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PubMed2026

Vitamin B12 Deficiency in Sickle Cell Disease: Method-Driven Estimates and Systematic Diagnostic Misclassification.

OBJECTIVES: To determine whether the reported 0%-70% prevalence of vitamin B12 deficiency in sickle cell disease (SCD) reflects true population variation or diagnostic misclassification. METHODS: We conducted a PRISMA 2020-compliant systematic review of observational studies (January 1, 2000-May 13, 2026; PROSPERO CRD420251087800) assessing B12 status in SCD. PubMed, AJOL, and Google Scholar were searched with citation tracking and dual screening. Diagnostic validity was assessed across biomarker strategy, analytical platform, thresholds, and confounder control using a proposed context-integrated framework to classify methodological robustness and discordance. RESULTS: Fourteen studies were included (57% high-income; 43% LMIC). The evidence base was dominated by limited diagnostic approaches: 71% used immunoassays, over one-third relied on circulating B12 alone, and functional biomarkers were inconsistently applied without systematic confounder adjustment. Prevalence estimates were strongly influenced by diagnostic methods rather than underlying population biology, ranging from 0% to 70% in single-marker studies (mostly 0%-7.1%, with outliers ~50%-70%) and 6.9%-53% in multi-marker studies. Discordance was substantial and greater in LMIC settings than HIC. CONCLUSION: Current diagnostic approaches in SCD appear method-dependent, generating heterogeneous prevalence estimates with uncertain clinical validity. These findings challenge existing estimates and have implications for clinical practice, research design, and diagnostic equity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: CRD420251087800.

Humans↗

PubMedDate not supplied

Prevalence and course of diabetes modified by fasting blood glucose levels: implications for diagnostic criteria.

Data from the epidemiologic survey in Sudbury, Massachusetts, demonstrate that the prevalence of new cases of diabetes, based on the USPHS criteria for the standard 3-h oral glucose tolerance test as originally published, was 0.7%. If a fasting blood sugar greater than or equal to 110 mg/dl had been required for those USPH diagnoses, the prevalence would have fallen to 0.28%. Further, if a peak serum insulin level of less than or greater than 60 microM/ml had been required, the original prevalence rate would have dropped to 0.02%. Data from a prospeh criteria for diabetes indicate by life table analyses that 41% show further deterioration of carbohydrate control over the first 13 yr of the study when the fasting blood sugar was less than 110 mg/dl in the initial diagnostic test and 82% when the fasting blood sugar was greater than or equal to 110 mg/dl. The relationship of fasting blood glucose to later decompensation proved to be a continuous one without evidence of a threshold effect. The implications of both of these studies for diagnostic criteria, particularly recent proposals, is discussed.

Adolescent↗

PubMedDate not supplied

Fundamental study of automatic cyto-screening for uterine cancer. III. New system of automated apparatus (CYBEST) utilizing the pattern recognition method.

An investigation was carried out, both from the point of view of combining features which are considered as being of the highest reliability based on pattern analysis of the nuclear structure and cytoplasm of cells, and the complexity of the apparatus. Several features such as "ambiguity" function were extracted by mathematical and statistical processing, and these were then made the parameters of a diagnostic logic. Also, a method in which a "differential histogram" and a "threshold value" are combined was developed for segmentation of cells. It became possible to operate an automatic scanning machine at a speed of about six minutes per slide using two-stage coarse and fine scanning of a flying spot scanner. The advantage of this system is flexibility of diagnostic program logic and speed of algorithms for a determined number of cellular features. An automatic focusing system was also developed and it functions satisfactorily at high speed on a fully extended regular object slide.

Cell Nucleus↗

PubMed1978

Basic principles of ROC analysis.

The limitations of diagnostic "accuracy" as a measure of decision performance require introduction of the concepts of the "sensitivity" and "specificity" of a diagnostic test. These measures and the related indices, "true positive fraction" and "false positive fraction," are more meaningful than "accuracy," yet do not provide a unique description of diagnostic performance because they depend on the arbitrary selection of a decision threshold. The receiver operating characteristic (ROC) curve is shown to be a simple yet complete empirical description of this decision threshold effect, indicating all possible combinations of the relative frequencies of the various kinds of correct and incorrect decisions. Practical experimental techniques for measuring ROC curves are described, and the issues of case selection and curve-fitting are discussed briefly. Possible generalizations of conventional ROC analysis to account for decision performance in complex diagnostic tasks are indicated. ROC analysis is shown to be related in a direct and natural way to cost/benefit analysis of diagnostic decision making. The concepts of "average diagnostic cost" and "average net benefit" are developed and used to identify the optimal compromise among various kinds of diagnostic error. Finally, the way in which ROC analysis can be employed to optimize diagnostic strategies is suggested.

Cost-Benefit Analysis↗

PubMed1977

Acoustic tumor detection with brain stem electric response audiometry.

Tumors that press on the audiotry nerve can cause a latency increase that is detectable from the scalp by electric response audiometry (BERA). The response delay is best seen by comparing the Jewett wave V, or P5, latencies for the two ears. This interaural latency difference is normally less than 0.2 msec, but was 0.4 msec or greater for 35 acoustic tumor cases and for seven of ten other temporal bone tumors. Acoustic tumor size can be estimated from the amount of latency delay.

Audiometry↗

PubMedDate not supplied

Cytophotometric study of premalignant and malignant cells of the cervix in an approach towards automated cytology.

Based on a cytophotometric procedure in combination with Feulgen reactive DNA and Pap-1 labeled specimens, the DNA values and hematoxylin-dense substances were examined in individual cells from 62 cases of premalignant and malignant lesions of the cervix, in contrast to normal squamous epithelia of 40 cases and 500 normal lyphocytes. The range of DNA values for the cells from benign proliferation and mild dysplasia cases was within a normal diploid-tetraploidy. In contrast, cases with carcinoma in situ and microinvasive carcinoma exhibited a DNA range which extended beyond hypertetraploidy with many cellspossessing a DNA value in excess of hexaploidy. Marked dysplasia from 11 cases also showed the same DNA range as carcinoma in situ. Our decision criteria derived from thresholding DNA value may be useful in an automatic cancer diagnostic test. In an aid to the manual measurement, an automatic glass fibrooptic system is now in preparation in an approach towards automation of uterine cytology for scanning of malignant cells.

Carcinoma in Situ↗

PubMed1978

An experimental study of visual averaged evoked responses (V. AER) and pain measures (PM) in patients with depressive disorders.

In a group of 100 patients admitted to the Department of Psychiatry in Umeå between January 1973 and July 1974 with depressive syndromes, pain measures - PM - and visual averaged evoked responses - V.AER - have been investigated and the patients have been rated by the doctor by means of the Cronholm-Ottosson depression rating scale. According to the results of V. AER patients have been grouped as augmenters or reducers, depending upon the tendency to augment or to reduce the intensity of incoming signals with increasing stimulus intensity. V. AER are found to vary with age but not with sex. Differences are found between patients with and those without a psychotic dimension of their depressive syndromes. Patients with depressive syndromes of psychotic dimension tend more often to be reducers. When patients are divided according to diagnostic groups no differences are found. PM are found to vary with sex and detection threshold - DT - are found to vary with age while pain threshold - PT - tolerance level - TL - and pain endurance - PE - do not vary with age. Patients with depressive syndromes of a psychotic dimension are found to have higher PM while there is no consistent picture when patients are divided according to diagnostic groups. Possible explanations for contradictory results found by other authors are discussed.

Bipolar Disorder↗

PubMed2025

Defining alarm thresholds for the load of pathogenic viruses in wastewater for decision making: An application to three French cities.

Wastewater monitoring has the potential to complement infectious disease surveillance systems. However, the absence of predefined viral signal thresholds in wastewater is often presented as a limiting factor in triggering public health action. To overcome this issue, the feasibility of defining alarm threshold for viral loads in wastewater samples was assessed by quantifying genome fragments of SARS-CoV-2, influenza A virus (IAV), respiratory syncytial virus (RSV), norovirus (NoV), and rotavirus (RoV) by RT-digital PCR (dPCR) in untreated wastewater samples from three treatment plants. Cut-point values were calculated for periods with a high rate of visits to emergency rooms or at-home visits by SOS Médecins for the related diseases. ROC curves were constructed, and the values of alarm threshold in wastewater were defined using the Youden index. For each targeted virus, alarm thresholds were close to each other across the three WWTPs. As indicated by likelihood ratios, evidence to rule in the diagnosis of high rate of visits when the alarm threshold was exceeded ranged from weak to strong and was highest for RSV and SARS-CoV-2. Evidence to rule out the diagnosis when the alarm threshold was not exceeded was strong or moderate for IAV, SARS-CoV-2 and RSV. Diagnostic performance of the test was not as high for NoV and RoV. Positive predictive value was highest for SARS-CoV-2 and RSV. For SARS-CoV-2 and RSV, the definition of an alarm threshold in wastewater could substantially inform the diagnosis of a period with a high rate of medical visits for COVID-19 and bronchiolitis, respectively.

Wastewater↗

PubMed1976

[Determination of antibody affinity using threshold values of serum activity in the passive hemagglutination test].

Agglutination of erythrocytes of the antigenic diagnostic agents with the IgG antibodies is attributed to the fact that the reactive centres of the same molecule of the antibody attached to the antigenic determinants located on different erythrocytes. A possibility of agglutination of erythrocytes under conditions of the maximal dilution of the immune serum depended on the number of molecules located on a single erythrocyte. When the erythrocytes are sensitized with the optimal dose of the antigen those serum antibodies are involved in the passive hemagglutination test (PHAT) which are characterized by the mean integrated association constant. When the antibodies participate in the PHAT with several batches of the erythrocytic diagnostic agent characterized by an average number of the antigen molecules on a single erythrocyte there appears a possibility of determining the extent of heterogeneity of the antibodies. Not only the amount of antibodies, but also their affinity can be ascertained by the PHAT, and also the heterogeneity of antibodies can be evaluated.

Antibodies↗

PubMed2026

An Integrative Morphological and Genomic Analysis With a Refined Fluorescence In Situ Hybridization (FISH) Threshold and Novel Kinase Fusions in a Large Asian Cohort of Spitzoid Neoplasms.

Differentiating atypical Spitz tumors (ASTs) from true Spitz melanomas (SMs) and conventional melanomas with spitzoid features (MSFs) remains a formidable diagnostic challenge. Because current molecular epidemiological data are overwhelmingly derived from Caucasian cohorts, the genomic landscape of Asian populations remains largely unexplored. To elucidate the molecular progression landscape and refine the diagnostic criteria, we performed a comprehensive multimodal analysis-integrating histomorphology, immunohistochemistry, multiprobe fluorescence in situ hybridization (FISH), and targeted RNA/DNA-based next-generation sequencing (NGS)-on a cohort of 140 spitzoid neoplasms. This cohort, comprising 126 ASTs, 8 SMs, and 6 MSFs, represents the largest Asian cohort to date. Malignant phenotype strongly correlated with lesional asymmetry, deep atypical mitoses, a sheet-like growth pattern, diffuse preferentially expressed antigen of melanoma positivity, and significant loss of p16 expression (64.3% in SM/MSF vs 9.5% in ASTs; P < .0001). Building upon the established melanoma FISH criteria, we optimized a prognostic threshold of ≥2 FISH abnormalities specifically tailored for spitzoid neoplasms. We demonstrated that isolated single chromosomal aberrations (particularly MYB loss) are relatively stable events that are frequent in indolent ASTs, whereas our refined ≥2 threshold yielded 100% sensitivity and 92.5% specificity for predicting regional lymph node metastasis/local recurrence. Molecularly, NGS identified mutually exclusive initiating driver alterations (comprising kinase fusions and HRAS mutations) in 89.9% of true Spitz neoplasms, a remarkably high prevalence suggesting a distinct genetic background in Asian populations. We also characterized 5 entirely novel kinase fusions (ZNF24::ROS1, PCBP1::ROS1, NUMA1::RET, CBWD1::ALK, and TPR::NTRK1). Furthermore, NGS definitively segregated true Spitz neoplasms from morphological mimics (MSF), which lacked fusions and were driven by canonical genomic alterations of the conventional melanoma pathway. Integrating these genomic landscapes validated a stepwise progression model. Although isolated kinase fusions drove indolent ASTs, malignant SM invariably harbored concurrent pathogenic secondary alterations, demonstrating a profound reliance on CDKN2A/B, TP53, and CDK4 aberrations. Ultimately, we propose an integrated diagnostic algorithm combining morphological evaluation, the refined FISH threshold, and comprehensive NGS profiling, providing a precise, evidence-based framework for pathway classification and clinical management of spitzoid neoplasms.

fluorescence in situ hybridization↗

PubMed1976

Vibrotactile and temperature sensory interaction in the human tongue.

Lingual vibrotactile thresholds were used to demonstrate an interaction between the lingual senses of vibrotaction and temperture. Thresholds were obtained on 10 Ss from the anterior midline of the lingual dorsum at a frequency of 250 Hz. Five temperature conditions were tested ranging in 10 degrees C steps from 17 degrees C to 57 degrees C. Thresholds were obtained before and after the introduction of the temperature stimuli. Comparison of mean pre- and post-experimental thresholds demonstrated that temperature is a determining factor in lingual vibrotactile threshold values. The data indicated that systematic variation from normal body temperature resulted in corresponding decreases in lingual vibrotactile sensitivity. Diagnostic and clinical implications of this interaction were discussed.

Adult↗

PubMed2026

Improving isolate recovery and identification of the Shiga toxin type in Shiga toxin nucleic acid test-positive feces.

UNLABELLED: Infections caused by Shiga toxin-producing Escherichia coli (STEC) strains carrying Shiga toxin 2 (stx2) are more likely to result in severe complications; however, most nucleic acid amplification tests used for STEC diagnosis do not differentiate between stx1 and stx2. We therefore sought to optimize stx typing and isolate recovery methods to guide clinical and public health management. stx polymerase chain reaction (PCR)-positive feces were cultured using CHROMagar STEC and gram-negative broth, with Stx1 and/or Stx2 antigen detection by enzyme immunoassay (EIA) on colony growth or turbid broth. When cultures were EIA-negative, growth from MacConkey agar (MAC), Trypticase soy broth, and the gram-negative broth was then tested using a lab-developed typing PCR for stx1 and stx2. Colonies were isolated on CHROMagar STEC or MAC and identified using the typing PCR. Using both EIA and typing PCR, the stx types were identified in 96.0% of cases (381/397). In 65.2% (259/397) of cases, culture was EIA-positive, of which 34.0% (87/256) were Stx2-positive. Among cultures that were EIA-negative but typing PCR-positive, 64.8% (79/122) were stx2-positive (P < 0.0001 compared to EIA-positive). Using both EIA and typing PCR resulted in 72.6% (286/394) of cases with successful attempts at isolate recovery, compared to 60.7% (239/394) with EIA alone. E. coli O157 was recovered from more EIA-positive cases (19.3%, 46/239) than EIA-negative ones (4.3%, 2/47) (P = 0.0097). Typing PCR on cultures improves stx typing (particularly stx2) and isolate detection compared to EIA alone. Screening BD Max PCR and subsequent typing PCR results showed excellent concordance. IMPORTANCE: Escherichia coli strains with one or both types of Shiga toxins (stx1 and stx2) are a common cause of bacterial diarrhea and can lead to serious complications such as kidney failure, especially in children. Infection by stx2-positive strains is more likely to do so. Therefore, knowing whether the infection is caused by a strain carrying stx2 is important for risk assessment and case follow-up. The conventional way to diagnose these infections is to grow the bacteria from stool, but most laboratories currently use nucleic acid detection (e.g., bacterial DNA detection by polymerase chain reaction [PCR]), and these assays do not differentiate between the two toxin genes. Culture is therefore required to determine toxin type, as well as for public health outbreak investigations, which require an isolate for whole-genome sequencing for serotyping and cluster analysis. We identified culture media and a PCR-based method to detect stx2 in culture that improved the detection of stx2 and isolate recovery. Our findings provide more accurate results for clinicians to improve patient care and tools for public health teams to control and prevent outbreaks.

Humans↗

PubMed2026

Metagenomic next-generation sequencing for tuberculosis diagnosis: enhanced performance and cost-effectiveness.

UNLABELLED: Metagenomic next-generation sequencing (mNGS) is a promising tool for diagnosing challenging infections like tuberculosis (TB). However, previous studies largely focused on case-specific application of mNGS in TB diagnosis. Thus, we conducted a retrospective observational study to first systematically evaluate the diagnostic performance and cost-effectiveness of mNGS for TB diagnosis. We retrieved a total of 16,776 results of the seven TB diagnostic assays, including mNGS, tuberculosis IgG antibody, TB interferon-γ release assay (TB-IGRA), TB-DNA, Xpert MTB/RIF (Xpert), culture, and acid-fast bacilli staining (AFS) from 3,757 participants with suspected TB infection at Sichuan Provincial People's Hospital from September 2021 to July 2024. Diagnostic metrics were compared against a composite reference standard. Microbial composition and a cost-utility analysis were performed. Among seven TB assays studied, the World Health Organization (WHO)-recommended assays AFS, culture, and Xpert, as well as TB-IGRA, were requested most frequently for TB diagnosis, whereas mNGS ranked last. mNGS demonstrated the highest specificity (100%), accuracy (72.3%), and area under the curve (AUC) (0.795). Its sensitivity in bronchoalveolar lavage fluid and tissue was 71.0% and 72.7%, respectively. Sequential use of mNGS after initial WHO-recommended tests (Xpert/Culture/AFS) significantly improved diagnostic performance (sensitivity, 70.4%; AUC, 0.823). Microbial analysis associated Candida albicans with TB. Cost-utility analysis showed sequential mNGS became cost-effective at higher willingness-to-pay thresholds (>200,000 RMB per correct diagnosis). mNGS offers superior specificity for TB diagnosis. A sequential strategy applying mNGS to conventional-test-negative cases provides enhanced diagnostic performance and is cost-effective at higher healthcare investment values, supporting its utility for diagnostically challenging TB. IMPORTANCE: This study systematically assesses the diagnostic performance and cost utility of metagenomic next-generation sequencing (mNGS) for tuberculosis (TB) in a large real-world cohort of 3,757 suspected patients, comparing it against six conventional assays (tuberculosis IgG antibody, TB interferon-γ release assay, TB-DNA, Xpert, culture, and acid-fast bacilli staining). mNGS demonstrated the highest specificity (100%), accuracy (72.3%), and area under the curve (AUC) (0.795), with sensitivities of 71.0% in bronchoalveolar lavage fluid and 72.7% in tissue. Notably, sequential use of mNGS after the World Health Organization-recommended tests significantly improved sensitivity to 70.4% and AUC to 0.823. Candida albicans showed significant differences among the three groups. The sequential mNGS strategy was cost-effective compared with no mNGS, and its cost-effectiveness increased with a rising willingness-to-pay threshold. Overall, these results highlight mNGS as a valuable supplementary tool for challenging TB cases, especially when conventional tests are inconclusive, and provide strong evidence for integrating it into diagnostic algorithms to optimize clinical decision-making and resource allocation.

Adult↗

PubMed1976

Human psychophysical analysis of receptive field-like properties. I. A new transient-like visual response using a moving windmill (Werblin-type) target.

A human transient-like visual response has been revealed psychophysically with a rotating windmill target, similar to that used by Werblin in his recent studies of the retina of Necturus. The windmill pattern evoked complex perceptual phenomena (important in and of themselves) which were minimized by using a high luminance for the "criterion" flashing test field (relative to its increment threshold), and by moving the four-vaned windmill pattern at a rate of two complete revolutions per second. The transient response, herein defined as the difference in threshold between the stationary and moving windmill conditions, was greatest when the windmill vanes fell completely within the sensitization (inhibition-like) portion of the Westheimer function determined at the same retinal locus. The test has been developed so that it may be readily adapted to available clinical equipment for future diagnostic purposes .

Differential Threshold↗

PubMed1979

A functional measure of brain activity: brain stem transmission time.

Surface-recorded auditory nerve and brain stem responses are being used routinely for diagnostic purposes in man. When interest is in auditory diagnosis, the electric response threshold is of primary importance. However, when used in neurological diagnosis, the wave form of the response is important. As a measure of one aspect of response wave form, this paper suggests the use of brain stem transmission time (BTT), defined as the time interval between the first earlobe-negative wave (response of the auditory nerve--the 'input' to the brain stem) and the earlobe-positive wave from the region of the inferior colliculus (the 'output' of the brain stem). The paper shows that BTT is longest in neonates, approaches adult values at the age of about 3 years, is relatively independent of click intensity, conductive hearing loss (middle ear lesion), click rate (except for high rates) and click frequency (filtered clicks). The finding that in a given age group, BTT is generally independent of most stimulus conditions, makes it a useful functional test of brain stem activity.

Adolescent↗

PubMed1977

Factors of the langugage of pain in patient and volunteer groups.

An empirical determination of the nature and minimum number of dimension necessary to describe responses to the McGill Pain Questionnaire, and a comparison of groups, experiencing clinical or experimentally induced pain, on the dimensions were carried out. Eighty-five patients referred to a low back pain diagnostic clinic and groups of 129 volunteer students exposed to electric shock to pain threshold and pain tolerance levels described their pain using the McGill Pain Questionnaire's descriptive words. An incomplete principle component factor analysis of subjects' ratings suggested that 5 factors should be retained. These factors were judged to reflect: (I) immediated anxiety, (II) perception of harm, (III) somesthetic pressure, (IV) cutaneous sensitivity, and (V) sensory information. Canonical Analysis of Variance and univariate comparisons of back pain, threshold, and tolerance groups on these dimensions were conducted and implications for clinical and laboratory research discussed.

Adult↗

PubMed1977

Clinical toxicology of mercury.

Based on an extensive literature search, general principles of mercury toxicity are outlined with respect to human individuals and populations. For the metal itself, as well as for its most important inorganic and organic compounds, the review discussed behavior in the body, characteristic clinical pictures, assessment of threshold levels, and evaluation as potential environmental hazards. Particular emphasis is placed on those diagnostic signs and symptoms which furnish early warning signals, permitting detection and elimination of overexposures.

Epidemiologic Methods↗

PubMed1977

[Registration of the early acoustically evoked potentials using monaural and binaural stimulation (author's transl)].

At seven normally hearing test persons the early acoustically evoked potentials were registered using monaural, binaural and contralateral click-stimulation with a repetition-rate of 10/sec at the intensities of 90 and 70 dB SPL. In comparison to the monaural stimulation the binaural stimulation yields in the mean no significant alteration of the potentials I, II and III at both intensities. The mean enlargement of potential IV by binaural stimulation amounts to about 40% and is highly significant, but this advantage does not apply always to everybody: the factor of magnification of potential IV covers the range from one to two. The average increase of 66% at potential V is weakly significant for the intensity of 90 dB SPL. As expected from the results of contralateral stimulation the registrations at patients suffering from unilateral hearing impairment show on both sides the potential's threshold of the better hearing ear when stimulating binaurally; therefore you cannot determine the better cochlea. In addition to this fact the binaural stimulation of patients suffering from an acoustic neuroma removes the diagnostically important tool to recognize differences between the two sides. These findings are demonstrated by examples. Since it is impossible to predict an increase of the amplitude in the individual case and since there are serious diagnostic disadvantages, we don't deem advisable a binaural stimulation.

Acoustic Stimulation↗