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Despite remarkable therapeutic advances, hepatitis C virus (HCV) infection continues to be a major global problem. While the development of highly effective direct-acting antivirals has ensured that almost all those who are treated achieve viral cure, progress toward HCV elimination globally has stalled due to challenges upstream of treatment in the cascade of care, namely diagnosis and linkage to care. The major challenge continues to be the relative complexity of HCV diagnosis with the current requirement for a confirmatory HCV RNA test after an initial antibody-positive result. In this review, challenges with the current paradigm are highlighted with a focus on new technologies, as well as simple strategies using existing tools, which may simplify diagnosis and improve linkage to care and treatment. To achieve HCV elimination, improvements in the HCV diagnostics field to allow for a simple single-step diagnosis are required. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO) has set targets to eliminate viral hepatitis, including hepatitis C virus (HCV) infection, by 2030. We present the results of the in‐hospital Reflex tEsting ALarm‐C (REAL‐C) model, which incorporates reflex HCV RNA testing and sending alerts to physicians. Methods: We conducted a retrospective study analysing the data of 1730 patients who newly tested positive for anti‐HCV between March 2020 and June 2023. Three distinct periods were defined: pre‐REAL‐C (n = 696), incomplete REAL‐C (n = 515) and complete REAL‐C model periods (n = 519). The primary outcome measure was the HCV RNA testing rate throughout the study period. Additionally, we assessed the referral rate to the gastroenterology department, linkage time for diagnosis and treatment and the treatment rate. Results: The rate of HCV RNA testing increased significantly from 51.0% (pre‐REAL‐C) to 95.6% (complete REAL‐C). This improvement was consistent across clinical departments, regardless of patients' comorbidities. Among patients with confirmed HCV infection, the gastroenterology referral rate increased from 57.1% to 81.1% after the REAL‐C model. The treatment rate among treatment‐eligible patients was 92.4% during the study period. The mean interval from anti‐HCV positivity to HCV RNA testing decreased from 45.1 to 1.9 days. The mean interval from the detection of anti‐HCV positivity to direct‐acting antiviral treatment also decreased from 89.5 to 49.5 days with the REAL‐C model. Conclusion: The REAL‐C model, featuring reflex testing and physician alerts, effectively increased HCV RNA testing rates and streamlined care cascades. Our model facilitated progress towards achieving WHO's elimination goals for HCV infection. [ABSTRACT FROM AUTHOR]

Universal screening for defective mismatch repair (dMMR) in colorectal cancer utilizes immunohistochemical staining for MLH1, MSH2, MSH6 and PSM2. Additionally, BRAF V600E mutations status and MLH1 hypermethylation should be performed to distinguish germline and somatic dMMR alterations. A decade of Danish population-based registries has been analysed regarding screening uptake, detection rate and referral to genetic counselling. MMR testing was performed in 71·8% (N = 34,664) of newly diagnosed colorectal cancers with an increasing trend to 88·8% coverage in the study's final year. The likelihood of undergoing MMR testing was reduced in males with 2% (95% CI 0·4–2·7, p = 0·008), with 4·1% in patients above age 70 years (95% CI 1·5–6·6, p = 0·003) compared in patients below age 51 years, with 16·3% in rectal cancers (95% CI 15·1–17·6, p < 0·001) and 1·4% left-sided colon cancers (95% CI 0·1–1·7, p = 0·03) compared to right-sided colon cancers. Tumour stage II and III increased the likelihood of being tested, with 3·7% for stage II (95% CI 2·2–5·6, p < 0·001) and 3·3% for stage III tumours (95% CI 1·8–4·8, p < 0·001) compared to stage I tumours, whereas the likelihood for stage IV tumours is reduced by 35·7% (95% CI 34·2–37·2, p < 0·001). Test rates significantly differed between the Danish health care regions. dMMR was identified in 15·1% (95% CI 14·8–15·6, p < 0·001) cases with somatic MMR inactivation in 6·7% of the cases. 8·3% tumours showed hereditary dMMR expression patterns, and 20·0% of those were referred to genetic counselling. Despite the high uptake rates, we found disparities between patient groups and missed opportunities for genetic diagnostics.

Background: Approximately 20% of breast cancers express HER2-positive receptors in the USA. HER2 receptor immunohistochemistry (IHC) staining with equivocal (2+) results commonly undergoes fluorescence in-situ hybridization (FISH) for further classification. Current guidelines do not recommend routine FISH testing in IHC-negative (0 or 1+) cases. This study investigates an institution that performs both IHC and FISH testing on all cases to identify the true HER2-positive rate. Patients and Methods: A retrospective chart review from 2015 to 2021 was conducted at an institution where both HER2 IHC and FISH testing were performed at the time of diagnosis for all invasive breast cancers. The rate of true HER2-positive patients was determined, and patient and tumor characteristics were further explored. Results: A total of 1835 invasive breast cancer cases were primarily treated at this institution. A total of 289 cases were HER2 positive on IHC and FISH testing (15.7%). An additional 38 cases were identified as HER2 negative on IHC, but reclassified as HER2 positive on reflex FISH testing. Total HER2 positive cases increased from 289 (15.7%) to 327 cases (17.8%) with reflex FISH testing. Conclusions: The additional HER2-positive cases after completing FISH testing on IHC-negative tumors suggests there may be a role for routine FISH testing in addition to standard IHC staining to determine HER2 status for breast cancer. The ethical, prognostic and even benefits of a correct diagnosis outweigh the added expense of FISH testing. [ABSTRACT FROM AUTHOR]

Chronic hepatitis D (CHD) is a severe form of viral hepatitis that leads to liver cirrhosis and hepatocellular carcinoma. CHD is underdiagnosed, and this study aimed to assess the impact of hepatitis D reflex testing in HBsAg‐positive individuals in Spain over the next 8 years. Two scenarios were compared: the current situation (7.6% of HBsAg‐positive patients tested for anti‐HDV) and reflex testing for all positive samples. A decision tree model was designed to simulate the CHD care cascade. Implementing reflex testing would increase anti‐HDV detection to 5498 cases and HDV‐RNA to 3225 cases. Additionally, 2128 more patients would receive treatment, with 213 achieving undetectable HDV‐RNA levels. The cost per anti‐HDV case detected would be €132. In the median time of the analysis, liver complications (decompensated cirrhosis, HCC and liver‐related deaths) would be reduced by 35%–38%, implying an estimated cost savings of 36 million euros associated with the management of such complications. By 2030, implementing anti‐HDV reflex testing would reduce the clinical and economic burden of CHD by 35%–38%. [ABSTRACT FROM AUTHOR]

Background: International guidelines recommend universal screening for Lynch syndrome (LS) through somatic DNA mismatch repair deficiency (dMMR) testing in all colorectal cancers (CRCs). However, LS remains largely underdiagnosed. Mainstreaming LS diagnosis through oncologist-driven genetic testing could increase detection rates, thus extending the benefits of precision prevention to patients with LS and their families. We aim to evaluate the feasibility of the mainstreaming diagnostic algorithm for LS. Patients and methods: ItaLynch is an ongoing, prospective, observational, multicenter, multidisciplinary, Italian study in patients with dMMR CRC. Being descriptive in nature, it does not attempt to test any specific, a priori, hypothesis. Patients with dMMR CRC are selected by universal screening by immunohistochemistry (IHC). In MLH1-deficient patients, reflex testing for BRAFV600E and, when appropriate, for MLH1 promoter hypermethylation is carried out. For all dMMR CRC, a ‘Lynch Alert’ is added to the pathology report: positive when a patient is at high risk for LS, due to reflex testing results or to loss of non-MLH1 proteins. Conversely, a ‘Lynch Alert’ is negative when the patient is likely to be a nonhereditary case (i.e. MLH1 loss and BRAFV600E or MLH1 promoter hypermethylation). In patients with a positive ‘Lynch Alert’, after providing a brief explanation about the risks and benefits of genetic testing, the oncologist asks patients for their consent to mainstream genetic testing. Thus a blood sample is drawn for constitutional variants of the MMR genes. Carriers of a germline variant are then referred to post-test genetic counseling. Referral to clinical genetic services is also advised for patients with clinical suspect criteria.

Introduction: Our aim was to measure hepatitis C virus (HCV) screening and linkage-to-care rates in an urban emergency department (ED) before and after implementing an HCV viral RNA (vRNA) reflex testing protocol within a HCV screening program for at-risk patients. Our hypothesis was that using a reflex testing protocol would increase HCV testing rates of at-risk patients in the ED, which would increase the linkage-to-care rate. Methods: In August 2018, our institution implemented an automated, electronic health record-based HCV screening protocol in the ED for at-risk patients. In January 2019, we implemented an HCV vRNA reflex testing protocol (reflex testing) for all positive HCV antibody (Ab) tests that were initiated through the screening protocol. We compared completion rates of HCV vRNA testing and the rate of linkage to care for patients with positive HCV Ab test results before and after implementation of reflex testing (five months per study period). Results: Prior to reflex testing implementation, 233/425 (55%) patients with a positive HCV Ab test had an HCV vRNA test performed, whereas 270/323 (84%) patients with a positive HCV Ab test result had vRNA testing after reflex testing implementation (odds ratio [OR], 4.2; 95% confidence interval (CI): 3.0-6.0; P < 0.001). Of the eligible patients with positive HCV Ab test results who could be linked to care, 45 (10.6%) were linked to care before HCV reflex implementation and 46 (14.2%) were linked to care with reflex testing (OR, 1.4; 95% CI: 0.9-2.2; P = 0.13). Conclusion: Implementing a reflex testing initiative into an HCV screening program in the ED can result in an increase of the percentage of patients who receive an HCV vRNA test after having had a positive HCV Ab. Hepatitis C virus vRNA reflex testing was not associated with a statistically significant increase in linkage-to-care rates for HCV Ab-positive patients; however, further studies are required.

Objective The aim of this study was to examine appropriate utilization of antinuclear antibody (ANA) screening tests with follow-up subserology tests (reflex testing) for diagnosing systemic autoimmune rheumatic disorder (SARD). Methods We conducted a retrospective chart review of 3003 SARD-test orders at an academic teaching hospital from January to December 2019. Testing patterns were categorized as American College of Rheumatology (ACR)-recommended reflex testing, panel testing, or single subserology testing. We described testing patterns, assessed their diagnostic accuracy, and explored factors associated with reflex testing. Results Reflex testing accounted for 79.7% of SARD test-ordering, whereas improper testing (panel or single subserology) accounted for the other 20.3%. Reflex testing was associated with significantly more SARD diagnoses than improper testing (P  = .004). Testing patterns were significantly associated with race/ethnicity (P  = .008), with reflex testing being less frequent than improper testing in Hispanics and Whites. Conclusion In summary, one-fifth (20.3%) of testing patterns for suspected SARD did not follow the ACR-recommended guidelines for using reflex testing. Use of reflex testing was associated with an increased frequency of SARD diagnosis. [ABSTRACT FROM AUTHOR]

Background: Silent aspiration (SA) is common post‐stroke and associated with increased risk of pneumonia, length of stay and healthcare costs. Clinical swallow examinations (CSEs) are unreliable measures of SA. There is no consensus on the clinical components that best detect SA. Cough reflex testing (CRT) is an alternative/adjunct whose SA detection accuracy also lacks consensus. Aims: To investigate the feasibility of CSE versus CRT against gold standard flexible endoscopic evaluation of swallowing (FEES) for SA identification and to estimate its prevalence in a hyperacute stroke setting. Methods & Procedures: A single‐arm preliminary, prospective, feasibility study of patients less than 72 h post‐stroke, over a 31‐day period on a hyperacute stroke unit: the Royal Victoria Infirmary, Newcastle‐upon‐Tyne, UK. Ethical approval for the study was obtained. The study tested the feasibility and acceptability of introducing CRT and developing a standardized CSE. Consent/assent was obtained for all participants. Patients unfit for study were excluded. Outcomes & Results: A total of 62% of patients less than 72 h post‐stroke (n = 61) were eligible. A total of 75% of those approached (n = 30) consented. A total of 23 patients completed all tests. The principal barrier was anxiety regarding FEES. Mean test time for CRT = 6 min; CSE = 8 min; FEES = 17 min. Patients rated CRT and FEES on average as moderately uncomfortable. A total of 30% (n = 7) of participants who received FEES presented with SA. Conclusions & Implications: CRT, CSE and FEES are feasible in 58% of hyperacute stroke patients in this setting. FEES anxiety is the main recruitment barrier and is not always well tolerated. Results support further work to establish optimum methods and differential sensitivity/specificity of CRT and CSE in hyperacute stroke for SA identification. WHAT THIS PAPER ADDS: What is already known on this subject: SA significantly increases the risk of pneumonia in the early days post‐stroke. CSEs are unreliable for identification of SA risk in this population. CRT is gaining popularity as a potential tool to identify stroke patients at risk of SA, though there are questions regarding the efficacy of the clinical protocol currently being used in the UK. What this study adds to existing knowledge: This study demonstrates that it is practical and feasible to carry out a larger scale study in this setting to compare CSE and CRT including a consideration of an approach combining both methods for clinical identification of SA versus FEES. Preliminary findings suggest that CSE may have higher levels of sensitivity than CRT for SA identification. What are the potential or actual clinical implications of this work?: The results of this study suggest that further work is needed to establish the optimum methods and differential sensitivity/specificity of clinical tools for SA detection in hyperacute stroke. [ABSTRACT FROM AUTHOR]

* SYNOPSIS: Neurological testing is essential for screening and diagnosing suspected peripheral neuropathies. Detecting changes in somatosensory and motor nerve function can also have direct implications for management decisions. Nevertheless, there is considerable variation in what is included in a bedside neurological examination and how it is performed. Neurological examinations are often used as screening tools to detect neurological deficits but not used to their full potential for monitoring progress or deterioration. Here, we advocate for better use of the neurological examination within a clinical reasoning framework. Constrained by the lack of research in this field, our Viewpoint is based on neuroscientific principles. We highlight 6 challenges for clinicians when conducting neurological examinations and propose ways to overcome these challenges in clinical practice. We challenge widely held ideas about how the results of neurological examinations for peripheral neuropathies are interpreted and how the examinations are performed in practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to the rarity and non-specific symptoms of myeloma, a key challenge in diagnosing myeloma in primary care is the clinician considering myeloma and initiating appropriate investigations. We developed an algorithm to identify those at high-risk of having undiagnosed myeloma based on results from routine blood tests taken for other reasons. We demonstrated that it is possible to combine signals and abnormalities in several routine blood test parameters to identify individuals at high-risk of having undiagnosed myeloma with high predictive accuracy. Identified high-risk individuals could then undergo further automatic testing in the laboratory (a reflex test) to test specifically for myeloma. We estimate the number of additional tests needed to diagnose one case at different model thresholds. Further work is needed to explore the full potential of such a strategy. If successful, automatic reflex testing would enable large-scale, low-cost case-finding for myeloma with a significant impact on the diagnosis of myeloma. Myeloma is one of the hardest cancers to diagnose in primary care due to its rarity and non-specific symptoms. A rate-limiting step in diagnosing myeloma is the clinician considering myeloma and initiating appropriate investigations. We developed and internally validated a risk prediction model to identify those with a high risk of having undiagnosed myeloma based on results from routine blood tests taken for other reasons. A case-control study, based on 367 myeloma cases and 1488 age- and sex-matched controls, was used to develop a risk prediction model including results from 15 blood tests. The model had excellent discrimination (C-statistic 0.85 (95%CI 0.83, 0.89)) and good calibration (calibration slope 0.87 (95%CI 0.75, 0.90)). At a prevalence of 15 per 100,000 population and a probability threshold of 0.4, approximately 600 patients would need additional reflex testing to detect one case. We showed that it is possible to combine signals and abnormalities from several routine blood test parameters to identify individuals at high-risk of having undiagnosed myeloma who may benefit from additional reflex testing. Further work is needed to explore the full potential of such a strategy, including whether it is clinically useful and cost-effective and how to make it ethically acceptable. [ABSTRACT FROM AUTHOR]

ABSTRACT Hepatitis A diagnosis relies on serology and occasionally on hepatitis A virus (HAV) RNA detection. For timely diagnosis and the avoidance of drawing additional blood, molecular testing is often performed as reflex testing by using blood specimens that were initially sent for anti-HAV serology. Reflex molecular testing is preferably performed from different sample aliquots, but, for limited sample quantities, it uses samples that have been preprocessed in an immunoassay analyzer. In 2012, we first observed sporadic HAV RNA-positive cases that were inconsistent with patients’ serological profiles and/or medical histories, suggesting that occasional laboratory contamination was causing false-positive PCR results. Multiple external quality assurance (EQA) and laboratory surface contamination checks were performed, questionable specimens were tested with various HAV RNA tests, and follow-up serum/stool samples were collected. All contamination-check samples and samples from healthy individuals tested HAV RNA-negative, and the laboratory successfully passed all EQAs. The HAV RNA-positive results were reproducible with various HAV RNA assays. No patients seroconverted, and their follow-up samples were consistently HAV RNA-negative. Finally, a detailed review of testing protocols revealed a correlation between HAV RNA false positivity and preceding anti-HAV testing with the Cobas-e411 automated immunoassay analyzer. HAV RNA was detected in the Cobas-e411 anti-HAV reagents, with the HAV sequences matching those from the false-positive samples. Preceding anti-HAV testing using two other immunoassay analyzers did not result in subsequent HAV RNA false positivity during reflex testing. The Cobas-e411 pipetting procedure with a single pipette tip collecting samples and anti-HAV reagents contaminated the original sample with the HAV RNA that was present in the immunoassay’s reagents, thereby resulting in HAV RNA false positivity during the reflex testing. IMPORTANCE We present the first report of sporadic HAV PCR false-positive results that have been observed during the reflex testing of serum samples that have previously been tested for anti-HAV antibodies and have been caused by contamination with HAV RNA that is present in the reagents of the commercial anti-HAV immunoassay, with potentially serious clinical consequences. Although HAV RNA was consistently detected in the anti-HAV reagents of all three automated immunoassay analyzers that were in use in our laboratory, only the use of one analyzer and the corresponding commercial anti-HAV immunoassay reagents resulted in contamination that led to false positive HAV RNA results, and this was due to a peculiar pipetting mode of action in which the analyzer uses a single pipette tip to collect both anti-HAV reagents and a sample, which consequently causes the permanent contamination of the original sample with HAV RNA. Manufacturers should strongly consider the occasional need for reflex molecular testing from preprocessed samples and design their analyzers in a way that prevents contamination.

Objective: The purpose of this analysis was to determine whether our "reflex testing" (RefT) intervention, implemented to address barriers in scheduling, communication, and diagnostic order placement for resolving BI-RADS 0 screening mammograms, resulted in decreased interval wait times (IWT) for patients with abnormal screening mammograms (abSM). Methods: All BI-RADS 0 cases over two six-month periods (pre-RefT and post-RefT) were analyzed. Timelines were generated for each BI-RADS 0 case. Elapsed days were computed from date of BI-RADS 0 report to the date of biopsy, additional diagnostic testing, and final resolution. The means of each endpoint within the pre-RefT and post-RefT cohorts were statistically analyzed using Pearson chi-square analysis to assess whether IWT differed significantly after RefT implementation. Results: The analytic cohort consisted of 1523 BI-RADS 0 cases (n(pre-RefT) = 647, n(post- RefT) = 876). Reflex testing decreased the overall mean IWT from 23.5 to 8.2 days (P < 0.001). For patients not requiring biopsy (1190/1523, 78.1%), the mean IWT from the BI-RADS 0 designation to first diagnostic test or resolution decreased from 29.7 to 10.8 days (P < 0.010). For patients who had biopsy (333/1523, 21.9%), RefT significantly decreased the IWT from BI-RADS 0 to first diagnostic test from 31.4 to 7.7 days (P < 0.001) and also significantly decreased the IWT from first diagnostic test to biopsy (20.9 to 17.7 days; P < 0.013). Conclusion: Reflex testing intervention streamlines the workflow and significantly decreases IWT for resolving BI-RADS 0 abSM. The RefT intervention could be considered to improve efficiency at other breast centers. [ABSTRACT FROM AUTHOR]

The use of dried blood spot (DBS) samples can facilitate the implementation of reflex testing by circumventing the need for centrifugation and freezing of venous blood samples. This systematic review assessed the accuracy of using DBS samples to diagnose chronic hepatitis C virus (HCV) infection. A comprehensive search was undertaken to identify articles published up to July 2020 evaluating the diagnostic accuracy of anti‐HCV, HCV‐RNA and HCV core antigen tests using DBS. Screening, data extraction, quality appraisal and Grading of Recommendations, Assessment, Development and Evaluations certainty of the evidence assessment were performed independently by two reviewers. Meta‐analysis, meta‐regression and sensitivity analyses were conducted. The evidence demonstrates that laboratory‐based anti‐HCV and HCV‐RNA tests using DBS samples have high diagnostic accuracy. All comparisons were between DBS and venous samples. For the detection of anti‐HCV, sensitivity was 95% (95% CI: 92%–97%) and specificity was 99% ([95% CI: 98%–99%]; n = 25; I2 = 81%; moderate certainty). For the detection of HCV‐RNA, the sensitivity was 95% (95% CI: 93%–97%) and specificity was 97% ([95% CI: 94%–98%]; n = 20; I2 = 52%; moderate certainty). The sensitivity of HCV core antigen tests was 86% (95% CI: 79%–91%) and specificity was 98% ([95% CI: 94%–99%]; n = 5; I2 = 37%; low certainty) compared with HCV‐RNA (the gold standard for detecting chronic HCV). DBS samples could facilitate diagnosis of chronic HCV infection as the necessary sequential tests (anti‐HCV and then HCV‐RNA or HCV core antigen) can be undertaken using the same blood sample. This could reduce loss of patient follow‐up and support international efforts towards HCV elimination in both high and low prevalence settings. [ABSTRACT FROM AUTHOR]

Background and Aims: Chronic hepatitis D infection is the most severe form of viral hepatitis and can rapidly progress to cirrhosis or hepatocellular carcinoma. Despite recommendations for systematic screening of hepatitis B surface antigen (HBsAg)-positive individuals, data from real-world studies have reported a low frequency of hepatitis D (or delta) virus (HDV) screening. Our cross-sectional analysis evaluated the diagnostic cascade for hepatitis D infection in tertiary centres and described the characteristics of HDV-positive patients., Methods: A total of 6772 individuals who tested HBsAg positive for the first time between 2018 and 2022 were retrospectively included. Demographic, clinical and laboratory data were analysed., Results: A total of 5748 HBsAg-positive individuals (84.9%) were screened for HDV infection. The screening rate varied from 63% to 97% according to the screening strategy used in the centres including or not HDV reflex testing. The prevalence of HDV infection was 6.3%. HDV RNA levels were determined in 285 of the 364 (78.3%) HDV antibody screening-positive patients, and 167 (58.6%) had active HDV infection. 66.8% were males, with a mean age of 44.9 years. A total of 97.5% were born abroad, and 92.9% were HBeAg negative. At the time of diagnosis, HDV RNA levels were 6.0 Log UI/mL; 60.1% had alanine aminotransferase >40 U/L, and 56.3% had significant fibrosis (≥F2), including 41.6% with cirrhosis. The most common genotype was HDV-1 (75.4%). Coinfections were not uncommon: 7.4% were HIV positive, and 15.0% were HCV antibody positive., Conclusions: The present study highlights the need for increased screening and monitoring of HDV infection. Reflex testing helps to identify HDV-infected individuals., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Universal screening for defective mismatch repair (dMMR) in colorectal cancer utilizes immunohistochemical staining for MLH1, MSH2, MSH6 and PSM2. Additionally, BRAF V600E mutations status and MLH1 hypermethylation should be performed to distinguish germline and somatic dMMR alterations. A decade of Danish population-based registries has been analysed regarding screening uptake, detection rate and referral to genetic counselling. MMR testing was performed in 71·8% (N = 34,664) of newly diagnosed colorectal cancers with an increasing trend to 88·8% coverage in the study's final year. The likelihood of undergoing MMR testing was reduced in males with 2% (95% CI 0·4-2·7, p = 0·008), with 4·1% in patients above age 70 years (95% CI 1·5-6·6, p = 0·003) compared in patients below age 51 years, with 16·3% in rectal cancers (95% CI 15·1-17·6, p < 0·001) and 1·4% left-sided colon cancers (95% CI 0·1-1·7, p = 0·03) compared to right-sided colon cancers. Tumour stage II and III increased the likelihood of being tested, with 3·7% for stage II (95% CI 2·2-5·6, p < 0·001) and 3·3% for stage III tumours (95% CI 1·8-4·8, p < 0·001) compared to stage I tumours, whereas the likelihood for stage IV tumours is reduced by 35·7% (95% CI 34·2-37·2, p < 0·001). Test rates significantly differed between the Danish health care regions. dMMR was identified in 15·1% (95% CI 14·8-15·6, p < 0·001) cases with somatic MMR inactivation in 6·7% of the cases. 8·3% tumours showed hereditary dMMR expression patterns, and 20·0% of those were referred to genetic counselling. Despite the high uptake rates, we found disparities between patient groups and missed opportunities for genetic diagnostics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

ROS1 rearrangements are identified in 1–2% of lung adenocarcinoma cases, and reflex testing is guideline-recommended. We developed a decision model for population-based ROS1 testing from a Canadian public healthcare perspective to determine the strategy that optimized detection of true-positive (TP) cases while minimizing costs and turnaround time (TAT). Eight diagnostic strategies were compared, including reflex single gene testing via immunohistochemistry (IHC) screening, fluorescence in-situ hybridization (FISH), next-generation sequencing (NGS), and biomarker-informed (EGFR/ALK/KRAS wildtype) testing initiated by pathologists and clinician-initiated strategies. Reflex IHC screening with FISH confirmation of positive cases yielded the best results for TAT, TP detection rate, and cost. IHC screening saved CAD 1,000,000 versus reflex FISH testing. NGS was the costliest reflex strategy. Biomarker-informed testing was cost-efficient but delayed TAT. Clinician-initiated testing was the least costly but resulted in long TAT and missed TP cases, highlighting the importance of reflex testing. Thus, reflex IHC screening for ROS1 with FISH confirmation provides a cost-efficient strategy with short TAT and maximizes the number of TP cases detected.

Introduction: Venereal Disease Research Laboratory (VDRL) test is commonly used for screening of syphilis. In India in some centres, the diagnosis of syphilis is based on VDRL test without confirmation by specific treponemal test resulting in Biological False Positives (BFPs) due to non specific nature of antigen used. Both hepatitis and syphilis are sexually transmitted diseases which are widely prevalent in India. Diagnosing syphilis aptly is important due to its association with various complications and social stigmas. Aim: To demonstrate the false-positivity of VDRL test in patients with Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection. Materials and Methods: This was a cross-sectional observational study in which 420 hepatitis B positive and 208 hepatitis C positive serum samples of patients >18 years of age were tested for syphilis by VDRL and Treponema pallidum Haemagglutination (TPHA). VDRL reactive and TPHA negative samples were considered as BFPs. Sera of 90 healthy individuals, which were negative for both Hepatitis B and C were included as control group. The data entry and analysis was done in the Microsoft Excel spreadsheet. Results: Out of 420 hepatitis B reactive samples, 64 (15.23%) and out of 208 hepatitis C reactive samples, 24 (11.5%) were observed to be BFPs. Of these 64 hepatitis B reactive patients, 46 (71.88%) were females and 18 (28.12%) were males with BFP VDRL test. Similarly, out of the 24 hepatitis C reactive patients, 18 (75%) were females and 6 (25%) were males with BFP VDRL test. BFP was observed to be 1.1% in control group. Conclusion: The study highlights that HBV and HCV infection are associated with increased chances of obtaining a BFP-VDRL test. If VDRL test is reactive, then reflex testing should be done with a specific treponemal test for a confirmatory diagnosis.

Background/Aims Obstacles exist in facilitating hepatitis C virus (HCV) care cascade. To increase timely and accurate diagnosis, disease awareness and accessibility, in-hospital HCV reflex testing followed by automatic appointments and a late call-back strategy (R.N.A. model) was applied. We aimed to compare the HCV treatment rate of patients treated with this strategy compared to those without. Methods One hundred and twenty-five anti-HCV seropositive patients who adopted the R.N.A. model in 2020 and another 1,396 controls treated in 2019 were enrolled to compare the gaps in accurate HCV RNA diagnosis to final treatment allocation. Results The HCV RNA testing rate was significantly higher in patients who received reflex testing than in those without reflex testing (100% vs. 84.8%, P

• Since 2022, we systematically initiated anti-HDV reflex testing when discovering an HBsAg carriage (new HBsAg carriers). • We evaluated the interest in anti-HDV reflex testing after one year of practice by comparing anti-HDV and HBsAg data over the last six years among the new HBsAg carriers and all the HBsAg carriers. • Implementing anti-HDV reflex testing leads to more than a 2-fold increase in diagnoses of HDV infection among all HBsAg carriers. • If the anti-HDV positive rate remains stable among the new HBsAg carriers, a significant increase in the anti-HDV positive rate from 6.8 % to 10.3 % was observed considering all HBsAg carriers. • Interestingly, the discovery of anti-HDV Abs positivity increased from 3.9 % to 6.5 % in 2022, allowing earlier identification of HBV-HDV-infected patients and a fast referral to hepatologists for adequate clinical management. Hepatitis Delta virus (HDV) infection is a major cause of liver-related morbidity and mortality in patients infected with HBV, with a global HDV prevalence uncertain. In France, 2 to 5 % of HBs antigen (HBsAg) carriers present anti-HDV antibodies (anti-HDV). The EASL recommends testing for anti-HDV in all HBsAg-positive patients. Since January 2022, we have systematically carried out anti-HDV serology when a positive HBsAg is discovered (new HBsAg carriers). We evaluated the benefit of anti-HDV reflex testing after one year of practice by comparing anti-HDV and HBsAg serology data over the last six years, among the new HBsAg carriers and all the HBsAg carriers. HBsAg and anti-HDV were screened using the Abbott Architect HBsAg quanti kit and the DIA.PRO HDVAb kit. Serological, demographic, virological, and clinical data were analyzed. Implementing anti-HDV reflex testing leads to more than a 2-fold increase in diagnoses of HDV infection among all HBsAg carriers. If the anti-HDV positive rate remains stable among the new HBsAg carriers, a significant increase in the anti-HDV positive rate from 6.8 % to 10.3 % was observed considering all HBsAg carriers. Interestingly, the discovery of anti-HDV carriage increased from 3.9 % to 6.5 % in 2022, allowing earlier identification of HBV-HDV-infected patients and a fast referral to hepatologists for adequate clinical management and, in some cases, the introduction of bulevirtide-based therapy. Our preliminary results at one year seem promising and evaluating the cost-effectiveness of reflex tests in real life with feedback would be helpful. [ABSTRACT FROM AUTHOR]

Myeloma is one of the hardest cancers to diagnose in primary care due to its rarity and non-specific symptoms. A rate-limiting step in diagnosing myeloma is the clinician considering myeloma and initiating appropriate investigations. We developed and internally validated a risk prediction model to identify those with a high risk of having undiagnosed myeloma based on results from routine blood tests taken for other reasons. A case-control study, based on 367 myeloma cases and 1488 age- and sex-matched controls, was used to develop a risk prediction model including results from 15 blood tests. The model had excellent discrimination (C-statistic 0.85 (95%CI 0.83, 0.89)) and good calibration (calibration slope 0.87 (95%CI 0.75, 0.90)). At a prevalence of 15 per 100,000 population and a probability threshold of 0.4, approximately 600 patients would need additional reflex testing to detect one case. We showed that it is possible to combine signals and abnormalities from several routine blood test parameters to identify individuals at high-risk of having undiagnosed myeloma who may benefit from additional reflex testing. Further work is needed to explore the full potential of such a strategy, including whether it is clinically useful and cost-effective and how to make it ethically acceptable.

Urinalysis is considered the world's oldest laboratory test. Today, many laboratories use macroscopic urinalysis as a screening tool to determine when to subject urine samples for a microscopic urinalysis and/or bacterial culture. While reflexive urine microscopy has been practiced for decades, and reflexive urine culture, more recently, evidence-based guidelines regarding optimal reflexive criteria and workflows are lacking. Standard approaches are hindered, in part, by a lack of harmonization of urinalysis and urine culture practices, heterogeneity in patient populations that are studied, and lack of provider adherence to recommended practices. This review summarizes studies that have evaluated the performance of reflexive urine microscopy and reflexive urine culture, particularly in the context of urinary tract infections. It also examines reported clinical outcomes from reflexive urinalysis interventions and their impact on antibiotic stewardship efforts. Finally, it discusses laboratory operational considerations for the implementation of reflexive algorithms. [ABSTRACT FROM AUTHOR]

Background: Autoimmune serology tests are central to the classification, screening, diagnosis, and monitoring of a variety of autoimmune disorders. To improve the appropriateness of serologic evaluation and support laboratory resource utilization, reflex testing approaches have been proposed and implemented across clinical laboratories. Reflex testing involves a staged approach where an initial test result triggers subsequent tests based on prespecified rules. Content: Various reflex testing approaches in the context of antinuclear antibody-associated rheumatic disease, antineutrophil cytoplasmic autoantibody-associated vasculitis, celiac disease, and myasthenia gravis are reviewed here. Clinical, analytical, and practical considerations of reflex testing implementation are addressed as well as associated limitations and challenges. Summary: Serology reflex testing algorithms for the evaluation of autoimmune diseases can support clinical diagnosis and laboratory resource use but may be challenging to implement and are often applied variably across institutions. Assessments of evidence-driven guidelines, clinical impact, and impact on laboratory workflow are essential to this task. [ABSTRACT FROM AUTHOR]

Infections caused by vancomycin-resistant enterococci (VRE) are common. Real-time PCR assays targeting vanA and vanB facilitate screening of patients in healthcare settings to limit the risk of dissemination, especially amongst those at high-risk of infection or with limited treatment options. Such assays are commonly performed as reflex testing procedures where they augment phenotypic techniques and shorten turnaround time to benefit timely clinical management. 'Random access' and 'sample-to-result' real-time PCR platforms are suited for this application as they are of low complexity and less technically demanding. Modelled on these attributes, we configured a real-time PCR assay (VRE BD) for detection of vanA/B in clinical isolates of enterococci, adapted for the BD Max System (Becton Dickinson). We applied an unconventional approach by testing suspensions of microorganisms in water to circumvent the traditional pre-analytical genomic extraction process. Our objective of this study was to assess the performance of this assay for detection of VRE in cultures by validating against a traditional real-time PCR assay based on the LightCycler 2.0 platform (Roche, VRE RO). A high level of analytical sensitivity and specificity (≥99.0%) for both genes was obtained when testing suspensions derived from blood agar. Results for suspensions obtained from chromID VRE (Edwards Group) showed a similar level of performance for vanA detection (100%), but not for the vanB target (≥90.9%) where a lesser number of isolates were available for testing. However, our results for VRE detection in isolates from these media were repeatable and reproducible, and equated to positive and negative predictive values of ≥95.2% and ≥97.8%, respectively. Furthermore, the VRE BD assay was also able to accurately detect VRE in clinical and spiked BacT/ALERT (bioMérieux) blood cultures. Thus, the technical simplicity, short turnaround time and robustness of this high performing assay for VRE is suitable for reflex testing. In addition, the format developed for the BD Max platform has potential application for reflex testing other molecular targets of clinical importance., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

ROS1 rearrangements are identified in 1–2% of lung adenocarcinoma cases, and reflex testing is guideline-recommended. We developed a decision model for population-based ROS1 testing from a Canadian public healthcare perspective to determine the strategy that optimized detection of true-positive (TP) cases while minimizing costs and turnaround time (TAT). Eight diagnostic strategies were compared, including reflex single gene testing via immunohistochemistry (IHC) screening, fluorescence in-situ hybridization (FISH), next-generation sequencing (NGS), and biomarker-informed (EGFR/ALK/KRAS wildtype) testing initiated by pathologists and clinicianinitiated strategies. Reflex IHC screening with FISH confirmation of positive cases yielded the best results for TAT, TP detection rate, and cost. IHC screening saved CAD 1,000,000 versus reflex FISH testing. NGS was the costliest reflex strategy. Biomarker-informed testing was cost-efficient but delayed TAT. Clinician-initiated testing was the least costly but resulted in long TAT and missed TP cases, highlighting the importance of reflex testing. Thus, reflex IHC screening for ROS1 with FISH confirmation provides a cost-efficient strategy with short TAT and maximizes the number of TP cases detected. [ABSTRACT FROM AUTHOR]

Tandem mass spectrometry (MS/MS) is the most universal platform currently available for the analysis of enzymatic activities and biomarkers in dried blood spots (DBS) for applications in newborn screening (NBS). Among the MS/MS applications in NBS, the most common is flow-injection analysis (FIA-) MS/MS, where the sample is introduced as a bolus injection into the mass spectrometer without the prior fractionation of analytes. Liquid chromatography combined with MS/MS (LC-MS/MS) has been employed for second-tier tests to reduce the false-positive rate associated with several nonspecific screening markers, beginning two decades ago. More recently, LC-MS/MS has been applied to primary screening for new conditions for which FIA-MS/MS or other methods, including genomic screening, are not yet adequate. In addition to providing a list of the currently used LC-MS/MS-based assays for NBS, the authors share their experience regarding the maintenance requirements of LC-MS/MS vs. FIA-MS/MS systems. The consensus is that the maintenance of LC-MS/MS and FIA-MS/MS instrumentation is similar, and LC-MS/MS has the advantage of allowing for a larger number of diseases to be screened for in a multiplex, cost-effective fashion with a high throughput and an adequate turnaround time.

Background: Our goal was to determine vitamin B12 (cobalamin) deficiency with different diagnostic strategies, to propose the best possible laboratory strategy, and to synthesize the relevance of biomarkers in the diagnosis of a cobalamin deficiency. Methods: We performed a secondary data analysis. The testing strategies were (i) vitamin B12 solely, (ii) holotranscobolamin solely, (iii) vitamin B12 and holotranscobolamin, and (iv) reflex testing of holotranscobalamin in samples with vitamin B12 < 300 pmol. A set of 3,044 laboratory samples with vitamin B12 and holotranscobalamin serum values from unselected in- and outpatients from a secondary care hospital. A sample was classified as cobalamin deficient when low values of vitamin B12 < 137 pmol/L or holotranscobalamin = 37 pmol/L were measured. Results: Low cobalamin values were identified in 591 (19.4%) samples either according to low vitamin B12 values (305; 10.0%) or low holotranscobalamin values (436; 14.3%). For 2,404 values with vitamin B12 < 300 pmol/L, the additional measurement of holotranscobalamin (reflex-testing) enabled the detection of an additional 278 (9.1%) deficiencies. When the grey zone was decreased to 138 - 219 pmol/L, the reflex testing of an additional 1,240 samples identified a total of 511 (16.8%) samples as cobalamin deficient. Conclusions: The identification of cobalamin deficiency or sufficiency highly depends on the diagnostic strategy. A reflex testing with a grey zone for vitamin B12 < 220 pmol/L identifies cobalamin deficiency cost efficiently in 86.5% cases (511 out of 591). Physicians should apply a uniform strategy on how to address the diagnosis of cobalamin deficiency and indication for treatment. In-hospital guidelines, which describe methodology and sensitivity of the locally used assays for vitamin B12 and holotranscobalamin could guide them. [ABSTRACT FROM AUTHOR]

Objectives: For men with intermediate prostate-specific antigen (PSA) levels (4-10 ng/mL), urine-based biomarkers and multiparametric magnetic resonance imaging (MRI) are increasingly used as reflex tests before prostate biopsy. We assessed the cost effectiveness of these reflex tests in the United States.Methods: We used an existing microsimulation model of prostate cancer (PCa) progression and survival to predict lifetime outcomes for a hypothetical cohort of 55-year-old men with intermediate PSA levels. Urine-based biomarkers-PCa antigen (PCA3), TMPRSS2:ERG gene fusion (T2:ERG), and the MyProstateScore (MPS) for any PCa and for high-grade (Gleason score ≥7) PCa (MPShg)-were generated using biomarker data from 1112 men presenting for biopsy at 10 United States institutions. MRI results were based on published sensitivity and specificity for high-grade PCa. Costs and utilities were sourced from literature and Medicare reimbursement schedules. Outcome measures included life years, quality-adjusted life years (QALYs), and lifetime medical costs per patient. Incremental cost-effectiveness ratios were empirically calculated on the basis of simulated life histories under different reflex testing strategies.Results: Biopsying all men provided the most life years and QALYs, followed by reflex testing using MPShg, MPS, MRI, T2:ERG, PCA3, and biopsying no men (QALY range across strategies 15.98-16.09). Accounting for costs, MRI and MPShg were dominated by other strategies. PCA3, T2:ERG, and MPS were likely to be the most cost-effective strategy at willingness-to-pay thresholds of $100 000/QALY, $125 000/QALY, and $150 000/QALY, respectively.Conclusions: Using PCA3, T2:ERG, or MPS as reflex tests has greater economic value than MRI, biopsying all men, or biopsying no men with intermediate PSA levels. [ABSTRACT FROM AUTHOR]

Background: Reflex testing algorithms are effective tools to reduce unnecessary laboratory testing. Direct (conjugated) bilirubin (DB) and total bilirubin (TB) are often ordered together at our institution. Therefore, the objective of our study was to evaluate the potential impact of performing reflex testing for DB when TB is elevated. Methods: We performed a retrospective review of test orders (patients ≥18 years of age) for DB, TB, or for both DB and TB on the same accession number received in our stat laboratory from January through April 2017. The orders were binned into 4 categories depending on the results from each individual test: (a) DB normal and TB normal, (b) DB normal and TB high, (c) DB high and TB normal, and (d) DB high and TB high. The percentage of orders and median (range) test result for each category was calculated. Results: During the months evaluated, a total of 4828 stat orders were placed for DB, TB, or both DB and TB. A total of 4296 stat orders (89%) were placed with both DB and TB on the same accession number for 4158 unique patients. Of those orders, the vast majority of tests (87.3%) contained normal results for both analytes; only 12.7% of orders contained ≥1 abnormal result. Conclusions: The majority of all bilirubin tests ordered stat for emergency department and hospitalized patients have values within the reference interval. Consequently, if reflex testing were executed on elevated TB, a large number of DB tests could be avoided. [ABSTRACT FROM AUTHOR]

We investigated the effects of contralateral movement on the soleus H-reflex during bilateral movement of the ankles. The soleus H-reflex was evoked during unilateral or in-phase or antiphase bilateral ankle movement in healthy humans. The soleus H-reflex amplitude during antiphase movement was not significantly different from that during in-phase movement. The H-reflex amplitude during in-phase movement was not significantly different from that during unilateral movement of the tested ankle. The H-reflex amplitude in the maximal plantar flexion phase of the tested ankle during antiphase movement was significantly smaller than that in the corresponding phase during unilateral movement. The amount of the decrease was 21%. The effect of contralateral movement is prominent during antiphase movement of the ankles. [ABSTRACT FROM AUTHOR]

Abstract Background Hereditary cancer screening (HCS) for germline variants in the 3′ exons of PMS2, a mismatch repair gene implicated in Lynch syndrome, is technically challenging due to homology with its pseudogene PMS2CL. Sequences of PMS2 and PMS2CL are so similar that next-generation sequencing (NGS) of short fragments—common practice in multigene HCS panels—may identify the presence of a variant but fail to disambiguate whether its origin is the gene or the pseudogene. Molecular approaches utilizing longer DNA fragments, such as long-range PCR (LR-PCR), can definitively localize variants in PMS2, yet applying such testing to all samples can have logistical and economic drawbacks. Methods To address these drawbacks, we propose and characterize a reflex workflow for variant discovery in the 3′ exons of PMS2. We cataloged the natural variation in PMS2 and PMS2CL in 707 samples and designed hybrid-capture probes to enrich the gene and pseudogene with equal efficiency. For PMS2 exon 11, NGS reads were aligned, filtered using gene-specific variants, and subject to standard diploid variant calling. For PMS2 exons 12–15, the NGS reads were permissively aligned to PMS2, and variant calling was performed with the expectation of observing four alleles (i.e., tetraploid calling). In this reflex workflow, short-read NGS identifies potentially reportable variants that are then subject to disambiguation via LR-PCR-based testing. Results Applying short-read NGS screening to 299 HCS samples and cell lines demonstrated >99% analytical sensitivity and >99% analytical specificity for single-nucleotide variants (SNVs) and short insertions and deletions (indels), as well as >96% analytical sensitivity and >99% analytical specificity for copy-number variants. Importantly, 92% of samples had resolved genotypes from short-read NGS alone, with the remaining 8% requiring LR-PCR reflex. Conclusion Our reflex workflow mitigates the challenges of screening in PMS2 and serves as a guide for clinical laboratories performing multigene HCS. To facilitate future exploration and testing of PMS2 variants, we share the raw and processed LR-PCR data from commercially available cell lines, as well as variant frequencies from a diverse patient cohort.

Aim: Lynch Syndrome is associated with a significant risk of colorectal carcinoma (CRC) and other cancers. Universal tumor screening is a strategy to identify high-risk individuals by testing all CRC tumors for molecular features suggestive of Lynch Syndrome. Patient interest in screening and preferences for consent have been underexplored. Methods: A postal survey was administered to CRC patients in a Canadian province. Results: Most patients (81.4%) were willing to have tumors tested if universal tumor screening were available and were willing to discuss test results with family members and healthcare professionals. The majority (62.6%) preferred informed consent be obtained prior to screening. Conclusion: Patients were supportive of universal screening. They expected consent to be obtained, contrary to current practice across Canada and elsewhere. [ABSTRACT FROM AUTHOR]

The aim of this study was to test the hypothesis that plasma sphingosine 1-phosphate (S1P) levels are associated with the risk of cardiovascular autonomic neuropathy (CAN) in type 2 diabetes patients. This cross-sectional study included 287 individuals with type 2 diabetes. CAN was evaluated using cardiovascular reflex tests. Logistic regression analyses were conducted to assess the relationship between plasma S1P levels and CAN. Plasma S1P concentrations were significantly lower in individuals with CAN than in those without CAN. There was a significant interaction between plasma S1P levels and sex with respect to CAN (p for interaction = 0.003). When stratified by sex, the association between plasma S1P levels and CAN exhibited a sex difference; in multivariable analysis, plasma S1P levels were significantly associated with CAN in women (odds ratio per standard deviation increase in the log-transformed value, 0.40; 95% confidence interval, 0.23–0.70, p = 0.001). However, there was no significant association between plasma S1P and CAN in men. Plasma S1P concentrations were inversely associated with CAN only in women with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Urinalysis (UA) reflex testing approaches, which offer potential for savings in labor and result turnaround time, may rely on the performance of a chemical UA screen to determine which urine samples need microscopic UA and/or urine culture.We correlated chemical UA, microscopic UA, and urine culture results to determine the performance of chemical UA as a screening tool for reflex testing approaches. Methods: Consecutive UA results for 9127 tests (simultaneous chemical UA and microscopic UA) were retrospectively reviewed and correlated. Urine culture results were also correlated for 3127 samples that had urine culture ordered within 24 h of UA. Positivity criteria for each UA method were predefined. Results: Chemical UA yielded the following performance specifications for predicting microscopic findings: 93.0% sensitivity, 56.9% specificity, 64.7% positive predictive value, 90.5% negative predictive value. 3.2% of samples were negative by chemical UA but positive by microscopic UA. Of the samples with urine culture results available, 6.3% were negative by chemical UA but had clinically-significant positive urine cultures. Conclusions: Reflex testing of microscopic UA and/or urine culture dependent from chemical UA results provides a feasible opportunity to reduce unnecessary testing. [ABSTRACT FROM AUTHOR]

• Use of data mining approaches as alternative to inappropriate reference ranges. • Optimization of thyrotropin cut-off values for the reflex addition of thyroxine. • Optimization of cut-off values enables an economic saving without clinical consequences. Measurement of serum thyrotropin is currently the recommended test for the screening of thyroid dysfunction, while serum free thyroxine is kept as a reflex test. In our laboratory, the strategy followed in adult individuals from Primary Care includes a 'safety margin' for requests with a thyrotropin ≤1.0 or ≥4.0 mIU/L (normal: 0.35–4.95 mIU/L). Our aim was to optimize the thyrotropin cut-off values for the addition of free thyroxine and, based on these cut-offs, to retrospectively analyze avoidable free thyroxine measurements and possible adverse clinical consequences. Retrospective observational study performed in a tertiary care hospital between 2013 and 2018. We considered all laboratory requests for screening of thyroid dysfunction (TD) in adult patients from Primary Care. Requests from patients with a previous diagnosis of thyroid disease or pregnant women were excluded. Different receiver operating characteristic (ROC) curves were performed and the obtained thyrotropin cut-off values were compared. Economic savings were assessed considering the current cost of free thyroxin assays in our laboratory. From a total of 554,529 TD protocols included, 119,504 requests had free thyroxine added. From the ROC curve that enables ≥95% of abnormal free thyroxine results to be detected, the thyrotropin values obtained were ≥4.58 mIU/L and ≤0.94 mIU/L. These thyrotropin cut-off values would lead to a saving of 22.7% of annual free thyroxine measurements without adverse clinical consequences. Setting optimized thyrotropin cutoffs for reflex testing of free thyroxine would reduce the need for this test. Clinical laboratories need to offer not only true results, but also become the cornerstone in the optimization of resources. [ABSTRACT FROM AUTHOR]

Georgia, with a high prevalence of HCV infection, launched the world's first national hepatitis C elimination program in April 2015. A key strategy is the identification, treatment, and cure of the estimated 150,000 HCV-infected people living in the country. We report on progress and key challenges from Georgia's experience. We constructed a care cascade by analyzing linked data from the national hepatitis C screening registry and treatment databases during 2015–2018. We assessed the impact of reflex hepatitis C core antigen (HCVcAg) testing on rates of viremia testing and treatment initiation (i.e. linkage to care). As of December 31, 2018, 1,101,530 adults (39.6% of the adult population) were screened for HCV antibody, of whom 98,430 (8.9%) tested positive. Of the individuals who tested positive, 78,484 (79.7%) received viremia testing, of whom 66,916 (85.3%) tested positive for active HCV infection. A total of 52,576 people with active HCV infection initiated treatment and 48,879 completed their course of treatment. Of the 35,035 who were tested for cure (i.e. , sustained virologic response [SVR]), 34,513 (98.5%) achieved SVR. Reflex HCVcAg testing, implemented in March 2018, increased rates of monthly viremia testing by 97.5% among those who screened positive for anti-HCV, however, rates of treatment initiation decreased by 60.7% among diagnosed viremic patients. Over one-third of people living with HCV in Georgia have been detected and linked to care and treatment, however, identification and linkage to care of the remaining individuals with HCV infection is challenging. Novel interventions, such as reflex testing with HCVcAg, can improve rates of viremia testing, but may result in unintended consequences, such as decreased rates of treatment initiation. Linked data systems allow for regular review of the care cascade, allowing for identification of deficiencies and development of corrective actions. This report describes progress in Georgia's hepatitis C elimination program and highlights efforts to promote hepatitis C virus screening and treatment initiation on a national scale. Georgia has made progress towards eliminating hepatitis C, treating over 50,000 people, approximately one-third of the number infected, and achieving cure for 98.5% of those tested. However, identifying infected individuals and linking them to care remains challenging. Novel approaches to increase diagnostic testing can have unintended consequences further down the care cascade. • One-third of HCV-infected individuals in Georgia have received treatment. • Use of reflex HCV core antigen greatly increased the number of individuals diagnosed with active infection • Identification of HCV-infected individuals and treatment initiation continue to be major challenges to HCV elimination in Georgia. [ABSTRACT FROM AUTHOR]

Background/aims: The addition of further tests to patient samples, whether by reflex (automated) methods or reflectively after result review, remains an important function of the diagnostic laboratory. This can assist clinicians with interpretation of results and aid further management. We aimed to investigate how this is performed within Clinical Biochemistry laboratories across the United Kingdom (UK). Methods: A questionnaire, consisting of 16 clinical scenarios, was circulated to Clinical Biochemistry laboratories across the UK via the Association for Clinical Biochemistry and Laboratory Medicine (ACB) office. The survey sought to examine opinion on what tests are considered reflex and reflective, which staff members are involved in addition of further tests, whether clinicians are contacted and how abnormal results are handled. Results: Responses were received from 74 laboratories, and data were compiled for each scenario surveyed. The majority of laboratories are adding calcium and magnesium, reflectively, to confirm hyperkalaemia or hypocalcaemia, and a number of additional endocrine tests are also commonly performed in particular scenarios. However, there are variations in what is regarded as reflex and reflective testing, in how this testing is conducted within the laboratory and in the level of communication with the requesting clinician. Discussion: We present the consensus views of the survey participants for a number of commonly used additional tests within Clinical Biochemistry and a discussion on current reflex and reflective testing practice based on the survey results and evidence, where it exists. There is a need for harmonization and national guidance in this area. [ABSTRACT FROM AUTHOR]

Context: Peroneal reaction to sudden inversion has been determined to be too slow to overcome the joint motion. A focused plyometric training program may decrease the muscle’s reaction time. Objective: To determine the effect of a 6-wk slyometric training program on peroneus longus reaction time. Design: Repeated measures. Setting: University research laboratory. Participants: 48 healthy volunteers (age 20.0 ± 1.2 y, height 176.1 ± 16.9 cm, weight 74.5 ± 27.9 kg) from a large Midwester university. Subjects were randomly assigned to either a training group or a control group. Interventions: Independent variables were group at 2 levels (training and no training) and time at 2 levels (pretest and posttest). The dependent variable was peroneal latency measured with surface electromyography. A custom-made trapdoor device capable of inverting the ankle to 30° was also used. Latency data were obtained from the time the trapdoor dropped until the peroneus longus muscle activated. Peroneal latency was measured before and after the 6-wk training period. The no-training group was instructed to maintain current activities. The training group performed a 6-wk plyometric protocol 3 times weekly. Data were examined with a repeated-measures ANOVA with 1 within-subject factor (time at 2 levels) and 1 between-subjects factor (group at 2 levels). A priori alpha level was set at P ≤ .05. Main Outcome Measures: Pretest and posttest latency measurements (ms) were recorded for the peroneus longus muscle. Results: The study found no significant group-by-time interaction (F1,46 = 0.03, P = .87). In addition, there was no difference between the pretest and posttest values (pretest = 61.76 ± 14.81 ms, posttest = 59.24 ± 12.28 ms; P = .18) and no difference between the training and no-training groups (training group = 59.10 ± 12.18 ms, no-training group = 61.79 ± 15.18 ms; P = .43). Conclusions: Although latency measurements were consistent with previous studies, the plyometric training program did not cause significant change in the peroneus longus reaction time. [ABSTRACT FROM AUTHOR]

The purpose of this study was to test the effect of arm swing on modulation of soleus H-reflexes amplitudes during walking. Fifteen subjects walked (1.07 m/s) on a treadmill in 4 arm swing conditions: 1-natural arm swing (control), 2-active restraint, 3-passive restraint, and 4-passive-assisted. Tibial nerve was electrically stimulated and soleus EMG was recorded. H-reflex amplitude was significantly greater during active than during passive restraint (p = .013). Remaining arm swing conditions were not significantly different. We detected a subtle effect of arm swing on soleus H-reflex amplitude. Descending regulation may serve as a gating mechanism to control the effect of arm movements on reflex pathways for leg muscles. This gating mechanism may be impaired postneural injury, potentially enhancing the modulation of peripheral sensory inputs on reflexes in leg muscles during walking. Future experiments to test additional conditions and evoking reflexes in more phases of walking are recommended. [ABSTRACT FROM AUTHOR]

Examines the H-reflex size in young and elderly adults of varying physical activity levels. Measurement of H-wave maximum and M-wave maximum ratios; Decrease H-reflexes among elderly group; Effect of age on H-reflexes.

Within the 180 SPE tests that were reflexively sent for AAT phenotyping, 142 were found to have a clinically relevant AAT phenotype (Table 1), including five ZZ (severely AAT deficient) phenotypes (2.8% or 1/36). The measured AAT ranged between <=0.2 and 1.7 g/L, with a median of 1.0 g/L. In 180 cases, the AAT level was <1.0 g/L, triggering further investigation with an AAT phenotype. In addition, data were gathered for both requests for serum AAT levels and AAT phenotype results from this period that did not have an associated SPE request ("targeted testing"). [Extracted from the article]

Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients BRAF mutation testing is recommended for stage III–IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.

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Background The Jaffe and enzymatic methods are the 2 most common methods for creatinine measurement. The Jaffe method is less expensive but subject to interferences. Some laboratory scientists have called for the Jaffe method to be retired. Objective To determine the most cost-effective and safe protocol for creatinine measurement. Method We performed a retrospective database review of all outpatient creatinine measurements for 1 year, testing the risk-based reflex testing protocol we had implemented for creatinine measurement. Samples were first measured using the Jaffe method and were reflexed to the enzymatic method if the estimated glomerular filtration rate (eGFR) was between 55 and 65 mL per min per 1.73 m2. Results There were 104,530 creatinine measurements, of which 11,420 (10.9%) were reflexed to the enzymatic method. The Jaffe method had a positive bias of 0.08 mg per dL (−6.14 mL/min/1.73 m2 eGFR). A total of 3.4% of the paired reflexed specimens were discordant. Also, 133 (1.2%) of the Jaffe results were classified as false negatives and 3411 (29.9%) were classified as false positives. None of the false-negative results and 5 of the false-positive results were considered clinically significant. Using the reflex protocol saved approximately $40,000 per year. Conclusions The reflex protocol for creatinine measurement can reduce costs with acceptable risk. [ABSTRACT FROM AUTHOR]

Background This review summarizes current knowledge about cardiovascular reflex tests (CVRTs) and other selected autonomic nervous system (ANS) assessment tests in systemic lupus erythematosus (SLE) patients and assesses their clinical utility in this group of patients. Methods The PubMed database was searched for terms associated with CVRTs and SLE. Only papers available in full text and published in English were considered. Ultimately, 13 were selected and analyzed. Results In most of the studies CVRTs results were reported more likely to be abnormal in patients with SLE when compared with controls. The reported prevalence of ANS dysfunction in SLE, diagnosed using CVRTs, ranged from 23.5% to 82.7% of patients, likely because of different definitions of ANS dysfunction, variability in methods of performing CVRTs, and potential confounding factors. In general CVRTs results did not correlate with SLE activity or disease duration, but some CVRTs results correlated with some peptides associated with ANS function, including neuropeptide Y and vasoactive intestinal peptide. Conclusion Patients with SLE generally have abnormal or borderline results of CVRTs, which indicate prevalent abnormalities of the ANS in SLE. Performance of CVRTs requires good standardization of test conditions and familiarity with the proper administration and interpretation of these tests. [ABSTRACT FROM AUTHOR]

Summary: A reliable assessment method is required to manage the gag reflex. We tested the inter‐ and intra‐examiner reliability and validity of a quantitative measurement method and evaluated the differences between sexes. This study included 21 healthy adults (10 women, 11 men; mean age, 27.1 ± 9.9 years). An examiner inserted a standard saliva ejector slowly down the participant's throat to determine the maximum tolerance of the gag reflex; the insertion depth was used as an index of gag reflex. The reflex was measured by one examiner during two sessions (S1 and S3) and by a second examiner during one session (S2) under the same conditions. The galvanic skin response (GSR) and heart rate (HR) were recorded during each session to test the method validity. Data were analysed using the intraclass correlation coefficient (ICC), paired t test, and two‐way repeated‐measures analysis of variance. The ICC of the gag reflex measurements was 0.91 between S1 and S2, and 0.93 between S1 and S3. The GSR and HR increased significantly after the maximum tolerance of the reflex in S1, S2, and S3 (GSR: P < 0.001, P = 0.004, P = 0.001, respectively; HR: all, P < 0.001). Differences in the measurements according to sex and session were not significant. Our method exhibited excellent inter‐ and intra‐examiner reliability and was unaffected by the participants’ sex. Measurement revealed significant autonomic reactivity, which is common for this reflex. Consequently, this method may be used in clinical and laboratory‐based applications. [ABSTRACT FROM AUTHOR]