTS: 110 laboratories participated (27,798,262 inhabitants). Close to 6 million TSH tests were requested, representing an expense of more than 10 million euros. That corresponds to 18 million euros when extrapolating for the whole Spanish population, only in reagent cost. The number of TSH requests per 1000 inhabitants in the different AACCs ranged from 198 to 289. FT4 was ordered more than twice as frequently in some regions compared to others. TPO request per 1000 inhabitants ranged from 0.2 to 11.2. CONCLUSIONS: There was a significant over-request and regional variability of thyroid laboratory tests in primary care in Spain, resulting in a high economic impact on society.

Clinical and immunological characteristics of a pediatric population with food protein-induced enterocolitis syndrome (FPIES) to fish.

BACKGROUND: Food protein-induced enterocolitis (FPIES) is an uncommon, non-IgE-mediated food allergy that usually debuts in infancy with profuse vomiting, lethargy, and pallor 2-4 h following ingestion of the offending food. Its immune mechanism is not known. We aimed to describe the clinical features and outcome of children with fish-FPIES as well as to investigate on cellular immune response implicated. METHODS: Prospective and follow-up clinical study of children with FPIES by fish over a period between 2004 and 2013 was conducted. Measurement in vitro of both cytokine production in peripheral blood mononuclear cells (PBMCs) and expression of HLA-DR in monocyte-derived dendritic cells stimulated with fish extracts. RESULTS: Sixteen children (seven male and nine female) were included, with a mean age of onset at 10 months. Diagnosis was established after a median of 4 reactions. Twelve patients were treated in emergency room, and two were admitted in intensive care. Patch tests were positive in six patients. Skin prick tests (SPTs) and specific IgE to all fish tested were negative. Only three children reached tolerance at a mean age of 4.5 years. Eight children avoided fish because of positive oral food challenge (OFC) after 6 years of age. Other patients have not been challenged because of parent refusal to OFC or a recent diagnosis. TNF-α was increased in patients, and a significant elevation of the HLA-DR marker was also observed in these patients vs. control donors. CONCLUSIONS: FPIES caused by fish in many cases presents with severe clinical manifestations. Patch test has poor diagnostic value, and OFC is the gold standard to test tolerance. The cytokine TNF-α may be implicated in the clinical symptoms. Higher expression of HLA-DR in dendritic cells has also been detected in our patients.

Requests of laboratory tests for the diagnosis and management of calcium-phosphate disorders in Spain.

BACKGROUND: Knowledge about the variability in the request of calcium-phosphate metabolism laboratory tests in primary care is important to design strategies to improve health system efficiency. AIM: To compare the inter-practice variability in calcium-phosphate metabolism laboratory tests requested by general practitioners from diverse regions across Spain. MATERIAL AND METHODS: One hundred and forty one clinical laboratories were invited to participate in an observational cross-sectional study. They informed the number of serum calcium, phosphate, parathyroid hormone and 25-hydroxyvitamin D requested by general practitioners. Appropriateness indicators were calculated as number of test requests per 1,000 inhabitants and ratio of related tests requests. The differences according to hospital setting, region and type of management were analyzed. RESULTS: We recruited 76 laboratories (17,679,195 inhabitants). General practitioners requested 3,260,894 calcium-phosphate metabolism tests. The rate of request ranged from 2.97 per 1,000 inhabitants for 25-hydroxyvitamin D to 98.89 per 1,000 inhabitants for calcium. The rates of request for calcium, phosphate, parathyroid hormone in some areas were 30, 100 and 340 times higher than in other areas. Parathyroid hormone and 25-hydroxyvitamin D were highly requested in private management areas. There were also differences in phosphate, parathyroid hormone and 25-hydroxyvitamin D requesting between regions across Spain. CONCLUSIONS: The high variability observed is difficult to explain by differences in patient case mix between regions. Depending on the area, calcium could be under requested to detect primary hyperparathyroidism.

Double positivity for rheumatoid factor and anti-CCP autoantibodies: improving referral from primary care of patients suspected of having rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic progressive autoimmune inflammatory disease with significant morbidity and mortality. The course of the disease can be modified if diagnosis is early and treatment appropriate. AIM: In this study, we aimed to evaluate a new strategy for early identification of RA patients in primary care settings (the 'diagnostic bottleneck') based on serological biomarkers and to manage inappropriate rheumatoid factor (RF) laboratory test requests. METHOD: A two-arm study was carried out. The first arm corresponded to a retrospective observational descriptive study of patients referred for RF testing from primary care using the current laboratory workflow. The second arm included the following prospective interventions: cancelation of RF requests corresponding to patients with previous negative results for RF over a one-year period; and automatic reflex testing antibodies against cyclic citrullinated proteins (anti-CCP) for patients displaying RF values >30 IU/ml. Outcomes from both arms were then compared. FINDINGS: As double positivity for RF and anti-CCP notably increases the positive likelihood ratio of RA. The intervention enabled a reduction of 2813 tests in 22 months. Moreover, the frequency of unnecessary referrals was reduced from 22% to 8.2%, while that of missed patients decreased slightly (from 21% to 16%), with the number of patients diagnosed per RF request remaining unchanged. In terms of costs, we saved 19.4 RF tests per anti-CCP test added.We developed a simple and cost-effective strategy for reducing the time to diagnosis of RA that can improve patients' quality of life. This approach was supported by primary and specialised care.

Management of procalcitonin test overuse in an emergency department through a computer algorithm.

OBJECTIVES: To show the procalcitonin (PCT) test demand from an emergency department (ED) over several years, to decrease PCT measurement via a computerized algorithm based on C-reactive protein (CRP) value, and to evaluate the subsequent economic savings. STUDY DESIGN: A cross-sectional study was performed from January 1, 2018, to May 31, 2019, to evaluate an intervention to avoid PCT measurement in the ED of Hospital Universitario San Juan in Alicante in Spain, when CRP values are low. METHODS: A PCT result of at least 1.5 ng/mL was agreed upon with ED providers in our study as the value for clinical decision-making, with values less than 1.5 ng/mL considered negative. We retrospectively reviewed all PCT and CRP values for ED patients and calculated the diagnostic indicators for PCT at 4 different CRP cutoffs using the PCT quantification as the gold standard. From July 1, 2019, to April 30, 2021, the agreed-upon strategy was implemented, and we counted the PCT tests avoided and calculated the savings. RESULTS: PCT was not measured when CRP values were less than the selected CRP cutoff of 0.8 mg/dL, at which false-negative results were 1% and the 99th percentile of PCT was 1.5 ng/mL. In the postintervention period, 1091 PCT values were not measured and $11,553.69 was saved. CONCLUSIONS: An intervention to decrease PCT measurement in the ED designed by the clinical laboratory staff in consensus with requesting clinicians and based on CRP values decreased PCT testing and generated significant economic savings.

Metformin treatment reduces inflammation, dysmyelination and disease severity in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation, death or damage of oligodendrocytes, and axonal degeneration. Current MS treatments are non-curative, associated with undesired side-effects, and expensive, highlighting the need for expanded therapeutic options for patients. There is great interest in developing interventions using drugs or therapeutics to reduce symptom onset and protect pre-existing myelin. Metformin is a well-tolerated drug used to treat Type 2 diabetes that has pleiotropic effects in the central nervous system (CNS), including reducing inflammation, enhancing oligodendrogenesis, increasing the survival/proliferation of neural stem cells (NSCs), and increasing myelination. Here, we investigated whether metformin administration could improve functional outcomes, modulate oligodendrocyte precursor cells (OPCs), and reduce inflammation in a well-established mouse model of MS- experimental autoimmune encephalomyelitis (EAE). Male and female mice received metformin treatment at the time of EAE induction ("acute") or upon presentation of disease symptoms ("delayed"). We found that acute metformin treatment improved functional outcomes, concomitant with reduced microglia numbers and decreased dysmyelination. Conversely, delayed metformin treatment did not improve functional outcomes. Our findings reveal that metformin administration can improve EAE outcomes when administered before symptom onset in both sexes.