A reanalysis of acid-base equilibria of 1,4-benzodiazepines in nonaqueous media.
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Acid-Base Equilibrium↗
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Symposium: Medical problem solving: a reanalysis and alternative perspectives.
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Clinical Competence↗
A critique of the collaborative cytogenetics study to measure and minimize interlaboratory variation.
A statistical reanalysis was performed on the data fecently reported on a 6-laboratory, collaborative cytogenetic study to measure and minimize interlaboratory variation. Three of the laboratories had mean values significantly different from the others on most of the 6 indexes of chemically-induced aberration; one laboratory with values higher and two with values lower. Furthermore, relative variability of the values around the means was consistently lower in one of the 6 participating laborabories. The results of the reanalysis of this collaborative study demonstrates that significant interlaboratory differences exist and that these should be adjusted or diminished before rat cytogenetic analysis can be an effective test system for evaluation of a compound for mutagenic potential.
Animals↗
Long-term follow-up of children who received rapid genomic sequencing.
PURPOSE: To explore long-term trajectories of children who received rapid genome sequencing (RGS) in intensive care settings. METHODS: We examined the electronic health records of 67 critically ill pediatric patients who received RGS 6 to 8 years ago with a collective initial diagnostic yield of 46%. RESULTS: The median length of follow-up was 6.2 years (interquartile range 4.0-7.2 years). RGS-diagnosed patients had a longer average follow-up time compared with undiagnosed patients (5.9 years vs 4.8 years, P = .026) and more subspecialty appointments per follow-up year (9.4 vs 6.9, P = .036). Mortality during the follow-up period was 9%. Patients averaged 2.1 hospital readmissions per follow-up year and 28.1 hospitalized days per follow-up year. Forty-four patients (66%) had a documented new phenotype in the electronic health records during their follow-up period. Seven patients received clinician-driven reanalysis during the follow-up period, yielding 1 new diagnosis. Systematic reanalysis of RGS performed as part of this study identified 4 new candidate diagnoses. CONCLUSION: Pediatric patients who receive RGS during intensive care unit hospitalizations continue to be high health care utilizers in subsequent years, regardless of whether RGS identified a diagnosis. Additionally, two-thirds of this cohort had a documented phenotypic change over the follow-up period, indicating dynamic clinical evolution in the years after RGS.
Humans↗
An economic evaluation of functional genomic testing for individuals with undiagnosed rare disorders.
PURPOSE: Functional genomics (FG) approaches, such as RNA-seq and proteomics, offer a complementary diagnostic modality for individuals whose cases remain unsolved after genomic sequencing. This study evaluates the cost-effectiveness and cost-benefit of FG for individuals with suspected monogenic disorders relative to manual reanalysis of genomic data at 18 months. METHODS: A decision tree model compared the costs and outcomes of FG and 18-month reanalysis using data from two Australian Undiagnosed Disease Programs. Deterministic and probability sensitivity analysis were performed. RESULTS: With a diagnostic yield of 13%, FG enabled 4 additional diagnoses per 100 individuals tested at an additional cost of $390 (US $240), resulting in an incremental cost-effectiveness ratio of $8,550 ($5,313) and an 85% probability of being cost-effective. CONCLUSION: Functional genomics enables timely diagnosis for individuals with suspected monogenic disorders by evaluating the functional impact of variants of uncertain significance, offering an advantage over reanalyzing genomic data at 18 months. Integration into the Australian healthcare system, supported by collaborative networks and secure data-sharing infrastructure, coupled with addressing barriers to accessing funded genomic testing, could lead to an annual net benefit of up to $1.1 million ($0.7 M).
Functional genomics↗
Germline ATM Testing in Hereditary Cancer Syndromes: Feedback from a Five-Year Center Cohort.
PURPOSE: Germline ATM pathogenic or likely pathogenic (P/LP) variants are increasingly recognized as clinically relevant in hereditary cancer predisposition, their integration into routine testing remains heterogeneous across countries. We describe the prevalence, tumor spectrum and relative risk associated with germline ATM P/LP variants in individuals with breast and pancreatic cancer. METHODS: We conducted a five-year retrospective (2019-2025) reanalysis of the ATM gene in 1,707 probands tested with hereditary breast and ovarian cancer (HBOC) or pancreatic cancer panels in our center. For all probands that underwent targeted ATM reanalysis, relative risks (RR) and odds ratios (OR) were calculated. Family-based segregation was performed when possible. RESULTS: Targeted ATM re-analysis identified 33 additional probands with P/LP variants, increasing diagnostic yield from 7.3% to 9.1% in HBOC and from 4.3% to 9.7% in pancreatic cancer. Among 22 breast-cancer probands, mean age at diagnosis was 47 years. Case-control comparison yielded OR 3.85 (95% CI 2.43-6.08; P=8.5×10-9) for breast cancer and OR 15.81 (95% CI 6.31-39.66; P=4.0×10-9) for pancreatic cancer. CONCLUSION: This work strengthens the role of ATM in cancer predisposition panels and supports its inclusion in French national hereditary cancer panel recommendations, together with implementation of appropriate surveillance and counseling for individuals harboring ATM P/LP variants.
ATM↗
Storage of blood samples containing alcohol.
The storage of blood alcohol samples was studied. The samples were analysed and then frozen and kept at -20 degrees for 6 months before reanalysis. The results from this reanalysis did not deviate to any significant extent from those originally obtained. The process of freezing and thawing the same samples before analysis was repeated three times without any significant difference from the results with the fresh blood samples.
Blood Chemical Analysis↗
Flow-cytometric analysis of chicken red blood cells.
Flow-cytometric analysis of acriflavin-Feulgen stained chicken erythrocytes shows a complex distribution of amounts of deoxyribonucleic acid fluorescence, the profile consisting of a main peak and a right hand shoulder. This bimodal distribution, an artifact characteristically seen on analysis of flattened cells using orthogonal flow systems, results from fluorescence emission in preferred directions stemming from the combined effects of refractility and orientation of the cells. The shoulder disappears on analysis of lysed erythrocyte ghosts, also on analysis of cells in a medium whose refractive index approximates that the cells. An orientation effect for matrue erythrocytes was indicated by reanalysis of fractions after sorting on the basis of high and low fluorescence or scatter signals. Both fractions gave the original range of values on reanalysis, although some changes in shape of the profile and in the peak positions for the sorted cells were seen. Sodium dodecyl sulfate treatment of stained cells "loosened" the cells' structure, yielding lowered scatter values, and fluorescence values approaching those of the shoulder. The average fluorescence emission of the erythrocytes was lower than that of reticulocytes and lymphocytes. The values of the latter correspond closely, although coincidently, to that the erythrocyte shoulder values. Dual parameter analysis of forward light scatter, and fluorescence, which was detected at 90 degrees to the laser beam, showed the low fluorescence to be accompanied by low scatter signal, and the high fluorescence among the cells with the high scatter signal. The lowered forward scatter signal is due to a wider scattering of light from cells oriented edge-on to the detector, and loss of signal beyond the acceptance angle of the detector. These results suggest that the preferred directions for fluorescence are in the plane of the cells, and the values are dependent on the cells' orientation in the stream. These interpretations were supported by the results of analysis of partially oriented cells. The approaches used and conclusions arrived at are similar to those of Gledhill et al (16), Van Dilla et al (37), in their analysis of fluorescence of flat sperm cells although the affects in the case of the erythrocytes are less extreme.
Animals↗
Early deaths in newly diagnosed cases of pediatric acute leukemia: a Southwest Oncology Group Study.
A reanalysis of all ten clinical trials conducted by the Southwest Oncology Group from 1958 thorugh 1976 in newly diagnosed pediatric acute leukemia was carried out to quantify the "early death" rate (i.e., rate of deaths during the first four weeks of remission induction) and to determine factors related to these deaths. Out of 1,964 patients registered, there were 126 (6.4%) early deaths. For the 1,375 acute lymphocytic leukemia (ALL) patients only, there were 75 (5.5%) early deaths. During the last eleven years on this study (1965 through 1976), the death rate for ALL patients appears to have remained stable at five deaths per 100 patients, despite the general improvement in overall survival. The most important prognostic factor was the initial platelet count: patients with a platelet count below 25,000 had a death rate over three times higher than that of patients with a platelet count over 75,000. Infants under one year of age also had a very high early death rate (6 of 41, 15%).
Age Factors↗
Genetic and environmental determinants of periodontal disease.
Reanalysis of data on periodontal disease in 241 families [Chung et al, 1977b], based on an extended and more satisfactory path model [Rao et al, 1979], failed to detect significant heritability, and concluded in favor of cultural inheritance only, without maternal effects or intergenerational differences. The most parsimonious hypothesis yields a relative variance component of 0.338 +/- 0.024 due to indexed environment for both children and adults, the remainder (1.0--0.338 = 0.662) being due to residual nongenetic factors.
Culture↗
Further morphometric studies of the ulna from the Omo Basin, Ethiopia.
A reanalysis of the L40-19 fossil ulna from the Omo Basin, Ethiopia is presented. Using covariance adjustment rather than ratios to correct metric data for variations due to body size, a comparative sample reflecting 21 contemporary Anthropoid taxa, and both distribution-free and multivariate statistical procedures, this study indicates that the earlier conclusion drawn by McHenry et al. ('76), viz., that the fossil is "unique" among Hominoids, is essentially correct. This study also concludes, however, that although the fossil is projected closer to Pan and Homo than to Pongo, the distances are considerably greater than found between behaviorally similar modern forms. Consequently, aside from assigning the fossil on morphometric grounds to the Hominoidea, little else can be said about its possible locomotor habits or its ancestry.
Animals↗
Detection of rare major genes in lipid levels.
A statistical test of polygenic inheritance (TPI) against the alternative of a rare major gene is presented. It is designed for a random sample of quantitative observations on index cases and siblings of those index cases (probands) selected on the basis of the observed measurements of these probands. The test focuses on an increase of the variance of siblings of probands over its value under polygenic inheritance, such an increase being expected in the presence of a major gene producing a shift of the quantitative observations. Certain data on lipids are then analyzed by this test. A major gene can tentatively be confirmed for triglycerides but not for cholesterol. In addition, the values of all index cases are subjected to an analysis of a mixture of normal distributions (NOCOMP computer program), resulting in a significant second component for triglycerides but not for cholesterol. For both TPI and NOCOMP, the exponent in a power transformation is estimated by maximum likelihood simultaneously with all other parameters, so that these analysis methods are robust against a wide range of skewness in the data, which is demonstrated by manipulation of the observations and their reanalysis.
Analysis of Variance↗
Concentration quenching in chlorophyll-alpha and relation to functional charge transfer in vivo.
Chlorophyll-alpha in ordinary solvents exhibits concentration quenching. Dimeric chlorophyll is reasonably well confirmed as the quenching species, by a critical reanalysis of available data on concentration dependence and on spectral features, in ordinary solvents, and in several analogous quenching environments. This quenching in the dimer in vitro is somewhat less firmly analyzed as due to a new fast internal conversion. Much peripheral evidence supports transient charge transfer as the cause of internal conversion. The same evidence points to a strong similarity to functional charge transfer in vivo. I suggest that inability to extract P680 may be due to its conversion to a form resembling P700 by addition of water. A number of straightforward experiments are suggested to test these proposals. In particular, it is desirable to test for the existence of a vibronic perturbation (from a higher npi* state) in the dimer, as an alternative to charge transfer for explaining the "observed" internal conversion. Such a vibronic cause would raise interesting problems for phototrap function in vivo.
Chlorophyll↗
The structured interview and questionnaire methods of assessing coronary-prone behavior in male and female college students.
Several self-report measures of type A behavior were compared with the Rosenman and Friedman structured interview method of assessment in male and female college students. The student version of the Jenkins Activity Survey was found to correlate relatively weakly with the interview for both males and females, while scales derived from the Gough and Thurstone inventories showed moderate correlations with interview typing for both sexes. A brief scale derived from a recent reanalysis of the Framingham study correlated with the interview appreciably greater for females than for males. In all, these data suggest the need for caution in using only paper-and-pencil tests to assess type A behavior.
Adolescent↗
Resolution of block neutralization test curves into components of the foot-and-mouth disease virus system.
Classic neutralization studies by Fazekas de St. Groth and Webster (8) on mixtures of influenza viruses and mixtures of rabbit antisera are reinterpreted in terms of a percentage contaminant in the stock used for the dilution series. A very small amount of a different virus changes the shape of quantal assay curves considerably, but even a large amount of a different antiserum has negligible effect on the shape and merely shifts the curve along the serum dilution axis. These conclusions are the reverse of the authors, who only considered an absolute amount of another component in all dilution tubes. An artificial mixture of 2.7 percent O8 in O1 foot-and-mouth disease virus strains was tested against anti-O1 serum assaying in suckling mice. The small amount of O8 virus greatly altered the shape of the neutralization curve in the direction expected from the reanalysis of the influenza literature data. Results from artificial mixtures are used to explain what were hitherto anomalously broad neutralization curves for some other foot-and-mouth disease strains given by Booth et al. (1) Many of the virus stocks studied can now be postulated as a natural mixture of related virus strains. In fact, the O1 and O8 stocks used might also be of themselves mixtures. These virus strains also exhibit still a further test complication in that the virus-antibody reaction appeared to shift away from complexes on dilution immediately prior to assay.
Antigen-Antibody Reactions↗
Bone fluoride concentrations associated with fluoridated drinking water.
Recently published bone fluoride values from Iowa are very high compared to earlier reports, suggesting an increase in fluoride intake. Reanalysis of the Iowa specimens shows levels one-fourth those reported by the Iowa laboratory indicating an error in the original report. Seventeen bone specimens, collected from long-term residents of Rochester, New York, drinking 1 ppm F- water, had a mean value of 2085 +/- 270 ppm F- on an ashed-weight basis. This value is not significantly different from that predicted by the data of Zipkin et al. in 1958. These data, therefore, do not support the contention that there has been an increase in fluoride intake.
Bone and Bones↗
Network-based integration of metabolomics data from large-scale repositories.
INTRODUCTION: Public metabolomics data repositories such as MetaboLights and Metabolomics Workbench host rapidly growing volumes of raw data, processed results, and metadata. As data deposition becomes a prerequisite for funding and publication, there is an increasing need for tools that enable integration and joint reanalysis of datasets across studies to maximise reuse and reproducibility. OBJECTIVES: This study aims to enable large-scale integrative meta-analysis of public metabolomics data, exploiting harmonised metabolite annotations to identify robust multi-study metabolite and pathway signatures and to provide global visual overviews of repository content. METHODS: We developed a network-based integration framework operating at both the study (dataset) level and the metabolite or pathway level. Metabolite-level meta-networks integrate studies with shared biological context using co-occurrences of differential metabolites represented as bipartite graphs. Study-level networks compare observed metabolites for overall repository exploration. Networks can be explored interactively using a dedicated Python Dash app available at https://github.com/EloisaRL/Metabolomic-data-analysis-app/tree/main . RESULTS: As an example, the approach was applied to six COVID-19 plasma datasets from MetaboLights generated using LC-MS and NMR. Ten metabolites were identified as differential in at least three studies, including consistently up-regulated pyroglutamic acid, in agreement with the literature. Pathway-level networks provided an overview of shared biological processes across studies. A global network of 1,181 studies in Metabolomics Workbench demonstrated clustering by assay coverage and associated metadata, as expected. CONCLUSION: Network-based integration of harmonised metabolomics data enables robust cross-study analyses and highlights the critical importance of standardised annotation pipelines. Such approaches enhance the reuse, reproducibility, and impact of public metabolomics datasets, accelerating biological discovery.
Metabolomics↗
Robust error-minimization in the genetic code across physicochemical metrics and variant codes: A graph-theoretic analysis in GF(2)6.
The standard genetic code reduces the impact of point mutations, but the robustness of this property across physicochemical metrics, naturally occurring variant codes, and codon-reassignment mechanisms remains incompletely quantified. Embedding the 64 codons in GF(2)6 represents the hypercube Q6 as a coordinate-dependent subgraph of the encoding-independent single-nucleotide mutation graph H(3,4), and enables continuous ρ-interpolation between the two. Under a quartet-pattern shuffle null (n=10,000), the standard code is significantly low-cost across four established, code-independent physicochemical distance metrics with partially overlapping content (Grant ham p=0.0062; Miyata p<0.001; Woese polar requirement p=0.003; Kyte-Doolittle hydropathy p=0.001), and the signal strengthens monotonically as ρ moves Q6→H(3,4). A structure-aware sensitivity analysis under the alignment-derived ProtSub matrix (Jia & Jernigan 2021) yields the most extreme percentile of any measure tested (p=0.0004; all five p-values pass Bonferroni at α=0.05). Across the 27 NCBI translation tables, near-optimality is preserved: 11 of 12 informative-distance variants retain top-5% placement after BH-FDR correction. Natural codon reassignments avoid disrupting codon-family connectivity: under the encoding-independent H(3,4) adjacency, observed events are topology-breaking at relative risk 0.32 versus the candidate landscape (permutation p≤10-4). The H(3,4) result is stable by construction; the Q6 decomposition is representation-specific and fails to show depletion under 8 of 24 base-to-bit encodings, so we report H(3,4) as the primary test and Q6 as a sensitivity. Event-level conditional-logit modelling shows that topology avoidance and local physicochemical cost provide complementary, only weakly correlated signal (rs=0.15), and that topology adds explanatory value beyond physicochemistry under both Q6 and encoding-independent H(3,4) adjacency. Retrospective reanalysis of nine genome-recoding datasets is consistent with codon-family topology operating as an evolutionary-trajectory constraint distinct from acute engineering fitness. The contribution is the second axis: code evolution is jointly constrained by physicochemical smoothness and codon-family topological integrity, and these two constraints are partly independent.
Codon reassignment↗