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PubMed1978

A systematic comparison of teaching hospital and remote-site clinical education.

This paper present a methodology for examining activities of medical students on multisite clinical clerkships to determine whether differences exist in the educational experience offered at various sites. Five criterion variables are explored: distribution of student activities, type or class of clinical conditions encountered by students, degree of "esoterism" of those conditions, type of student role, and flexibility of student role. A format for data collection, employing a specially designed activity recording pad, was developed as part of the study. Application of this method to a clerkship in obstetrics and gynecology documents the existence of systematic differences in the educational experiences offered at different sites, particularly with regard to type of activities undertaken and conditions encountered. Most notably, the results suggest that it is fallacious to dichotomize clerkship sites as "academic" or "community" based. It is found that community hospitals themselves can differ markedly and offer an experience paralleling that of the academic referral center.

Clinical Competence↗

PubMed2026

The Fragile Site Landscape of Induced Pluripotent Stem Cells: Hierarchy, Variability, Tissue Specificity, and Links to Culture-Acquired Rearrangements.

Induced pluripotent stem cells (iPSCs) are prone to genomic instability during prolonged culture, with recurrent chromosomal aberrations conferring selective advantages. Replication stress is a major driver of this instability, yet the repertoire of replication stress-sensitive loci in iPSCs remains largely unexplored. Here, we mapped aphidicolin-sensitive fragile sites (asFS) in three independent iPSC lines using classical cytogenetic break analysis combined with Monte Carlo simulation and MiDAS mapping directly on banded metaphase chromosomes. We identified 28 asFS, which segregated into a highly active Major cluster (8 sites, accounting for 59% of breaks among asFS) and a less active Minor cluster (20 sites). Five universal asFS (9p21, 6q25-26, 20p11-12, 10q22, Xq25) were present in all three lines, representing a fragility signature associated with the pluripotent state, with Xq25 shifting into the Major cluster after correction for X chromosome dosage. Minor asFS showed preferential co-localization with physical breakpoints or minimal overlapping regions of recurrent culture-acquired aberrations, including 20q11.21 (BCL2L1), 1q32 (MDM4), 8q24 (MYC), 17q21 (WNT3-WNT9B), and 18q21 (DCC/FRA18B). MiDAS mapping validated most asFS and revealed additional replication stress-sensitive loci in pericentromeric and subtelomeric regions that are difficult to score by conventional G-banding. Comparison with fragile site maps from other cell types revealed that the iPSC asFS repertoire is distinct in rank order and relative activity, characteristic of the pluripotent state. Collectively, our findings indicate that the asFS repertoire in iPSCs is hierarchically organized into a stable universal core and a variable peripheral component, and suggest that Minor asFS may contribute to, or be associated with, the genesis of culture-acquired rearrangements. This work provides a framework for understanding how replication stress and clonal selection shape the mutational landscape of pluripotent stem cells.

Induced Pluripotent Stem Cells↗

PubMed2025

The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI): Overview of consortium sites and anticipated enrollment.

INTRODUCTION: The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS: We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS: Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site-level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION: We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. HIGHLIGHTS: The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi-etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

Humans↗

PubMed2026

Systematic review of the mutations in the active antigenic site Ø of the prefusion F protein of the Respiratory Syncytial Virus (RSV) following the implementation of monoclonal antibody prophylaxis.

BACKGROUND: Monoclonal antibody (mAb) nirsevimab, which targets the antigenic site Ø of the prefusion F protein (pre-F) of RSV, was introduced for RSV prophylaxis in several countries. METHODS: A systematic search was conducted between January 1, 2022, and July 31, 2026 for studies analyzing substitutions within the epitope of pre-F RSV protein, which is the target of nirsevimab, after the implementation of the mAb. We searched across PubMed, Scopus, Web of Science and ClinicalTrial.gov for studies involving children with confirmed RSV infection, that conducted genomic analysis. RESULTS: Seven studies (five observational and two randomized controlled trials) including 2156 RSV-positive samples (RSV-A: 1347, RSV-B: 809) were analyzed. RSV-A strains showed limited variability within antigenic site Ø, with K65R being the most common substitution and K209E being the only intermediate-resistance RSV-A substitution. RSV-B strains demonstrated substantially higher substitution frequencies, particularly involving I206M, Q209R, and S211N. Most identified substitutions appeared to represent naturally occurring polymorphisms and retained susceptibility to nirsevimab, while multiple RSV-B substitutions and combinations involving residues 64-68 and 204-208 demonstrated reduced susceptibility or high-level resistance. Resistance-associated variants were detected in 28 of 2156 (1.3%) RSV-positive samples and exclusively among nirsevimab breakthrough infections. In a sub-analysis restricted to nirsevimab-treated individuals, resistance-associated variants were significantly more frequent among RSV-B than RSV-A (9.8% vs 0.5%; p < 0.001). CONCLUSION: Most substitutions that were detected within the nirsevimab antigenic site reflect ongoing natural RSV evolution and do not significantly affect nirsevimab susceptibility. However, detection of resistance-associated variants highlights the importance of continuous genomic and phenotypic surveillance.

Humans↗

PubMed1977

Antiestrogens in treatment of breast cancer.

The antiestrogens represent a group of compounds, not necessarily steroidal, which are able to decrease the specific uptake of estrogens in vitro and in vivo by various target tissues in the rat and in man. This action is explained either by competitive binding to estrogen receptor sites or, more probably, by failure of the antiestrogen complex, translocated into the nucleus, to stimulate neoformation of receptors in the cytoplasm. This explains the transient estrogenic effect of antiestrogen. Antiestrogens used in humans are hormone specific and antagonize also non-steroidal estrogens, like stilbestrol. Three compounds have been used in advanced breast cancer with the same indications as the older hormonal treatments. They are clomiphene citrate, nafoxidine and tamoxifen. Nafoxidine and tamoxifen are probably equally active. The response rate is between 28 and 35%, with a median duration of nine months. Nafoxidine is toxic for the skin and tamoxifen is the preferred compound. A randomized trial comparing ethinyl estradiol and an antiestrogen showed similar rates of response with the two compounds in advanced breast cancer. The uniformity of results of treatment of advanced breast cancer by hormonal agents including antiestrogens and their limitations, probably justifies the present-day concept which assigns hormonal treatment a secondary role, either as a supplement to cytotoxic chemotherapy or for old and debilitated patients. However, as a supplemented to chemotherapy, hormonal agents are probably important since recent studies have shown that apparently all breast cancers have positive receptor sites, albeit in variable amounts. Because of their lack of toxicity, antiestrogens are probably the best hormonal agents available at present.

Adult↗

PubMed2025

vcfsim: flexible simulation of all-sites VCFs with missing data.

BACKGROUND |: VCFs are the most widely used data format for encoding genetic variation. By design, standard VCFs do not include data from sites where all individuals are homozygous for the reference allele ("invariant sites") and thus do not differentiate these from sites where data are completely missing. However, missing data are a key feature of biological datasets across all domains of genomics, and many recent studies have shown that missing data can introduce a variety of statistical biases in the estimation of key population genetic parameters. A solution to this limitation is to include invariant sites in a standard VCF, creating an "all-sites VCF", exposing missing and invariant sites explicitly. One hurdle to the wider adoption of all-sites VCFs is a reliable parameterized simulation framework for generating biologically realistic all-sites VCFs. RESULTS |: Here, we introduce an open-source command line tool, vcfsim, that interfaces with the popular coalescent simulation platform msprime and provides convenience functions for simulating all-sites VCFs with variable levels of ploidy and missing data. We show that the post-processed VCFs generated using vcfsim align precisely with population genetic expectations (i.e. are statistically identical to raw msprime output), accurately introduce missing data, and permit the simulation of data with varying ploidy levels, including the simulation of intraindividual ploidy variation (e.g. heterogametic sex chromosomes) and population structures. CONCLUSIONS |: Our results vcfsim is a useful and easy-to-use tool for the benchmarking of new software tools, performing population genetic inference, training of machine learning models, and the exploration of the effects of missing data in genomics data sets.

Benchmarking↗

PubMed1978

Volume and polarity changes accompanied by amino acid substitutions in protein evolution.

We evaluated the volume and polarity changes accompanied by amino acid substitutions along branches of the phylogenetic trees of cytochrome c, myoglobin and hemoglobin alpha and beta chains. In most cases the volume changes accompanied by the substitutions were found to be much larger than the volume of cavities existing in the interior of X-ray-analysed proteins. This implies that the interior of the proteins is very flexible and the necessary space for a larger amino acid residue substitution can be provided by adjusting nearby structures. Also, the volume and polarity changes are not particularly dependent on whether the substituted site is located in the exterior or interior of the proteins. This result supports the concept of the covarions by Fitch and Markowitz, when combined with the known fact that the exterior sites are more variable than the interior ones during protein evolution.

Amino Acids↗

PubMed2026

Multilayered nucleotide organization reveals purifying selection and host-driven adaptation in CPV and FPV.

Since feline panleukopenia virus (FPV) is considered the most likely ancestor of canine parvovirus (CPV), comprehensive comparisons of nucleotide organization in corresponding viral genes between CPV and FPV may provide novel insights into the evolutionary dynamics underlying the divergence of these two viruses. Here, we characterize the evolutionary patterns of CPV and FPV genes across multiple levels of nucleotide organization. Both viruses exhibited highly conserved nucleotide usage at nonsynonymous sites, with Ka/Ks patterns consistent with strong purifying selection, whereas synonymous sites showed greater variability. CpG dinucleotides were markedly underrepresented across all four viral genes, suggesting host-associated selective pressure and/or intrinsic nucleotide compositional constraints. Extensive nonrandom biases in synonymous codon usage, codon neighboring nucleotide context, and codon pair usage further revealed fine-scale genomic optimization shaped by natural selection and nucleotide compositional constraints. Structural protein genes (VP1 and VP2) displayed stronger codon usage bias and higher tRNA adaptation than nonstructural genes. Moreover, CPV genes showed greater translational adaptation to feline hosts than to canine hosts. These findings highlight how closely related parvoviruses exploit flexible nucleotide organization to facilitate host adaptation while maintaining essential protein functions.

Animals↗

PubMed1979

Sequences of five potential recombination sites encoded close to an immunoglobulin kappa constant region gene.

Immunoglobulin kappa chain gene formation involves site-specific somatic recombination between one of several hundred germ-line variable region genes and a joining site (or "J segment") encoded close to the constant region gene. We have cloned and determined the nucleotide sequence of major portions of the recombination region of the mouse kappa gene and discovered a series of five such J segments spread out along a segment of DNA 2.4 kilobases from the kappa constant region gene. These J segments encode the 13 COOH-terminal amino acids of the variable region, probably including amino acids involved in the antigen combining site and in heavy/light chain contacts. The J segments also display striking sequence homology to one another in both their coding and immediately flanking sequences. Major elements of a short palindrome--CAC(TA)GTG--are preserved adjacent to the recombination sites of both variable and J region genes and constitute inverted repeats at both ends of the sequences to be joined. These palindromes can be written as a hypothetical stem structure that draws variable and J regions together, providing a possible molecular basis for the DNA joining event. Four of the J segments that we have discovered encode amino acid sequences already found in myeloma proteins. By altering the frame of recombination, we can account for additional light chain amino acid sequences, suggesting that the V/J joining event might generate antibody diversity somatically both by using different combinations of variable and J region genes and by using alternative joining frames.

Animals↗

PubMed1979

In vitro testing of immunoresponsiveness in patients with inflammatory bowel disease: prevalence and relationship to disease activity immunoresponsiveness in IBD.

Abnormalities in the numbers and function of thymus and function of thymus-derived and bone marrow-derived lymphocytes (T and B cells) and K cells were determined in sixty-nine consecutive patients with Crohn's disease or ulcerative colitis. Rosetting techniques to identify subpopulations of lymphocytes showed a significant decrease in E-rosettes (T cells) and significant increase in EA- and EAC-rosettes (B cells) in patients with inflammatory bowel disease when compared to normals. In vitro lymphocyte transformation responses to mitogens and antigens were depressed to a variable degree. Mean levels of K cell activity were not significantly different from normal controls. A considerable degree of individual variation was noted in all groups. When the results of each groups were considered, none of the laboratory variables correlated with the site, duration or activity of disease, therapy, presence of iron deficiency anemia, weight loss or hypoalbuminaemia. Thus, in vitro evidence of abnormal immune responses in patients with inflammatory bowel disease cannot be directly related to clinical or laboratory variables and probably reflects a multi-factorial aetiology.

Adolescent↗

PubMed2026

Care Models for the Genetic Evaluation of Dilated Cardiomyopathy at Sites of the DCM Consortium.

BACKGROUND: Clinical genetic evaluation for patients with dilated cardiomyopathy (DCM) is minimally implemented and models of care are not defined. To understand current genetics care for DCM, a systematic needs assessment was conducted. METHODS: Principal Investigators (PIs) of the DCM Consortium convened at the Summer Scientific Symposium in July 2025. An electronic needs assessment was collected from the 24 PIs in advance to define current care models by evaluating which Heart Failure Society of America-recommended genetic evaluation components are conducted, by whom, and time required. Descriptive statistics were generated to characterize model features. Focus group discussions explored barriers and facilitators to implementing genetic services. RESULTS: Four care models emerged from the PI responses: 1 - Traditional-Synchronous (25%, n=6, requiring the most time per patient), 2 - Traditional-Asynchronous (33%, n=8), 3 - Externally Sourced (17%, n=4), and 4 - Physician/Advanced Practice Provider Conducted (25%, n=6, requiring the least time per patient). All models used genetic testing, whereas other components were implemented variably or not at all. Models 1 (15.7±4.1) and 2 (15.4±3.0) were rated more acceptable than Model 4 (9.8±2.9; 1 vs 4: p=0.027; 2 vs 4, p=0.023). Notably, 88% of PIs used genetic information for treatment decisions, including ICD placement (83%; n=20) or cardiac transplant (63%; n=15). Major facilitator themes from focus group discussions included having a genetic counselor on the HF team and developing authoritative standards directing provision of DCM genetic services. Barrier themes included operational challenges, limited personnel, clinician under-recognition, need for new service delivery models, and billing/reimbursement. CONCLUSIONS: DCM genetic care models and components were highly variable across the 24 sites of the DCM Consortium, even though all sites discussed similar factors that enable or hinder implementing genetic services for DCM. Understanding the basis of practice model variability may provide insight to yield more scalable care approaches.

clinical genetics↗

PubMed2026

Care Models for the Genetic Evaluation of Dilated Cardiomyopathy at Sites of the DCM Consortium.

BACKGROUND: Clinical genetic evaluation for patients with dilated cardiomyopathy (DCM) is minimally implemented, and models of care are not well defined. To understand current genetic care for DCM, a systematic needs assessment was conducted. METHODS: Principal investigators of the DCM Consortium convened at the Summer Scientific Symposium in July 2025. An electronic needs assessment was conducted among the 24 principal investigators in advance to define current care models by evaluating which genetic evaluation components recommended by the Heart Failure Society of America were conducted, by whom, and the time required for each component. Descriptive statistics were generated to characterize model features. Focus group discussions explored barriers and facilitators to implementing genetic services. RESULTS: Four care models emerged from the principal investigator responses: model 1: Traditional-Synchronous (25%, n=6, requiring the most time per patient); model 2: Traditional-Asynchronous (33%, n=8); model 3: Externally Sourced (17%, n=4); and model 4: Physician/Advanced Practice Provider Conducted (25%, n=6, requiring the least time per patient). All models used genetic testing, whereas other components were implemented variably or not at all. Models 1 (15.7±4.1) and 2 (15.4±3.0) were rated more acceptable than model 4 (9.8±2.9; model 1 versus model 4; P=0.027; model 2 versus model 4; P=0.023). Notably, 88% of principal investigators used genetic information for treatment decisions, including implantable cardioverter defibrillator placement (83%; n=20) and cardiac transplantation (63%; n=15). Major facilitator themes from focus group discussions included having a genetic counselor as part of the heart failure team and developing authoritative standards directing provision of DCM genetic services. Barrier themes included operational challenges, limited personnel, clinician under-recognition, need for new service delivery models, and billing/reimbursement. CONCLUSIONS: DCM genetic care models and components were highly variable across the 24 sites of the DCM Consortium, although all sites discussed similar factors that enable or hinder the implementation of genetic services for DCM. Understanding the basis of practice model variability may provide insight to yield more scalable care approaches.

cardiomyopathy, dilated↗

PubMed2026

Laparoscopic Surgery Is Associated With Reduced Small Bowel Obstruction Risk After Colorectal Cancer Surgery: A Nationwide Cohort Study of 5458 Patients.

INTRODUCTION: Postoperative small bowel obstruction (SBO) is a major complication following colorectal cancer surgery, yet evidence-based prevention strategies remain unclear. We aimed to clarify site-specific risk factors for SBO and evaluate the effectiveness of laparoscopic surgery and adhesion prevention materials (APMs) in preventing SBO after colorectal cancer surgery. METHODS: This retrospective cohort study analyzed 5458 patients who underwent colorectal cancer surgery at 32 Japanese institutions between 2012 and 2014. The primary endpoint was the 5-year risk of SBO. We evaluated the effects of laparoscopic surgery, APM use, and stoma creation on SBO risk. Clinical variables included demographics, tumor site, operative approach, operative details, and postoperative complications. Hospital-level clustering was addressed using mixed-effects logistic regression. RESULTS: Overall SBO incidence was 5.2% (n = 283). Rectal cancer had the highest risk, whereas all colonic sites except the descending colon showed significantly lower odds. Laparoscopic surgery was associated with a 42% reduction in odds (OR 0.58; 95% CI 0.45-0.74; p < 0.001), with significant reductions in ascending (NNT = 22.2, p = 0.001) and sigmoid colon surgery (NNT = 30.2, p = 0.003). APMs showed no protective effect (OR 1.01; 95% CI 0.78-1.32; p = 0.94). Stoma creation significantly increased SBO risk (OR 1.84; 95% CI 1.35-2.51; p < 0.001). Secondary analysis identified reoperation and postoperative ileus as additional independent risk factors. DISCUSSION: Laparoscopic surgery was associated with reduced long-term SBO risk, with significant benefits in ascending and sigmoid colon surgery. APMs showed no measurable benefit. Stoma creation increased SBO risk, with no observed difference between ileostomy and colostomy.

adhesion prevention material↗

PubMed1978

Acinic cell tumors of minor salivary gland origin.

Acinic cell tumors of minor salivary glands are most uncommon. Search of the English language literature revealed twenty previously reported cases. Nine additional cases are newly described. Most patients presented with asymptomatic swellings, but pain and tenderness were experienced by some. Sites of involvement were variable, with the palate, tongue, and floor of the mouth being the most commonly afflicted. One new case occurred centrally within the mandible. There was no sex predominance. A spectrum of histomorphologic characteristics included solid, microcystic, papillary cystic, and follicular patterns composed of acinic, intercalated duct, vacuolated, and nonspecific glandular cells. Follow-up data on ten cases from the literature and the nine new cases revealed that one patient died of tumor, one was alive with distant metastases, and one had been successfully treated for local recurrence. The patient representing the single fatality was treated by irradiation only. Surgical excision with a border of normal tissue seems to be effective treatment. The use of "carcinoma" as an appropriate designation for this neoplasm is questioned.

Adult↗

PubMed2025

Human genetic variation reveals FCRL3 is a lymphocyte receptor for Yersinia pestis.

Yersinia pestis is the bacterium responsible for plague, one of the deadliest diseases in history. To discover human genetic determinants of Y. pestis infection, we utilized nearly 1,000 genetically diverse lymphoblastoid cell lines in a cellular genome-wide association study. A nonsynonymous SNP, rs2282284 (N721S), in Fc receptor-like 3 (FCRL3) was associated with bacterial invasion of host cells (p = 9 × 10-8). Overexpressed FCRL3 facilitated attachment and invasion of Y. pestis and colocalized with Y. pestis at attachment sites. These properties were variably conserved across the FCRL family, revealing an immunoglobulin-like domain and signaling motifs shared by FCRL3 and FCRL5 to be necessary for attachment and invasion. Direct binding to FCRL5 extracellular domain was confirmed, and B cells (the primary cells that express FCRLs) were preferentially invaded by Y. pestis. Thus, Y. pestis hijacks FCRL proteins, possibly taking advantage of an immune receptor to create a lymphocyte niche during infection.

Yersinia pestis↗

PubMed1978

Estimation of the antral and duodenal gastrin cell population removed by gastrectomy from patients with peptic ulcer.

The total number of gastric and duodenal gastrin cells was determined in the gastrectomy specimens from eight patients with peptic ulcer. Planimetry was used to determine the antral and duodenal surface. The immunoperoxydase method with specific antigastrin antibodies was used for staining gastrin cells, and the mean concentration of nucleated gastrin cells per square millimeter of antral and duodenal surface was determined by light microscopy. The mean number of duodenal gastrin cells in the resected duodenum was 4.8 per cent of the total gastric gastrin cell mass. The concentration of gastrin cells in the antrum was quite variable from one mucosal site to another. The degree of extension of the antral gastritic areas was a major factor influencing the mean concentration value. The total number of gastrin cells in the stomach varied from approximately 7 to 74 million cells. Our data indicate that hyperplasia of gastrin cells cannot be demonstrated by studies performed in small specimens taken for biopsy.

Cell Count↗

PubMed1977

[Surgery of aneurysm of the thoracic aorta. Operative results in 47 cases (author's transl)].

The authors report personal experience of surgical treatment of 47 aneurysms of the thoracic aorta, showing that the symptoms, the etiology, the treatment and the prognosis are variable depending on the site of the aneurysm. One may note regression of syphilis as a cause and an increase in the number of degenerative and traumatic aneurysms. In aneurysms of the ascending aorta, total replacement of the ascending aorta with reimplantation of the coronary arteries, according to a simplified technic, seems to give the best immediate and long term results.

Adult↗

PubMed1978

Restriction endonuclease fingerprinting of herpes simplex virus DNA: a novel epidemiological tool applied to a nosocomial outbreak.

In a blind study, 14 isolates of herpes simplex virus type 1 (HSV-1) that included nine isolates from a temporal cluster of HSV infections in a hospital Pediatric Intensive Care Unit and five unrelated isolates were analyzed by digestion of their DNA with four restriction endonucleases. These enzymes (HsuI, BglII, EcoRI, and HpaI) cleave the DNA in about 52 sites. To date, at least 16 sites have been found to be variable in the sense that they may be present or absent independently of any other cleavage site. This characteristic is stable, and no change was observed on serial propagation of the strains in culture or following repeated isolation, as long as 12 years apart, from humans. Analyses of the isolates readily discriminated between those belonging to the temporal cluster of hospital infections and the unrelated strains. They also showed that there were two independent introductions of HSV-1 into the Pediatric Intensive Care Unit resulting in two clusters of epidemiologically related infections. This type of analysis has the potential of becoming a powerful tool for tracing the spread of HSV-1 and very likely of other herpesviruses in the human population.

Autoradiography↗