Identifying and Linking Patients At Risk for MASLD with Advanced Fibrosis to Care in Primary Care.

BACKGROUND AND AIMS: Severity of fibrosis is the driver of liver-related outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD), and non-invasive testing such as fibrosis-4 (FIB-4) score is utilized for risk stratification. We aimed to determine if primary care patients at risk for MASLD and advanced fibrosis were evaluated with subsequent testing. A secondary aim was to determine if at-risk patients with normal aminotransferases had advanced fibrosis. METHODS: Primary care patients at increased risk for MASLD with advanced fibrosis (n = 91,914) were identified using previously established criteria. Patients with known alternative/concomitant etiology of liver disease or cirrhosis were excluded. The study cohort included patients with calculated FIB-4 score in 2020 (n = 52,006), and stratified into low, indeterminate, and high likelihood of advanced fibrosis. Among those at indeterminate/high risk, rates of subsequent testing were measured. RESULTS: Risk stratification with FIB-4 characterized 77% (n = 40,026) as low risk, 17% (n = 8847) as indeterminate, and 6% (n = 3133) as high risk. Among indeterminate/high-risk patients (n = 11,980), 78.7% (n = 9433) had aminotransferases within normal limits, 0.95% (n = 114) had elastography, and 8.2% (n = 984) were referred for subspecialty evaluation. CONCLUSION: In this cohort of primary care patients at risk for MASLD with fibrosis, the FIB-4 score identified a substantial proportion of indeterminate/high-risk patients, the majority of which had normal aminotransferase levels. Low rates of subsequent testing were observed. These data suggest that a majority of patients at increased risk for liver-related outcomes remain unrecognized and highlight opportunities to facilitate their identification.

Innovative Non-Invasive and Non-Intrusive Precision Thermometry in Stainless-Steel Tanks Using Ultrasound Transducers.

Measuring temperature inside chemical reactors is crucial to ensuring process control and safety. However, conventional methods face a number of limitations, such as the invasiveness and the restricted dynamic range. This paper presents a novel approach using ultrasound transducers to enable accurate temperature measurements. Our experiments, conducted within a temperature range of 28.8 to 83.8 °C, reveal a minimal temperature accuracy of 98.6% within the critical zone spanning between 70.5 and 75 °C, and an accuracy of over 99% outside this critical zone. The experiments focused on a homogeneous environment of distilled water within a stainless-steel tank. This approach will be extended in a future research in order to diversify the experimental media and non-uniform environments, while promising broader applications in chemical process monitoring and control.

Assessment of portal hypertension severity using machine learning models in patients with compensated cirrhosis.

BACKGROUND & AIMS: In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD. METHODS: A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e., HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. RESULTS: Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively). CONCLUSIONS: Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation. IMPACT AND IMPLICATIONS: We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension.

The use of current knowledge and non-invasive testing modalities for predicting at-risk non-alcoholic steatohepatitis and assessing fibrosis.

There is ongoing recognition of the burden of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), with fibrosis being the most important histological feature that is associated with progression to cirrhosis and the occurrence of major adverse liver outcomes. Liver biopsy is the gold standard applied to detect NASH and determine the stage of fibrosis, but its use is limited. There is a need for non-invasive testing (NIT) techniques to identify patients considered at-risk NASH (NASH with NAFLD activity score > 4 and ≥ F2 fibrosis). For NAFLD-associated fibrosis, several wet (serological) and dry (imaging) NITs are available and demonstrate a high negative predictive value (NPV) for excluding those with advanced hepatic fibrosis. However, identifying at-risk NASH is more challenging; there is little guidance on how to use available NITs for these purposes, and these NITs are not specifically designed to identify at-risk NASH patients. This review discusses the need for NITs in NAFLD and NASH and provides data to support the use of NITs, focusing on newer methods to non-invasively identify at-risk NASH patients. This review concludes with an algorithm that serves as an example of how NITs can be integrated into care pathways of patients with suspected NAFLD and potential NASH. This algorithm can be used for staging, risk stratification and the effective transition of patients who may benefit from specialty care.

FIB-4 and incident severe liver outcomes in patients with undiagnosed chronic liver disease: A Fine-Gray competing risk analysis.

BACKGROUND AND AIMS: The Fibrosis-4 index (FIB-4) can reliably assess fibrosis risk in patients with chronic liver disease, and advanced fibrosis is associated with severe liver disease (SLD) outcomes. However, CLD is underdiagnosed in primary care. We examined the association between FIB-4 risk strata and the incidence of SLD preceding a CLD diagnosis while considering incident CLD diagnoses as competing risks. METHODS: Using primary care clinic data between 2007 and 2018, we identified patients with two FIB-4 scores and no liver disease diagnoses preceding the index FIB-4. Patients were followed from index FIB-4 until an incident SLD (a composite of cirrhosis, hepatocellular carcinoma or liver transplantation), CLD or were censored. Hazard ratios were computed using a Fine-Gray competing risk model. RESULTS: Of 20 556 patients, there were 54.8% in the low, 34.8% in the indeterminate, 6.6% in the high and 3.8% in the persistently high-risk FIB-4 strata. During a mean 8.2 years of follow-up, 837 (4.1%) patients experienced an SLD outcome and 11.5% of the sample received a CLD diagnosis. Of patients with an SLD event, 49% received no preceding CLD diagnosis. In the adjusted Fine-Gray model, the indeterminate (HR 1.41, 95% CI 1.17-1.71), high (HR 4.65, 95% CI 3.76-5.76) and persistently high-risk (HR 7.60, 95% CI 6.04-9.57) FIB-4 risk strata were associated with a higher incidence of SLD compared to the low-risk stratum. CONCLUSIONS: FIB-4 scores with indeterminate- and high-risk values are associated with an increased incidence of SLD in primary care patients without known CLD.

Screening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice.

PURPOSE OF REVIEW: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease affecting 30% of the global population. In this article, we summarize current expert guidelines, review clinical practice implications, and provide insight into the utility of non-invasive tests (NITs). RECENT FINDINGS: The burden of MASLD is growing with the obesity epidemic, yet disease awareness and diagnosis is low. Patients can progress to metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), which can advance to liver fibrosis, cirrhosis, hepatic decompensation, and liver cancer. NITs help identify high-risk patients who may benefit from specialty referral and MASH-directed therapy. Global societies offer various recommendations for the screening and diagnosis of MASLD utilizing evidence-based, widely accessible methods such as serum indices, NITs, and liver biopsy. Several targeted steatotic liver disease (SLD) screening tools and novel therapies are under development.

Gaps in Confirmatory Fibrosis Risk Assessment in Primary Care Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND: As recommendations for non-invasive fibrosis risk assessment in nonalcoholic fatty liver disease (NAFLD) emerge, it is not known how often they are performed in primary care. AIMS: We investigated the completion of confirmatory fibrosis risk assessment in primary care patients with NAFLD and indeterminate-risk or greater Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Scores (NFS). METHODS: This retrospective cohort study of electronic health record data from a primary care clinic identified patients with diagnoses of NAFLD from 2012 through 2021. Patients with a diagnosis of a severe liver disease outcome during the study period were excluded. The most recent FIB-4 and NFS scores were calculated and categorized by advanced fibrosis risk. Charts were reviewed to identify the outcome of a confirmatory fibrosis risk assessment by liver elastography or liver biopsy for all patients with indeterminate-risk or higher FIB-4 (≥ 1.3) and NFS (≥ - 1.455) scores. RESULTS: The cohort included 604 patients diagnosed with NAFLD. Two-thirds of included patients (399) had a FIB-4 or NFS score greater than low-risk, 19% (113) had a high-risk FIB-4 (≥ 2.67) or NFS (≥ 0.676) score, and 7% (44) had high-risk FIB-4 and NFS values. Of these 399 patients with an indication for a confirmatory fibrosis test, 10% (41) underwent liver elastography (24) or liver biopsy (18) or both (1). CONCLUSIONS: Advanced fibrosis is a key indicator of future poor health outcomes in patients with NAFLD and a critical signal for referral to hepatology. Significant opportunities exist to improve confirmatory fibrosis risk assessment in patients with NAFLD.

Diagnosing Tuberculosis: What Do New Technologies Allow Us to (Not) Do?

New tuberculosis (TB) diagnostics are at a crossroads: their development, evaluation, and implementation is severely damaged by resource diversion due to COVID-19. Yet several technologies, especially those with potential for non-invasive non-sputum-based testing, hold promise for efficiently triaging and rapidly confirming TB near point-of-care. Such tests are, however, progressing through the pipeline slowly and will take years to reach patients and health workers. Compellingly, such tests will create new opportunities for difficult-to-diagnose populations, including primary care attendees (all-comers in high burden settings irrespective of reason for presentation) and community members (with early stage disease or risk factors like HIV), many of whom cannot easily produce sputum. Critically, all upcoming technologies have limitations that implementers and health workers need to be cognizant of to ensure optimal deployment without undermining confidence in a technology that still offers improvements over the status quo. In this state-of-the-art review, we critically appraise such technologies for active pulmonary TB diagnosis. We highlight strengths, limitations, outstanding research questions, and how current and future tests could be used in the presence of these limitations and uncertainties. Among triage tests, CRP (for which commercial near point-of-care devices exist) and computer-aided detection software with digital chest X-ray hold promise, together with late-stage blood-based assays that detect host and/or microbial biomarkers; however, aside from a handful of prototypes, the latter category has a shortage of promising late-stage alternatives. Furthermore, positive results from new triage tests may have utility in people without TB; however, their utility for informing diagnostic pathways for other diseases is under-researched (most sick people tested for TB do not have TB). For confirmatory tests, few true point-of-care options will be available soon; however, combining novel approaches like tongue swabs with established tests like Ultra have short-term promise but first require optimizations to specimen collection and processing procedures. Concerningly, no technologies yet have compelling evidence of meeting the World Health Organization optimal target product profile performance criteria, especially for important operational criteria crucial for field deployment. This is alarming as the target product profile criteria are themselves almost a decade old and require urgent revision, especially to cater for technologies made prominent by the COVID-19 diagnostic response (e.g., at-home testing and connectivity solutions). Throughout the review, we underscore the importance of how target populations and settings affect test performance and how the criteria by which these tests should be judged vary by use case, including in active case finding. Lastly, we advocate for health workers and researchers to themselves be vocal proponents of the uptake of both new tests and those - already available tests that remain suboptimally utilized.

Increasing uptake of colon cancer screening in a medically underserved population with the addition of blood-based testing.

BACKGROUND: Adherence to colorectal cancer screening in the United States is suboptimal, particularly in medically underserved populations due to significant barriers to care. Unique accessible, low-cost, and non-invasive screening tests for this population could greatly benefit current rates. In this article, we assess patient preference and the impact of offering a blood-based test on screening rates in a cost-free health fair setting from April 2017 to April 2019. METHODS: Participants who met colorectal cancer screening eligibility criteria set forth by the United States Preventive Services Task Force were recommended to attend the colon cancer screening station. Those participants who elected to attend were offered various, accepted screening methods, and if they declined, were offered alternative blood-based testing. Screening rates, test outcomes, and the rate of follow up completion of colonoscopy were measured and compared with historic screening outcomes. RESULTS: Of 1401 participants who were recommended to attend, 640 (45.7%) participants were evaluated at the colon cancer screening station, of whom 460 were eligible for testing. Amongst these, none selected colonoscopy, 30 (6.5%) selected fecal immunochemical testing, and 430 (93.5%) selected blood-based testing. Only 2 participants returned the fecal immunochemical tests. In the blood test cohort, 88 were positive and 20 received a follow up colonoscopy. CONCLUSIONS: Based on this assessment, blood-based testing is an effective method to increase screening rates in medically underserved populations, though efforts to further improve access to follow up colonoscopy are necessary.

The Enhanced Liver Fibrosis test maintains its diagnostic and prognostic performance in alcohol-related liver disease: a cohort study.

BACKGROUND: Alcohol is the main cause of chronic liver disease. The Enhanced Liver Fibrosis (ELF) test is a serological biomarker for fibrosis staging in chronic liver disease, however its utility in alcohol-related liver disease warrants further validation. We assessed the diagnostic and prognostic performance of ELF in alcohol-related liver disease. METHODS: Observational cohort study assessing paired ELF and histology from 786 tertiary care patients with chronic liver disease due to alcohol (n = 81) and non-alcohol aetiologies (n = 705). Prognostic data were available for 64 alcohol patients for a median of 6.4 years. Multiple ELF cut-offs were assessed to determine diagnostic utility in moderate fibrosis and cirrhosis. Survival data were assessed to determine the ability of ELF to predict liver related events and all-cause mortality. RESULTS: ELF identified cirrhosis and moderate fibrosis in alcohol-related liver disease independently of aminotransferase levels with areas under receiver operating characteristic curves of 0.895 (95% CI 0.823-0.968) and 0.923 (95% CI 0.866-0.981) respectively, which were non-inferior to non-alcohol aetiologies. The overall performance of ELF was assessed using the Obuchowski method: in alcohol = 0.934 (95% CI 0.908-0.960); non-alcohol = 0.907 (95% CI 0.895-0.919). Using ELF < 9.8 to exclude and ≧ 10.5 to diagnose cirrhosis, 87.7% of alcohol cases could have avoided biopsy, with sensitivity of 91% and specificity of 85%. A one-unit increase in ELF was associated with a 2.6 (95% CI 1.55-4.31, p < 0.001) fold greater odds of cirrhosis at baseline and 2.0-fold greater risk of a liver related event within 6 years (95% CI 1.39-2.99, p < 0.001). CONCLUSIONS: ELF accurately stages liver fibrosis independently of transaminase elevations as a marker of inflammation and has superior prognostic performance to biopsy in alcohol-related liver disease.

Appropriate utilization of cardiac computed tomography for the assessment of stable coronary artery disease.

BACKGROUND: Appropriate use criteria (AUC) have been developed in response to growth in cardiac imaging utilization and concern regarding associated costs. Cardiac computed tomography angiography (CCTA) has emerged as an important modality in the evaluation of coronary artery disease, however its appropriate utilization in actual practice is uncertain. Our objective was to determine the appropriate utilization of CCTA in a large quaternary care institution and to compare appropriate utilization pre and post publication of the 2013 AUC guidelines. We hypothesized that the proportion of appropriate CCTA utilization will be similar to those of other comparable cardiac imaging modalities and that there would be a significant increase in appropriate use post AUC publication. METHODS: We employed a retrospective cohort study design of 2577 consecutive patients undergoing CCTA between January 1, 2012 and December 30, 2016. An appropriateness category was assigned for each CCTA. Appropriateness classifications were compared pre- and post- AUC publication via the chi-square test. RESULTS: Overall, 83.5% of CCTAs were deemed to be appropriate based on the AUC. Before the AUC publication, 75.0% of CCTAs were classified as appropriate whereas after the AUC publication, 88.0% were classified as appropriate (p < 0.001). The increase in appropriate utilization, when extrapolated to the Medicare population of the United States, was associated with potential cost savings of approximately $57 million per year. CONCLUSIONS: We report a high rate of appropriate use of CCTA and a significant increase in the proportion of CCTAs classified as appropriate after the AUC publication.

Prediction of liver fibrosis severity in alcoholic liver disease by human microfibrillar-associated protein 4.

BACKGROUND: Alcoholic liver disease (ALD) is a public health concern that is the cause of half of all cirrhosis-related deaths. Early detection of fibrosis, ideally in the precirrhotic stage, is a key strategy for improving ALD outcomes and for preventing progression to cirrhosis. Previous studies identified the blood-borne marker human microfibrillar-associated protein 4 (MFAP4) as a biomarker for detection of hepatitis C virus (HCV)-related fibrosis. AIM: To evaluate the diagnostic accuracy of MFAP4 to detect ALD-induced fibrosis. METHOD: We performed a prospective, liver biopsy-controlled study involving 266 patients with prior or current alcohol overuse. Patients were split into a training and a validation cohort. RESULTS: MFAP4 was present in fibrotic hepatic tissue and serum MFAP4 levels increased with fibrosis grade. The area under the receiver operating characteristic curve (AUROC) for detection of cirrhosis was 0.91 (95% CI 0.85-0.96) in the training cohort and 0.91 (95% CI 0.79-1.00) in the validation cohort. For detection of advanced fibrosis, the AUROC was 0.88 (95% CI 0.81-0.94) in the training cohort and 0.92 (95% CI 0.83-1.00) in the validation cohort. The diagnostic accuracy did not differ between MFAP4 and the enhanced liver fibrosis (ELF) test or transient elastography (TE) in an intention-to-diagnose analysis. MFAP4 did not predict hepatic decompensation in a time-to-decompensation analysis in a subgroup of patients with cirrhosis. CONCLUSION: MFAP4 is a novel biomarker that can detect ALD-related fibrosis with high accuracy.

Physical Validation of a Residual Impedance Rejection Method during Ultra-Low Frequency Bio-Impedance Spectral Measurements.

Accurate and reliable measurement of the electrical impedance spectrum is an essential requirement in order to draw relevant conclusions in many fields and a variety of applications; in particular, for biological processes. Even in the state-of-the-art methods developed for this purpose, the accuracy and efficacy of impedance measurements are reduced in biological systems, due to the regular occurrence of parameters causing measurement errors such as residual impedance, parasitic capacitance, generator anomalies, and so on. Recent observations have reported the necessity of decreasing such inaccuracies whenever measurements are performed in the ultra-low frequency range, as the above-mentioned errors are almost entirely absent in such cases. The current research work proposes a method which can reject the anomalies listed above when measuring in the ultra-low frequency range, facilitating data collection at the same time. To demonstrate our hypothesis, originating from the consideration of the determinant role of the measuring frequency, a physical model is proposed to examine the effectiveness of our method by measuring across the commonly used vs. ultra-low frequency ranges. Validation measurements reflect that the range of frequencies and the accuracy is much greater than in state-of-the-art methods. Using the proposed new impedance examination technique, biological system characterization can be carried out more accurately.

Oral fluid testing facilitates understanding of hepatitis A virus household transmission.

The public health response to sporadic hepatitis A virus (HAV) infection, hepatitis A, can be complex especially when the index case is a child and no obvious source is identified. Identifying an infection source may avoid mass immunisation within schools when transmission is found to have occurred within the household. Screening of asymptomatic contacts via venepuncture can be challenging and unacceptable, as a result non-invasive methods may facilitate public health intervention. Enzyme-linked immunoassays were developed to detect HAV immunoglobulin M (IgM) and immunoglobulin G (IgG) in oral fluid (ORF). A validation panel of ORF samples from 30 confirmed acute HAV infections were all reactive for HAV IgM and IgG when tested. A panel of 40 ORF samples from persons known to have been uninfected were all unreactive. Two hundred and eighty household contacts of 72 index cases were screened by ORF to identify HAV transmission within the family and factors associated with household transmission. Almost half of households (35/72) revealed evidence of recent infection, which was significantly associated with the presence of children ⩽11 years of age (odds ratio 9.84, 95% confidence interval: 2.74-35.37). These HAV IgM and IgG immunoassays are easy to perform, rapid and sensitive and have been integrated into national guidance on the management of hepatitis A cases.

The Role of Non-invasive Testing in Evaluation and Diagnosis of Pediatric Lower Urinary Tract Dysfunction.

PURPOSE OF REVIEW: The symptoms of lower urinary tract dysfunction (LUTD) including urinary incontinence, frequency, and urgency are among the most common reasons children are referred to pediatric urologists. Despite this, the workup for LUTD is often time consuming and a source of frustration for patients, parents, and clinicians alike. In the current review, we summarize the important role non-invasive testing plays in the diagnosis and management of children with LUTD and to show how use of these tests can help avoid the need for more invasive testing in the majority of children. RECENT FINDINGS: Non-invasive tests such urine studies, uroflowmetry ± simultaneous electromyography, assessment of post-void residual, renal/bladder ultrasound, and pelvic ultrasound when used appropriately can provide valuable information to facilitate decision making during the evaluation of children with LUTD. While these tests should be employed prior to more invasive testing such as urodynamic studies, they can often act as a surrogate for the more invasive tests. Non-invasive tests can help us in our goal of improving diagnostic ability to better classify the child's LUTD into an actual condition which allows targeted treatment in the hope of better outcomes and more satisfied patients and families.

Targeted antenatal anti-D prophylaxis program for RhD-negative pregnant women - outcome of the first two years of a national program in Finland.

INTRODUCTION: The aim of this study was to assess the accuracy of the non-invasive fetal RHD test at 24-26 weeks of gestation as part of the national antenatal screening program to target routine antenatal anti-D prophylaxis (RAADP) at 28-30 weeks at women carrying an RhD-positive fetus. MATERIAL AND METHODS: A prospective cohort study involving all maternity care centers and delivery hospitals in Finland between February 2014 and January 2016. Fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed with real-time polymerase chain reaction in a centralized setting. The results were systematically compared with the serological newborn RhD typing. The main outcome measure was the accuracy of the fetal RHD assay; the secondary variable was compliance with the newly introduced RAADP program. RESULTS: Fetal RHD was screened from 10 814 women. For the detection of fetal RHD, sensitivity was 99.99% [95% confidence interval (CI) 99.92-99.99] and specificity 99.81% (95% CI 99.60-99.92). One false-negative and seven false-positive results were reported by the delivery hospitals in two years. The negative predictive value of the test was 99.97% (95% CI 99.81-99.99). At the end of the study period, over 98% of the RhD-negative women participated in the new screening program. CONCLUSIONS: The targeted RAAPD program was implemented effectively in the national maternity care program in Finland. An accurate fetal RHD screening test allows discontinuation of newborn testing without risking the postnatal prophylaxis program. In the future, the main area to investigate will be the clinical effect of RAADP on subsequent pregnancies.

Fetal analysis with invasive method (FA-I) and fetal analysis with non-invasive method (FA-NI): replacing current, deceptively imprecise clinical nomenclature.

There is a problem with the current nomenclature of prenatal evaluation. The current nomenclature of "prenatal testing" and "prenatal screening" - along with their subsets of "ultrasound testing," "ultrasound screening," "non-invasive prenatal testing," "non-invasive prenatal screening," and "prenatal diagnosis" - has become so imprecise that clinical misinterpretation and distortion of the informed consent process are increasingly difficult to avoid. To remedy this problem, we propose a new, precise nomenclature: "fetal analysis with invasive method" (FA-I) and "fetal analysis with non-invasive method," (FANI) using various techniques. This new nomenclature is designed to be precise and therefore facilitate effective communication among physicians and with pregnant women. For ease of use the new nomenclature can be formulated as an abbreviation: FA-I and FA-NI.

Expanding non-invasive prenatal testing beyond chromosomes 21, 18, 13, X and Y.

Non-invasive prenatal testing (NIPT) based on cell-free DNA in maternal plasma is being expanded to include additional chromosome abnormalities beyond those involving chromosomes 21, 18, 13, X and Y. Review of population cytogenetic data provides insight into the likely number of additional abnormalities detectable. Additional clinically significant and cytogenetically recognizable abnormalities are present in less than 0.1% of newborns but clinically significant, or potentially significant, sub-microscopic imbalances are expected to be present in 1.7%. Cytogenetic studies on chorionic villus samples suggests that after excluding abnormalities involving chromosomes 21, 18, 13, X and Y, approximately 0.6% of NIPT results may be positive for an unbalanced abnormality attributable to mosaicism but most of these will not be confirmed at amniocentesis or in newborns. NIPT has also been developed for specific microdeletion syndromes and initial experience is now available. Laboratory procedures such as deeper sequencing and additional data analytics are rapidly evolving but even with existing protocols, it is already clear that NIPT does not necessarily need to be limited to trisomies 21, 18, 13 and the sex-chromosome abnormalities. Patient educational materials and genetic counseling services need to be available for women offered expanded NIPT.

Recent advances in preimplantation genetic diagnosis and screening.

Preimplantation genetic diagnosis/screening (PGD/PGS) aims to help couples lower the risks of transmitting genetic defects to their offspring, implantation failure, and/or miscarriage during in vitro fertilization (IVF) cycles. However, it is still being debated with regard to the practicality and diagnostic accuracy of PGD/PGS due to the concern of invasive biopsy and the potential mosaicism of embryos. Recently, several non-invasive and high-throughput assays have been developed to help overcome the challenges encountered in the conventional invasive biopsy and low-throughput analysis in PGD/PGS. In this mini-review, we will summarize the recent progresses of these new methods for PGD/PGS and discuss their potential applications in IVF clinics.

Clinical outcomes of fractional flow reserve by computed tomographic angiography-guided diagnostic strategies vs. usual care in patients with suspected coronary artery disease: the prospective longitudinal trial of FFR(CT): outcome and resource impacts study.

AIMS: In symptomatic patients with suspected coronary artery disease (CAD), computed tomographic angiography (CTA) improves patient selection for invasive coronary angiography (ICA) compared with functional testing. The impact of measuring fractional flow reserve by CTA (FFRCT) is unknown. METHODS AND RESULTS: At 11 sites, 584 patients with new onset chest pain were prospectively assigned to receive either usual testing (n = 287) or CTA/FFR(CT) (n = 297). Test interpretation and care decisions were made by the clinical care team. The primary endpoint was the percentage of those with planned ICA in whom no significant obstructive CAD (no stenosis ≥50% by core laboratory quantitative analysis or invasive FFR < 0.80) was found at ICA within 90 days. Secondary endpoints including death, myocardial infarction, and unplanned revascularization were independently and blindly adjudicated. Subjects averaged 61 ± 11 years of age, 40% were female, and the mean pre-test probability of obstructive CAD was 49 ± 17%. Among those with intended ICA (FFR(CT)-guided = 193; usual care = 187), no obstructive CAD was found at ICA in 24 (12%) in the CTA/FFR(CT) arm and 137 (73%) in the usual care arm (risk difference 61%, 95% confidence interval 53-69, P< 0.0001), with similar mean cumulative radiation exposure (9.9 vs. 9.4 mSv, P = 0.20). Invasive coronary angiography was cancelled in 61% after receiving CTA/FFR(CT) results. Among those with intended non-invasive testing, the rates of finding no obstructive CAD at ICA were 13% (CTA/FFR(CT)) and 6% (usual care; P = 0.95). Clinical event rates within 90 days were low in usual care and CTA/FFR(CT) arms. CONCLUSIONS: Computed tomographic angiography/fractional flow reserve by CTA was a feasible and safe alternative to ICA and was associated with a significantly lower rate of invasive angiography showing no obstructive CAD.