bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical Techniques in Nontraumatic Midcarpal Instability: Evaluating the Dorsal Capsulodesis and 3-Ligament Tenodesis Technique
Authors: Hakkesteegt Stefanie N. , Jongen Isabel C. , Hundepool Caroline A. , van der Oest Mark J. W. , Duraku Liron S. , Feitz Reinier ,   The Hand-Wrist Study Group, Zuidam J. Michiel
Published: April 2024

Background:

Surgical management of midcarpal instability (MCI), also referred to as carpal instability nondissociative, remains controversial because of limited evidence on different techniques. This study aimed to assess and compare differences in patient-reported pain, hand and wrist function, satisfaction, range of motion, and return to work in patients with nontraumatic MCI who underwent surgical treatment either through dorsal wrist capsulodesis or 3-ligament tenodesis (3LT).

Methods:

Patients with MCI and persisting complaints after conservative therapy treated with 3LT or dorsal capsulodesis were included. Patients with posttraumatic instability were excluded. Primary endpoints included the Patient Rated Wrist Evaluation and Satisfaction with Treatment Result Questionnaire at 12 months postoperatively. All data were analyzed retrospectively.

Results:

A total of 91 patients treated with dorsal capsulodesis and 21 treated with 3LT between December of 2011 and December of 2019 were included. At 12 months postoperatively, both treatment groups reported significant improvements in pain and function scores. However, at 3 months postoperatively, the dorsal capsulodesis group exhibited significantly better outcomes, followed by a greater return-to-work rate (72%) compared with the 3LT group (50%). However, the capsulodesis group demonstrated a decreased range of motion at 3 months that was restored at 12 months postoperatively. No significant difference in satisfaction with treatment was observed.

Conclusions:

Both 3LT and dorsal capsulodesis demonstrate promising results for addressing nontraumatic MCI. However, considering the quicker recovery and faster return to work associated with dorsal capsulodesis, the authors recommend favoring capsulodesis over 3LT when both surgical options are deemed suitable for the patient.
Risk and predictors of penile cancer in US Veterans with HIV
Authors: Zhao Jing , Dong Yongquan , Clark Eva , Garcia Jose M. , White Donna L. , Kramer Jennifer R. , Mazul Angela L. , Hartman Christine , Chiao Elizabeth Y.
Published: April 2024

Objectives:

People with HIV (PWH) may have an increased burden of penile cancer. We aimed to evaluate the risk of penile cancer in PWH compared with that of the general population.

Design:

We conducted a nationwide retrospective matched cohort study of penile cancer incidence among veterans with HIV (VWH) compared with veterans without HIV.

Methods:

We compared penile cancer incidence rates in 44 173 VWH to those of veterans without HIV (N = 159 443; 4 : 1 matched in age). We used Cox regression models to estimate hazard ratios and 95% confidence intervals (CIs) for associations with HIV infection and for penile cancer risk factors.

Results:

HIV positivity was associated with an increased risk of penile cancer, with adjusted hazard ratios of 2.63 (95% CI 1.64–4.23) when adjusting for age, race/ethnicity, baseline BMI, smoking and alcohol use, economic means test, and history of condyloma. The risk increased to hazard ratio = 4.25 (95% CI 2.75–6.57) when adjusting for all factors except history of condyloma. Risk factors for penile cancer in VWH included lower nadir CD4+ count, less than 50% of follow-up time with undetectable HIV viral load, and history of condyloma.

Conclusion:

VWH – particularly those with low CD4+ counts, detectable HIV viral loads, or history of condyloma – are at increased risk of penile cancer, suggesting the penile cancer prevention activities are needed in this population.
Role of mucositis in predicting gut microbiota composition in people with cancer
Authors: Scott Jacqui S. , Li Anna , Wardill Hannah R.
Published: April 2024

Purpose of review

Disruption of the precious ecosystem of micro-organisms that reside in the gut – the gut microbiota – is rapidly emerging as a key driver of the adverse side effects/toxicities caused by numerous anti-cancer agents. Although the contribution of the gut microbiota to these toxicities is understood with ever increasing precision, the cause of microbial disruption (dysbiosis) remains poorly understood. Here, we discuss current evidence on the cause(s) of dysbiosis after cancer therapy, positioning breakdown of the intestinal mucosa (mucositis) as a central cause.

Recent findings

Dysbiosis in people with cancer has historically been attributed to extensive antibiotic use. However, evidence now suggests that certain antibiotics have minimal impacts on the microbiota. Indeed, recent evidence shows that the type of cancer therapy predicts microbiota composition independently of antibiotics. Given most anti-cancer drugs have modest effects on microbes directly, this suggests that their impact on the gut microenvironment, in particular the mucosa, which is highly vulnerable to cytotoxicity, is a likely cause of dysbiosis. Here, we outline evidence that support this hypothesis, and discuss the associated clinical implications/opportunities.

The concept that mucositis dictates microbiota compositions provides two important implications for clinical practice. Firstly, it reiterates the importance of prioritising the development of novel mucoprotectants that preserve mucosal integrity, and indirectly support microbial stability. Secondly, it provides an opportunity to identify dysbiotic events and associated consequences using readily accessible, minimally invasive biomarkers of mucositis such as plasma citrulline.
“I′m not a risk taker”
Authors: Behrens Liza L. , Anderson Hannah L. , Kowalchik Kaléi H. , Mogle Jacqueline , Roman Jones Joanne , Van Haitsma Kimberly , Hodgson Nancy , Boltz Marie
Published: April 2024

Background:

Persons living with Alzheimer disease and related dementia (ADRD) in nursing homes (NH) are often excluded from conversations about their health/safety. These omissions impinge on personhood and the rights to have care preferences heard and honored. While persons with ADRD maintain the ability to communicate their preferences long after their decision-making abilities are affected, little is known about how persons with ADRD understand the risks associated with their preferences.

Methods:

As part of a larger focused ethnography, in-depth interviews and an adapted risk propensity questionnaire explored the risk perceptions of NH residents with ADRD (N=7) associated with their preferences for care and activities of daily living.

Results:

Residents generally self-identified as risk avoiders (M=3.2±1.84) on the risk propensity scale and were able to rate risk associated with preferences described within 5 thematic categories: 1) participation in decision-making, 2) risk awareness, 3) paying attention to safety, 4) reliance on nursing home staff and family, and 5) impacts on quality of life and quality of care.

Discussion:

Results suggest NH residents with ADRD can express risk surrounding their preferences and should be encouraged to participate in discussions about their health and safety.
Altered functional connectivity strength of primary visual cortex in subjects with thyroid-associated ophthalmopathy
Authors: Qi Chen-Xing , Wen Zhi , Huang Xin
Published: April 2024

Our objective was to explore the disparities in the intrinsic functional connectivity (FC) patterns of primary visual cortex (V1) between patients with thyroid-associated ophthalmopathy (TAO) and healthy controls (HCs) utilizing resting-state functional MRI. Twenty-one patients with TAO (14 males and 7 females; mean age: 54.17 ± 4.83 years) and 21 well-matched HCs (14 males and 7 females; mean age: 55.17 ± 5.37 years) underwent functional MRI scans in the resting-state. We assessed modifications in the intrinsic FC patterns of the V1 in TAO patients using the FC method. Subsequently, the identified alterations in FC regions in the analysis were selected as classification features to distinguish TAO patients from HCs through the support vector machine (SVM) method. The results indicated that, in comparison to HCs, patients with TAO exhibited notably reduced FC values between the left V1 and the bilateral calcarine (CAL), lingual gyrus (LING) and superior occipital gyrus, as well as between the right V1 and the bilateral CAL/LING and the right cerebellum. Furthermore, the SVM classification model based on FC maps demonstrated effective performance in distinguishing TAO patients from HCs, achieving an accuracy of 61.9% using the FC of the left V1 and 64.29% using the FC of the right V1. Our study revealed that patients with TAO manifested disruptions in FC between the V1 and higher visual regions during rest. This might indicate that TAO patients could present with impaired top-down modulations, visual imagery and vision-motor function. These insights could be valuable in understanding the underlying neurobiological mechanisms of vision impairment in individuals with TAO.
Escalating Surgical Treatment for Left Ventricular Assist Device Infection and Expected Mortality: Clinical Risk Prediction Score
Authors: Finnan Michael J , Chi David , Chiang Sarah N , Vader Justin M , Cabrera Nicolo L , Kells Amy F , Masood Muhammad F , Kotkar Kunal D , Fox Ida K
Published: April 2024

BACKGROUND:

Left ventricular assist devices (LVAD) improve survival for patients with cardiac failure, but LVAD-specific infection (VSI) remains a challenge with poorly understood predictive risk factors. The indications and use of escalating medical treatment to surgical debridement and potential flap reconstruction are not well characterized.

STUDY DESIGN:

A retrospective review of consecutive patients undergoing primary LVAD implantation at a tertiary academic center was performed. The primary outcome measures were 90-day and overall mortality after VSI. Cox proportional hazards regression was used to generate a risk prediction score for mortality.

RESULTS:

Of the 760 patients undergoing primary LVAD implantation, 255 (34%) developed VSI; of these patients, 91 (36%) were managed medically, 134 (52%) with surgical debridement, and 30 (12%) with surgical debridement and flap reconstruction. One-year survival after infection was 85% with median survival of 2.40 years. Factors independently associated with increased mortality were diabetes (hazard ratio [HR] 1.44, p = 0.04), MRSA infection (HR 1.64, p = 0.03), deep space (pump pocket or outflow cannula) involvement (HR 2.26, p < 0.001), and extracorporeal membrane oxygenation after LVAD (HR 2.52, p < 0.01). Factors independently associated with decreased mortality were flap reconstruction (HR 0.49, p = 0.02) and methicillin-sensitive Staphylococcus aureus infection (HR 0.63, p = 0.03). A clinical risk prediction score was developed using these factors and showed significant differences in median survival, which was 5.67 years for low-risk (score 0 to 1), 3.62 years for intermediate-risk (score 2), and 1.48 years for high-risk (score ≥3; p < 0.001) patients.

CONCLUSIONS:

We developed a clinical risk prediction score to stratify patients with VSI. In selected cases, escalating surgical treatment was associated with increased survival. Future work is needed to determine whether early surgical debridement and flap reconstruction can alter outcomes in select cases of VSI.
The eco-evolutionary dynamics of strategic species
Authors: Roy Sourav , Ghosh Subrata , Saha Arindam , Chandra Mali Prakash , Perc Matjaž , Ghosh Dibakar
Published: April 2024

Much research has in recent years been devoted to better our understanding of the intricate relationships between ecology and the evolutionary success of species. These explorations have often focused on understanding the complex interplay among ecological factors and evolutionary rhythms of the species in various environments. Central to these studies is the concept of the survival of the fittest, proposed by Charles Darwin, where evolutionary circumstances, often portrayed as social dilemmas, favour the welfare of self-interested over others. To further advance this line of research, we here develop a theoretical framework that features three interconnected traits in an evolutionary setting, namely: prey, predator and parasite, each adopting distinct strategies akin to a social dilemma and resembling a Rock-Paper-Scissors scenario. These traits, which we term strategic species, adhere to the eco-evolutionary game dynamics. We further extend our analysis by conducting a sensitivity assessment of the system’s payoff parameters using the Sobol indices.
Comparative analysis of virulence gene profiles of Escherichia coli from clinical and non-clinical sources in Rivers State, Nigeria

Authors: Abeni Barira Azeez , Frank-Peterside Nnenna , Otokunefor Kome
Published: April 2024

Traditionally, the presence of virulence features have been thought to be a key factor in differentiating pathogenic from commensal strains. An understanding of virulence potential of Escherichia coli isolates from various sources is essential to help shed light on potential contamination/transmission rates between the various sources. This study was therefore aimed at exploring the occurrence of specific virulence genes and gene profiles associated with Escherichia coli from clinical and non-clinical sources in Rivers State, Nigeria.
Two hundred samples from clinical (urine and feces) and non-clinical (soil and poultry droppings) sources (50 each) were analyzed using standard microbiological procedures. DNA was extracted from isolates presumptively identified as Escherichia coli using PrestoTM Mini gDNA Bacteria-Kit Quick protocol following the manufacturer’s instructions. Isolate identities were confirmed using E. coli specific 16S rRNA primers and confirmed isolates screened for the presence of six virulence genes (Afimbriae binding adhesin (afa), type 1 fimbriae (fimH), P-fimbrial Usher Protein (papC)), iron acquisition systems: aerobactin (aer), Cytotoxic necrotizing factor I (cnf1) and alpha hemolysin (hly).
Results showed that all isolates haboured at least one of the tested virulence genes, with fimH (97%) as the most prevalent virulence gene and papC the least commonly occurring (35%). A higher occurrence of virulence genes was noted in non-clinical isolates though hly and cnf were not detected at all in any of the isolates studied (0%). Ten different profiles were observed with the afaCc-aer-fimH profile the most commonly occurring virulence gene profile in general (33.3%). For non-clinical isolates however, the aer-afaCc-fimH-papC was the most commonly occurring profile (42.9%).
This study shows that the test Escherichia coli from clinical and non-clinical sources do not carry distinct virulence gene profiles. Studies on a larger subset of isolates would however be necessary to determine if indeed the virulence genes tested for in this study really cannot be used to tell whether an isolate is from a clinical source or not in the South-South of Nigeria.
2010 and 2013 incidence peaks in narcolepsy and idiopathic hypersomnia linked to type A H1N1 and type B Victoria influenza strains
Authors: Zhang Zhongxing , Gool Jari K. , Sirotkin Pavel , Dauvilliers Yves , Barateau Lucie , Plazzi Giuseppe , Pizza Fabio , Biscarini Francesco , Sonka Karel , Galuskova Karolina , Wierzbicka Aleksandra , Högl Birgit , Feketeova Eva , Del Río Villegas Rafael , Fronczek Rolf , Lammers Gert Jan , Khatami Ramin
Published: April 2024

Introduction

Increased narcolepsy type 1 (NT1) incidence rates have been reported globally in 2010, and were linked to the type A H1N1 2009-2010 influenza pandemic and Pandemrix vaccination. A European child-specific NT1 incidence peak was additionally observed in 2013 post the H1N1 pandemic. Thus, the relationship between NT1 and influenza infection remains unclear. Whether other influenza viruses may also trigger NT1 or other central disorders of hypersomnolence (CDH), is unknown. This study investigated annual European incidence patterns of all CDH in complete samples from multiple European centers, in relation to the severity of individual flu strains in preceding influenza seasons.

Methods

Incidence rates of NT1 (N=981) and the combined group of narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) (N=545) from eight European countries were temporally analysed to identify possible incidence peaks from 1995 to 2019. Linear mixed models and spearman correlations were conducted between hypersomnolence disorder incidence rates and the number of influenza infections of preceding influenza season, split for types A H1N1 and H3N2, and in the Netherlands also types B Victoria and Yamagata influenza.

Results

2010 and 2013 incidence peaks were present in NT1, and a 2010 children peak was unexpectedly found in the combined group of NT2 and IH. Both hypersomnolence groups exhibited a significantly positive relationship with preceding H1N1 influenza season severity and a negative relationship with H3N2 influenza. NT1 was additionally significantly positively correlated with influenza type B Victoria in the Netherlands and showed highest correlation in children.

Conclusions

Besides H1N1 influenza, the temporal association and severity correlation suggest that influenza type B Victoria may be a novel potential trigger for NT1 that requires further investigation. We additionally provide insights into possible immune-related pathophysiologies of NT2 and IH associated with the 2009-2010 H1N1 influenza pandemic. Further immunological investigations are warranted to unravel the complexities of these relationships and their implications for CDH.
Lesion-induced impairment of therapeutic capacities of olfactory ensheathing cells in an autologous transplantation model for treatment of spinal cord injury
Authors: Delarue Quentin , Brodier Matthis , Neveu Pauline , Moncomble Laurine , Hugede Alizée , Blondin Axelle , Robac Amandine , Raimond Clémence , Lecras Pamela , Riou Gaëtan , Guérout Nicolas
Published: April 2024

Abstract

Spinal cord injury (SCI) is a serious pathology of the central nervous system that results in loss of motor, sensory and autonomic functions below the level of the lesion and for which, unfortunately, there is currently no cure. In addition to the loss of function, SCI induces a systemic inflammation that is not confined to the spinal cord and whose effects are increasingly well characterized. In particular, SCI causes cerebral inflammation, which is responsible for the impairment of hippocampal and bulbar neurogenesis. Many therapies have been tested as potential treatments for SCI. In animal models, cell therapies have shown interesting effects such as spinal scar reduction, anti-inflammatory properties, axonal regrowth or neuronal survival, allowing better functional recovery. However, in human studies, their therapeutic capacities are less significant. Beyond obvious differences in pathophysiology and cell culture procedures, a key paradigm of cell transplantation differs between humans and animals. In animal models, transplanted cells are systematically taken from healthy individuals, whereas in humans the immune incompatibility leads to the realization of autologous transplantation. Therefore, we were interested in the lesion effects on the neuro-repairing potential of olfactory ensheathing cells (OECs) harvested from olfactory bulbs.

Using functional sensory-motor studies, histological and gene expression analyses, we were able to demonstrate for the first time that the lesion negatively affects the therapeutic properties of cells used to treat SCI. These innovative results shed new light on the future use of cell transplantation in autologous transplantation after SCI.
Redefining FLASH RT: the impact of mean dose rate and dose per pulse in the gastrointestinal tract
Authors: Liu Kevin , Waldrop Trey , Aguilar Edgardo , Mims Nefetiti , Neill Denae , Delahoussaye Abagail , Li Ziyi , Swanson David , Lin Steven H. , Koong Albert C. , Taniguchi Cullen M. , Loo Billy W. , Mitra Devarati , Schüler Emil
Published: April 2024

Background

The understanding of how varying radiation beam parameter settings affect the induction and magnitude of the FLASH effect remains limited.

Purpose

We sought to evaluate how the magnitude of radiation-induced gastrointestinal (GI) toxicity (RIGIT) depends on the interplay between mean dose rate (MDR) and dose per pulse (DPP).

Methods

C57BL/6J mice were subjected to total abdominal irradiation (11-14 Gy single fraction) under conventional irradiation (low DPP and low MDR, CONV) and various combinations of DPP and MDR up to ultra-high-dose-rate (UHDR) beam conditions. The effects of DPP were evaluated for DPPs of 1-6 Gy while the total dose and MDR were kept constant; the effects of MDR were evaluated for the range 0.3– 1440 Gy/s while the total dose and DPP were kept constant. RIGIT was quantified in non-tumor–bearing mice through the regenerating crypt assay and survival assessment. Tumor response was evaluated through tumor growth delay.

Results

Within each tested total dose using a constant MDR (>100 Gy/s), increasing DPP led to better sparing of regenerating crypts, with a more prominent effect seen at 12 and 14 Gy TAI. However, at fixed DPPs >4 Gy, similar sparing of crypts was demonstrated irrespective of MDR (from 0.3 to 1440 Gy/s). At a fixed high DPP of 4.7 Gy, survival was equivalently improved relative to CONV for all MDRs from 0.3 Gy/s to 104 Gy/s, but at a lower DPP of 0.93 Gy, increasing MDR produced a greater survival effect. We also confirmed that high DPP, regardless of MDR, produced the same magnitude of tumor growth delay relative to CONV using a clinically relevant melanoma mouse model.

Conclusions

This study demonstrates the strong influence that the beam parameter settings have on the magnitude of the FLASH effect. Both high DPP and UHDR appeared independently sufficient to produce FLASH sparing of GI toxicity, while isoeffective tumor response was maintained across all conditions.
Probing sensitivity to statistical structure in rapid sound sequences using deviant detection tasks
Authors: Milne Alice E. , Chait Maria , Conway Christopher M.
Published: April 2024

Statistical structures and our ability to exploit them are a ubiquitous component of daily life. Yet, we still do not fully understand how we track these sophisticated statistics and the role they play in sensory processing. Predictive coding frameworks hypothesize that for stimuli that can be accurately anticipated based on prior experience, we rely more strongly on our internal model of the sensory world and are more “surprised” when that expectation is unmet. The current study used this phenomenon to probe listeners’ sensitivity to probabilistic structures generated using rapid 50 milli-second tone-pip sequences that precluded conscious prediction of upcoming stimuli. Over three experiments we measured listeners’ sensitivity and response time to deviants of a frequency outside the expected range. Predictable sequences were generated using either a triplet-based or network-style structure and deviant detection contrasted against the same set of tones but in a random, unpredictable order. All experiments found structured sequences enhanced deviant detection relative to random sequences. Additionally, Experiment 2 used three different instantiations of the community structure to demonstrate that the level of uncertainty in the structured sequences modulated deviant saliency. Finally, Experiment 3 placed the deviant within an established community or immediately after a transition between communities, where the perceptual boundary should generate momentary uncertainty. However, this manipulation did not impact performance. Together these results demonstrate that probabilistic contexts generated from statistical structures modulate the processing of an ongoing auditory signal, leading to an improved ability to detect unexpected deviant stimuli, consistent with the predictive coding framework.
Development of the pulmonary vasculature in the gray short-tailed opossum (Monodelphis domestica) – 3D reconstruction by microcomputed tomography
Authors: Ferner Kirsten
Published: April 2024

The marsupial gray short-tailed opossum (Monodelphis domestica) is born at the late canalicular stage of lung development and the lungs are structurally immature compared to eutherians. The majority of lung development, including the maturation of pulmonary vasculature, takes place in ventilated functioning state during the postnatal period.

The current study uses X-ray computed tomography (µCT) to three-dimensionally reconstruct the vascular trees of the pulmonary artery and pulmonary vein in the marsupial gray short-tailed opossum to investigate the vascular genesis during the postnatal period. The development of the pulmonary vasculature was examined in 15 animals from neonate to postnatal day 57. The final 3-D reconstructions of the pulmonary artery and pulmonary vein in the neonate and at 21, 35 and 57 dpn were transformed into a centerline model of the vascular trees. Based on the reconstructions, the generation of end-branching vessels, the median and maximum generation and the number of vessels were calculated for the lungs.

The pulmonary vasculature follows the lung anatomy with six pulmonary lobes indicated by the bronchial tree. The pulmonary arteries follow the bronchial tree closely, in contrast to the pulmonary veins, which run between the pulmonary segments. At birth the pulmonary vasculature has a simple branching pattern with a few vessel generations. Compared to the bronchial tree, the pulmonary vasculature appears to be more developed and extends to the large terminal air spaces. The pulmonary vasculature of the lungs from neonate to postnatal day 57 develops along the bronchial tree and shows a marked gain in volume and a progressive increase in vascular complexity and density. The gray short-tailed opossum resembles the assumed mammalian ancestor and is suitable to inform on the evolution of the mammalian lung. Vascular genesis in the marsupial bears resemblance to developmental patterns described in eutherians. Lung development in general seems to be highly conservative within mammalian evolution.
The impact of health inequity on regional variation of COVID-19 transmission in England
Authors: Rawson Thomas , Hinsley Wes , Sonabend Raphael , Semenova Elizaveta , Cori Anne , Ferguson Neil M
Published: April 2024

Considerable spatial heterogeneity has been observed in COVID-19 transmission across administrative regions of England throughout the pandemic. This study investigates what drives these differences. We constructed a probabilistic case count model for 306 administrative regions of England across 95 weeks, fit using a Bayesian evidence synthesis framework. We include the mechanistic impact of acquired immunity, of spatial exportation of cases, and 16 spatially-varying socio-economic, socio-demographic, health, and mobility variables. Model comparison assesses the relative contributions of these respective mechanisms. We find that regionally-varying and time-varying differences in week-to-week transmission were definitively associated with differences in: time spent at home, variant-of-concern proportion, and adult social care funding. However, model comparison demonstrates that the mechanistic impact of these terms was of negligible impact compared to the role of spatial exportation between regions. While these results confirm the impact of some, but not all, measures of regional inequity in England, our work corroborates the finding that observed differences in regional disease transmission during the pandemic were predominantly driven by underlying epidemiological factors rather than the demography and health inequity between regions.

Author Summary

During the COVID-19 pandemic, different geographic areas of England saw different patterns in the number of confirmed cases over time. This study investigated whether demographic differences between these areas (such as the amount of deprivation, the age and ethnicity of the populations, or differences in where people spent their time) were linked to these differences in disease transmission. We also considered whether this was associated with the number of cases in neighbouring areas as well. Using a mathematical model fit to multiple data streams, we discovered that a statistically significant link between some demographic variables (time spent at home, COVID-19 variant, and the amount of adult social care funding) and week-to-week transmission exists, but this relationship is very small, and the influence of cases in neighbouring areas was far more impactful in explaining differences in transmission between areas over time.
A Breast Cancer Polygenic Risk Score Validation in 15,490 Brazilians using Exome Sequencing
Authors: Rius Flávia Eichemberger , Guindalini Rodrigo Santa Cruz , Viana Danilo , Salomão Júlia , Gallo Laila , Freitas Renata , Bertolacini Cláudia , Taniguti Lucas , Imparato Danilo , Antunes Flávia , Sousa Gabriel , Achjian Renan , Fukuyama Eric , Gregório Cleandra , Ventura Iuri , Gomes Juliana , Taniguti Nathália , Maistro Simone , Krieger José Eduardo , Zheng Yonglan , Huo Dezheng , Olopade Olufunmilayo I. , Koike Maria Aparecida , Schlesinger David
Published: April 2024

Background

Brazil has a highly admixed population. Polygenic Risk Scores (PRS) have mostly been developed from European population studies, and their application to other populations is challenging. To assess the use of PRS for breast cancer (BC) risk in Brazil, we evaluated four PRSs in the Brazilian population.

Methods

We analyzed a Brazilian cohort composed of 6,206 women with a history of breast cancer and 8,878 unphenotyped adults as controls. Genomic variants were imputed from exomes and scores were calculated for all samples.

Results

After excluding individuals with known pathogenic or likely pathogenic variants inBRCA1,BRCA2,PALB2,PTEN, orTP53genes, and first-degree relatives of the probands, 5,598 cases and 8,767 controls remained. Four PRS models were compared, and PRS3820from Mavaddatet al.2019 study showed the best performance, with an Odds Ratio (OR) of 1.43 per standard deviation increase (p-value: < 0.001) and an OR of 1.88 (p-value: < 0.001) for the top decile. PRS3820also performed well for different ancestry groups: East Asian majority (OR 1.59, p-value 0.004), Non-European majority (OR 1.45, p-value: <0.001), and European majority (OR: 1.43, p-value: <0.001).

Conclusion

Among different PRS, the PRS3820performed better in the highly admixed Brazilian population. This will allow a more precise BC risk assessment of mutation-negative women in Brazil.
Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors
Authors: Ozkan Abdulkadir , Padmanabhan Hari K. , Shipman Seth L. , Azim Eiman , Kumar Priyanka , Sadegh Cameron , Basak A. Nazli , Macklis Jeffrey D.
Published: April 2024

Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitryin vivo, or for optimally informative disease modeling and/or therapeutic screeningin vitro, it is important to reproduce the type or subtype of neurons involved. No such appropriatein vitromodels exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factorSox6is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and thatSox6suppresses a latent neurogenic program by repressing inappropriate proneuralNeurog2expression by progenitors. We FACS-purify these genetically accessible progenitors from postnatal mouse cortex and establish a pure culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activatingNeurog2, Fezf2, while antagonizingOlig2withVP16:Olig2). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors, and find that these neurons differentiate with remarkable fidelity compared with corticospinal neuronsin vivo. They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employedNeurog2-driven differentiation. Neurons induced byNeurog2instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from genetically accessible cortical progenitors sets a precedent and foundation forin vitromechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.
Enhancing Genetic Association Power in Endometriosis through Unsupervised Clustering of Clinical Subtypes Identified from Electronic Health Records
Authors: Guare Lindsay , Humphrey Leigh Ann , Rush Margaret , Pollie Meredith , Luo Yuan , Weng Chunhua , Wei Wei-Qi , Kottyan Leah , Jarvik Gail , Elhadad Noemie ,   Penn Medicine Biobank,   Regeneron Genetics Center, Zondervan Krina , Missmer Stacey , Vujkovic Marijana , Velez-Edwards Digna , Senapati Suneeta , Setia-Verma Shefali
Published: April 2024

Background

Endometriosis affects 10% of reproductive-age women, and yet, it goes undiagnosed for 3.6 years on average after symptoms onset. Despite large GWAS meta-analyses (N > 750,000), only a few dozen causal loci have been identified. We hypothesized that the challenges in identifying causal genes for endometriosis stem from heterogeneity across clinical and biological factors underlying endometriosis diagnosis.

Methods

We extracted known endometriosis risk factors, symptoms, and concomitant conditions from the Penn Medicine Biobank (PMBB) and performed unsupervised spectral clustering on 4,078 women with endometriosis. The 5 clusters were characterized by utilizing additional electronic health record (EHR) variables, such as endometriosis-related comorbidities and confirmed surgical phenotypes. From four EHR-linked genetic datasets, PMBB, eMERGE, AOU, and UKBB, we extracted lead variants and tag variants 39 known endometriosis loci for association testing. We meta-analyzed ancestry-stratified case/control tests for each locus and cluster in addition to a positive control (Total Nendometriosis cases= 10,108).

Results

We have designated the five subtype clusters as pain comorbidities, uterine disorders, pregnancy complications, cardiometabolic comorbidities, and EHR-asymptomatic based on enriched features from each group. One locus,RNLS, surpassed the genome-wide significant threshold in the positive control. Thirteen more loci reached a Bonferroni threshold of 1.3 x 10-3(0.05 / 39) in the positive control. The cluster-stratified tests yielded more significant associations than the positive control for anywhere from 5 to 15 loci depending on the cluster. Bonferroni significant loci were identified for four out of five clusters, includingWNT4andGREB1for the uterine disorders cluster,RNLSfor the cardiometabolic cluster,FSHBfor the pregnancy complications cluster, andSYNE1andCDKN2B-AS1for the EHR-asymptomatic cluster. This study enhances our understanding of the clinical presentation patterns of endometriosis subtypes, showcasing the innovative approach employed to investigate this complex disease.
Heterogeneous metabolomic aging across the same age and prediction of health outcome
Authors: Jia Xueqing , Fan Jiayao , Wu Xucheng , Cao Xingqi , Ma Lina , Abdelrahman Zeinab , Bizzarri Daniele , van den Akker Erik B , Slagboom P. Eline , Deelen Joris , Zhou Dan , Liu Zuyun
Published: April 2024

Existing metabolomic clocks exhibit deficiencies in capturing the heterogeneous aging rates among individuals with the same chronological age. Yet, the modifiable and non-modifiable factors in metabolomic aging have not been systematically studied. Here, we leveraged metabolomic profiles of 239,291 UK Biobank participants for 10-year all-cause mortality prediction to generate and validate a new aging measure--MetaboAgeMort. The MetaboAgeMort showed significant associations with all-cause mortality, cause-specific mortality, and diverse incident diseases. Adding MetaboAgeMort to conventional risk factors model improved the predictive ability of 10-year mortality. We identified 99 modifiable factors for MetaboAgeMort, where 16 factors representing pulmonary function, body composition, socioeconomic status, dietary quality, smoking status, alcohol intake, and disease status showed quantitatively stronger associations. The genetic analyses revealed 99 genomic risk loci and 271 genes associated with MetaboAgeMort. Our study illuminates heterogeneous metabolomic aging across the same age, which provides avenues for developing anti-aging therapies and personalized interventions.
A Development and Implementation of a Preconception Counseling Program for Black Women and Men in the Southeastern United States: A Pilot Protocol
Authors: Hernandez-Green N. , Haiman M. , McDonald A. , Rollins L. , Franklin C.G. , Farinu O.T.O , Clarke L. , Huebshmann A. , Fort M. , Chandler R. , Brocke P. , McLaurin-Glass D. , Harris E. , Berry K. , Suarez A. , Williams T.
Published: April 2024

Introduction

Racial/ethnic disparities in maternal mortality rates represent one of the most significant areas of disparities amongst all conventional population perinatal health measures in the U.S. The alarming trends and persistent disparities of outcomes by race/ethnicity and geographic location reinforce the need to focus on ensuring quality and safety of maternity care for all women. Despite complex multilevel factors impacting maternal mortality and morbidity, there are evidence-based interventions that, when facilitated consistently and properly, are known to improve the health of mothers before, during and after pregnancy. The objective of this project is to test implementation of pre-conception counseling with father involvement in community-based settings to improve cardiovascular health outcomes before and during pregnancy in southeastern United States.

Methods and Analysis

This study has two components: a comprehensive needs and assets assessment and a small-scale pilot study. We will conduct a community informed needs and assets assessment with our diverse stakeholders to identify opportunities and barriers to preconception counseling as well as develop a stakeholder-informed implementation plan. Next, we will use the implementation plan to pilot preconception counseling with father involvement in community-based settings. Finally, we will critically assess the context, identify potential barriers and facilitators, and iteratively adapt the way preconception counseling can be implemented in diverse settings. Results of this research will support future research focused on identifying barriers and opportunities for scalable and sustainable public health approaches to implementing evidence-based strategies that reduce maternal morbidity and mortality in the southeastern United States’ vulnerable communities.

Discussion

Findings will demonstrate that preconception counseling can be implemented in community health settings in the southeastern United States. Furthermore, this study will build the capacity of community-based organizations in addressing the preconception health of their clients. We plan for this pilot to inform a larger scaled-up clinical trial across community health settings in multiple southeastern states.
EZH2: A Critical Competing Endogenous RNA in Cancer Research - A Scoping Review
Authors: Salehi-Mazandarani Sadra , Mahmoudian-Hamedani Sharareh , Farajzadegan Ziba , Nikpour Parvaneh
Published: April 2024

In recent years, research on the competing endogenous RNAs (ceRNAs) in cancer is in full swing. These investigations are discovering the importance of critical RNAs in cancer progression. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is one of these RNAs that has been identified as a potential therapeutic target in many types of cancer. Up to now, many studies have been conducted to elucidate ceRNA role ofEZH2in cancer. Due to EZH2’s dual role as an oncogene and tumor suppressor in cancer, a more thorough exploration of its ceRNA functions may enhance clinical approaches to cancer treatment. In the current scoping review, we searched online databases including PubMed, Web of Science, Scopus, Embase, Cochrane Library, and Google Scholar to identify experimentally-validated ceRNA axes includingEZH2in human cancers. We identified 62 unique axes consisting of 30 microRNAs (miRNAs), 31 long non-coding RNAs (lncRNAs), 9 messenger RNAs (mRNAs), and 14 circular RNAs (circRNAs). Notably,SPRY4-IT1- miR-101-3p -EZH2andXIST- miR-101-3p -EZH2were recurrent axes observed in multiple cancer types. Among the most frequent miRNAs were miR-101-3p, miR-144-3p, and miR-124-3p, and ceRNAs includingSPRY4-IT1,XIST,SNHG6,HOXA11-AS,MALAT1, andTUG1emerged as frequent competitors ofEZH2for miRNA binding. This scoping review highlights the prevalence and diversity ofEZH2-containing ceRNA axes in cancer, suggesting their potential as therapeutic targets. Future research should delve deeper into these axes to elucidate their functional significance and assess their clinical applicability.
Evaluation ofin silico toolsfor variant classification in missense variants of solid cancer with actionable genetic targets
Authors: Hong Ilene , Yu Emma , Song Chiwoo , Kim Eugene , Lee Grace , Lee Alice , Chae Young Kwang
Published: April 2024

Advancement in next-generation sequencing technologies has led to a rise in discovery of variants of uncertain significance, which are not clearly categorized as pathogenic or benign. In silico tools, which have been developed to help classify these variants, exhibit variations in outcome. This study aims to evaluate the performance of 6 widely-used in silico tools in predicting the pathogenicity of drug-actionable gene variants in 9 solid cancers.

We selected drug-actionable genes according to NCCN guidelines on breast, ovarian, colorectal, melanoma of skin, thyroid, bladder, pancreatic, prostate, and biliary cancer. From these genes, we gathered information on 1161 total missense variants (pathogenic = 606, benign = 555). Each variant’s pathogenicity was determined based on assertions from three databases: ClinVar, OncoKB, and My Cancer Genome. We selected variants with one or more concordant databases and excluded variants with conflicting classifications. The performance of the in silico tools (Align-GVGD, CADD, FATHMM, MutationTaster2021, Polyphen-2 (HumDiv), and Polyphen-2 (HumVar)) was evaluated by calculating and comparing their overall accuracy, sensitivity, specificity, and Matthews correlation coefficient (MCC).

Overall, all of the in silico tools demonstrated high sensitivity (0.738-0.927) and moderately-high accuracy (0.555-0.829). Excluding MutationTaster2021, all tools demonstrated low specificity (0.242-0.559) and MCC (0.107-0.413). MutationTaster2021 exhibited the highest performance overall and across solid cancer types. Conversely, Align-GVGD exhibited low performance overall and across cancer types.

Tools demonstrating high sensitivity (CADD: 0.983, MutationTaster2021: 0.927, REVEL: 0.851) could be used to rule out the pathogenic variants. MutationTaster2021, with a comparatively high specificity (0.721), could be considered as an additional test to rule in the pathogenic variants. However, given the varying performance and limitations of the tools according to solid cancer type, clinicians should remain cautious in their usage.
Optimizing Input Selection for Cardiac Model Training and Inference: An Efficient 3D CNN-based Approach to Automate Coronary Angiogram Video Selection
Authors: Chang Shih-Sheng , Rostami Behrouz , LoRusso Gerardo , Liu Chia-Ha , Alkhouli Mohamad
Published: April 2024

Background

Research leveraging deep learning (DL) for medical image analysis is increasingly using dynamic coronary angiography from cardiac catheterizations to train neural networks. Yet, an efficient, automatic method to select appropriate dynamic images for training is still largely missing.

Methods

We developed DL models using 254 coronary angiographic studies from the Mayo Clinic. We utilized two state-of-the-art Convolutional Neural Networks (CNN: ResNet and X3D), to identify low quality angiograms through binary classification (satisfactory/unsatisfactory). Ground truth for the quality of the input angiogram was determined by two experienced cardiologists. We validated the developed model in an independent dataset of 3,208 procedures from 3 Mayo sites.

Results

3D-CNN models outperformed their 2D counterparts, with the X3D model achieving superior performance across all metrics (AUC 0.98, precision 0.86, and sensitivity 0.89). The 2D models processed the video clips faster than 3D models. Despite having a 3D architecture, the X3D model had lower computational demand (2.56 GMAC) and parameter count (2.98 M) than 2D models. When validating models on the independent dataset, slight decreases in AUC and sensitivity were observed but accuracy and specificity remained robust (0.88 and 0.89, respectively for the X3D model).

Conclusion

We developed a rapid and effective method for automating the selection of coronary angiogram video clips using 3D-CNNs, potentially improving model accuracy and efficiency in clinical applications. The X3D-S model demonstrates a balanced trade-off between computational efficiency and complexity, making it suitable for real-life clinical applications.