bluuebunny/crossref_metadata_2025 huggingface dataset:
The geometry of admixture in population genetics: the blessing of dimensionality
Authors: Oteo José-Angel , Oteo-García Gonzalo
Published: August 2024

We present a geometry-based interpretation of the f-statistics framework, commonly used in population genetics to estimate phylogenetic relationships from genomic data. The focus is on the determination of the mixing coefficients in population admixture events subject to post-admixture drift. The interpretation takes advantage of the high dimension of the dataset and analyzes the problem as a dimensional reduction issue. We show that it is possible to think of the f-statistics technique as an implicit transformation of the genomic data from a phase space into a subspace where the mapped data structure is more similar to the ancestral admixture configuration. The 2-way mixing coefficient is, as a matter of fact, carried out implicitly in this subspace. In addition, we propose the admixture test to be evaluated in the subspace because the comparison with the conventional one provides an important assessment of the admixture model. The overarching geometric framework provides slightly more general formulas than the f-formalism by using a different rationale as a starting point. Explicitly addressed are 2- and 3-way admixtures. The mixture proportions are provided by suitable linear fits, in 2 or 3 dimensions, that can be easily visualized. The difficulties encountered with introgression and gene flow are also addressed. The developments and findings are illustrated with numerical simulations and real-world cases.
Direct inference of the distribution of fitness effects of spontaneous mutations from recombinant inbred Caenorhabditis elegans mutation accumulation lines
Authors: Crombie Timothy A , Rajaei Moein , Saxena Ayush Shekhar , Johnson Lindsay M , Saber Sayran , Tanny Robyn E , Ponciano José Miguel , Andersen Erik C , Zhou Juannan , Baer Charles F
Published: August 2024

The distribution of fitness effects of new mutations plays a central role in evolutionary biology. Estimates of the distribution of fitness effect from experimental mutation accumulation lines are compromised by the complete linkage disequilibrium between mutations in different lines. To reduce the linkage disequilibrium, we constructed 2 sets of recombinant inbred lines from a cross of 2 Caenorhabditis elegans mutation accumulation lines. One set of lines (“RIAILs”) was intercrossed for 10 generations prior to 10 generations of selfing; the second set of lines (“RILs”) omitted the intercrossing. Residual linkage disequilibrium in the RIAILs is much less than in the RILs, which affects the inferred distribution of fitness effect when the sets of lines are analyzed separately. The best-fit model estimated from all lines (RIAILs + RILs) infers a large fraction of mutations with positive effects (∼40%); models that constrain mutations to have negative effects fit much worse. The conclusion is the same using only the RILs. For the RIAILs, however, models that constrain mutations to have negative effects fit nearly as well as models that allow positive effects. When mutations in high linkage disequilibrium are pooled into haplotypes, the inferred distribution of fitness effect becomes increasingly negative-skewed and leptokurtic. We conclude that the conventional wisdom—most mutations have effects near 0, a handful of mutations have effects that are substantially negative, and mutations with positive effects are very rare—is likely correct, and that unless it can be shown otherwise, estimates of the distribution of fitness effect that infer a substantial fraction of mutations with positive effects are likely confounded by linkage disequilibrium.
A Rapid and Scalable Multiplex PCR-Based Next-Generation Amplicon Sequencing Method for Familial Hypercholesterolemia Genetic Screening
Authors: Imran Mohamed , Arvinden V R , Mehanathan Pabithadevi Balaiah , Rajagopal Raskin Erusan , Muthu Suriya Prabha , Arunachalam Arul Subbiah , Bhoyar Rahul C , Vignesh Harie , Mitra Samya , Jha Ganga Nath , Gupta Aayush , Kumar Manoj , Bhowmick Rohit , Bhunia Niladri Sekhar , Dutta Atanu Kumar , Scaria Vinod , Sivasubbu Sridhar
Published: August 2024

Background

Familial hypercholesterolemia (FH) is a frequently underdiagnosed genetic disorder characterized by elevated low-density lipoprotein (LDL) levels. Genetic testing of LDLR, APOB, and PCSK9 genes can identify variants in up to 80% of clinically diagnosed patients. However, limitations in time, scalability, and cost have hindered effective next-generation sequencing of these genes. Additionally, pharmacogenomic variants are associated with statin-induced adverse effects in FH patients. To address these challenges, we developed a multiplex primer-based amplicon sequencing approach for FH genetic testing

Methods

Multiplex primers were designed for the exons of the LDLR, APOB, and PCSK9 genes, as well as for pharmacogenomic variants rs4149056 (SLCO1B1:c.521T > A), rs2306283 (SLCO1B1:c.388A > G), and rs2231142 (ABCG2:c.421C > A). Analytical validation using samples with known pathogenic variants and clinical validation with 12 FH-suspected probands were conducted. Library preparation was based on a bead-based tagmentation method, and sequencing was conducted on the NovaSeq 6000 platform.

Results

Our approach ensured no amplicon dropouts, with over 100× coverage on each amplicon. Known variants in 2 samples were successfully detected. Further, we identified one heterozygous LDLR (p.Glu228Ter) variant and 2 homozygous cases of LDLR (p.Lys294Ter) and LDLR (p.Ser177Leu) variants in patients. Pharmacogenomic analysis revealed that overall 3 patients may require reduced statin doses. Our approach offered reduced library preparation time (approximately 3 h), greater scalability, and lower costs (under $50) for FH genetic testing.

Conclusions

Our method effectively sequences LDLR, APOB, and PCSK9 genes including pharmacogenomic variants that will guide appropriate screening and statin dosing, thus increasing both efficiency and affordability.
Cancer information and population health resource: a resource for catchment area data and cancer outcomes research
Authors: Baggett Christopher D , Jackson Bradford E , Green Laura , Kuo Tzy-Mey , Kim KyungSu , Zhou Xi , Reeder-Hayes Katherine E , Lund Jennifer L , Wheeler Stephanie B , Olshan Andrew F
Published: August 2024

Background

The University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center has developed a novel data resource, the Cancer Information and Population Health Resource (CIPHR), for conducting catchment area evaluation and cancer population health research that links the North Carolina Central Cancer Registry (NCCCR) to medical and pharmacy claims data from Medicare, Medicaid, and private plans operating within North Carolina. This study’s aim was to describe the CIPHR data and provide examples of potential cohorts available in those data.

Methods

We present the underlying populations included in the NCCCR and claims data before linkage and demonstrate estimated sample sizes when these data are linked and commonly used insurance enrollment criteria are applied.

Results

Data for the years 2003-2020 are present in CIPHR and include 947 977 cancer cases from the NCCCR and 21.6 million enrollees in public and private health insurance (cancer and noncancer cases). When limited to first or only cancers (n = 672 377), 86% could be linked to insurance enrollment for at least 1 month during 2003-2020 (n = 582 638), with 62% of individuals linking to enrollment during the month of cancer diagnosis. Among all registry cancer cases, 47% (n = 317 898) had continuous insurance enrollment for at least 12 months before and after cancer diagnosis.

Conclusion

CIPHR illustrates the utility of establishing and maintaining a statewide, comprehensive cancer population health database. This resource serves to characterize the cancer center catchment area and aids in tracking cancer outcomes and trends in care delivery as well as identifying disparities that require intervention and policy focus.
Immune checkpoint inhibitor–associated nephritis—treatment standard
Authors: Barbir Elena-Bianca , Kitchlu Abhijat , Herrmann Sandra M
Published: August 2024

Over the last 13 years, the use of immune checkpoint inhibitor (ICI) therapy has grown remarkably, owing to their unprecedented anti-tumor efficacy in certain tumor groups. With increased use of ICIs, we are seeing immune-related adverse events (irAEs) more frequently. Renal irAEs, such as ICI-associated acute kidney injury (ICI-AKI), are reported in 2%–5% of patients treated with ICIs, with acute tubulointerstitial nephritis (ATIN) as the most common histopathologic lesion, though various forms of glomerulonephritis have also been reported. Modifiable risk factors for ICI-AKI include concurrent use of ATIN-associated drugs, like proton pump inhibitors, non-steroidal anti-inflammatory drugs and antibiotics, and dual ICI therapy with both Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) and Programmed Cell Death Protein 1 and its ligand (PD1/PDL-1) blockade. Kidney biopsies remain the diagnostic modality of choice, though several promising non-invasive biomarkers, which have not yet been broadly clinically validated have emerged. The treatment of ICI-AKI involves holding ICIs, discontinuation of ATIN-associated drugs and initiation of immunosuppression with corticosteroids as first-line therapy. With prompt treatment initiation, most patients achieve full or partial renal recovery, allowing for re-challenge with ICI. However, a subset of patients will require additional steroid-sparing therapies for corticosteroid-dependent or refractory ICI-AKI. Here we review developments in our understanding of the pathophysiology of ICI-AKI, the approach to diagnosis (with a focus on the emergence of novel diagnostic tools), prognostic factors and the current evidence for establishing treatment standards for ICI-AKI. As the evidence base remains largely retrospective, we identify questions that would benefit from future prospective studies in the diagnosis, management and prognostication of ICI-AKI.
An image-domain deep-learning denoising technique for accelerated parallel brain MRI: prospective clinical evaluation
Authors: Onac Laura , Dobai Lorand , Mouraviev Andrei , Badila Mihai A , Yap Denise , Kennedy Samantha , Nguyen Annie , Gal Emi , Sodickson Daniel K
Published: August 2024

Background

Parallel imaging can accelerate MRI acquisitions, but excessive accelerations can introduce amplified noise and aliasing artifacts.

Purpose

To evaluate a vendor-agnostic AI-based approach to remove image degradation artifacts in highly accelerated MRI scans, improving image quality and reducing scan time.

Materials and methods

Training was performed by retrospectively degrading standard accelerated images. Evaluation was performed with both retrospective and prospectively-collected highly accelerated images. Retrospective data were taken from ∼2000 MRI studies obtained between August 2016 and October 2022, and prospective data were collected in >200 subjects between June and November 2022, using scanners from multiple vendors and locations. Scan time data were collected from prospective studies and used to compute time savings per sequence and per protocol for each vendor. Images were evaluated qualitatively by 5 board-certified radiologists and quantitatively by assessing noise, contrast, and spatial resolution. Paired Wilcoxon signed-rank tests were used to compare model outputs to model inputs and low-acceleration images.

Results

Images from 101 adults from 5 sites and 6 scanner models from different vendors were enrolled. 89% of imaged subjects had noteworthy imaging features or pathology. Model outputs were rated superior to model inputs (P < .001) and most were either non-inferior (Pinf > .05) or superior (Psup < .05) to baseline images in qualitative metrics of image quality and feature visibility. Quantitative evaluation of signal-to-noise ratio and contrast-to-noise ratio improved for model outputs compared to inputs (P < .001) or baseline images (P < .005). Apparent resolution measured using the full width at half maximum or minimum was either enhanced (Psup < .05) or preserved (non-superior Psup > .05 and non-inferior Pinf > .05). The scan time was reduced by an average of 29% (19%-41% per sequence).

Conclusion

This vendor-agnostic AI-based method achieved robust scan time savings without loss of image quality, potentially allowing for reduced cost and improved patient experience.
A New Vector of Xylella fastidiosa: The Role of Mesoptyelus impictifrons as a Vector in Israel
Authors: Tomer Maor , Gidron-Heinemann Liat , Chiel Elad , Sharon Rakefet
Published: August 2024

In recent years, the bacterium Xylella fastidiosa has been spreading in almond orchards (causing almond leaf scorch) and in grapevines (causing Pierce's disease) in northern Israel. Sucking insects specialized for xylem sap-feeding transmit this plant pathogen, but the identity of the vector(s) in Israel has not been determined. Hence, we sought to determine the main potential vector(s) of X. fastidiosa in Israel. In our surveys in northern Israel, we collected and identified four species of spittlebugs: Neophilaenus campestris, Philaenus arslani, Cercopis intermedia, and Mesoptyelus impictifrons. The first two species were found in very low numbers. C. intermedia was found only in spring and did not transmit X. fastidiosa in controlled experiments. M. impictifrons was the most abundant and widely distributed species in our survey and was found in and around infected vineyards in northern Israel. In controlled experiments, we found that 35 to 39% of M. impictifrons adults acquire X. fastidiosa from infected vines and almonds and subsequently transmit it to vines and almonds. Taken together, this study suggests that M. impictifrons is an important new vector of X. fastidiosa in almond orchards and vineyards in northern Israel. Further studies are needed on M. impictifrons’ biology, ecology, and role as a vector of X. fastidiosa.
Interferon‐gamma signaling drives epithelial TNF‐alpha receptor‐2 expression during colonic tissue repair
Authors: Watson Sean , Cabrera‐Silva Rodolfo I. , Parkos Charles A. , Nusrat Asma , Quiros Miguel
Published: August 2024

Interferon‐gamma (IFNγ) is traditionally recognized for its pro‐inflammatory role during intestinal inflammation. Here, we demonstrate that IFNγ also functions as a pro‐repair molecule by increasing TNFα receptor 2 (TNFR2 protein/TNFRSF1B gene) expression on intestinal epithelial cells (IEC) following injury in vitro and in vivo. In silico analyses identified binding sites for the IFNγ signaling transcription factor STAT1 in the promoter region of TNFRSF1B. Scratch‐wounded IEC exposed to IFNγ exhibited a STAT1‐dependent increase in TNFR2 expression. In situ hybridization revealed elevated Tnfrsf1b mRNA levels in biopsy‐induced colonic mucosal wounds, while intraperitoneal administration of IFNγ neutralizing antibodies following mucosal injury resulted in impaired IEC Tnfrsf1b mRNA and inhibited colonic mucosal repair. These findings challenge conventional notions that “pro‐inflammatory” mediators solely exacerbate damage by highlighting latent pro‐repair functions. Moreover, these results emphasize the critical importance of timing and amount in the synthesis and release of IFNγ and TNFα during the inflammatory process, as they are pivotal in restoring tissue homeostasis.
Fetomaternal Hemorrhage and Choriocarcinoma
Authors: Farmer Meredith
Published: August 2024

Background:

This case describes chronic anemia of a late preterm infant secondary to maternal–fetal hemorrhage and subsequent findings of maternal choriocarcinoma.

Clinical Findings:

This infant was born at 35 6/7 weeks gestational age via cesarean section for non-reassuring fetal heart tones. The mother presented with decreased fetal movement and the biophysical profile was 4/8. Following delivery, the infant did not require respiratory support, was vigorous with extreme pallor, and had a hemoglobin of less than 5 on cord gas.

Primary Diagnosis:

Chronic anemia secondary to fetomaternal hemorrhage.

Interventions:

The infant’s initial hemoglobin was 2.4 and hematocrit was 8.1. The mother’s Kleihauer-Betke test was elevated at 7%. The infant required a partial exchange transfusion following admission to the neonatal intensive care unit. Following the partial exchange transfusion, the infant began to experience increasing respiratory distress and required respiratory support. An echocardiogram showed severe persistent pulmonary hypertension of the neonate. The mother was subsequently diagnosed with choriocarcinoma.

Outcomes:

The infant fully recovered from chronic anemia and persistent pulmonary hypertension of the neonate and was discharged home with the mother. The infant required follow-up testing for choriocarcinoma outpatient.

Practice Recommendations:

Newborns diagnosed with early chronic anemia should be evaluated, the cause investigated, and appropriate treatment considered. If the cause of blood loss is unknown, a maternal Kleihauer-Betke test should be considered. In this case, a partial exchange transfusion was performed to avoid cardiovascular volume overload, but another course of treatment could include small aliquots of packed red blood cell transfusions.
The Effect of Oral Colostrum Application on the Condition of the Mouth and Incidence of Late-Onset Sepsis Among Premature Infants
Authors: Barizeh Leila , Jabraeili Mahnaz , Hoseini Mohammad Bagher , Rahkar Farshi Mahni , Martyn Julie-Anne , Thapa Deependra Kaji , Cleary Michelle
Published: August 2024

Background:

Premature infants have higher risks of infection due to their underdeveloped immune systems and changes to the oral cavity’s normal flora colonization.

Purpose:

To assess the effect of oral colostrum application on the condition of the mouth and the incidence of late-onset sepsis (LOS) among premature infants.

Methods:

In this randomized controlled trial, 70 newborn premature infants were randomly allocated to colostrum or sterile water groups. The Mouth Care Assessment Tool was used to evaluate the condition of the mouth for 5 days after oral colostrum application. The incidence of LOS was measured using clinical and laboratory indicators from 72 hours after birth until discharge.

Results:

The condition of the mouth was significantly different on days 4 and 5, demonstrating that the colostrum group had less need for oral care (P < .001) compared to the control group. There was no significant difference between the 2 groups in clinical symptoms and laboratory values related to LOS (P > .05).

Implications for practice:

Oral colostrum application can benefit oral mucosal health and reduce the need for oral care among premature infants. It is also safe alternative oral care for premature infants who cannot breastfeed during the first few days of life. Future research should include infants of different gestational ages and mechanically ventilated infants to assess the effect of oral colostrum application on serum immune factors.
Hearing Loss and Annual Earnings Over a 20-Year Period: The HUNT Cohort Study
Authors: Jørgensen Astrid Ytrehus , Engdahl Bo , Bratsberg Bernt , Mehlum Ingrid Sivesind , Hoffman Howard J. , Aarhus Lisa
Published: August 2024

Objectives:

The association between hearing loss and income has only been examined in cross-sectional studies. We aim to study annual increase in earnings over 20 years, comparing people with and without hearing loss.

Design:

We used data from a population-based hearing study in Norway (The Trøndelag Health Study, 1996–1998), including 14,825 persons (46.2% men, mean age at baseline 30.6 years, age range 20 to 40 years). Hearing loss was defined as the pure-tone average threshold of 0.5 to 4 kHz in the better hearing ear ≥20 dB HL (n = 230). Annual earnings were assessed from 1997 to 2017. Longitudinal analyses were performed with linear mixed models adjusted for age, sex, and education.

Results:

People without hearing loss at baseline (before age 40) had a greater annual increase in earnings over a 20-year follow-up period compared with people with hearing loss. For people with normal hearing, annual earnings over 20 years increased by 453 Euro (EUR) (95% confidence interval [CI] = 384 to 522) or 13.2% more per year than for people with hearing loss, adjusted for age and sex. The difference in annual earnings over 20 year was greater among women (462 EUR, 95% CI = 376 to 547) than men (424 EUR, 95% CI = 315 to 533), greater among younger than older adults, and greater among lower than higher educated persons. When including adjustment for education in the model, in addition to age and sex, the difference in annual earnings over 20 years between persons with and without hearing loss was reduced (337 EUR, 95% CI = 269 to 405).

Conclusions:

The results from this large population-based study indicates that people with hearing loss experience lower long-term earnings growth compared with people with normal hearing. The findings highlight the need for increased interventions in the workplace for people with hearing loss.
Granulomatous Folliculotropic Secondary Syphilis: An Unusual Histopathological Clue
Authors: Sánchez-Martínez Eva , Schaller Jörg
Published: August 2024

Syphilis is a sexually transmitted disease that can present a wide variety of clinical and histopathological manifestations. We present the case of a 75-year-old patient with a persistent maculopapular rash on the trunk and extremities, in which the biopsy showed an exclusively perifollicular granulomatous infiltrate. In the immunohistochemical staining with anti-Treponema pallidum antibodies, spirochetes scattered within the perifollicular inflammatory infiltrate were identified. These findings together with the serological analysis allowed the diagnosis of secondary syphilis. Folliculotropic nonalopecic syphilis is rare, and the pathogenic mechanisms that cause this specific tropism are unknown. On the other hand, granulomatous inflammation is a pattern typically described in tertiary syphilis but also occasionally found in secondary syphilis. We present a case of secondary syphilis with the combination of both histopathological findings, an uncommon constellation for dermatopathologists to consider.
Unveiling the Tempest: Dermal Plasmacytoid Dendritic Cell Proliferation as the Harbinger of Acute Myeloid Leukemia
Authors: Zelman Brandon , Barragan Victor , Fathima Samreen , Gupta Rachit , Hanif Faaris , Mirza Kamran , Speiser Jodi
Published: August 2024

Plasmacytoid dendritic cell neoplasms are rare neoplasms originating from plasmacytoid dendritic cells (pDCs). They are subclassified into 2 types: blastic plasmacytoid dendritic cell neoplasm and mature plasmacytoid dendritic cell proliferation. Neoplastic expansion of pDCs has also been found to be associated with myeloid neoplasia. We present the diagnostically challenging case of a 62-year-old woman who presented to the emergency department with numerous hemorrhagic nodules and papules on the face and extensor surfaces near the elbows and neutropenic fevers. The patient had a history notable for lupus erythematosus and a recently performed excisional lymph node biopsy involved by a “plasmacytoid dendritic cell proliferation.” A punch biopsy was performed, which showed a robust dermal infiltrate of atypical intermediate-sized mononuclear cells. The infiltrate was positive for CD4, CD43, and CD123. CD3 and CD8 highlighted background T cells. The infiltrate was negative for CD10, CD34, CD56, CD68, CD117, myeloperoxidase, lysozyme, TdT, and TCL-1. The findings favored a diagnosis of cutaneous involvement of the plasmacytoid dendritic cell proliferation. Given the association with acute leukemias, a subsequent bone marrow biopsy was recommended. The bone marrow biopsy was performed, which showed increased blasts (68% on a 500 differential cell count). Furthermore, immunohistochemical stains were performed, which highlighted the blasts to be positive for CD34 and BEST (alpha-naphthyl butyrate esterase) cytochemical stain. This diagnosis was consistent with bone marrow involvement of acute myelomonocytic leukemia. Given the overlapping presenting symptoms (skin lesions, adenopathy, marrow involvement) of pDC neoplasms and myeloid neoplasia and the possibility of presenting concurrently, increased awareness is of pivotal importance to help prevent potential misdiagnosis, missed diagnosis, and prompt investigation of possible associated neoplasms.
A Comparison of Parent-Reported Severe Autism With Mild/Moderate Autism Among US Children
Authors: Carbone Paul S. , Stipelman Carole H. , Villalobos Michele E. , Ellzey Allison , Stuart Ashley , Stoddard Gregory J. , Campbell Kathleen
Published: August 2024

Objective:

An expert commission has proposed the term “profound” autism for children on the spectrum who are minimally verbal or nonverbal and have intellectual disability (ID), behavioral challenges, and co-occurring conditions. It is unknown whether parents' rating of “severe” autism aligns with the definition of “profound” autism. Using the National Survey of Children's Health, we sought to (1) estimate the prevalence of parent-reported severe autism, (2) identify child characteristics that are associated with severe autism, (3) compare health care utilization, and (4) compare caregiver stress and resilience between families of children with severe versus mild/moderate autism.

Methods:

Parent responses on the 2018 to 2019 NSCH were used to compare school-age children with parent-reported severe autism and those with mild/moderate autism. Descriptive statistics, χ2 tests, and logistic regression were used for statistical analysis.

Results:

Among parents of 1,368 US children with autism, 10.1% characterized their child's autism as severe, a prevalence of 1 in 333. Parents of children with severe autism were more likely to report ID (45% vs 12.1%, p < 0.001), language delay (88% vs 58.7%, p < 0.001), and difficulties in dressing and bathing (67% vs 19.2%, p < 0.001). Children with severe autism had more behavioral problems and co-occurring conditions but were no more likely to see specialists or receive autism-specific behavioral therapy. Their caregivers reported more stress and less resilience.

Conclusion:

The characteristics of “profound” autism and parent-reported “severe” autism significantly overlap, allowing the use of the NSCH for studies of this vulnerable population. Children with profound/severe autism could benefit from more behavioral therapy, specialty care, and family support.
Transcutaneous electrical nerve stimulation and catheter-related bladder discomfort following transurethral resection of bladder tumour
Authors: Park Jun-Young , Yu Jihion , Kim Chan-Sik , Baek Ji-Won , Mun Taeho , Kim Young-Kug
Published: August 2024

BACKGROUND

Catheter-related bladder discomfort (CRBD) is problematic in patients with a urinary catheter. Transcutaneous electrical nerve stimulation (TENS) is a non-invasive analgesic modality used to relieve various types of pain.

OBJECTIVES

We evaluated the effect of TENS on CRBD after transurethral resection of bladder tumours (TURBT).

DESIGN

A randomised controlled trial.

SETTING

A large university tertiary hospital, from October 2022 to March 2023.

PATIENTS

Patients requiring urinary catheterisation after TURBT.

INTERVENTION

In this randomised controlled trial, patients were randomly allocated to the TENS (n 
= 56) or control (n 
= 56) groups. CRBD manifests as a burning sensation with an urge to void or discomfort in the suprapubic area. Moderate to severe CRBD was defined as patients self-reporting CRBD symptoms with or without behavioural response, including attempts to remove the urinary catheter, intense verbal reactions, and flailing limbs. TENS was performed from the end of surgery to 1 h postoperatively.

MAIN OUTCOME MEASURE

The primary endpoint was considered moderate to severe CRBD immediately postoperatively. Secondary endpoints included moderate to severe CRBD at 1, 2 and 6 h postoperatively. Additionally, postoperative pain, patient satisfaction, and TENS-related adverse effects were evaluated.

RESULTS

Moderate to severe CRBD immediately postoperatively was significantly less frequent in the TENS group than in the control group: 10 (17.9%) vs. 34 (60.7%); P < 0.001; relative risk (95% CI) = 0.294 (0.161 to 0.536); absolute risk reduction = 0.43; number needed to treat = 2.3. Moderate to severe CRBD differed between the two groups at 1 h postoperatively: 1 (1.8%) vs. 16 (28.6%); P < 0.001; relative risk = 0.06 (95% CI 0.01 to 0.46); absolute risk reduction = 0.27; number needed to treat = 3.7. The TENS group exhibited a significantly lower score for postoperative pain at 1 h (1.8 ± 0.6 vs. 2.2 ± 0.4; P < 0.001, mean difference (95% CI) = 0.4 (0.2 to 0.6) and a higher score for patient satisfaction, 5.0 (4.0 to 6.0) vs. 3.0 (3.0 to 4.0); P < 0.001; median difference (95% CI) = 2.0 (1.0 to 2.0).

CONCLUSIONS

TENS reduced moderate to severe CRBD, decreased postoperative pain, and increased patient satisfaction after TURBT.

CLINICAL TRIAL REGISTRY

Clinical Research Information Service (KCT0007450)
Efficacy and safety of bintrafusp alfa in 2 phase I expansion cohorts with advanced HCC
Authors: Lim Ho Yeong , Heo Jeong , Peguero Julio A. , Ryoo Baek-Yeol , Decaens Thomas , Barlesi Fabrice , Moehler Markus H. , Jehl Genevieve , Eggleton S. Peter , Bajars Marcis , Gulley James L.
Published: August 2024

Background and Aims:

Simultaneous inhibition of the TGF-β and programmed cell death 1 ligand 1 pathways provides a potential novel treatment approach. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking programmed cell death 1 ligand 1, was evaluated in patients with advanced HCC.

Approach and Results:

In this global, open-label, phase I study (NCT02517398), patients with programmed cell death 1 ligand 1–unselected HCC who failed or were intolerant to ≥1 line of sorafenib received bintrafusp alfa 1200 mg every 2 weeks in a dose-escalation (n = 38) or dose-expansion (n = 68) cohort until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was the best overall response per Response Evaluation Criteria in Solid Tumors version 1.1 by an independent review committee. Secondary endpoints included investigator-assessed best overall response, safety, and pharmacokinetics. Median follow-up times (range) were 41.4 (39.8–44.2) and 38.6 (33.5–39.7) months in the dose-escalation and dose-expansion cohorts, respectively. The objective response rate was below the prespecified 20% objective response rate threshold set to evaluate the efficacy of bintrafusp alfa in both cohorts (10.5% and 8.8%, respectively). Median overall survival and progression-free survival, respectively, were 13.8 and 1.5 months in the dose-escalation cohort and 13.5 and 1.4 months in the dose-expansion cohort. Treatment-related adverse events occurred in 78.9% and 64.7% of patients in the respective cohorts (grade ≥3 in 18.4% and 25.0% of patients).

Conclusions:

Bintrafusp alfa showed moderate clinical activity and a safety profile consistent with previous studies of bintrafusp alfa in patients with advanced HCC.
Describing the Physician Associate Clinical Training Site Compensation Market
Authors: White Ryan D.
Published: August 2024

Introduction

Inadequate clinical training site availability may inhibit physician assistant/associate (PA), advanced practice nursing (APN), and physician workforce growth. Educational institutions increasingly incentivize clinical training sites with financial compensation, with potential implications for educational costs and enrollment. This study investigated compensation trends among PA programs.

Methods

Data from the 2013 to 2019 PA Education Association Program Reports were examined. Multivariate logistic and linear regressions were estimated to identify the influence of PA program characteristics on clinical training site compensation. The effect of compensation on program enrollment was determined with a difference-in-differences estimator.

Results

Physician assistant/associate programs collectively paid nearly $19 million to clinical training sites in 2019. The percentage of programs that offer financial incentives increased from 22.2% in 2013 to 52.3% in 2019. Over this time, public institutions affiliated with academic health centers (AHCs) were least likely to offer compensation. Higher compensation rates were observed in Census divisions with greater number of programs, and programs located in New England were the most likely to offer compensation. Offering compensation did not influence growth in programs' enrollment.

Discussion

Compensation trends highlight increasing demand for PA clinical training sites, especially in areas with greater regional competition. Compensation is primarily driven by private institutions unaffiliated with AHCs. Programs likely offer compensation to maintain, rather than grow, enrollment. Additional investigation should incorporate medical school and APN program data to more fully examine the impact of these costs on learners, institutions, and the health care workforce.
Evaluating the association between time to skin grafting for truncal burn patients and complications: a comparative cohort study using the National Trauma Data Bank
Authors: Wang Szu-Han , Chien Chih-Ying , Fu Chih-Yuan , Bokhari Faran
Published: August 2024

Background:

The split-thickness skin graft (STSG) procedure is frequently used in the reconstruction of burn-injured patients. This study assessed the impact of graft timing on associated skin complications in patients with torso burns using a comprehensive national database.

Methods:

Truncal burn (2nd-degree and 3rd-degree burns covering 20–89% TBSA) patients who underwent STSG in the National Trauma Data Bank from 2011 to 2015 were studied. The outcomes examined were graft-related complications (superficial surgical site infections, deep surgical site infections, and graft failure), overall mortality and hospital length of stay (LOS). Patients were compared based on the presence or absence of grafting complications. A linear regression model was used to assess the relationship between hospital LOS and graft timing, considering other variables.

Results:

Among the 853 studied patients, the cohort with graft complications exhibited a significantly prolonged time to STSG (413.0 h compared to 264.6 h, P<0.001) and a higher percentage of patients with pre-existing diabetes (18.5 vs. 8.0%, P=0.008). The multiple logistic regression analysis revealed that both the extended time to STSG (odds=1.001, P=0.003) and pre-existing diabetes (odds=2.790, P=0.010) significantly elevated the likelihood of complications associated with STSG. Notably, this delay did not elevate mortality risks. A positive relationship was found between grafting delay and LOS.

Conclusion:

The findings underscore that a prolonged duration to skin grafting contributes to extended hospital stays and increased graft-related complications. However, the role of grafting delay in influencing the mortality of truncal burn patients appeared inconsequential, indicating that mortality may be influenced by various factors.
Statins inhibit paclitaxel-induced PD-L1 expression and increase CD8+ T cytotoxicity for better prognosis in breast cancer
Authors: Li Lei , Wang Hongbin , Zhang Shiyuan , Gao Song , Lu Xiuxin , Pan You , Tang Wei , Huang Rong , Qiao Kun , Ning Shipeng
Published: August 2024

Background:

In recent years, the widespread use of lipid-lowering drugs, especially statins, has attracted people’s attention. Statin use may be potentially associated with a reduced risk of breast cancer.

Objective:

To explore the relationship between statin use and cancer risk. And further explore the potential role of statins in the adjuvant treatment of breast cancer.

Methods:

Data for the Mendelian randomization portion of the study were obtained from genome-wide association studies of common cancers in the UK Biobank and FinnGen studies and from the Global Lipid Genetics Consortium’s low density lipoprotein (LDL). In addition, the impacts of statins and chemotherapy drugs on breast cancer were examined using both in vitro and in vivo models, with particular attention to the expression levels of the immune checkpoint protein PD-L1 and its potential to suppress tumor growth.

Results:

Data from about 3.8 million cancer patients and ~1.3 million LDL-measuring individuals were analyzed. Genetically proxied HMGCR inhibition (statins) was associated with breast cancer risk reduction (P=0.0005). In vitro experiments showed that lovastatin significantly inhibited paclitaxel-induced PD-L1 expression and assisted paclitaxel in suppressing tumor cell growth. Furthermore, the combination therapy involving lovastatin and paclitaxel amplified CD8+ T-cell infiltration, bolstering their tumor-killing capacity and enhancing in vivo efficacy.

Conclusion:

The utilization of statins is correlated with improved prognoses for breast cancer patients and may play a role in facilitating the transition from cold to hot tumors. Combination therapy with lovastatin and paclitaxel enhances CD8+ T-cell activity and leads to better prognostic characteristics.
The Channel Branches & Network Channels on the Tianhui Lacquered Meridian Figurine — Taking the Heart-Regulated Channel as an Example
Authors: Qi Zhou , Springer Lena
Published: August 2024

Along with the surge of unearthed medical literature and cultural relics in recent years, the network of channels in the system of medical channels (meridians) during the early Western Han dynasty have become much clearer gradually. Among them, the increasing number of channel branches, network channels and needle insertion holes (acupoints) is an important feature of the development of classical channel medicine during the Western Han dynasty. This is not only a reflection of the expanding requirements of the theoretical system of the main trunk channels, but also an inevitable result of the continuous enrichment and accumulation of clinical experience. This article integrates the information about channel branches, network channels, inscriptions, dots and further relics on the Tianhui (天回) Lacquered Meridian Figurine to compare the unearthed literature of the channel genre with the transmitted classical literature about acupuncture. The "Heart-Regulated Channel" in Medical Manuscripts on Bamboo Slips from Tianhui (《天回医简》) serves as an example to explain the occurrence, development and changes of the channel branches and network channels in the early system of medical channels.
Understanding Diagnosis Delay in Children With Cancer: Evidence From a Single Institution in Jordan
Authors: Al-Nassan Anwar , Almanaseer Tariq , Malkawi Saja , Al-Bitar Farah , Jibrin Dayana , El-qurnah Omaima , Bataineh Shaima , Kamal Maen , Sweidan Salsabeel , Abu-shanab Mayada , Sultan Iyad
Published: August 2024

Background:

This study aimed to evaluate the factors associated with diagnosis delay in children with cancer who are treated at a single institution, which caters to most children with cancer in Jordan.

Methods:

This was a cross-sectional study with a retrospective chart review of selected patients who were diagnosed from August 2018 to December 2021. Data on patient and household characteristics, medical history, and diagnostic delay were collected through structured interviews. Univariable and multivariable linear and logistic regression models were used to identify predictors of delay.

Results:

The study included a cohort of 202 patient-caregiver pairs, with a median total delay from symptom onset to treatment initiation of 47 days (interquartile range [IQR], 21 to 114 d). Notably, 86% of families pursued medical consultation within a month of recognizing symptoms. A regression model revealed CNS tumors as a significant independent predictor of increased total delay (P=0.002), with affected patients experiencing a median delay markedly longer than those with other cancer types. In addition, older patient age predicted longer total delay (P=0.025). Symptomatology played a pivotal role in the timeliness of the diagnosis; specifically, visible symptoms such as pallor, bruises, and jaundice were associated with more expedient medical attention, with significantly shorter delays (P values: 0.011, <0.001, and 0.045, respectively). Furthermore, our investigation disclosed a notable variance in symptom prevalence across different cancer categories, elucidating the complex relationship between clinical presentation and diagnostic timelines.

Conclusions:

This study highlights the importance of the diagnosis of CNS tumors, patient age, and symptoms in predicting diagnosis delay in pediatric oncology patients. These findings can inform interventions to reduce delays in diagnosis and improve outcomes for these patients. These insights are crucial for developing targeted educational programs aimed at healthcare professionals and families to accelerate the recognition and referral of pediatric cancer cases.
Changes in functional outcomes in people with high-energy ankle trauma after the use of the ReAktiv Posterior Dynamic Element™ orthosis and a rehabilitation program: A case series
Authors: Gardner Sarah , Frecklington Mike , Rose Kirsten , Carroll Matthew R.
Published: August 2024

The aim of this study was to examine lower-limb function in 2 patients that received a ReAktiv Posterior Dynamic Element™ (PDE) orthosis and 6-week rehabilitation program after a high-energy trauma injury to the lower limb. Lower-limb function was assessed using the lower extremity functional score, walking performance through the 2-minute walk test, and dynamic mobility and balance through the single-leg balance, timed stair ascent, and the 4-square step test. A 6-week physiotherapy-led rehabilitation program was also implemented. Data showed improvements in lower extremity function, walking performance, mobility, and balance measures after 8 weeks of wearing the ReAktiv PDE™ orthosis and completion of the rehabilitation program. The ReAktiv PDE™ orthosis combined with a lower-limb rehabilitation program shows potential as a treatment option to improve lower-limb function and walking performance and return sufferers of high-energy trauma injury to functional levels seen in healthy cohorts.
Morphometric Study of Malleus, Incus, and Stapes of Middle Ear Along With Associated Clinical Significance
Authors: Goel Naresh Chandra , Singh Rajani
Published: August 2024

The ear ossicles transmit sound from the external ear to the inner ear. The aplasia, hypoplasia, erosion, and trauma to the ear ossicles cause conductive deafness, which can be corrected by ossiculoplasty, for which detailed knowledge of morphometry of the ear ossicles is very essential. So, the study was carried out. The aim of the study is to analyze the morphometric data and correlate it with clinical significance. The study was conducted in the Department of Anatomy using 47 malleus, 46 incus, and 10 stapes of known age, sex, and side. The various parameters of these ossicles were measured with vernier calipers. The parameters were compared with other studies, and associated clinical significance was elaborated. The means in mm of the total length, length of handle, length, and width of the head of the malleus are 6.8 ± 0.5, 4.4 ± 0.4, 2.7 ± 0.3, and 2.6 ± 0.3, respectively. The mean of the total length, width, length of long process and short process of incus in mm are 6.7 ± 0.5, 4.7 ± 0.4, 3.7 ± 0.3, and 2.7 ± 0.4, respectively. The mean of the total height, length, and width of the foot plate of stapes in millimeters are 3.2 ± 0.4, 2.7 ± 0.2, and 0.8 ± 0.3, respectively. The various parameters associated with ear ossicles of different populations were found to vary on the right and left sides and also in different sexes. The data will be of immense use in ossiculoplasty and the designing of prostheses to restore hearing.
Stress or strain?
Authors: Li Shuguang
Published: August 2024

This article is intended to reconcile the stress-based and strain-based formulations for material failure criteria, where a long-standing and deep division is present. The two approaches do not naturally agree with each other, and they do not genuinely complement each other, either. Most popular criteria are stress-based when originally proposed, including the maximum stress, Tresca, von Mises, Raghava–Caddell–Yeh and the Mohr criteria. Their formulations are unique and self-consistent, i.e. capable of reproducing the input data. Their strain-based counterparts, with the maximum strain criterion being considered as the strain-based counterpart of the maximum stress criterion, are neither unique nor necessarily self-consistent. It has been proven in this article that the self-consistent ones reproduce their respective stress-based counterparts identically in effect with a disadvantage of requiring an additional material property to apply, without a single benefit. For the Mohr criterion as a special case, a strain-based counterpart is simply infeasible in general. All undesirable features of strain-based criteria are rooted in a single source: the failure strains can only be measured under a uniaxial stress state, which corresponds to a combined strain state in general, not a uniaxial strain state! Given the arguments presented, the reconciliation proves to be biased completely towards the stress-based side if mathematics, logic and common sense prevail over perception and prejudice.
Reducing blood culture contamination: an environmental imperative
Authors: Gregg Sophie , Purcell Niamh , Doyle Maeve , Chan Grace
Published: August 2024

Abstract
Blood culture (BC) investigation remains the gold standard for diagnosis of bloodstream infections. However, BC contamination can have clinical implications for the patient, cost implications for service providers and less well documented, environmental impacts. Efforts to reduce BC contamination are a longstanding theme in quality improvement initiatives in emergency departments and hospitals, prompted by the hospital costs, healthcare inefficiencies and antimicrobial stewardship efforts [1,2].  The WHO global analysis of health care waste in the context of COVID-19, has reported that tens of thousands of tonnes of extra medical waste was produced from the response to the COVID-19 pandemic, basing its estimates on the quantity of personal protective equipment (PPE) [3]. Additionally, recent literature has also shown increased BC contamination rates during the COVID-19 pandemic. Our study reviews the trend of BC contamination during the COVID-19 pandemic in our institution’s Emergency Department.  We further discuss some of the potential implications of BC contamination, including potential environmental, economic and efficiency implications.