bluuebunny/crossref_metadata_2025 huggingface dataset:
Learning Curve Analysis for Robotic-assisted Harvest of Deep Inferior Epigastric Perforator Flap
Authors: Moreira Andrea , Chen Brian , Bailey Elizabeth , Nelson William , Murariu Daniel
Published: October 2024

The deep inferior epigastric perforator (DIEP) flap is the preferred method for autologous breast reconstruction after mastectomy, but risks the development of hernia, bulge, and decreased core strength. Robotic harvest of DIEP vessels may limit abdominal wall morbidity through smaller fascial incisions and preservation of motor nerves. This study shows the expected learning curve (LC) for robotic harvest and compares the LC between a general surgeon (GS) and a plastic surgeon (PS). A retrospective cohort study was performed for patients who underwent bilateral robotic DIEP flap harvest from October 2021 to September 2022. We evaluated robotic pedicle dissection time (DT) and compared the times between GS and PS. We calculated LC for each surgeon using the cumulative sum (CUSUM) method,

. The LC was identified as the peak of the CUSUM graph. Forty-four flap dissections were recorded during the collection period: 27 by the PS and 17 by the GS. There was no significant difference in DT between the GS and the PS (P = 0.366), and both surgeons saw a decrease in DT over time. Using the CUSUM method, we see the peak of the plot at patient 9 for the PS and the peak of the plot at patient 5 for the GS, after which cumulative DT decreased. As robotic harvest of DIEP flaps becomes accepted, plastic surgeons who wish to incorporate it into their practice may achieve proficiency in their DT within 10 flap harvests and a similar DT compared with robotic-trained GSs.
Impact of social determinants of health on hepatocellular carcinoma surveillance, treatment, and health care costs
Authors: Singal Amit G. , Kilgore Karl M. , Shvets Elizabet , Parikh Neehar D. , Mehta Neil , Burak Ozbay A. , Teigland Christie , Hafez Omar , Schroeder Amy , Yang Audrey , Schinkel Jill
Published: October 2024

Background:

The impact of clinical factors and social determinants of health on treatment patterns and health care costs among patients with HCC is unknown.

Methods:

Using 100% Medicare Fee-For-Service claims and a commercial multipayor claims database, we identified patients diagnosed with HCC from January 1, 2017, to December 31, 2020. Surveillance receipt was defined 12 months prior to HCC diagnosis, whereas treatment and health care costs were assessed post-HCC diagnosis. Multinomial logistic regression was used to assess the association between demographics, social determinants of health, and surveillance or HCC treatment. Multivariable generalized linear regression was used to identify factors associated with total health care costs.

Results:

Of the 32,239 patients with HCC (mean age 68 y, 67% male, 73% White), 70% received surveillance and only half (51%) received any treatment. Curative treatment receipt was higher among those with prior surveillance (24% with CT/MRI and 18% with ultrasound vs. 9% with no surveillance). Curative treatment was independently associated with HCC surveillance and inversely associated with Black race, lower education level, and diagnosis in the year 2020 (COVID-19 year). Higher health care costs were independently associated with Black race, low English proficiency, living alone, and diagnosis in 2018–2020, and inversely associated with CT/MRI-based surveillance.

Conclusions:

Race and social determinants of health were independently associated with curative treatment receipt and health care costs. Increasing access to high-quality HCC surveillance may improve treatment receipt and reduce health disparities among patients with HCC.
Longitudinal outcomes of iStent inject with cataract surgery compared with cataract surgery alone: real-world data from the Fight Glaucoma Blindness registry
Authors: Clement Colin I. , Nguyen Vuong , Howes Frank , Danks Jenny , Lee Vincent , Wechsler David , Gregory-Roberts Emily , Gillies Mark , Lawlor Mitchell
Published: October 2024

Purpose:

To compare combined phacoemulsification and iStent inject with phacoemulsification alone.

Setting:

Fight Glaucoma Blindness (FGB) registry, Sydney, Australia.

Design:

Prospective observational registry study.

Methods:

Eyes that had combined phacoemulsification with iStent inject (iStent group), n = 1257 were compared with eyes that had phacoemulsification only (cataract alone, n = 163). The primary outcome was percentage of eyes achieving >20% intraocular pressure (IOP) reduction from baseline 12 months postoperatively. Secondary outcomes included mean IOP and medication reduction, adverse events, and secondary procedures.

Results:

At 12 months, the percentage of eyes achieving >20% reduction of IOP was significantly higher in the iStent group compared with the cataract-alone group (40.9% vs 30.1% P < .001). Adverse events occurred at a low rate in both groups, and secondary IOP-lowering procedures were significantly less frequent in the iStent group compared with cataract alone.

Conclusions:

Real-world outcomes from the FGB registry at 12 months show that phacoemulsification combined with iStent inject has a higher efficacy and reduced need for secondary IOP-lowering surgery compared with phacoemulsification alone.
Viewing Medical Education Through the Lens of Second Language Acquisition
Authors: Loder Rayne
Published: October 2024

The domains of second language learning and medical learning, although different in many ways, share several commonalities. In both, there is an element of declarative learning, such as memorizing terms and rules and understanding schema. However, both domains also classically include immersive learning in authentic environments with experts (fluent speakers in language, experienced clinicians in medicine) as a means to achieve mastery. Physician assistant (PA) educators may benefit from considering these commonalities and how they may apply to their own educational practices. Several hypotheses from Stephen Krashen's monitor model of second language acquisition (acquisition-learning distinction, the monitor hypothesis, affective filter) are presented with parallels to PA education. As the study of a second language is a common experience within the United States, explicit discussion of the similarities between language and medical learning may be a tool that PA educators can use particularly to help learners as they transition from didactic to clinical learning.
Image reconstruction parameters and the standardized uptake value ratios in brain amyloid PET
Authors: Takeshi Nii , Shota Hosokawa , Tomoya Kotani , Yasunori Nakamura , Ryotaro Kondo , Yasuyuki Takahashi
Published: October 2024

Objectives

The present study investigated various image reconstruction protocols for amyloid PET using phantom test criteria published by the Japanese Society of Nuclear Medicine (JSNM) and compared them with the composite standardized uptake value ratio (cSUVR) in clinical imaging.

Methods

Hoffman 3D phantoms and cylindrical phantoms were collected for 30 min according to the JSNM guidelines. Images were created under various reconstruction protocols by three physical evaluation items in the guidelines and were assessed: gray matter/white matter contrast (%contrast), uniformity (SDuROImean), and image noise [coefficient of variation (CV)]. We compared the cSUVR of images reconstructed under 15 protocols using 18F-flutemetamol and 18F-florbetapir in 15 cases each and the guidelines for physical evaluation of reconstruction parameters.

Results

No significant differences were observed in cSUVR between reconstruction protocols that satisfied the guidelines’ criteria for %contrast and CV and those that did not; however, the visual impression of images differed. SDuROImean, which evaluated uniformity, met the criteria in all data.

Conclusion

Reconstruction protocols should be selected appropriately using guidelines and other information, as cSUVR remains largely the same even if the visual impression of the images differs between different reconstruction protocols. When the relationship between %contrast and CV is expressed in terms of several reconstruction protocols, the graph shows a curved shape, and the optimal protocols for both %contrast and CV are near its center. Since cSUVR is similar to optimal parameters, even under parameters outside this range, multiple parameters need to be considered when selecting image reconstruction protocols for amyloid PET.
Institution-Wide Moral Distress Among Nurses
Authors: Booth Adam T. , Dobson Bridget F. , Christian Becky J. , Clark Paul R. , Sha Shuying
Published: October 2024

BACKGROUND

Moral distress is the inability to do the right thing due to imposed constraints.

OBJECTIVE

Explore the presence of moral distress among nurses.

METHODS

A quantitative, exploratory, cross-sectional study at a level 1 trauma center using the Measure of Moral Distress for Healthcare Professionals (MMD-HP).

RESULTS

Ninety-seven nurses completed the MMD-HP. The top 3 items contributing to moral distress included inadequate staffing, inadequate resources, and lack of administrative support. Nurses who considered leaving had more moral distress. Moral distress explained 28.5% of the variance associated with nurses' “intent to leave” and “primary unit” (P < 0.001). Moral distress for nurses 40 to 49 years of age was higher compared with nurses 50 years or older.

CONCLUSIONS

Moral distress involved deficiencies in staffing, resources, and administrative support. Research should explore interventions to mitigate moral distress among nurses by promoting safe staffing levels, the provision of adequate resources, and increased administrative support.
Evaluating associations between social risks and health care utilization in patients with chronic low back pain
Authors: Pak Sang S. , Jiang Yuxi , Lituiev Dmytro S. , De Marchis Emilia H. , Peterson Thomas A.
Published: October 2024

Introduction:

Care and outcomes for patients with chronic low back pain (cLBP) are influenced by the social risk factors that they experience. Social risk factors such as food insecurity and housing instability have detrimental effects on patient health and wellness, healthcare outcomes, and health disparities.

Objectives:

This retrospective cross-sectional study examined how social risk factors identified in unstructured and structured electronic health record (EHR) data for 1,295 patients with cLBP were associated with health care utilization. We also studied the impact of social risk factors, controlling for back pain–related disability on health care utilization.

Methods:

Included patients who received outpatient spine and/or physical therapy services at an urban academic medical center between 2018 and 2020. Five identified social risks were financial insecurity, housing instability, food insecurity, transportation barriers, and social isolation. Outcomes included 4 categories of health care utilization: emergency department (ED) visits/hospitalizations, imaging, outpatient specialty visits related to spine care, and physical therapy (PT) visits. Poisson regression models tested associations between the presence of identified social risks and each outcome measure.

Results:

Identified social risks in 12.8% of the study population (N = 166/1,295). In multivariate models, social isolation was positively associated with imaging, specialty visits, and PT visits; housing instability was positively associated with ED visits/hospitalizations and imaging; food insecurity was positively associated with ED visits/hospitalizations and specialty visits but negatively associated with PT visits; and financial strain was positively associated with PT visits but negatively associated with ED visits/hospitalization.

Conclusion:

These associations were seen above and beyond other factors used as markers of socioeconomic marginalization, including neighborhood-level social determinants of health, race/ethnicity, and insurance type. Identifying and intervening on social risk factors that patients with cLBP experience may improve outcomes and be cost-saving.
The impact of a customized aesthetic prosthetic leg cover on social interaction cues and attitudes in the general UK population: Two experimental studies
Authors: Phelps Ceri , Hutchings Paul Barry , Stokes Tim , Cooke Zoe , Williams Mark , Jenkins Sean
Published: October 2024

Objectives:

To explore the impact of an aesthetic prosthetic leg cover on attitudes toward individuals with lower-limb amputation and associated social interaction cues among the general UK population.

Study Design:

Two novel experimental methodologies.

Methods:

In study 1, participants (n = 188) viewed 1 of 3 images of an individual: (1) wearing a traditional stem prosthetic, (2) wearing an aesthetic leg cover, or (3) as a nonamputee. They then completed an attitude scale and rated the personality of the individual using the 10-item Big Five Inventory. Study 2 (n = 31) used eye tracking and facial expression software to explore gaze and facial arousal when viewing 1 of 9 manipulated videos of the same individual talking about 3 different scenarios.

Results:

In study 1, the aesthetic leg cover led to significantly higher ratings of agreeableness than stem and nonamputee images and significantly higher ratings of extraversion than the nonamputee image. Attitudes toward an individual with a prosthesis did not significantly differ depending on which image they viewed and were generally positive. In study 2, all participants focused mainly on the individual's face regardless of scenario topic or leg condition, although participants focused more around the leg cover in more active contexts.

Conclusions:

Customized aesthetic leg covers may help individuals living with amputation to be perceived more positively in social situations. These experimental methodologies could be extended to explore the differential impact of context, functionality, and activity of specific types of customized aesthetic prosthetics and could help inform shared decision-making processes in clinical settings.
Effective Pediatric Blood Management in Craniosynostosis Surgery: A Long-Term Update
Authors: Moore Reece , Pfershy Hanna , Pletcher Jocelyn , Boville Brian , Girotto John A. , Carlson Anna R.
Published: October 2024

Background:

Blood transfusion is common in cranial vault surgery, and protocolized efforts to minimize transfusion have been reported in recent years. This study assesses the long term, prospective outcomes of a pediatric blood management protocol for the cranial vault reconstruction (CVR) population.

Materials and Methods:

Data from a retrospective control cohort and a prospective cohort employing a protocol for preoperative hematologic optimization of patients undergoing CVR from January 2015 to October 2023 was reviewed. Preoperative hemoglobin (Hgb) determined the preoperative protocol. Intraoperative tranexamic acid (TXA) and/or aminocaproic acid, cell-saver technology, and postoperative iron or erythropoietin alfa supplementation were also used in the protocol. For statistical analysis, P<0.05 was deemed significant.

Results:

The cohort consisted of 194 successive patients (20 control and 174 treatment). Age, sex, and weight were not significantly different between groups. Mean postoperative Hgb was significantly higher in the control group (P<0.01). No difference was observed in Hgb at discharge between control and treatment groups. Mean estimated blood loss, volume of intraoperative packed red blood cells, rate of packed red blood cell transfusion, and mean total transfusion volume during hospitalization were significantly higher in the control group compared with the treatment group (P<0.01). Mean length of stay did not differ between groups.

Conclusion:

Efforts to optimize blood management in the CVR population are critical. This prospective study represents a robust and reproducible protocol for pediatric blood management with significant reductions in transfusion requirements.
Abbe Flap for Secondary Cleft Lip Deformity
Authors: Davidson Amelia L. , Mehta Nina R. , Curtis Caitrin M. , Runyan Christopher M.
Published: October 2024

The objective of cleft lip surgery is to restore the structure and function of the upper lip. Despite initial repair, some patients develop secondary cleft lip deformity encompassing a shortened philtrum, reduced vermillion height, with excessive tooth visibility. The Abbe flap is a well-described approach for the management of this deformity. The following case describes a 33-year-old female with a history of bilateral cleft lip and palate who presented with secondary cleft lip deformity. She was successfully treated with an Abbe lip-switch flap. Anthropometric measurements supported improved facial aesthetics similar to those in the supplemental literature review. This case also illustrates how oral mucosa from the resected, scarred philtrum can be used to repair nasolabial fistulae.
Evaluating the Learning Curve and Patient Outcomes in Endoscopically Assisted Craniosynostosis Surgery: A 20-Year Analysis
Authors: Chargi Najiba , Kregel Mark , Xi Tong , Dormaar Titiaan , Borstlap Wilfred , van Lindert Erik , Delye Hans , Nienhuijs Marloes
Published: October 2024

Objectives:

To analyze the learning curve associated with endoscopic-assisted craniosynostosis surgery (EACS) at a single institution over a period of 2 decades.

Material and methods:

Patients who underwent EACS between 2004 and 2023 were included in this retrospective study. The impact of surgical experience was assessed by analyzing the duration of surgery and anesthesia, blood loss, need for blood transfusion, postoperative complications, and length of hospital stay, in relation to the number of surgeries performed.

Results:

On the basis of 310 patients, the overall complication rate was low, with only 23 patients (7.4%) experiencing postoperative complications and 33 patients (10.6%) requiring a blood transfusion. The median length of hospital stay was 3 days (range 1–7 days). The results showed a statistically significant learning curve associated with EACS, with each additional surgery reducing the odds of postoperative complications by 0.7% (P<0.001) and the odds of blood transfusion by 0.8% (P<0.001). In addition, there were significant reductions in the duration of anesthesia, duration of surgery, and length of hospital stay over time (P<0.001).

Conclusion:

EACS is a safe and effective technique for treating craniosynostosis with low complication rates and a significant learning curve over time. Surgeons can expect to achieve better outcomes with greater surgical experience.
Use of Financial Hardship as a Metric for Assessing Financial Toxicity in Surgical Trauma Patients
Authors: Ehsan Anam N. , Saha Shivangi , Hathi Preet , Vengadassalapathy Srinivasan , Sana Hamaiyal , Ganesh Praveen , Huang Chuan-Chin , Chauhan Shashank , Singhal Maneesh , Weissman Joel S. , Atun Rifat , Sabapathy Shanmuganathan Raja , Ranganathan Kavitha
Published: October 2024

Background:

Financial toxicity is the detrimental impact of health care costs that must be mitigated to achieve universal health coverage. Catastrophic health expenditure (CHE) is widely used to measure financial toxicity but does not capture patient perspectives of unaffordable health care costs. Financial hardship (FH), a patient-reported outcome measure, is currently underutilized but may be an important adjunct metric. The authors compare CHE to FH as metrics evaluating financial toxicity.

Methods:

A prospective, multicenter cohort study was conducted across 3 public and private tertiary-care hospitals in India. Adult surgical trauma inpatients in plastic and orthopedic surgery departments were assessed. The development of CHE, health expenditures >10% of annual income, and FH, the patient-reported impact of financial toxicity in the form of asset liquidation, debt acquisition, and job loss, were compared by the health system and using logistic regression models.

Results:

Among 744 surgical trauma patients, low income, longer hospital stays, and increased injury severity were significantly associated with the likelihood of incurring CHE and FH (P<0.05). Only FH was significantly associated with lack of insurance (OR: 0.22; 95% CI: 1.14–2.71). Public hospitals had higher rates of FH than CHE (55% versus 23%). Private hospitals had more CHE than FH (53% versus 32%).

Conclusions:

FH is an important metric of financial toxicity that provides important adjunct information to CHE for at-risk populations. FH is particularly informative for public institutions with low direct medical costs. Nuanced utilization of CHE and FH provides a more comprehensive, patient-oriented approach to evaluating unaffordable health care costs that can help shape financial risk protection policy.
Bioinformatics analysis of the antigenic epitopes of L7/L12 protein in the B- and T-cells active against Brucella melitensis
Authors: Zhang Jingjie , Baigued Huricha , Chen Shana , Borigen Haiyan , Tana Tana , Quan Fu , Yang Dezhi
Published: October 2024

Abstract

The objective is to analyse the physicochemical properties, spatial structure and protein–protein interactions (PPIs) of L7/L12 protein using bioinformatics methods and predict their B- and T-cell epitopes to lay a theoretical foundation for developing a novel multiepitope vaccine (MEV). The National Center for Biotechnology Information (NCBI) database was searched for the amino acid sequences of L7/L12 from Brucella melitensis. In addition, the online softwares, ProtParam and ProtScale, were used to predict the physicochemical properties: NetPhos3.1 and CD-search to predict the phosphorylation sites and conserved domains; SOMPA and SWISS-MODEL to predict the secondary and tertiary structures; the STRING database to analyse the PPIs; and the IEDB, ABCpred, SVMTrip and SYFPEITHI databases to predict the B- and T-cell epitopes. L7/L12 was docked to Toll-like receptor 4 (TLR4), B-cell receptor (BCR), Major histocompatibility complex I-T cell receptor (MHC I-TCR) and MHC II-TCR complexes, respectively, and the binding ability of L7/L12 to the targeted receptors was tested. L7/L12, consisting of 124 amino acids, was determined to be a stable, intracellular, hydrophilic protein containing 6 phosphorylation sites and ribosomal protein-related conserved domains. α-helices accounted for 70.16 %, β-turns for 2.42 %, extended strands for 8.87 % and irregular coils for 18.55 % of the secondary structure. The PPIs indicated that L7/L12 was involved in the constitution of ribosomes and regulating the accuracy of the translation process. Three B-cells, two cytotoxic T lymphocytes and three helper T lymphocyte epitopes were finally screened by comparing multiple databases. L7/L12 binds to TLR4, BCR, MHC I-TCR and MHC II-TCR complexes and forms stable hydrogen bonds, respectively. L7/L12, which governs the translation curate of proteins, possesses several potentially advantageous epitopes, laying a theoretical foundation for designing MEVs.
Polyphenol-rich fraction of Bergenia ligulata (Wall.) Engl. sensitizes colon and breast cancer metastasis in vivo: Evidence of cell-type specific mechanism
Authors: De Samhita , Ghosh Suvranil , Roy Somesh , Jana Kuladip , Mandal Subhas C , Pal Mahadeb
Published: October 2024

Background

Colon and breast cancer are one of the leading causes of mortality worldwide. Limited efficacies of present treatments highlighted an urgent need for improvement. Bergenia ligulata is known for its anticancer properties in Indian traditional and folk medicine though the molecular basis of its effects, particularly its anti-metastatic properties, is not well understood. Anti-prostate cancer activity of a LCMS defined polyphenol-rich fraction fromBergenia ligulata(PFBL) rhizome extract has already been published showing promising results in preclinical models.

Purpose

The present study aims to explore anti-cancer activity and anti-metastatic potentials of PFBL against colon and breast cancers in both in vitro and preclinical settings.

Study design and methods

PFBL alone or in synergy with standard chemotherapeutic drugs was tasted in CT26 and 4T1 subcutaneous solid tumors in BALB/c mice. The effect of PFBL was analyzed in terms of changes in tumor mass and different molecular marker levels. Anti-metastatic potential of PFBL was evaluated in CT26 and 4T1 lung metastasis model in mice focusing on the number of lung nodules and lung size.

Results

Our results evidenced that PFBL efficiently regressed both CT26 and 4T1-induced solid tumors alone and in combination with 5FU/doxorubicin without affecting the health of normal host. Notably, PFBL suppressed lung metastasis of 4T1 and CT26 cells in mice with great efficacy. Analysis of tumor and cell extracts suggested that colon cancer cells died by autophagy, while breast cancer cells majorly died by caspase-dependent apoptosis. PFBL actions involved AMPK-dependent inhibition of mTORC1 and subsequent increase in LC3II, PARP1, CDK4 and Cyclin D1 levels in both HCT116 and MCF7 cells; an elevation of intracellular ROS level was the major cause of death in both the cancer types. PFBL treatment also reversed the EMT marker expressions in in vivo and in vitro.

Conclusion

PFBL regressed colon and breast cancer metastasis through distinct mechanisms with little effect on healthy mice. The present study underscored PFBL as a novel anti-tumor and anti-metastasis candidate warranting further testing in clinical settings.
Limitations of the radiotheranostic concept in neuroendocrine tumors due to lineage-dependent somatostatin receptor expression on hematopoietic stem and progenitor cells
Authors: Nguyen Nghia , Min Yu , Rivière Jennifer , van der Garde Mark , Ghosh Sukhen , Bartos Laura M. , Brendel Matthias , Bassermann Florian , Azhdarinia Ali , Weber Wolfgang A. , Götze Katharina S. , Kossatz Susanne
Published: October 2024

Radiopharmaceutical therapy (RPT) has become an effective treatment option for neuroendocrine tumors (NETs) and castration-resistant prostate cancer and is in clinical development for a growing number of indications. One of the major advantages of theranostic RPT is that the distribution of radiopharmaceuticals in the human body can be imaged, and radiation doses to the patient’s organs can be calculated. However, accurate dosimetry may be fundamentally limited by microscopic heterogeneity of radiopharmaceutical distribution. We developed fluorescent analogs of somatostatin-receptor-subtype 2 (SSTR2) targeting Lutetium-177 labelled radiopharmaceuticals that are clinically used in patients with neuroendocrine tumors (NETs) and studied their uptake by hematopoietic stem and progenitor cells (HSPC). Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) showed high and specific SSTR2-ligand uptake, which was at similar levels as neuroendocrine tumor cells. Furthermore, they displayed a several-fold higher uptake of SSTR2-antagonists than of SSTR2-agonists. HSPC treatment with a177Lu-labelled antagonist and agonist showed a stronger reduction of HSC proliferation by the antagonist. Due to the scarcity of HSCs and MPPs, their contribution to total bone marrow uptake of SSTR2-ligands is not detectable in imaging-based dosimetry studies. This likely explains why SSTR2-antagonists caused pancytopenia in clinical trials despite safe dosimetry estimates. In conclusion, target expression heterogeneity can lead to underestimation of radiopharmaceutical toxicity and should be considered when designing clinical trials for new radiopharmaceuticals. The implications of our findings go beyond somatostatin receptor-targeted radiopharmaceuticals and suggest more generally that first-in-human studies should not only be guided by radiation dosimetry from imaging studies but should also include careful escalation of the administered therapeutic activity. The MMC technology is modular and can be applied to other peptide or protein-based radiopharmaceuticals to study cellular distribution and potential bone marrow uptake prior to clinical testing.
Evaluation of Silica and Bioglass Nanomaterials in Pulp-Like Living Materials
Authors: Akoa Daline Mbitta , Avril Anthony , Hélary Christophe , Poliard Anne , Coradin Thibaud
Published: October 2024

Although silicon is a widespread constituent in dental materials, its possible influence on teeth formation and repair remains largely unexplored. Here we have studied the effect of two silicic acid-releasing nanomaterials, silica and bioglass, on a living model of pulp consisting of dental pulp stem cells seeded in dense type I collagen hydrogels. Silica nanoparticles and released silicic acid had little effect on cell viability and mineralization efficiency but impacted metabolic activity, delayed matrix remodeling and led to heterogeneous cell distribution. Bioglass improved cell metabolic activity and led to a homogenous dispersion of cells and mineral deposits within the scaffold. These results suggest that the presence of calcium ions in bioglass is not only favorable to cell proliferation but can also counter-balance the negative effects of silica and silicic acid. Both chemical and biological processes should therefore be considered when investigating the effect of silicon-containing materials on dental tissues.
Postglacial Genetic Legacies, Demography, and Climate Change: Setting Conservation Priorities for Silver Fir
Authors: Balao Francisco , Rios Marc , Sanchez-Robles Jose Manuel , Lorenzo Maria Teresa , Linares Juan Carlos , Terrab Anass
Published: October 2024

Aim: Climate change challenges the adaptive capacity of several tree species. This study explores the genetic diversity and past range dynamics of silver fir (Abies alba) with the objective of set hotspots of population diversity and priorities for conservation based on climate change-induced dieback. Location: Mediterranean, Europe Methods: We perform genome-wide analysis by RAD-seq to range-wide 26 A. alba populations. Results: We identified two lineages in the southern range, formed by populations from the Apennine chain, from the west side, and those from the Balkans and Carpathians, from the east side. Northern range populations showed two lineages, with definite genetic differences between the westernmost populations from those from the eastern. Populations from the Northern Balkans and the NE Apennine were situated in the introgression zones between postglacial recolonization routes, indicating their intermediate positions. Regarding demographics, southern populations remained stable as glacial refuges, while northern populations experienced a population decline during the middle Pleistocene due to glaciations. Although the demographic events that shaped the current spatial structure of genetic diversity of silver fir go back to the Pleistocene, human pressure during the Holocene likely led to an abrupt range decline, while recent drought events have caused widespread dieback. Main Conclusions: We provide a generic framework for setting silver fir conservation priorities based on the phylogeographical lineages and current dieback symptoms induced by climate change. Our results support that rear edge populations might be disproportionately important for the adaptive capacity of silver fir under a climate change scenario.
Sperm quality metrics exhibit annual fluctuations in a critically endangered amphibian managed under human care
Authors: Julien Allison R. , Burger Isabella J. , Kouba Carrie K. , Barber Diane
Published: October 2024

The Puerto Rican crested toad (PRCT) is Puerto Rico’s only endemic toad and has undergone rapid population decline within the last 40 years. As a hedge against extinction, captive assurance colonies have been established at several zoological institutions for breeding and reintroduction. However, reproductive output has remained low, despite the use of hormone therapies to attempt to bypass missing abiotic cues and stimulate reproductive behaviors. This low output necessitates a better understanding of natural fluctuations in gamete, specifically sperm, quality in captive individuals. To generate an understanding of natural gametic cycles in captive PRCTs, we administered male PRCTs (n = 86) housed under natural temperature and photoperiod cycles with exogenous hormones monthly for one year. Samples were analyzed for motility and concentration to assess variations in sperm quality by month. Spermiation was successfully stimulated every month, but quality fluctuated; sperm motility was highest in June and July, while sperm concentration was highest in December, January, and March. These results indicate that, while hormones can be utilized to stimulate gamete production in PRCTs year-round, sperm quality is not consistent. Furthermore, the seasonal occurrence of peak sperm production of captive males differed from natural peaks reported for wild PRCTs. Our results illustrate the need for more biologically informed strategies for breeding of at-risk anuran populations.
Amygdala Subregion Volumes and Apportionment in Preadolescents — Associations with Age, Sex, and Body Mass Index
Authors: Overholtzer L. Nate , Torgerson Carinna , Morrel Jessica , Ahmadi Hedyeh , Tyszka J. Michael , Herting Megan M.
Published: October 2024

Importance

The amygdala, a key limbic structure, plays a critical role in emotional, social, and appetitive behaviors that develop throughout adolescence. Composed of a heterogeneous group of nuclei, questions remain about potential differences in the maturation of its subregions during development.

Objective

To characterize the associations between developmental variables and amygdala subregion volumes during preadolescence.

Design, Setting, and Participants

Cross-sectional Adolescent Brain Cognitive DevelopmentSM(ABCD®) Study data was collected from 3,953 9- and 10-year-old children between September 1, 2016, and October 15, 2018. Data analysis was conducted between June 1, 2023, and July 30, 2024.

Main Outcomes and Measures

Using theCIT168 Amygdala Atlas, nine amygdala subregion volumes were quantified from high-quality MRI scans. Linear mixed-effects models were used to examine the effects of age, sex, pubertal stage, and body mass index z-score (BMIz) on subregion volumes and their relative apportionment within the amygdala.

Results

The study population consisted of 3,953 preadolescents (mean [SD] age, 120 [7.41] months; 1,763 [44.6%] female; 57 [1.4%] Asian, 527 [13.3%] Black, 740 [18.7%] Hispanic, 2,279 [57.7%] white, and 350 [8.9%] from other racial/ethnic groups [identified by parents as American Indian/Native American, Alaska Native, Native Hawaiian, Guamanian, Samoan, other Pacific Islander, or other race]). Distinct associations were observed between age, sex, and BMIz and whole amygdala volume, subregion volumes, and subregion apportionment. Pubertal stage was not related to amygdala subregion volumes. Age was associated with near-global expansion of amygdala subregions during this developmental period. Female sex was linked to smaller volumes in most amygdala subregions, with larger relative apportionment in dorsal amygdala subregions and smaller apportionment in the basolateral ventral paralaminar subregion. Higher BMIz was associated with smaller volumes in large laterobasal subregions, with increased relative apportionment in smaller subregions.

Conclusions and Relevance

This cross-sectional study suggests that age, but not pubertal stage, is associated with near-global expansion of the amygdala at ages 9 and 10, while sex and BMIz are linked to distinct changes in amygdala subregions that explain observed differences in total volumes. These findings provide a foundational context for understanding how developmental variables influence amygdala structure in preadolescents, with implications for understanding future risk for brain disorders.
Extending mathematical frameworks to investigate neuronal dynamics in the presence of microglial ensheathment
Authors: Garcia Nellie , Handy Gregory
Published: October 2024

Recent experimental evidence has shown that glial cells, including microglia and astrocytes, can ensheathe synapses, positioning them to disrupt neurotransmitter flow between pre- and post-synaptic terminals. This study extends micro- and network-scale theoretical models to explore how varying degrees of synaptic ensheathment affect synaptic communication and network dynamics. Consistent with previous studies, our microscale model shows that ensheathment accelerates synaptic transmission while reducing its strength and reliability, with the potential to effectively switch off synaptic connections. Building on these findings, we integrate an “effective” glial cell model into a large-scale neuronal network. Specifically, we analyze a network with highly heterogeneous synaptic strengths and time constants, where glial proximity parametrizes synaptic parameters. Unlike previous models that assumed normal parameter distributions, our model uses parameters drawn from distinct distributions. This framework is applied to large networks of exponential integrate-and-fire neurons, extending linear response theory to analyze not only firing rate distributions but also noise correlations across the network. Despite the significant heterogeneity in the system, a mean-field approximation accurately captures network statistics. We demonstrate the utility of our model by reproducing experimental findings, showing that microglial ensheathment leads to post-anesthesia hyperactivity in excitatory neurons of mice. Furthermore, we explore how glial ensheathment may be used in the visual cortex to target specific neuronal subclasses, tuning higher-order network statistics.
Apollo: A comprehensive GPU-powered within-host simulator for viral evolution and infection dynamics across population, tissue, and cell
Authors: Perera Deshan , Li Evan , van der Meer Frank , Lynch Tarah , Gill John , Church Deirdre L. , Huber Christian D. , van Marle Guido , Platt Alexander , Long Quan
Published: October 2024

Modern sequencing instruments bring unprecedented opportunity to study within-host viral evolution in conjunction with viral transmissions between hosts. However, no computational simulators are available to assist the characterization of within-host dynamics. This limits our ability to interpret epidemiological predictions incorporating within-host evolution and to validate computational inference tools. To fill this need we developed Apollo, a GPU-accelerated, out-of-core tool for within-host simulation of viral evolution and infection dynamics across population, tissue, and cellular levels. Apollo is scalable to hundreds of millions of viral genomes and can handle complex demographic and population genetic models. Apollo can replicate real within-host viral evolution; accurately recapturing observed viral sequences from an HIV cohort derived from initial population-genetic configurations. For practical applications, using Apollo-simulated viral genomes and transmission networks, we validated and uncovered the limitations of a widely used viral transmission inference tool.
Dopamine and cortical iPSC-derived neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction: implications for protein deposition versus selective cell loss
Authors: Chedid Jessica , Li Yan , Labrador-Garrido Adahir , Abu-Bonsrah Dad , Pavan Chiara , Fraser Tyra , Ovchinnikov Dmitry , Zhong Melanie , Davis Ryan , Strbenac Dario , Johnston Jennifer A. , Thompson Lachlan H. , Kirik Deniz , Parish Clare L. , Halliday Glenda M. , Sue Carolyn M. , Wali Gautam , Dzamko Nicolas
Published: October 2024

Background

Mutations causing Parkinson’s disease (PD) give diverse pathological phenotypes whose cellular correlates remain to be determined. For example, those withPRKNloss of function mutations have significantly earlier selective vulnerability of dopamine neurons, those withSNCAmutations have increased alpha-synuclein deposition, while those withLRRK2mutations have additional deposition of tau. Yet all three mutation types are implicated in mitochondrial and/or lysosomal dysfunction. Direct comparison of cell models with these mutations would clarify the relative cellular dysfunctions associated with these different pathological phenotypes.

Methods

An unbiased high-content imaging platform using orthogonal probes to assess both lysosomal and mitochondrial dysfunction, along with alpha-synuclein and tau protein deposition was established using induced pluripotent stem cell (iPSC) derived cortical and ventral midbrain neurons. Three mutation types,SNCAA53T,LRRK2R1441G andPRKNloss of function (lof), were selected as exemplars of divergent PD pathological phenotypes and compared to each other, and to control iPSC from subjects without PD.

Results

Different PD mutations caused cell type specific dysfunctions, likely to impact on both selective neuronal vulnerability and the pathologies observed in PD. Comparison of dopamine neurons identified that both lysosomal and mitochondrial dysfunction were predominant withPRKNlof mutations, whereas immunofluorescent staining revealed thatSNCAA53T andLRRK2R1441G mutations had increased tau deposition. In contrast, cortical neurons withSNCAandLRRK2mutations both had mitochondrial and autophagy impairments without protein deposition, withLRRK2cells additionally showing decreased glucocerebrosidase activity and increased alpha-synuclein phosphorylation.

Conclusions

Lysosomal and mitochondrial dysfunction are predominant in dopamine neurons withPRKNlof mutations, and may drive the early selective loss of dopamine neurons inPRKNmutation carriers. More subtle cellular abnormalities in theSNCAA53T cell lines are likely to predispose to alpha-synuclein aggregation and tau protein deposition over time. TheLRRK2R1441G may also predispose to tau deposition, but despite substantial lysosomal dysfunction with increased alpha-synuclein phosphorylation, pathological alpha-synuclein accumulations were not observed. Understanding the mechanistic differences in how lysosomal and mitochondrial dysfunction impact on PD pathogenesis in different disease subtypes may be important for therapeutic development.
Metabolomic Profiling Reveals Potential of Fatty Acids as Regulators of Stem-like Exhausted CD8 T Cells During Chronic Viral Infection
Authors: Kazane Katelynn R , Labarta-Bajo Lara , Zangwill Dina R , Liimatta Kalle , Vargas Fernando , Weldon Kelly C , Dorrestein Pieter C , Zúñiga Elina I
Published: October 2024

Chronic infections drive a CD8 T cell program termed T cell exhaustion, characterized by reduced effector functions. While cell-intrinsic mechanisms underlying CD8 T cell exhaustion have been extensively studied, the impact of the metabolic environment in which exhausted CD8 T cells (Tex) operate remains less clear. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model we investigated systemic metabolite changes early and late following acute versus chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the acute phase of the sustained infection. This included nutrient changes that were independent of viral loads and partially associated with CD8 T cell-induced anorexia and lipolysis. One remarkable observation was the elevation of medium- and long-chain fatty acid (FA) and acylcarnitines during the early phase after chronic infection. During this time, virus-specific CD8 T cells from chronically infected mice exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly stem-like Tex (TexSTEM), a subset that generates effector-like TexINTwhich directly limit viral replication. Notably, only TexSTEMincreased oxidative metabolism and ATP production upon FA exposure. Consistently, short-term reintroduction of FA during late chronic infection exclusively improved TexSTEMmitochondrial fitness, percentages and numbers. This treatment, however, also reduced TexINT, resulting in compromised viral control. Our study offers a valuable resource for investigating the role of specific metabolites in regulating immune responses during acute and chronic viral infections and highlights the potential of long-chain FA to influence TexSTEMand viral control during a protracted infection.

Significance

This study examines systemic metabolite changes during acute and chronic viral infections. Notably, we identified an early, transient nutrient shift in chronic infection, marked by an increase in medium- and long-chain fatty acid related species. Concomitantly, a virus-specific stem-like T cell population, essential for maintaining other T cells, displayed high lipid avidity and was capable of metabolizing exogenous fatty acids. Administering fatty acids late in chronic infection, when endogenous lipid levels had normalized, expanded this stem-like T cell population and enhanced their mitochondrial fitness. These findings highlight the potential role of fatty acids in regulating stem-like T cells in chronic settings and offer a valuable resource for studying other metabolic signatures in both acute and persistent infections.
FIThe Effects of Curcumin Supplementation on Body Weight, Body Mass Index, and Waist Circumference in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Alivand Noorbakhsh , Alivand Soleyman , masoumi Seyed jalil , foshati Sahar , Abbasi Ebrahim
Published: October 2024

The study investigates the effects of curcumin on obesity and its related factors in diabetic patients, given that obesity can lead to insulin resistance and complicate diabetes management. An analysis of nine randomized controlled trials (RCTs) involving 699 participants was conducted to evaluate curcumin’s impact on body weight (BW), body mass index (BMI), and waist circumference (WC). The results indicated a significant reduction in BW (WMD: −1.65 kg), BMI (WMD: −0.69 kg/m2), and WC (WMD: - 0.93 cm) with curcumin consumption compared to controls. Higher doses of curcumin (>1000 mg/day) were notably more effective in reducing BW, BMI, and WC than lower doses. The study concludes that curcumin supplementation effectively reduces BW, BMI, and WC in diabetic patients, especially at higher doses, and suggests the need for further studies to explore these benefits.
CRISPR tiling deletion screens reveal functional enhancers of neuropsychiatric risk genes and allelic compensation effects (ACE) on transcription
Authors: Ren Xingjie , Zheng Lina , Maliskova Lenka , Tam Tsz Wai , Sun Yifan , Liu Hongjiang , Lee Jerry , Takagi Maya Asami , Li Bin , Ren Bing , Wang Wei , Shen Yin
Published: October 2024

Precise transcriptional regulation is critical for cellular function and development, yet the mechanism of this process remains poorly understood for many genes. To gain a deeper understanding of the regulation of neuropsychiatric disease risk genes, we identified a total of 39 functional enhancers for four dosage-sensitive genes,APP,FMR1,MECP2, andSIN3A, using CRISPR tiling deletion screening in human induced pluripotent stem cell (iPSC)-induced excitatory neurons. We found that enhancer annotation provides potential pathological insights into disease-associated copy number variants. More importantly, we discovered that allelic enhancer deletions atSIN3Acould be compensated by increased transcriptional activities from the other intact allele. Such allelic compensation effects (ACE) on transcription is stably maintained during differentiation and, once established, cannot be reversed by ectopicSIN3Aexpression. Further, ACE atSIN3Aoccurs through dosage sensing by the promoter. Together, our findings unravel a regulatory compensation mechanism that ensures stable and precise transcriptional output forSIN3A, and potentially other dosage-sensitive genes.