Potential Sampling Error Research Articles

Enhancing Diagnostic Precision and Clinical Outcomes With FNAC in Parotid Gland Masses.

Parotid gland masses encompassing both neoplastic and non-neoplastic conditions present diagnostic challenges. Fine-needle aspiration cytology (FNAC) is commonly used to differentiate between benign and malignant lesions but has limitations such as variable sensitivity and potential sampling errors. This study assesses FNAC's accuracy for parotid gland lesions, evaluates the Milan Salivary Gland Cytopathology Reporting System (MSRSGC), and compares FNAC results with histopathological findings. This retrospective study at our medical center analyzed data from 2321 patients who underwent parotid gland FNAC followed by surgical resection over 20 years. Patients were included if they had both cytological analysis and surgery between January 2004 and July 2024. Surgical procedures varied based on mass characteristics and FNAC results, and all samples were assessed using MSRSGC. Statistical analysis compared FNAC results with histopathology findings, calculating sensitivity, specificity, and accuracy. This study included 352 patients who underwent both FNAC and surgical resection. FNAC had an overall accuracy of 93.9%, with a sensitivity of 78.3% and specificity of 91.5%. The risk of malignancy was 30% for Milan Category I (nondiagnostic), 6.3% for Category II (non-neoplastic), 0% for Category III (Atypia of Undetermined Significance), 2.3% for Category IVa (benign neoplasm), 5.8% for Category IVb (neoplasm of uncertain malignant potential), 58.8% for Category V (suspicious for malignancy), and 95% for Category VI (malignant). The false negative rate was 2.4%, while the false positive rate was 3.4%. The malignancy risk increased with age, and malignant masses were larger and more likely to cause facial paralysis. FNAC is a key diagnostic tool for parotid gland masses, offering high specificity and accuracy despite some limitations. Patients with young ages and inappropriate histories should be assessed more carefully. MSRSGC is a useful system to show appropriate risk of malignancy.

Feasibility and effectiveness of a foam rolling intervention in pregnant women requiring bed rest for foetal protection: a randomised controlled trial

BackgroundBed rest during pregnancy can lead to reduced physical activity, impairing lower limb venous blood flow and increasing the risk of deep vein thrombosis (DVT) and muscle atrophy. We investigated the clinical efficacy of foam rolling intervention (FRI) in enhancing lower limb venous blood flow, mitigating the risk of DVT and muscle atrophy in pregnant women on bed rest.MethodsThis single-blind, randomised controlled trial enrolled 86 pregnant women with long-term bed rest for foetal protection (≥ 7 days), gestational age ≥ 20 weeks, and maternal age < 40 years. Participants were randomly assigned to a control or experimental group using a random number table. The control group received standard care, whereas the experimental group underwent FRI. Researchers and statisticians were aware of the treatment groups, however, the participants were blinded. Lower limb blood flow velocity, D-dimer levels, incidence of DVT, and the extent of lower limb muscle atrophy were assessed in both groups at baseline and post-intervention (day 7). To account for a 5% attrition rate and potential sampling error, the estimated sample size for each experimental and control group was 40.ResultsBefore the intervention, no significant differences were observed between the experimental and control groups in peak blood flow, mean flow velocity, D-dimer values, or leg circumference (P > 0.05), however, the peak blood velocities of the popliteal veins were significantly higher in the control group (P = 0.031). On the seventh day post-intervention, the experimental group had significantly higher mean and peak blood velocities in femoral and popliteal veins, significantly (P < 0.05), lower mean D-dimer levels (P = 0.035), and a significantly smaller reduction in thigh and calf circumference (P < 0.001). Consequently, the rate of thigh muscle atrophy was significantly slower in the experimental group (P = 0.011).ConclusionsFRI is an effective intervention for improving lower limb venous blood flow, mitigating the risk of DVT and muscle atrophy in pregnant women on bed rest.Trial registrationThis trial was retrospectively registered with the Chinese Clinical Trial Registry on June 18, 2024 (registration number: ChiCTR2400085770).

Heterogeneous Pathological Changes in Liver Lobes During Liver Disease: A Perspective Review.

Liver diseases have a global prevalence of 25%, accounting for 4% of all deaths worldwide, and are associated with a 36% increased risk of fatal and nonfatal cardiovascular events. Metabolic dysfunction-associated steatotic liver disease constitutes the liver expression of metabolic syndrome and represents the primary type of liver disease. Microscopical analysis of biopsies, which allows the evaluation of a small portion of tissue with inferences made to the entire organ, is considered the gold standard for determining the presence of liver diseases. However, potential sampling errors in liver biopsies are conceivable because the obtained tissue represents only a tiny fraction of the entire liver mass and may not accurately reflect the true pathological state. Studies have demonstrated the existence of sampling errors in liver biopsies, particularly concerning the severity of inflammation, degree of fibrosis, and the presence of cirrhosis. Also, clinical studies have shown that histopathological abnormalities are better detected in humans when liver samples are collected from both the right and the left lobes. However, a gap exists in clinical investigation to clarify the role of differences between these lobes in improving the diagnostic and prognostic for liver diseases. Building upon the heterogeneous nature of pathological alterations observed in liver lobes, this perspective review provided recommendations to enhance the precision of diagnosis and prognostic accuracy of liver diseases.

Spatial Heterogeneity of Glomerular Phenotypes Affects Kidney Biopsy Findings.

Detection of rare glomerular phenotypes can impact diagnosis in indication kidney biopsies and in kidney tissue used for research studies. Nephropathologists are aware of potential sampling error when assessing needle biopsy cores but quantitative data are lacking. Kidney tissue from patients undergoing total nephrectomy enrolled in an observational, cross-sectional cohort study was used to characterized glomeruli as typical or atypical, which included globally sclerosed glomeruli (GSG), segmentally sclerosed glomeruli (SSG), ischemic-like, and imploding. A 2D map of the glomerular annotations was generated. Spatial centrality of atypical glomeruli using the L2 metric and differences in pairwise distances between typical or atypical glomeruli were calculated. To determine how the yield of capturing atypical glomerular phenotype was affected by biopsy depth (i.e. not including the renal capsule), simulated kidney biopsies were generated from the 2D map. The mean number of glomeruli in a nephrectomy specimen was 209 (SD 143), and GSG were the most common type of atypical glomeruli (median: 13% [IQR: 5,31]). Typical glomeruli were more likely to be surrounded by other glomeruli (i.e. centrally located in kidney cortex) than GSG, SSG, ischemic-like and imploding glomeruli. Atypical glomeruli were 7.3% (95% CI 4.1, 10.4) closer together than typical glomeruli and were more likely to be closer together in older patients or those with hypertension. In simulated kidney biopsies, failure to capture the capsule was associated with under-detection of GSG, ischemic-like and imploding glomeruli. Spatial analysis of large sections of kidney tissue provided quantitative evidence of spatial heterogeneity of glomerular phenotypes including clustering of atypical glomeruli in individuals with hypertension or older age. Most importantly, deep kidney biopsies that lack subcapsular area under-detect atypical glomerular phenotypes, suggesting that capturing the renal capsule as an important quality control measure for kidney biopsies.

Noninvasive disease severity assessment in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease affecting one-fourth population globally. It is also anticipated to be the major cause of liver-related morbidity and transplantation worldwide in the future decades.1 Of note the Asia-Pacific has a tremendous burden because of the rapid Westernization of the region and the racial characteristics.2-4 Currently, NAFLD represents a clinical field possessing several unmet needs. The major one is currently no reliable biomarker for disease severity, disease course, or outcome measurement. Therefore, a reliable and confident biomarker for the purposes deserves exploration. The effort is no doubt more challenging than for viral hepatitis infection. Cheng et al. presented the study results of the correlation of Mac-2 binding protein glycosylation isomer (M2BPGi) serum level with the other documented noninvasive biomarkers or panels in a single-center retrospective NAFLD database.5 M2BPGi has been vigorously studied as a marker for fibrosis in chronic hepatitis B virus infection, chronic hepatitis C virus infection, nonalcoholic steatohepatitis, and even hepatocellular carcinoma.6-9 The cross-sectional study measured the serum levels of the recently-identified glycosylation isoform of Mac-2 binding protein in both NAFLD and healthy controls. The results showed that the serum levels of M2BPGi were significantly correlated with the levels of AST to platelet ratio index, fibrosis 4 score (FIB-4), and NAFLD fibrosis score, respectively. The M2BPGi levels were significantly higher in females and had an incremental increase with age in both NAFLD patients and the healthy controls. In addition, the M2BPGi level was significantly higher in those intermediate or high risk for advanced fibrosis (defined as FIB-4 level ≥ 1.45) than their low-risk counterparts (FIB-4 level < 1.45). The results thus provided a piece of work addressing the noninvasive fibrosis assessment for the complex metabolic liver disorder. Generally, the degree of liver fibrosis is the major determinant and the significant predictor of long-term outcomes in patients with NAFLD. There is a higher risk of mortality associated with a higher stage of fibrosis in NAFLD.10, 11 Moreover, the risk of liver-related mortality increased on an exponential rather than linear scale with an increase in fibrosis stage.12 Liver biopsy remains an expensive and invasive procedure associated with potential complications, sampling error, and interobserver variability. Besides imaging- and elastography-based methods, several serum-based panels have been developed for the noninvasive approach to disease severity. Recently, the easy-to-access FIB-4 method has been validated in providing an accurate prediction of liver fibrosis and liver-related events. The algorithm has been adapted by major societies as a clinically useful tool for advanced fibrosis assessment.13-15 Nonetheless, further validation efforts across disease etiology, ethnicities, and other clinical factors are mandatory. In this direction, the current study provided a real-world validation approach for the performance of the serum biomarker in a clinical setting. Some issues remain under investigation despite the achievements of the study. The transition between fibrosis stages in the disease spectrum of NAFLD remains elusive, which mainly depends on histopathological interpretation. The lack of histopathological data could partly undermine the results and clinical implications. Second, although FIB-4 is widely used to predict the presence of advanced fibrosis, it is a tool for excluding advanced fibrosis rather than diagnosis per se. The cut-off values for FIB-4 in determining different risk levels have been extensively validated in the past decade. The results of the current study could be affected by using different values. In addition, the performance of a single biomarker could be significantly increased by combination with other biomarkers.7 Last but not least, results from a longitudinal follow-up study, preferably with other noninvasive methods, will provide more sufficient and convincing evidence in this regard. In conclusion, M2BPGi is a useful noninvasive biomarker for liver fibrosis assessment in NAFLD patients. Future validation of the performance for outcome prediction in a longitudinal manner will be a promising perspective. The author thanks secretary help from Taiwan Liver Research Foundation (TLRF) and Fatty Liver Special Interest Group of Taiwan Association for the Study of the Liver (TASL). The Foundation and the Association did not influence how the study was conducted or the approval of the manuscript. Jee-Fu Huang: Consultant of Roche, BMS, Gilead, Merck, Sysmex, Pharmaessential, Polaris, Aligos, and Instylla. Speaker for Abbvie, BMS, Gilead, Merck, Sysmex, and Roche.

Escape from Cellular Senescence Is Associated with Chromosomal Instability in Oral Pre-Malignancy.

An escape from cellular senescence through the development of unlimited growth potential is one of the hallmarks of cancer, which is thought to be an early event in carcinogenesis. In this review, we propose that the molecular effectors of senescence, particularly the inactivation of TP53 and CDKN2A, together with telomere attrition and telomerase activation, all lead to aneuploidy in the keratinocytes from oral potentially malignant disorders (OPMD). Premalignant keratinocytes, therefore, not only become immortal but also develop genotypic and phenotypic cellular diversity. As a result of these changes, certain clonal cell populations likely gain the capacity to invade the underlying connective tissue. We review the clinical implications of these changes and highlight a new PCR-based assay to identify aneuploid cell in fluids such as saliva, a technique that is extremely sensitive and could facilitate the regular monitoring of OPMD without the need for surgical biopsies and may avoid potential biopsy sampling errors. We also draw attention to recent studies designed to eliminate aneuploid tumour cell populations that, potentially, is a new therapeutic approach to prevent malignant transformations in OPMD.

Best Practices in Liver Biopsy Histologic Assessment for Nonalcoholic Steatohepatitis Clinical Trials: Expert Opinion

Background. In most clinical trials focusing on precirrhotic nonalcoholic steatohepatitis (NASH), a liver biopsy is required for confirmation of diagnosis, staging fibrosis, and grading steatohepatitis activity. Reliance on the biopsy, both as a requisite for study entry, as well as for a primary endpoint in clinical trials, poses several challenges that need to be overcome: patient reluctance to undergo the procedure; potential sampling error; concern regarding the handling, processing and shipping of the biopsy of the biopsy material to the central reader(s); and the degree of pathologists’ intra- and interobserver variability in biopsy interpretation. Aims. To provide recommendations for improving the liver biopsy process in order to maximize the accuracy of its histological interpretation in NASH clinical trials. Methods and Results. These recommendations were created by an expert panel of participants from the United States and European Union who met multiple times and reached alignment through review of available data and their individual clinical experiences. The recommendations include the methodology for biopsy procedure, central lab and pathology processing of the specimen, and recommendations to minimize the intra- and intersubject variability. Finally, we are discussing digital pathology technology and machine learning applications as important additions to enhance liver biopsy interpretation.Conclusions. Liver biopsy poses multiple challenges in clinical trials in NASH, and there is a need to standardize the processes to maximize accuracy and minimize variability. Many questions remained unanswered due to limited available data. New evolving modalities may help in the future, but generation of robust data is warranted.

Are Incisional Biopsies Reliable to Select Definitive Treatment in Patients with Ameloblastoma of the Jaws? A 15-year Interdisciplinary Retrospective Study

Ameloblastomas are tumors of odontogenic epithelium that, although benign, can have a locally aggressive course causing significant morbidity. WHO classifies ameloblastomas as 1 of 3 variants: solid/multicystic, unicystic, and peripheral. Resection, the standard treatment, is deemed curative, but can be debilitating to the patient. Unicystic subtype is considered less aggressive and could be treated with enucleation and curettage. The mercurial presentation of ameloblastomas makes the chosen treatment modality essential in decreasing the recurrence rates and associated morbidity. Definitive treatment is chosen based on an incisional biopsy, but a true diagnosis of unicystic ameloblastoma requires the entire specimen. The aim of this study is to assess the potential sampling error with an incisional biopsy and potential consequences on treatment outcomes at long-term follow-up.This is a retrospective cohort study for patients with ameloblastoma of the jaws treated at the Virginia Commonwealth University Department of Oral and Maxillofacial Surgery between 2005 to 2020. Patients with biopsy-proven ameloblastoma with a minimum of 1-year follow-up after definitive treatment and complete documentation were included. Predictor variables include radiographic findings, incisional biopsy, and histologic samples. Outcome variable is concordance between initial incisional biopsy and final treatment pathology, as well as recurrence rate.A total of 23 patients, 14 males and 9 females, met the inclusion criteria. Table 1 presents demographics and study variables for the sample. On initial incisional biopsy, 4 (17.4%) cases showed a “cystic” mention in the pathology report, 18 cases (78.3%) exhibited solid ameloblastoma, and 1 (4.3%) showed peripheral ameloblastoma. Final pathology after definitive treatment showed solid/multi-cystic ameloblastoma in 20 (87%) cases, 2 (8.7%) were unicystic, and 1 (4.3%) was peripheral ameloblastoma. Overall, initial incisional biopsy and final pathology were concordant in 21 (91%) cases. After histologic investigation, the initial biopsy for 3 (13%) cases exhibited sampling error, which is defined as the sampled tissue not being representative of the entire lesion (Table 2).Segmental resection was the definitive treatment in 14 (60.9%) cases while enucleation and curettage (E&C) were used on 6 (26.1%), and decompression followed by enucleation and curettage on 3 (13%) patients (Table 3). Postoperative follow-up from the day of definitive treatment ranged from 1 year to 15.6 years (mean 3.50 ± 3.22). Four patients (17.4%) had recurrent lesions, with 100% of them seen following conservative management (i.e., E&C or decompression with E&C). The time of recurrence after treatment ranged from 6 months to 10.75 years (mean 4.62 ± 4.25), with 1 case having more than 1 recurrence.Incisional biopsies are acceptably reliable when combined with clinical exam of the lesion and radiographic presentation to select definitive surgical treatment for ameloblastoma. The chance of sampling error should be included in the informed consent with a low threshold for second incisional biopsy when clinical/radiographic findings are not consistent with histopathological report. Consult with an oral and maxillofacial pathologist is essential, both at initial and final histopathology evaluation. Future development of less-invasive treatments that combine medical and/or surgical management, given the benign nature of ameloblastoma, will help patients achieve cure in the long term.

Conducting conservation social science surveys online.

The coronavirus (COVID‐19) pandemic is affecting the environment and conservation research in fundamental ways. Many conservation social scientists are now administering survey questionnaires online, but they must do so while ensuring rigor in data collection. Further, they must address a suite of unique challenges, such as the increasing use of mobile devices by participants and avoiding bots or other survey fraud. We reviewed recent literature on online survey methods to examine the state of the field related to online data collection and dissemination. We illustrate the review with examples of key methodological decisions made during a recent national study of people who feed wild birds, in which survey respondents were recruited through an online panel and a sample generated via a project participant list. Conducting surveys online affords new opportunities for participant recruitment, design, and pilot testing. For instance, online survey panels can provide quick access to large and diverse samples of people. Based on the literature review and our own experiences, we suggest that to ensure high‐quality online surveys one should account for potential sampling and nonresponse error, design survey instruments for use on multiple devices, test the instrument, and use multiple protocols to identify data quality problems. We also suggest that research funders, journal editors, and policy makers can all play a role in ensuring high‐quality survey data are used to inform effective conservation programs and policies.

Fusing crash data and surrogate safety measures for safety assessment: Development of a structural equation model with conditional autoregressive spatial effect and random parameters

Most existing efforts to assess safety performance require sufficient crash data, which generally takes a few years to collect and suffers from certain limitations (such as long data collection time, under-reporting issue and so on). Alternatively, the surrogate safety measure (SSMs) based approach that can assess traffic safety by capturing the more frequent “near-crash” situations have been developed, but it is criticized for the potential sampling and measurement errors. This study proposes a new safety performance measure—Risk Status (RS), by fusing crash data and SSMs. Real-world connected vehicle data collected in the Safety Pilot Model Deployment (SPMD) project in Ann Arbor, Michigan is used to extract SSMs. With RS treated as a latent variable, a structural equation model with conditional autoregressive spatial effect and corridor-level random parameters is developed to model the interrelationship among RS, crash frequency, risk identified by SSMs, and contributing factors. The modeling results confirm the proposed interrelationship and the necessity to account for both spatial autocorrelation and unobserved heterogeneity. RS can integrate both crash frequency and SSMs together while controlling for observed and unobserved factors. RS is found to be a more reliable criterion for safety assessment in an implementation case of hotspot identification.

Accuracy of electrospun fiber diameters: The importance of sampling and person-to-person variation

Potential sampling errors (regional variation) on an electrospun mat were explored and person-to-person (analyst affect) variation in image analysis of the fiber diameter were investigated via detailed statistical analyses. Scanning electron microscope (SEM) samples were prepared from the vertical midline of a single non-woven mat of electrospun polyethylene oxide. Thirteen analysts with identical training and instructions measured the diameters of the nanofibers from the six SEM images and statistical analyses were performed on the resulting data. The fiber diameters were significantly different in the lower region than the upper and center regions. Furthermore, the fiber diameters in the lower region—from micrographs taken only millimeters apart—were statistically different demonstrating a statistically significant regional variation in the sample. Furthermore, statistically significant variation between the analysts also was observed, with the average fiber diameter ranging from 166 nm to 276 nm.

High Sensitivity Detection of Residual Disease in Multiple Myeloma from Blood

As effectiveness of treatments for multiple myeloma (MM) continues to increase, a greater proportion of MM patients are achieving deep response. Since traditional serum based assays are not sensitive enough, bone marrow (BM) based MRD methods have become available: a molecular-based method and multicolor flow cytometry (MFC). Limitations to BM based testing include expense, discomfort and potential sampling error in instances of patchy disease. Currently there are no blood-based high sensitivity assays clinically available to detect MRD in patients.

Proper sampling for archeometric discrimination of Bronze-age fields on Bornholm, Denmark – Archaeology meets TOS meets Chemometrics

Author Summary: In archaeology it is of interest to ascertain whether a particular Bronze-age field has been cultivated or not based on traditional archaeological evidences, but these often deal with one chemical element only, Phosphorous. We here augment this endeavour to include multi-element geochemistry characteristics. A pilot study sampling campaign was carried out (2014) on the island of Bornholm with the objective to discriminate between well-documented cultivated and un-cultivated Bronze-age agricultural fields based on multivariate data analysis (chemometrics) of soil chemistry (metal concentrations, ICP-MS). All samples originate from the same soil depth corresponding to the paleo-cultivated layer, or the equivalent depth in uncultivated fields. The experimental design focused on proper field sampling (Theory of Sampling), including replicate sampling at two levels. Applying Principal Component Analysis (PCA), the first three components corresponds to 68 % of the most discriminative variance in the 15 variable/41 sample array. The first and third PC-component reveals a complete discrimination of un-cultivated vs.3 cultivated fields; it is likely that general soil chemistry features are compensated for by the second component in the PCA solution. We present the specifics pertaining to the field sampling procedure, including the hierarchical two-level experimental design, which allow assessment of the local vs. field-wide heterogeneities in order better to understand the successful discrimination achieved. Five elements appear to be particularly involved in the discrimination [P, Fe, Mn, Zn, Pb], currently undergoing paleo-agricultural/geochemical interpretation. Based on these first results we plan a full test-set validation campaign in 2015 which will be the ultimate performance test for this type of archeometric discrimination. This contribution illustrates the versatility and power of multivariate data analysis (chemometrics) applied to data with a substantial proportion of potential sampling errors, in need of effective management (TOS).

Optimal number and location of Bluetooth sensors considering stochastic travel time prediction

Determining the optimal number and location of sensors is essential to effectively manage traffic on highways. Optimal solutions dealing with dynamic traffic patterns and relocation of sensors have received little attention. In this study, existing fixed sensors are used to estimate travel time prediction errors at candidate locations where we deploy portable sensors. Potential sampling error of each candidate location is also counted in selecting optimal locations. A two-stage stochastic formulation considers uncertainty of traffic conditions based on scenarios generated by principal component analysis and clustering analysis to uncover the underlying spatial correlations and temporal patterns. The first stage decision, determining the optimal number of sensors, is made before the deployment. The second stage, evaluating the expected travel time prediction errors, specifies sensor arrangements in each scenario. A dynamic model has predefined rearrangement stages. At each stage, sensor locations are modified as the pattern of travel time error changes over time, considering sensor acquisition and relocation expenses. The deterministic and stochastic solutions serve as a lower bound and an upper bound for the dynamic solution. Higher relocation expense leads to more sensors being used, while higher sensor costs leads to fewer sensors being used with more frequent relocations.

Theory of sampling: four critical success factors before analysis.

Food and feed materials characterization, risk assessment, and safety evaluations can only be ensured if QC measures are based on valid analytical data, stemming from representative samples. The Theory of Sampling (TOS) is the only comprehensive theoretical framework that fully defines all requirements to ensure sampling correctness and representativity, and to provide the guiding principles for sampling in practice. TOS also defines the concept of material heterogeneity and its impact on the sampling process, including the effects from all potential sampling errors. TOS's primary task is to eliminate bias-generating errors and to minimize sampling variability. Quantitative measures are provided to characterize material heterogeneity, on which an optimal sampling strategy should be based. Four critical success factors preceding analysis to ensure a representative sampling process are presented here.

Cytohistologic Correlation in Premenopausal and Postmenopausal Women

Objective: This study was conducted to compare the correlation between Pap smear and colposcopic biopsy findings in premenopausal and postmenopausal women. Study design: A total of 68,738 ThinPrep Pap smears were done in 2011 in our institution, and of these, 865 of the women (787 premenopausal and 78 postmenopausal) had subsequent colposcopic directed biopsies performed within 3 months of obtaining the results. Results: We discovered that 52.5% of the Pap smears in postmenopausal women versus 33.6% in premenopausal women were classified as false positive (FP), with respect to the biopsy, and of these, 47.6 vs. 17% cases had no transformation zone (TZ) on the subsequent biopsies, respectively. Interestingly, with respect to high-risk human papilloma virus (hrHPV) testing in patients having both Pap smear and biopsies performed, we found the Pap smear diagnoses were a better predictor of positive hrHPV than the respective colposcopic biopsies. Conclusion: As many of the FP postmenopausal women had an absent TZ (47.6%) on biopsy, and because the majority (83.3%) of those which had hrHPV testing were positive, we suggest that this indicates a potential sampling error on biopsy, perhaps due to an inability to visualize the involved area in older women due to an upward migration of the TZ.

The Impact of Thyroid Nodule Size on the Risk of Malignancy and Accuracy of Fine-Needle Aspiration: A 10-Year Study from a Single Institution

False-negative rates for thyroid fine-needle aspiration (FNA) vary from 0.4% to 13%, but the effect of nodule size on the accuracy of thyroid FNA remains controversial. We hypothesized that large thyroid nodule size does not contribute to the risk of malignancy or the risk of a false-negative FNA. All thyroid FNAs performed at the Walter Reed Army Medical Center during September 2001-August 2011 were reviewed. A strict correlation between the biopsy site, location, and size of nodule on ultrasound (US) and pathology report was ensured. FNA results were classified as benign, atypical, follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), suspicious for malignancy (SM), or malignant, and the pathology result was categorized as either benign or malignant. Nodules were analyzed by size: 0.5-0.9 cm (group A), 1.0-3.9 cm (group B), and ≥ 4 cm (group C). Incidental thyroid cancer was not included. Of 3013 patients undergoing FNA, 667 (22.1%) had surgery. Patients were excluded for nodules <0.5 cm, nondiagnostic FNA, or no preoperative US, leaving 540 patients with 695 nodules. Among patients referred for surgery, FNA results were benign in 417 nodules (60%), atypical in 22 (3.2%), FN/SFN in 122 (17.6%), SM in 77 (11.1%), and malignant in 57 (8.2%). Postoperative malignancy rates by FNA result were 7% if benign, 4.5% if atypical, 23% if FN/SFN, 33.8% if SM, and 78.9% if malignant. FNA accuracy was 60% in group A, 68.5% in group B, and 80.3% in group C (p=0.01). False-negative rates for FNA were 7.0% overall, 15.8% in group A, 6.3% in group B, and 7.1% in group C (p=0.25). Sensitivity and negative predictive value were highest in group B at 81.6% and 93.7%, respectively. The prevalence of malignancy was not different between groups. Our results show that the thyroid nodule size ≥ 4 cm increases neither the risk of false-negative FNA results, nor the overall risk of malignancy. We also show a tendency toward a higher false-negative rate in subcentimeter nodules. We conclude that a large nodule size should not prompt automatic referral for thyroidectomy. An increased awareness of potential sampling error in subcentimeter nodules is warranted.

The “Ligamentization” Process in Anterior Cruciate Ligament Reconstruction

Background: Surgical anterior cruciate ligament reconstruction using tendon grafts has become the standard to treat the functionally unstable anterior cruciate ligament–deficient knee. Although tendons clearly differ biologically from ligaments, multiple animal studies have shown that the implanted tendons indeed seem to remodel into a ligamentous “anterior cruciate ligament–like” structure. Purpose: The goal of this study was to systematically review the current literature on the “ligamentization” process in human anterior cruciate ligament reconstruction. Study Design: Systematic review. Methods: A computerized search using relevant search terms was performed in the PubMed, MEDLINE, EMBASE, and Cochrane Library databases, as well as a manual search of reference lists. Searches were limited to studies examining the healing of the intra-articular portion of the tendon graft based on biopsies of this graft obtained from a living human. Results: Four studies were determined to be appropriate for systematic review, none of them reaching a level of evidence higher than 3. All reports considered autografts. Biopsy specimens were evaluated by light or electron microscopy and analyzed for vascularization, cellular aspects, and appearance of extracellular matrix. All authors universally agreed that the tendon grafts survive in the intra-articular environment. Based on changes observed in the healing grafts with regard to vascularization, cellular aspects, and properties of the extracellular matrix, different chronologic stages in the ligamentization process were discerned. Conclusion: The key finding of this systematic review is that a free tendon graft replacing a ruptured human anterior cruciate ligament undergoes a series of biologic processes termed “ligamentization.” The graft seems to remain viable at any time during this course. Histologically, the mature grafts may resemble the normal human anterior cruciate ligament, but ultrastructural differences regarding collagen fibril distribution do persist. Different stages of the ligamentization process are described, but no agreement exists on their time frame. Problematic direct transmission of animal data to the human situation, the limited number of reports considering the ligamentization process in humans, and the potential biopsy sampling error attributable to superficial graft biopsies necessitate further human studies on anterior cruciate ligament graft ligamentization.

Targeted Contrast-Enhanced Ultrasound: An Emerging Technology in Abdominal and Pelvic Imaging

In vivo molecular imaging provides the ability to measure expression levels of molecules by quantifying imaging signals generated with the help of contrast agents accumulating at sites of molecular target expression. These contrast agents can be directed to bind various molecular targets in vivo (eg, proteins, DNA, etc), thereby quantifying disease processes at the molecular level in various disease processes. Thus, molecular imaging has the potential to obtain tissue expression profiles in a volumetric manner without invasive tissue sampling procedures and without the limitation of potential sampling errors from biopsies. Emerging research in ultrasound technology and contrast agent design for ultrasound imaging has paved the way for targeted contrast-enhanced ultrasound imaging to be translated to clinical applications in the near future.1–6 Ultrasound imaging is a widely available, inexpensive, and real-time imaging modality that does not expose patients to irradiation. It is already the first-line imaging modality for assessment of many diseases in the abdomen and pelvis. Through the introduction of ultrasound contrast agents (eg, lipid-shelled, gas-filled, 1- to 4-micron-sized microbubbles), the sensitivity and specificity of ultrasound for detection and characterization of for example focal liver lesions7,8 has been substantially improved. Recently, targeted contrast-enhanced ultrasound (molecular ultrasound) imaging has gained great momentum in preclinical research by the introduction of ultrasound contrast microbubbles that are targeted at molecular markers overexpressed on the vasculature of certain diseases (Figure 1A and Supplementary Figure 1). By combining the advantages of ultrasound with the ability to image molecular signatures of diseases, molecular ultrasound has great potential as a highly sensitive and quantitative method that could be used for various clinical applications, including screening for early stage diseases (such as cancer); further characterization of focal lesions and quantitative monitoring of disease processes at the molecular level; assisting in image-guided procedures (eg, biopsy, surgery, or ablation); enhancing drug delivery; and confirming target expression for treatment planning and monitoring (including novel drug candidates in preclinical studies).1,4,6,9,10 Figure 1 Principles of nontargeted and molecularly targeted contrast-enhanced ultrasound imaging with contrast microbubbles. (A) The gas core of lipid- or protein-shelled microbubbles (left) makes them highly echogenic compared to surrounding tissue and blood. ... We describe herein concepts and applications in contrast-enhanced and molecular ultrasound imaging with particular focus on imaging cancer and inflammatory diseases in the abdomen and pelvis.

Transient elastography in patients with cystic fibrosis

Hepatic involvement is frequent in patients with cystic fibrosis (CF), with focal biliary cirrhosis being the pathognomonic hepatic manifestation. In around one-quarter of CF patients, it results in CF-associated liver disease (CFLD). This occurs as a relatively early complication with the majority of patients presenting in childhood or their early teens. However, a normal US does not preclude significant liver fibrosis and liver biopsy is an invasive procedure that is hampered by potential sampling errors. Transient elastography (TE) (Fibroscan) is a non-invasive, user-friendly and quick technique that provides an objective and reproducible measure of liver stiffness. This is accomplished with a device using an US probe mounted in the axis of a vibrator. Vibrations are transmitted by the transducer, inducing an electronic shear wave that propagates through the underlying tissue. We aimed to prospectively compare TE and transabdominal US scanning in children and adults attending a CF clinic. A total of 134 consecutive patients with documented CF were prospectively studied. In each case, transient elastography measurement was performed immediately after the routine annual US evaluation of the liver. Sonographic appearance of the liver was classified from 1 to 5. Ten validated TE measurements were performed in each patient with the result expressed in kilopascals (kPa). The median value was considered representative of the elastic modulus of the liver. Measurements were performed in 59 CF adults, 75 CF children and 31 control children. There was no relationship between age and liver stiffness in either the control group or CF patients. Elasticity values of controls, CF pancreatic sufficient (PS) patients and pancreatic insufficient (PI) CF patients with a US score <3 were comparable and significantly lower than in CF patients with a US score > or = 3 (all PI) (P < 0.002). Median elasticity in CF patients was significantly higher in males (4.7 kPa) than in females (3.9 kPa) (P = 0.0013). Considering the limitations of US and the low risk-benefit rate of liver biopsy in most CF patients, this preliminary study suggests that TE is an attractive non-invasive way to assess and follow-up liver disease in these patients.