Cost-effectiveness of incorporating Ebola prediction score tools and rapid diagnostic tests into a screening algorithm: A decision analytic model.

BACKGROUND: No distinctive clinical signs of Ebola virus disease (EVD) have prompted the development of rapid screening tools or called for a new approach to screening suspected Ebola cases. New screening approaches require evidence of clinical benefit and economic efficiency. As of now, no evidence or defined algorithm exists. OBJECTIVE: To evaluate, from a healthcare perspective, the efficiency of incorporating Ebola prediction scores and rapid diagnostic tests into the EVD screening algorithm during an outbreak. METHODS: We collected data on rapid diagnostic tests (RDTs) and prediction scores' accuracy measurements, e.g., sensitivity and specificity, and the cost of case management and RDT screening in EVD suspect cases. The overall cost of healthcare services (PPE, procedure time, and standard-of-care (SOC) costs) per suspected patient and diagnostic confirmation of EVD were calculated. We also collected the EVD prevalence among suspects from the literature. We created an analytical decision model to assess the efficiency of eight screening strategies: 1) Screening suspect cases with the WHO case definition for Ebola suspects, 2) Screening suspect cases with the ECPS at -3 points of cut-off, 3) Screening suspect cases with the ECPS as a joint test, 4) Screening suspect cases with the ECPS as a conditional test, 5) Screening suspect cases with the WHO case definition, then QuickNavi™-Ebola RDT, 6) Screening suspect cases with the ECPS at -3 points of cut-off and QuickNavi™-Ebola RDT, 7) Screening suspect cases with the ECPS as a conditional test and QuickNavi™-Ebola RDT, and 8) Screening suspect cases with the ECPS as a joint test and QuickNavi™-Ebola RDT. We performed a cost-effectiveness analysis to identify an algorithm that minimizes the cost per patient correctly classified. We performed a one-way and probabilistic sensitivity analysis to test the robustness of our findings. RESULTS: Our analysis found dual ECPS as a conditional test with the QuickNavi™-Ebola RDT algorithm to be the most cost-effective screening algorithm for EVD, with an effectiveness of 0.86. The cost-effectiveness ratio was 106.7 USD per patient correctly classified. The following algorithms, the ECPS as a conditional test with an effectiveness of 0.80 and an efficiency of 111.5 USD per patient correctly classified and the ECPS as a joint test with the QuickNavi™-Ebola RDT algorithm with an effectiveness of 0.81 and a cost-effectiveness ratio of 131.5 USD per patient correctly classified. These findings were sensitive to variations in the prevalence of EVD in suspected population and the sensitivity of the QuickNavi™-Ebola RDT. CONCLUSIONS: Findings from this study showed that prediction scores and RDT could improve Ebola screening. The use of the ECPS as a conditional test algorithm and the dual ECPS as a conditional test and then the QuickNavi™-Ebola RDT algorithm are the best screening choices because they are more efficient and lower the number of confirmation tests and overall care costs during an EBOV epidemic.

Refining Timely Diagnosis of Early Syphilis by Using Treponema pallidum PCR or IgM Immunoblotting Next to Conventional Serology for Syphilis.

Treponema pallidum subsp. pallidum is a fastidious spirochete and the etiologic agent of syphilis, a sexually transmitted infection (STI). Syphilis diagnoses and disease staging are based on clinical findings and serologic testing. Moreover, according to most international guidelines, PCR analysis of swab samples from genital ulcers is included in the screening algorithm where possible. It has been suggested that PCR might be omitted from the screening algorithm due to low added value. As an alternative to PCR, IgM serology might be used. In this study, we wanted to establish the added value of PCR and IgM serology for diagnosing primary syphilis. Added value was defined as finding more cases of syphilis, preventing overtreatment, or limiting the extent of partner notification to more recent partners. We found that both PCR and IgM immunoblotting could aid the timely diagnosis of early syphilis in ~24% to 27% of patients. PCR has the greatest sensitivity and can be applied to cases with an ulcer with suspected reinfection or primary infection. In the absence of lesions, the IgM immunoblot could be used. However, the IgM immunoblot has better performance in cases with suspected primary infection than in reinfections. The target population, testing algorithm, time pressures, and costs should determine whether either test provides sufficient value to be implemented in clinical practice.

Portable and cost-effective genetic detection and characterization of Plasmodium falciparum hrp2 using the MinION sequencer.

The prevalence of Plasmodium falciparum hrp2 (pfhrp2)-deleted parasites threatens the efficacy of the most used and sensitive malaria rapid diagnostic tests and highlights the need for continued surveillance for this gene deletion. While PCR methods are adequate for determining pfhrp2 presence or absence, they offer a limited view of its genetic diversity. Here, we present a portable sequencing method using the MinION. Pfhrp2 amplicons were generated from individual samples, barcoded, and pooled for sequencing. To overcome potential crosstalk between barcodes, we implemented a coverage-based threshold for pfhrp2 deletion confirmation. Amino acid repeat types were then counted and visualized with custom Python scripts following de novo assembly. We evaluated this assay using well-characterized reference strains and 152 field isolates with and without pfhrp2 deletions, of which 38 were also sequenced on the PacBio platform to provide a standard for comparison. Of 152 field samples, 93 surpassed the positivity threshold, and of those samples, 62/93 had a dominant pfhrp2 repeat type. PacBio-sequenced samples with a dominant repeat-type profile from the MinION sequencing data matched the PacBio profile. This field-deployable assay can be used alone for surveilling pfhrp2 diversity or as a sequencing-based addition to the World Health Organization's existing deletion surveillance protocol.

Fitness Costs of pfhrp2 and pfhrp3 Deletions Underlying Diagnostic Evasion in Malaria Parasites.

BACKGROUND: Rapid diagnostic tests based on detection of histidine-rich proteins (HRPs) are widely used for malaria diagnosis, but parasites carrying pfhrp deletions can evade detection and are increasing in frequency in some countries. Models aim to predict conditions under which pfhrp2 and/or pfhrp3 deletions will increase, but a key parameter-the fitness cost of deletions-is unknown. METHODS: We removed pfhrp2 and/or pfhrp3 from a Malawian parasite clone using gene editing approaches) and measured fitness costs by conducting pairwise competition experiments. RESULTS: We observed significant fitness costs of 0.087 ± 0.008 (1 standard error) per asexual cycle for pfhrp2 deletion and 0.113 ± 0.008 for the pfhrp2/3 double deletion, relative to the unedited progenitor parasite. Selection against deletions is strong and comparable to that resulting from drug resistance mutations. CONCLUSIONS: Prior modeling suggested that diagnostic selection may drive increased frequency of pfhrp deletions only when fitness costs are mild. Our experiments show that costs of pfhrp deletions are higher than these thresholds, but modeling and empirical results can be reconciled if the duration of infection is short. These results may inform future modeling to understand why pfhrp2/3 deletions are increasing in some locations (Ethiopia and Eritrea) but not in others (Mekong region).

Price, quality, and market dynamics of malaria rapid diagnostic tests: analysis of Global Fund 2009-2018 data.

BACKGROUND: Rapid diagnostic tests (RDTs) for malaria are a vital part of global malaria control. Over the past decade, RDT prices have declined, and quality has improved. However, the relationship between price and product quality and their larger implications on the market have yet to be characterized. This analysis used purchase data from the Global Fund together with product quality data from the World Health Organization (WHO) and Foundation for Innovative New Diagnostics (FIND) Malaria RDT Product Testing Programme to understand three unanswered questions: (1) Has the market share by quality of RDTs in the Global Fund's procurement orders changed over time? (2) What is the relationship between unit price and RDT quality? (3) Has the market for RDTs financed by the Global Fund become more concentrated over time? METHODS: Data from 10,075 procurement transactions in the Global Fund's database, which includes year, product, volume, and price, was merged with product quality data from all eight rounds of the WHO-FIND programme, which evaluated 227 unique RDT products. To describe trends in market share by quality level of RDT, descriptive statistics were used to analyse trends in market share from 2009 to 2018. A generalized linear regression model was then applied to characterize the relationship between price and panel detection score (PDS), adjusting for order volume, year purchased, product type, and manufacturer. Third, a Herfindahl-Hirschman Index (HHI) score was calculated to characterize the degree of market concentration. RESULTS: Lower-quality RDTs have lost market share between 2009 and 2018, as have the highest-quality RDTs. No statistically significant relationship between price per test and PDS was found when adjusting for order volume, product type, and year of purchase. The HHI was 3,570, indicating a highly concentrated market. CONCLUSIONS: Advancements in RDT affordability, quality, and access over the past decade risk stagnation if health of the RDT market as a whole is neglected. These results suggest that from 2009 to 2018, this market was highly concentrated and that quality was not a distinguishing feature between RDTs. This information adds to previous reports noting concerns about the long-term sustainability of this market. Further research is needed to understand the causes and implications of these trends.

Automated assessment of Ki-67 proliferation index in neuroendocrine tumors by deep learning.

The Ki-67 proliferation index (PI) is a prognostic factor in neuroendocrine tumors (NETs) and defines tumor grade. Analysis of Ki-67 PI requires calculation of Ki-67-positive and Ki-67-negative tumor cells, which is highly subjective. To overcome this, we developed a deep learning-based Ki-67 PI algorithm (KAI) that objectively calculates Ki-67 PI. Our study material consisted of NETs divided into training (n = 39), testing (n = 124), and validation (n = 60) series. All slides were digitized and processed in the Aiforia® Create (Aiforia Technologies, Helsinki, Finland) platform. The ICC between the pathologists and the KAI was 0.89. In 46% of the tumors, the Ki-67 PIs calculated by the pathologists and the KAI were the same. In 12% of the tumors, the Ki-67 PI calculated by the KAI was 1% lower and in 42% of the tumors on average 3% higher. The DL-based Ki-67 PI algorithm yields results similar to human observers. While the algorithm cannot replace the pathologist, it can assist in the laborious Ki-67 PI assessment of NETs. In the future, this approach could be useful in, for example, multi-center clinical trials where objective estimation of Ki-67 PI is crucial.

Advantages of score-based delirium detection compared to a clinical delirium assessment-a retrospective, monocentric cohort study.

PURPOSE: Delirium is an underdiagnosed complication on intensive care units (ICU). We hypothesized that a score-based delirium detection using the Nudesc score identifies more patients compared to a traditional diagnosis of delirium by ICU physicians. METHODS: In this retrospective study, all patients treated on a general medical ICU with 30 beds in a university hospital in 2019 were analyzed. Primary outcome was a documented physician diagnosis of delirium, or a delirium score ≥2 using the Nudesc. RESULTS: In 205/943 included patients (21.7%), delirium was diagnosed by ICU physicians compared to 438/943 (46.4%; ratio 2.1) by Nudesc≥2. Both assessments were independent predictors of ICU stay (p<0.01). The physician diagnosis however was no independent predictor of mortality (OR 0.98 (0.57-1.72); p = 0.989), in contrast to the score-based diagnosis (OR 2.31 (1.30-4.10); p = 0.004). Subgroup analysis showed that physicians underdiagnosed delirium in case of hypoactive delirium and delirium in patients with female gender and in patients with an age below 60 years. CONCLUSION: Delirium in patients with hypoactive delirium, female patients and those below 60 years was underdiagnosed by physicians. The score-based delirium diagnosis detected delirium more frequently and correlated with ICU mortality and stay.

Mobile Hysteroscopy With the Use of a Smartphone as a Cost-Effective, Diagnostic Technique.

BACKGROUND: Smartphone technology can be adapted to promote cable-free, wireless, and cost-effective diagnostic mobile office hysteroscopy. INSTRUMENT: We developed a new cable-free setup by coupling a rigid 30°, 2-mm-diameter hysteroscope to a smartphone using a commercially available adapter and using a portable and rechargeable light-emitting diode cold light source. The new setup cost is considerably lower compared with that of a typical endoscopic tower. EXPERIENCE: We performed both standard hysteroscopy and hysteroscopy using the new portable setup in 40 patients for a variety of benign gynecologic indications. The operating time was compared between the two methods, as was the pain perceived by the patients. Videos from the two setups were blindly reviewed and scored by experts regarding image resolution, brightness, color, and overall image quality. The new technique was acceptable for diagnosis in 97.5% of the videos. CONCLUSION: We report a promising initial experience using a smartphone to provide a convenient, cable-free, low-cost, office hysteroscopy system.

Trends in fever case management for febrile inpatients in a low malaria incidence setting of Tanzania.

OBJECTIVES: In 2010, WHO published guidelines emphasising parasitological confirmation of malaria before treatment. We present data on changes in fever case management in a low malaria transmission setting of northern Tanzania after 2010. METHODS: We compared diagnoses, treatments and outcomes from two hospital-based prospective cohort studies, Cohort 1 (2011-2014) and Cohort 2 (2016-2019), that enrolled febrile children and adults. All participants underwent quality-assured malaria blood smear-microscopy. Participants who were malaria smear-microscopy negative but received a diagnosis of malaria or received an antimalarial were categorised as malaria over-diagnosis and over-treatment, respectively. RESULTS: We analysed data from 2098 participants. The median (IQR) age was 27 (3-43) years and 1047 (50.0%) were female. Malaria was detected in 23 (2.3%) participants in Cohort 1 and 42 (3.8%) in Cohort 2 (p = 0.059). Malaria over-diagnosis occurred in 334 (35.0%) participants in Cohort 1 and 190 (17.7%) in Cohort 2 (p < 0.001). Malaria over-treatment occurred in 528 (55.1%) participants in Cohort 1 and 196 (18.3%) in Cohort 2 (p < 0.001). There were 30 (3.1%) deaths in Cohort 1 and 60 (5.4%) in Cohort 2 (p = 0.007). All deaths occurred among smear-negative participants. CONCLUSION: We observed a substantial decline in malaria over-diagnosis and over-treatment among febrile inpatients in northern Tanzania between two time periods after 2010. Despite changes, some smear-negative participants were still diagnosed and treated for malaria. Our results highlight the need for continued monitoring of fever case management across different malaria epidemiological settings in sub-Saharan Africa.

Assessment of malaria diagnostic methods and treatments at a Ghanaian health facility.

INTRODUCTION: it has been more than a decade since the World Health Organization (WHO) recommended parasitological confirmation of malaria before treatment begins. Light microscopy and rapid diagnostic tests are currently being used for diagnosing malaria in routine clinical care settings. Many clinicians have however raised questions about the competencies of laboratory staff who perform these tests and the performance of these diagnostic methods. This study aimed at assessing the performance of microscopy and two rapid diagnostic test kits in the hands of routine laboratory staff compared to expert microscopy as well as assess the performance of clinical diagnosis. METHODS: this was a cross sectional study involving 799 participants of all ages who visited the out patient department of the University of Cape Coast Hospital with symptoms suggestive of malaria. RESULTS: when the different methods were compared to expert microscopy, the rapid diagnostic test kits had the highest sensitivities, Wondfo 94.83% (95% CI: 85.62-98.20) and CareStart 91.38 (95% CI: 81.02-97.14). Microscopy by laboratory staff had a sensitivity of 68.79 (95% CI: 55.46-80.46) whilst clinical diagnosis had the lowest sensitivity of 17.24 (95% CI: 8.59-29.43). Cohen´s kappa coefficient was used to measure the level of agreement of the methods with expert microscopy. Microscopy by laboratory staff, CareStart and Wondfo showed substantial measures of agreement (k = 0.737, 0.683, and 0.691 respectively). CONCLUSION: these findings suggest that clinical diagnosis is highly unreliable whilst rapid diagnostic tests and microscopy performed by routine laboratory staff could be trusted by clinicians as reliable diagnostic methods.

Assessment of the required performance and the development of corresponding program decision rules for neglected tropical diseases diagnostic tests: Monitoring and evaluation of soil-transmitted helminthiasis control programs as a case study.

Recently, the World Health Organization established the Diagnostic Technical Advisory Group to identify and prioritize diagnostic needs for neglected tropical diseases, and to ultimately describe the minimal and ideal characteristics for new diagnostic tests (the so-called target product profiles (TPPs)). We developed two generic frameworks: one to explore and determine the required sensitivity (probability to correctly detect diseased persons) and specificity (probability to correctly detect persons free of disease), and another one to determine the corresponding samples sizes and the decision rules based on a multi-category lot quality assurance sampling (MC-LQAS) approach that accounts for imperfect tests. We applied both frameworks for monitoring and evaluation of soil-transmitted helminthiasis control programs. Our study indicates that specificity rather than sensitivity will become more important when the program approaches the endgame of elimination and that the requirements for both parameters are inversely correlated, resulting in multiple combinations of sensitivity and specificity that allow for reliable decision making. The MC-LQAS framework highlighted that improving diagnostic performance results in a smaller sample size for the same level of program decision making. In other words, the additional costs per diagnostic tests with improved diagnostic performance may be compensated by lower operational costs in the field. Based on our results we proposed the required minimal and ideal diagnostic sensitivity and specificity for diagnostic tests applied in monitoring and evaluating of soil-transmitted helminthiasis control programs.

Autoantibody Discovery, Assay Development and Adoption: Death Valley, the Sea of Survival and Beyond.

Dating to the discovery of the Lupus Erythematosus (LE) cell in 1948, there has been a dramatic growth in the discovery of unique autoantibodies and their cognate targets, all of which has led to the availability and use of autoantibody testing for a broad spectrum of autoimmune diseases. Most studies of the sensitivity, specificity, commutability, and harmonization of autoantibody testing have focused on widely available, commercially developed and agency-certified autoantibody kits. However, this is only a small part of the spectrum of autoantibody tests that are provided through laboratories world-wide. This manuscript will review the wider spectrum of testing by exploring the innovation pathway that begins with autoantibody discovery followed by assessment of clinical relevance, accuracy, validation, and then consideration of regulatory requirements as an approved diagnostic test. Some tests are offered as "Research Use Only (RUO)", some as "Laboratory Developed Tests (LDT)", some enter Health Technology Assessment (HTA) pathways, while others are relegated to a "death valley" of autoantibody discovery and become "orphan" autoantibodies. Those that achieve regulatory approval are further threatened by the business world's "Darwinian Sea of Survival". As one example of the trappings of autoantibody progression or failure, it is reported that more than 200 different autoantibodies have been described in systemic lupus erythematosus (SLE), a small handful (~10%) of these have achieved regulatory approval and are widely available as commercial diagnostic kits, while a few others may be available as RUO or LDT assays. However, the vast majority (90%) are orphaned and languish in an autoantibody 'death valley'. This review proposes that it is important to keep an inventory of these "orphan autoantibodies" in 'death valley' because, with the increasing availability of multi-analyte arrays and artificial intelligence (MAAI), some can be rescued to achieve a useful role in clinical diagnostic especially in light of patient stratification and precision medicine.

Determining Gut Microbial Dysbiosis: a Review of Applied Indexes for Assessment of Intestinal Microbiota Imbalances.

Assessing "dysbiosis" in intestinal microbial communities is increasingly considered a routine analysis in microbiota studies, and it has added relevant information to the prediction and characterization of diseases and other adverse conditions. However, dysbiosis is not a well-defined condition. A variety of different dysbiosis indexes have been suggested and applied, but their underlying methodologies, as well as the cohorts and conditions for which they have been developed, differ considerably. To date, no comprehensive overview and comparison of all the different methodologies and applications of such indexes is available. Here, we list all types of dysbiosis indexes identified in the literature, introduce their methodology, group them into categories, and discuss their potential descriptive and clinical applications as well as their limitations. Thus, our focus is not on the implications of dysbiosis for disease but on the methodological approaches available to determine and quantify this condition.

A faster and less costly alternative for RNA extraction of SARS-CoV-2 using proteinase k treatment followed by thermal shock.

One of the biggest challenges during the pandemic has been obtaining and maintaining critical material to conduct the increasing demand for molecular tests. Sometimes, the lack of suppliers and the global shortage of these reagents, a consequence of the high demand, make it difficult to detect and diagnose patients with suspected SARS-CoV-2 infection, negatively impacting the control of virus spread. Many alternatives have enabled the continuous processing of samples and have presented a decrease in time and cost. These measures thus allow broad testing of the population and should be ideal for controlling the disease. In this sense, we compared the SARS-CoV-2 molecular detection effectiveness by Real time RT-PCR using two different protocols for RNA extraction. The experiments were conducted in the National Institute of Health (INS) from Peru. We compared Ct values average (experimental triplicate) results from two different targets, a viral and internal control. All samples were extracted in parallel using a commercial kit and our alternative protocol-samples submitted to proteinase K treatment (3 µg/µL, 56°C for 10 minutes) followed by thermal shock (98°C for 5 minutes followed by 4°C for 2 minutes); the agreement between results was 100% in the samples tested. In addition, we compared the COVID-19 positivity between six epidemiological weeks: the initial two in that the Real time RT-PCR reactions were conducted using RNA extracted by commercial kit, followed by two other using RNA obtained by our kit-free method, and the last two using kit once again; they did not differ significantly. We concluded that our in-house method is an easy, fast, and cost-effective alternative method for extracting RNA and conducing molecular diagnosis of COVID-19.

Assessment of the Multiple Rapid Swallows Test for Gauging Esophageal Reflux Burden in Patients with Refractory Gastroesophageal Reflux Disease.

BACKGROUND The multiple rapid swallows (MRS) test is used to assess esophageal contraction reserve. In this study, we characterized the expression of the MRS test in patients with reflux burden and other symptomatic phenotypes with refractory gastroesophageal reflux disease (rGERD). MATERIAL AND METHODS Patients with rGERD who underwent high-resolution manometry (HRM) and esophageal pH-impedance monitoring (EIM) between September 2018 and January 2020 were retrospectively studied. RESULTS We enrolled 151 patients and divided them into 4 phenotypes according to the results of EIM. In phenotype 1, the MRS distal contractile integral (DCI) was significantly positively correlated with acid-liquid reflux episodes. In phenotype 2, lower esophageal sphincter pressure (LES) length was significantly positively correlated with MRS DCI, and MRS/single-swallow (SS) DCI ratio. In phenotype 3, MRS DCI was negatively correlated with the DeMeester score, acid exposure time (AET), upright AET, long-term acid reflux episodes, acid-mixed reflux episodes, recumbent acid reflux episodes, and total acid reflux episodes. There was a significant negative correlation between MRS/SS DCI and recumbent acid reflux episodes. In phenotype 4, nonacid-liquid episodes and recumbent nonacid reflux episodes were significantly higher in the abnormal MRS group. However, acid-gas episodes, weakly acid-gas episodes, and upright gas reflux episodes were higher in the normal MRS group than in the abnormal MRS group. CONCLUSIONS Esophageal contraction reserve is heterogeneous within the reflux burden and symptomatic phenotypes of patients with rGERD.

Rabies control in Liberia: Joint efforts towards zero by 30.

Despite declaration as a national priority disease, dog rabies remains endemic in Liberia, with surveillance systems and disease control activities still developing. The objective of these initial efforts was to establish animal rabies diagnostics, foster collaboration between all rabies control stakeholders, and develop a short-term action plan with estimated costs for rabies control and elimination in Liberia. Four rabies diagnostic tests, the direct fluorescent antibody (DFA) test, the direct immunohistochemical test (dRIT), the reverse transcriptase polymerase chain reaction (RT-PCR) assay and the rapid immunochromatographic diagnostic test (RIDT), were implemented at the Central Veterinary Laboratory (CVL) in Monrovia between July 2017 and February 2018. Seven samples (n=7) out of eight suspected animals were confirmed positive for rabies lyssavirus, and molecular analyses revealed that all isolates belonged to the Africa 2 lineage, subgroup H. During a comprehensive in-country One Health rabies stakeholder meeting in 2018, a practical workplan, a short-term action plan and an accurately costed mass dog vaccination strategy were developed. Liberia is currently at stage 1.5/5 of the Stepwise Approach towards Rabies Elimination (SARE) tool, which corresponds with countries that are scaling up local-level interventions (e.g. dog vaccination campaigns) to the national level. Overall an estimated 5.3 - 8 million USD invested over 13 years is needed to eliminate rabies in Liberia by 2030. Liberia still has a long road to become free from dog-rabies. However, the dialogue between all relevant stakeholders took place, and disease surveillance considerably improved through implementing rabies diagnosis at the CVL. The joint efforts of diverse national and international stakeholders laid important foundations to achieve the goal of zero dog-mediated human rabies deaths by 2030.

Plasma PCSK9 levels and sepsis severity: an early assessment in the emergency department.

The aim of the study is to evaluate the prognostic value of early PCSK9 levels in non-intubated septic patients admitted to the emergency department. This report utilized a portion of the data collected in a prospective study, with the aim of identifying reliable biomarkers for an early sepsis diagnosis. In the period November 2011-December 2016, we enrolled 268 patients, admitted to our High-Dependency Unit from the emergency department with a diagnosis of sepsis. Study-related blood samplings were performed at ED-HDU admission (T0), after 6 h (T6) and 24 h (T24). The primary endpoint was in-hospital mortality rate. PCSK9 circulating levels were higher than the normal value (≤ 313 ng/mL): at T0 661 ± 405 ng/mL, at T6 687 ± 417 ng/mL, at T24 718 ± 430 ng/mL. We divided the study population based on T0 quartiles distribution (≤ 370, 370-600, 600-900 and > 900 ng/ml). At T0, patients with normal PCSK9 showed the highest mortality compared to those in higher quartiles (T0: 39%, 20%, 23% and 18%, p = 0.036). By T6, the mortality curve tended to become U-shaped, with the lowest mortality among patients in the intermediate subgroups and an adverse prognosis in the presence of normal or very high levels of PCSK9 (35%, 26%, 18% and 23%, p = 0.235). A Kaplan-Meier analysis showed an increased mortality in patients with T0 and T6 PCSK9 ≤ 313 ng/ml (T0: 55 vs. 80%, p = 0.001; T6: 62 vs. 78%, p = 0.034). In subgroups with increasing levels of PCSK9, we found the best prognosis in the intermediate subgroups and an increased mortality among patients with normal and high values.

A multicentre assessment of contemporary laboratory assays for heparin induced thrombocytopenia.

Heparin induced thrombocytopenia (HIT) is a rare but potentially fatal complication of heparin therapy. In some patients, HIT causes platelet activation and thrombosis (sometimes abbreviated HITT), which leads to adverse clinical sequalae ('pathological HIT'). The likelihood of HIT is initially assessed clinically, typically using a scoring system, of which the 4T score is that most utilised. Subsequent laboratory testing to confirm or exclude HIT facilitates exclusion or diagnosis and management. The current investigation comprises a multicentre (n=9) assessment of contemporary laboratory testing for HIT, as performed over the past 1-3 years in each site and comprising testing of over 1200 samples. The primary laboratory test used by study participants (n=8) comprised a chemiluminescence procedure (HIT-IgG(PF4-H)) performed on an AcuStar instrument. Additional immunological testing performed by study sites included lateral flow (STiC, Stago), enzyme linked immunosorbent assay (ELISA), Asserachrom (HPIA IgG), PaGIA (BioRad), plus functional assays, primarily serotonin release assay (SRA) or platelet aggregation methods. The chemiluminescence procedure yielded a highly sensitive screening method for identifying functional HIT, given high area under the curve (AUC, generally ≥0.9) in a receiver operator characteristic (ROC) analysis against SRA as gold standard. ELISA testing resulted in lower ROC AUC scores (<0.8) and higher levels of false positives. Although there is clear association with the likelihood of HIT, the 4T score had less utility than literature suggests, and was comparable to a previous study reported by some of the authors.

Assessment of Prevalence and Cost of Care Cascades After Routine Testing During the Medicare Annual Wellness Visit.

Importance: For healthy adults, routine testing during annual check-ups is considered low value and may trigger cascades of medical services of unclear benefit. It is unknown how often routine tests are performed during Medicare annual wellness visits (AWVs) or whether they are associated with cascades of care. Objective: To estimate the prevalence of routine electrocardiograms (ECGs), urinalyses, and thyrotropin tests and of cascades (further tests, procedures, visits, hospitalizations, and new diagnoses) that might follow among healthy adults receiving AWVs. Design, Setting, and Participants: Observational cohort study using fee-for-service Medicare claims data from beneficiaries aged 66 years and older who were continuously enrolled in fee-for-service Medicare between January 1, 2013, and March 31, 2015; received an AWV in 2014; had no test-relevant prior conditions; did not receive 1 of the 3 tests in the 6 months before the AWV; and had no test-relevant symptoms or conditions in the AWV testing period. Data were analyzed from February 13, 2019, to June 8, 2020. Exposure: Receipt of a given test within 1 week before or after the AWV. Main Outcomes and Measures: Prevalence of routine tests during AWVs and cascade-attributable event rates and associated spending in the 90 days following the AWV test period. Patient, clinician, and area-level characteristics associated with receiving routine tests were also assessed. Results: Among 75 275 AWV recipients (mean [SD] age, 72.6 [6.1] years; 48 107 [63.9%] women), 18.6% (14 017) received at least 1 low-value test including an ECG (7.2% [5421]), urinalysis (10.0% [7515]), or thyrotropin test (8.7% [6534]). Patients were more likely to receive a low-value test if they were younger (adjusted odds ratio [aOR], 1.69 for ages 66-74 years vs ages ≥85 years [95% CI, 1.53-1.86]), White (aOR, 1.32 compared with Black [95% CI, 1.16-1.49]), lived in urban areas (aOR, 1.29 vs rural [95% CI, 1.15-1.46]), and lived in high-income areas (aOR, 1.26 for >400% of the federal poverty level vs <200% of the federal poverty level [95% CI, 1.16-1.37]). A total of 6.1 (95% CI, 4.8-7.5) cascade-attributable events per 100 beneficiaries occurred in the 90 days following routine ECGs and 5.4 (95% CI, 4.2-6.5) following urinalyses, with cascade-attributable cost per beneficiary of $9.62 (95% CI, $6.43-$12.80) and $7.46 (95% CI, $5.11-$9.81), respectively. No cascade-attributable events or costs were found to be associated with thyrotropin tests. Conclusions and Relevance: In this study, 19% of healthy Medicare beneficiaries received routine low-value ECGs, urinalyses, or thyrotropin tests during their AWVs, more often those who were younger, White, and lived in urban, high-income areas. ECGs and urinalyses were associated with cascades of modest but notable cost.