bluuebunny/crossref_metadata_2025 huggingface dataset:
Acceptance and Factors Associated With Participation in Functional Cure–Related Trials Among People Living With HIV: A Cross-sectional Study in Southern China
Authors: Deng Zhaomin , Shi Minjuan , Yuan Yue , Cao Guangjin , Wen Chunyan , Chen Lijuan , Fan Xueying , Wu Linan , Yuan Jianhui , Zou Huachun , Li Linghua , Sun Caijun
Published: January 2024

HIV remains a global health challenge, and research efforts directed towards a functional cure require people living with HIV (PLHIV) involvement in clinical trials. Our study assessed willingness to participate in HIV functional cure–related clinical trials and associated factors among PLHIV in Guangzhou, China, using a questionnaire survey approach. We analyzed responses from 718 questionnaires, finding that 71.2% were willing to participate in Phase III trials, while 51.7% were willing to participate in Phase I trials and 42.9% expressed acceptability for analytic treatment interruption. Multivariate logistic regression demonstrated that male PLHIV, those with awareness of functional cure, and PLHIV, who had been on antiretroviral therapy (ART) for less than 1 year, were more willing to participate in Phase III trials. Those with a body mass index greater than 24, and those without resistance to ART drug were more willing to participate in Phase I trials. The major motivations for participation in Phase III trials were access to cutting-edge treatments (62.6%) and supporting research (55.3%). Safety was the main concern contributing to hesitancy. Our study revealed a high willingness to participate in HIV functional cure–related trials among PLHIV in Guangzhou, China, and willingness varied across different trial phases and was influenced by multiple factors. This study provides valuable references for future clinical trial recruitment strategies and public health policy formulation.
The Crohn’s Disease–Health Index
Authors: Varma Anika , Weinstein Jennifer , Seabury Jamison , Rosero Spencer , Wagner Ellen , Zizzi Christine , Kaat Aaron , Luebbe Elizabeth , Dilek Nuran , Heatwole John , Saubermann Lawrence , Temple Larissa , Rogoff Scott , Heatwole Chad
Published: January 2024

Objective:

We sought to develop and validate the Crohn’s Disease–Health Index (CD-HI), a disease-specific, patient-reported outcome measure that serially measures Crohn’s disease (CD) symptomatic burden in adults with CD.

Background:

As therapeutic interventions are tested among patients with CD, responsive outcome measures are needed to track disease progression and therapeutic gain during clinical trials.

Patients and Methods:

We conducted a national cross-sectional study of individuals with CD to identify the most prevalent and impactful symptoms of CD. The most relevant symptoms were included in the CD-HI. We used factor analysis, qualitative patient interviews, test-retest reliability evaluation, and known group validity testing to evaluate and optimize the CD-HI.

Results:

The CD-HI contains 12 subscales that comprehensively measure CD burden using the patient’s perspective. Fifteen adults with CD beta tested the CD-HI and found the instrument to be clear, easy to use, and relevant to them. Twenty-three adults with CD participated in an assessment of test-retest reliability, which indicated high reliability of individual questions, subscales, and the full instrument (intraclass correlation coefficient = 0.84 for the full instrument). The CD-HI and its subscales demonstrated a high internal consistency (Cronbach α = 0.98 for the full instrument). The CD-HI distinguished between groups of individuals with CD known to differ in disease severity.

Conclusions:

This research supports the use of the CD-HI as a valid, sensitive, reliable, and relevant patient-reported outcome to determine the multifactorial disease burden of those with CD, assess the relevance and merit of future CD therapies, and support drug labeling claims.
Efficacy, Feasibility, and Safety of the X-Tack Endoscopic HeliX Tacking System
Authors: Canakis Andrew , Dawod Sanad Maher , Dawod Enad , Simons Malorie , Di Cocco Bianca , Westerveld Donevan Richard , Trasolini Roberto Paolo , Berzin Tyler M. , Marshall Christopher A. , Abdelfattah Ahmed Maher , Marya Neil B. , Smallfield George B. , Kaspar Matthew , Campos Guilherme M. , Skef Wasseem , Kedia Prashant , Smith Terrence A. , Aihara Hiroyuki , Moyer Matthew T. , Sampath Kartik , Mahadev Srihari , Carr-Locke David L. , Sharaiha Reem Z.
Published: January 2024

Background and Aims:

The application of endoscopic suturing has revolutionized defect closures. Conventional over-the-scope suturing necessitates removal of the scope, placement of the device, and reinsertion. A single channel, single sequence, through-the-scope suturing device has been developed to improve this process. This study aims to describe the efficacy, feasibility, and safety of a through-the-scope suturing device for gastrointestinal defect closure.

Methods:

This was a retrospective multicenter study involving 9 centers of consecutive adult patients who underwent suturing using the X-Tack Endoscopic HeliX Tacking System (Apollo Endosurgery). The primary outcomes were technical success and long-term clinical success. Secondary outcomes included adverse events, recurrence, and reintervention rates.

Results:

In all, 56 patients (mean age 53.8, 33 women) were included. Suturing indications included fistula repair (n=22), leak repair (n=7), polypectomy defect closure (n=12), peroral endoscopic myotomy (POEM) site closure (n=7), perforation repair (n=6), and ulcers (n=2). Patients were followed at a mean duration of 74 days. Overall technical and long-term clinical success rates were 92.9% and 75%, respectively. Both technical and clinical success rates were 100% for polypectomies, POEM-site closures, and ulcers. Success rates were lower for the repair of fistulas (95.5% technical, 54.5% clinical), leaks (57.1%, 28.6%), and perforations (100%, 66.7%). No immediate adverse events were noted.

Conclusion:

This novel, through-the-scope endoscopic suturing system, is a safe and feasible method to repair defects that are ≤3 cm. The efficacy of this device may be better suited for superficial defects as opposed to full-thickness defects. Larger defects will need more sutures and probably a double closure technique to provide a reinforcement layer.
The Role of Intraoperative Pancreatoscopy in the Surgical Management of Intraductal Papillary Mucinous Neoplasms
Authors: Grewal Mahip , Habib Joseph R. , Paluszek Olivia , Cohen Steven M. , Wolfgang Christopher L. , Javed Ammar A.
Published: January 2024

Objectives

Most patients with intraductal papillary mucinous neoplasms (IPMNs) are diagnosed with a solitary lesion; however, the presence of skip lesions, not appreciable on imaging, has been described. Postoperatively, these missed lesions can continue to grow and potentially become cancerous. Intraoperative pancreatoscopy (IOP) may facilitate detection of such skip lesions in the remnant gland. The aim of this scoping review was to appraise the evidence on the role of IOP in the surgical management of IPMNs.

Materials and Methods

Studies reporting on the use of IOP during IPMN surgery were identified through searches of the PubMed, Embase, and Scopus databases. Data extracted included IOP findings, surgical plan modifications, and patient outcomes. The primary outcome of interest was the utility of IOP in surgical decision making.

Results

Ten studies reporting on the use of IOP for IPMNs were identified, representing 147 patients. A total of 46 skip lesions were identified by IOP. Overall, surgical plans were altered in 37% of patients who underwent IOP. No IOP-related complications were reported.

Conclusions

The current literature suggests a potential role of integration of IOP into the management of patients with IPMNs. This tool is safe and feasible and can result in changes in surgical decision making.
School Attendance Among Pediatric Oncology Patients During the COVID-19 Pandemic in Ontario, Canada
Authors: Carson Jacob Joel Kirsh , Coo Helen , Al Nuaimi Mohammed , Punnett Angela , Leifso Kirk , Wheaton Laura
Published: January 2024

Supporting schooling for current and past pediatric oncology patients is vital to their quality of life and psychosocial recovery. However, no study has examined the perspectives toward in-person schooling among pediatric oncology families during the COVID-19 pandemic. In this online survey study, we determined the rate of and attitudes toward in-person school attendance among current and past pediatric oncology patients living in Ontario, Canada during the 2020–2021 school year. Of our 31-family cohort, 23 children (74%) did attend and 8 (26%) did not attend any in-person school during this time. Fewer children within 2 years of treatment completion attended in-person school (5/8; 62%) than those more than 2 years from treatment completion (13/15; 87%). Notably, 22 of 29 parents (76%) felt that speaking to their care team had the greatest impact compared to other potential information sources when deciding about school participation, yet 13 (45%) were unaware of their physician’s specific recommendation regarding whether their child should attend. This study highlights the range in parental comfort regarding permitting in-person schooling during the COVID-19 pandemic. Pediatric oncologists should continue to address parental concerns around in-person school during times of high transmission of COVID-19 and potentially other communicable diseases in the future.
Normal Erythroid Precursors in Diamond-Blackfan Anemia: A Rare Case Highlighting Challenges That Remain
Authors: Prior Daniel , Sowa Anna , Pashankar Farzana
Published: January 2024

Diamond-Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome that is both genetically and clinically heterogeneous. The diagnosis of DBA has changed over time, with advancements in our understanding of the varied genetic etiologies and phenotypic manifestations of the disease. We present a rare case of a patient who never developed erythroid precursor hypoplasia, adding to the understanding of atypical manifestations of DBA. Our patient had spontaneous remission followed by subsequent relapse, both atypical and poorly understood processes in DBA. We highlight important considerations in diagnostically challenging cases and review major outstanding questions surrounding DBA.
The effect of the four pharmacological pillars of heart failure on haemoglobin level
Authors: Hullon Darshan , Taherifard Erfan , Al-Saraireh Taif Haitham
Published: January 2024

Anaemia, a condition characterized by low levels of haemoglobin, is frequently observed in patients with heart failure (HF). Guideline-directed medical therapy improves HF outcomes by using medications like beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, along with mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors. In this study, we aimed to review the pathophysiology of anaemia in patients with HF and present the current evidence regarding the relationship between the main recommended medications for these patients and haemoglobin levels. The authors conducted a comprehensive search in the medical literature for relevant original clinical articles in which the four pharmacological pillars of HF were given to the patients; we, then, assessed whether the association of use of these medications and haemoglobin level or development of anaemia was provided. These common medications have been shown in the literature that may exacerbate or ameliorate anaemia. Besides, it has been shown that even in the case that they result in the development of anaemia, their use is associated with positive effects that outweigh this potential harm. The literature also suggests that among patients receiving medications with negative effects on the level of haemoglobin, there was no difference in the rate of mortality between anaemic and non-anaemic patients when both were on treatment for anaemia; this point highlights the importance of the detection and treatment of anaemia in these patients. Further research is needed to explore these relationships and identify additional strategies to mitigate the risk of anaemia in this population.
Consensus on resuscitative endovascular balloon occlusion of the aorta (REBOA) in civilian (pre-hospital) trauma care: a Delphi study
Authors: van de Voort Jan C. , Kessel Boris , Borger van der Burg Boudewijn L.S. , DuBose Joseph J. , Hörer Tal M. , Hoencamp Rigo
Published: January 2024

Background

REBOA could prevent lethal exsanguination and support cardiopulmonary resuscitation. In pre-hospital trauma and medical emergency settings, a small population with high mortality rates could potentially benefit from early REBOA deployment. However, its use in these situations remains highly disputed. Since publication of the first Delphi study on REBOA, in which consensus was not reached on all addressed topics, new literature has emerged. Aim of this study was to establish consensus on the use and implementation of REBOA in civilian pre-hospital settings for non-compressible truncal hemorrhage and out-of-hospital cardiac arrest as well as for various in-hospital settings.

Methods

A Delphi study consisting of three rounds of questionnaires was conducted based on a review of recent literature. REBOA-experts with different medical specialties, backgrounds and work environments were invited for the international panel. Consensus was reached when a minimum of 75% of panelists responded to a question and at least 75% (positive) or less than 25% (negative) of these respondents agreed on the questioned subject.

Results

Panel members reached consensus on potential (contra-)indications, physiological thresholds for patient selection, the use of ultrasound and practical, and technical aspects for early femoral artery access and pre-hospital REBOA.

Conclusion

The international expert panel agreed that REBOA can be used in civilian pre-hospital settings for temporary control of non-compressible truncal hemorrhage, provided that personnel are properly trained and protocols are established. For pre-hospital REBOA and early femoral artery access, consensus was reached on (contra-) indications, physiological thresholds and practical aspects. The panel recommends the initiation of a randomized clinical trial investigating the use of pre-hospital REBOA for non-compressible truncal hemorrhage.

Level of evidence

Delphi study (original research, care management), level 5
Reverse shock index multiplied by the motor component of the Glasgow Coma Scale predicts mortality and need for intervention in pediatric trauma patients
Authors: Smida Tanner , Bonasso Patrick , Bardes James , Price Bradley S. , Seifarth Federico , Gurien Lori , Maxson Robert , Letton Robert
Published: January 2024

BACKGROUND

Timely identification of high-risk pediatric trauma patients and appropriate resource mobilization may lead to improved outcomes. We hypothesized that reverse shock index times the motor component of the Glasgow Coma Scale (GCS) (rSIM) would perform equivalently to reverse shock index times the total GCS (rSIG) in the prediction of mortality and the need for intervention following pediatric trauma.

METHODS

The 2017–2020 National Trauma Data Bank data sets were used. We included all patients 16 years or younger who had a documented prehospital and trauma bay systolic blood pressure, heart rate, and total GCS. We excluded all patients who arrived at the trauma center without vital signs and interfacility transport patients. Receiver operating characteristic curves were used to model the performance of each metric as a classifier with respect to our primary and secondary outcomes, and the area under the receiver operating characteristic curve (AUROC) was used for comparison. Our primary outcome was mortality before hospital discharge. Secondary outcomes included blood product administration or hemorrhage control intervention (surgery or angiography) <4 hours following hospital arrival and intensive care unit admission.

RESULTS

After application of exclusion criteria, 77,996 patients were included in our analysis. Reverse shock index times GCS-motor and rSIG performed equivalently as predictors of mortality in the 1- to 2- (p = 0.05) and 3- to 5-year-old categories (p = 0.28), but rSIM was statistically outperformed by rSIG in the 6- to 12- (AUROC, 0.96 vs. 0.95; p = 0.04) and 13- to 16-year-old age categories (AUROC, 0.96 vs. 0.95; p < 0.01). Reverse shock index times GCS-motor and rSIG also performed similarly with respect to prediction of secondary outcomes.

CONCLUSION

Reverse shock index times GCS-total and rSIM are both outstanding predictors of mortality following pediatric trauma. Statistically significant differences in favor of rSIG were noted in some age groups. Because of the simplicity of calculation, rSIM may be a useful tool for pediatric trauma triage.

LEVEL OF EVIDENCE

Diagnostic Tests or Criteria; Level III.
Pediatric thoracic cage fractures—Mind the sternum: A retrospective analysis of the ACS-TQIP database
Authors: di Natale Anthony , Mak Allison L. , Hwang Rosa , Allukian Myron , Nace Gary W. , Nance Michael L.
Published: January 2024

BACKGROUND

The thoracic cage is an anatomical entity formed by the thoracic spine, ribs, and sternum. As part of this osteoligamentous complex, the sternum contributes substantially to the stability of the thoracic spine. This study investigates the influence of a concomitant sternal fracture (SF) on the treatment and hospital course of pediatric patients with a thoracic vertebral fracture (TVF).

METHODS

The Trauma Quality Improvement Program data sets from 2016 to 2020 were reviewed. Patients aged 0 year to 19 years with TVF with or without SF following blunt trauma were identified using the Abbreviated Injury Scale codes and selected for further data collection. Patients with transverse or spinous process fractures or incomplete data were excluded. Data collected included demographics, mechanisms of injury, clinical variables, procedures, intensive care unit admission and length of stay, total length of stay and in-hospital mortality. Continuous variables were analyzed with Wilcoxon rank sum test, categorical variables with χ2 test.

RESULTS

A total of 13,434 patients were identified, of which 10,292 had isolated TVF (TVF), 788 TVF and concomitant SF (TVF + SF), 2,225 isolated SF (excluded), and 126 incomplete data (excluded). Motor vehicle collisions were the most common mechanism of injury in both groups (TVF, 75%; TVF + SF, 88%), followed by falls (TVF: 23%, TVF + SF: 12%). Spinal cord injuries were more common among TVF + SF patients (6.4% vs. 4%). Median injury severity score (17 vs. 12), age (17 vs. 15 years), LOS (5 vs. 3 days), and mortality (5.6% vs. 2.3%) were significantly higher and the need for operative treatment (69% vs. 56%) and ICU admission (53% vs. 36%) significantly more frequent in patients with TVF + SF.

CONCLUSION

Concomitant SF occur in 7% of all pediatric patients with TVF and are associated with increased morbidity and mortality. This combination of injuries is likely the result of greater energy transmission and injury potential.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Use of a statewide solid organ injury procotcol to optimize triage, treatment, and transfer for pediatric abdominal trauma
Authors: Swendiman Robert A. , Russell Katie W. , Larsen Kezlyn , Eyre Matthew , Fenton Stephen J.
Published: January 2024

BACKGROUND

The Utah Pediatric Trauma Network (UPTN) is a non-competitive collaboration of all 51 hospitals in the state of Utah with the purpose of improving pediatric trauma care. Created in 2019, UPTN has implemented evidence-based guidelines based on hospital resources and capabilities with quarterly review of data collected in a network-specific database. A blunt solid organ injury (SOI) protocol was developed to optimize treatment of these injuries statewide. The purpose of this study was to review the effectiveness of the SOI guideline.

METHODS

The UPTN REDCap® database was retrospectively reviewed from 2021 through 2022. We compared admissions from the Level 1 pediatric trauma center (PED1) to non-pediatric hospitals (non-PED1) of children with low-grade (I-II) and high-grade (III-V) SOIs.

RESULTS

In 2 years, 172 patients were treated for blunt SOI, with or without concomitant injuries. There were 48 (28%) low-grade and 124 (72%) high-grade SOIs. 33 (69%) patients were triaged with low-grade SOI injuries at a non-PED1 center, and 17 (35%) were transferred to the PED1 hospital. Most had multiple injuries, but 7 (44%) were isolated, and none required a transfusion or any procedure/operation at either hospital. Of the 124 patients with high-grade injuries, 41 (33%) primarily presented to the PED1 center, and 44 (35%) were transferred there. Of these, 2 required a splenectomy and none required angiography. Thirty-nine children were treated at non-PED1 centers without transfer, and 4 required splenectomy and 6 underwent angiography/embolization procedures. No patient with an isolated SOI died.

CONCLUSION

Implementation of SOI guidelines across UPTN successfully allowed non-pediatric hospitals to safely admit children with low-grade isolated SOI, keeping families closer to home, while standardizing pediatric triage for blunt abdominal trauma in the state.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Brain death/death by neurologic criteria: What you need to know
Authors: Larson Nicholas J. , Dries David J. , Blondeau Benoit , Rogers Frederick B.
Published: January 2024

Since the beginning of time, man has been intrigued with the question of when a person is considered dead. Traditionally, death has been considered the cessation of all cardiorespiratory function. At the end of the last century a new definition was introduced into the lexicon surrounding death in addition to cessation of cardiac and respiratory function: Brain Death/Death by Neurologic Criteria (BD/DNC). There are medical, legal, ethical, and even theological controversies that surround this diagnosis. In addition, there is no small amount of confusion among medical practitioners regarding the diagnosis of BD/DNC. For families enduring the devastating development of BD/DNC in their loved one, it is the duty of the principal caregiver to provide a transparent presentation of the clinical situation and clear definitive explanation of what constitutes BD/DNC. In this report, we present a historical outline of the development of BD/DNC as a clinical entity, specifically how one goes about making a determination of BD/DNC, what steps are taken once a diagnosis of BD/DNC is made, a brief discussion of some of the ethical/moral issues surrounding this diagnosis, and finally the caregiver approach to the family of a patient who had been declared with BD/DNC. It is our humble hope that with a greater understanding of the myriad of complicated issues surrounding the diagnosis of BD/DNC that the bedside caregiver can provide needed closure for both the patient and the family enduring this critical time in their life.
The Impact of the Donor Card Holder Prioritization Program on Kidney Allocation in Israel
Authors: Mor Eytan , Bloom Meitar , Ghinea Ronen , Anteby Roi , Pasvolsky-Gutman Ronit , Loewenthal Ron , Nachmani Ido , Hod Tammy
Published: January 2024

Background.

Since 2014, as part of a priority program within the Israeli Transplant Law, additional points were given to waitlisted candidates with donor cards. We assessed the impact on deceased donor kidney allocation.

Methods.

This study enrolled all patients older than 18 y who underwent deceased donor kidney transplantation (January 2016–December 2019). Data were obtained from the National HLA Tissue Laboratory registry at the Sheba Medical Center. Patients were grouped by donor card status (ADI group) (not signed, 0 points; relative signed, 0.1 points; patient signed, 2 points; and relative donated, 9 points). The primary outcome was waiting time until kidney transplantation with and without the additional score.

Results.

Four hundred forty-four patients underwent kidney transplantation during the study period: 281 (63%) were donor card holders (DCH) and 163 (37%) were not DCH. DCH with extra points waited 68.0 (±47.0) mo on average, compared with 94.6 (±47.3) mo for not DCH (P < 0.001). Donor card signers had a shorter time until transplant in a multivariable model. Without extra points, 145 recipients (32.6%) would have missed organs allocated to higher-scored candidates. Allocation changes occurred in 1 patient because of an additional 0.1 points, in 103 candidates because of an additional 2 points, and in 41 candidates because of an additional 9 points.

Conclusions.

Additional DCH scores improved allocation and reduced waiting time for donor card signers and those with donating relatives. To enhance fairness, consideration should be given to reducing the score weight of this social criterion and raising scores for other factors, especially dialysis duration.
Differed spontaneous dissociative symptoms following the use of esketamine intranasal spray in a patient suffering from treatment-resistant depression: a case report
Authors: Chevalier Louis , Bulteau Samuel , Cheval Louis , Charron Jalal , Sauvaget Anne , Laurin Andrew
Published: January 2024

Intranasal esketamine is used in France for treatment-resistant depression. Dissociative symptoms are common side effects during treatment sessions. We report a case of delayed spontaneous dissociative symptoms following esketamine administration. A 20-year-old female with treatment-resistant depression received esketamine treatment. Dissociative symptoms occurred during sessions and persisted at a distance, often accompanied by anxiety. Delayed dissociative phenomena disappeared within the fourth week of treatment by esketamine. The literature mainly discusses dissociation during esketamine treatment sessions, with limited data on differed spontaneous episodes. Three hypotheses are discussed concerning the mechanism of occurrence of these dissociative phenomena, including esketamine’s direct effect, central nervous system sensitization, and anxiety-induced dissociation. We present the first case of differed spontaneous dissociative effects after intranasal esketamine administration for treatment-resistant depression. Our main hypothesis suggests that esketamine may act as a ‘pattern’ for dissociative experiences, heightening the patient’s ability to discern these phenomena during other instances of dissociation, such as acute anxiety attacks. Further research is needed to validate this hypothesis.
The role of benzodiazepines in common conditions: a narrative review focusing on lormetazepam
Authors: Pallanti Stefano
Published: January 2024

This review aimed to examine the place of benzodiazepines, specifically lormetazepam, in the treatment of insomnia, including during pregnancy or in patients with psychodermatoses. PubMed was searched for the term “lormetazepam” in association with MeSH terms encompassing anxiety, insomnia/sleep disorders, pregnancy/gestation, and psychodermatoses/skin disorders. English-language articles up to 31 July 2022 were identified. Ad hoc searches for relevant literature were performed at later stages of review development. Multiple randomized, placebo-controlled studies have demonstrated that lormetazepam dose-dependently increases total sleep time, decreases wakefulness over a dosing range of 0.5–2.0 mg, and improves subjective assessments of sleep quality. Lormetazepam is as effective as other benzodiazepines in improving sleep duration and quality, but is better tolerated than the long-acting agents with minimal next-day effects. Benzodiazepines can be used as short-term monotherapy at the lowest effective dose during the second or third trimesters of pregnancy; lormetazepam is also a reasonable choice due to its limited transplacental passage. Insomnia associated with skin disorders or pregnancy can be managed by effective symptom control (especially itching), sleep hygiene, treatment of anxiety/depression, and a short course of hypnotics.
Tumor Agnostic Drug Delivery with Self-Agglomerating Nanohydrogels (SANGs)
Authors: Housley Stephen N. , Lee Sebinne , Matyunina Lilya V. , Herrmann Olivia A. , Satpathy Minati , Arboleda Johana C. , McDonald John F. , Finn M.G.
Published: January 2024

RNA interference (RNAi) holds unique potential as a clinically viable modality to pharmacologically regulate oncogenes in sequence-specific manner. Despite its potential, systemic delivery of RNAi to tumors encounters myriad obstructions and strategies to overcome barriers have largely consisted of academic demonstrations, with few approaches reaching patients. Here, we report the development of a self-agglomerating nanohydrogel (SANGs) platform that is efficiently internalized by cancer cells, is agnostic to RNAi payload, and achieves functional suppression of multiple oncogene targets. After intravenous injection, SANGs preferentially accumulated and were retained ubiquitously in primary and metastatic loci in three aggressive cancer models in a species-agnostic manner. SANGs efficiently delivered multiple RNAi payloads that significantly suppressed oncogene expression and sensitized previously resistance tumorsin vivo. SANGs were found to be safe and well tolerated in simulated clinical applications across three species. We then propose and verify a novel emergent mechanism by which SANGs achieve durable solid-tumor delivery without direct functionalization. Overall, our SANGs platform is an enabling technology for RNAi-based cancer therapeutics and is poised for advanced pharmaceutical development with multiple solid-tumor indications.

One-Sentence Summary

Our nanostructure achieves safe and durable tumor-agnostic delivery through a newly described environmentally-responsive mechanism.
Activity-driven chromatin organization during interphase: compaction, segregation, and entanglement suppression
Authors: Chan Brian , Rubinstein Michael
Published: January 2024

In mammalian cells, the cohesin protein complex is believed to translocate along chromatin during interphase to form dynamic loops through a process called active loop extrusion. Chromosome conformation capture and imaging experiments have suggested that chromatin adopts a compact structure with limited interpenetration between chromosomes and between chromosomal sections. We developed a theory demonstrating that active loop extrusion causes the apparent fractal dimension of chromatin to cross over between two and four at contour lengths on the order of 30 kilo-base pairs (kbp). The anomalously high fractal dimensionD= 4 is due to the inability of extruded loops to fully relax during active extrusion. Compaction on longer contour length scales extends within topologically associated domains (TADs), facilitating gene regulation by distal elements. Extrusion-induced compaction segregates TADs such that overlaps between TADs are reduced to less than 35% and increases the entanglement strand of chromatin by up to a factor of 50 to several Mega-base pairs. Furthermore, active loop extrusion couples cohesin motion to chromatin conformations formed by previously extruding cohesins and causes the mean square displacement of chromatin loci during lag times (Δt) longer than tens of minutes to be proportional to Δt1/3. We validate our results with hybrid molecular dynamics – Monte Carlo simulations and show that our theory is consistent with experimental data. This work provides a theoretical basis for the compact organization of interphase chromatin, explaining the physical reason for TAD segregation and suppression of chromatin entanglements which contribute to efficient gene regulation.

SIGNIFICANCE STATEMENT

During interphase, cells must compact chromatin such that gene promoters and their regulatory elements frequently contact each other in space. However, cells also need to insulate promoters from regulatory elements in other genomic sections. Using polymer physics theory and computer simulations, we propose that the cohesin protein complex actively extrudes chromatin into topologically associated domains (TADs) with an anomalously high fractal dimension ofD≈ 4 while suppressing spatial overlap between different TADs. Our model suggests that the fast kinetics of active loop extrusion compared to the slow relaxation of chromatin loops maintains a dense chromatin organization. This work presents a physical framework explaining how cohesin contributes to effective transcriptional regulation.
LeucaenaandAcaialeaf litter negatively affect the survivorship of tadpoles of the South Asian frogMicrohyla ornata
Authors: Pathak-Broome Aranya , Gour-Broome Vivek , Mukherjee Shomen
Published: January 2024

Leaf litter from terrestrial plants forms an essential source of organic food matter for many freshwater aquatic organisms. However, leaves of some species are known to alter water quality, affecting the development and survivorship of amphibians. While amphibians from North and South America are affected by terrestrial leaf litter, similar studies are missing from Asia, a region with high amphibian diversity (mainly from the south and south-east Asia). At different tadpole densities, we tested the effect of different leaf litter (two non-native trees and a grass species) on the survivorship of ornate narrow-mouthed frog tadpoles (Microhyla ornata), a common frog in South Asia. We found the tadpole probability of survival extremely low inLeucaenabut high inThemeda. While the odds of survivorship were nearly twelvefold higher inAcaciathanLeucaena, it was not as high as inThemeda. A tadpole also had a lower odds of survival if raised in a high-density environment. In addition,Leucaenalitter water had significantly higher pH levels than other litter types. Since bothLeucaenaandAcaciaare non-native trees actively grown for agroforestry in South Asia, our results highlight another potential threat to amphibians in this region. Given the high amphibian diversity in this region, there is an urgent need for similar studies on other anurans and aquatic organisms.
Experts fail to reliably detect AI-generated histological data
Authors: Hartung Jan , Reuter Stefanie , Kulow Vera Anna , Fähling Michael , Spreckelsen Cord , Mrowka Ralf
Published: January 2024

AI-based methods to generate images have seen unprecedented advances in recent years challenging both image forensic and human perceptual capabilities. Accordingly, they are expected to play an increasingly important role in the fraudulent fabrication of data. This includes images with complicated intrinsic structures like histological tissue samples, which are harder to forge manually. We use stable diffusion, one of the most recent generative algorithms, to create such a set of artificial histological samples and in a large study with over 800 participants, we study the ability of human subjects to discriminate between such artificial and genuine histological images. Although they perform better than naive participants, we find that even experts fail to reliably identify fabricated data. While participant performance depends on the amount of training data used, even low quantities result in convincing images, necessitating methods to detect fabricated data and technical standards such as C2PA to secure data integrity.
XKidneyOnco: An Explainable Framework to Classify Renal Oncocytoma and Chromophobe Renal Cell Carcinoma with a Small Sample Size
Authors: Javaheri Tahereh , Heidari Samar , Yang Xu , Yerra Sandeep , Seidi Khaled , Gharib Mohammad Hadi , Setayesh Tahereh , Zhang Guanglan , Chitkushev Lou , Castro Patricia , Salar Sayeeduddin Shahida , Sayeeduddin Zahida , Zarrin-Khameh Neda , Haeri Mohammad , Rawassizadeh Reza
Published: January 2024

Renal oncocytoma and chromophobe renal cell carcinoma are two kidney cancer types that present a diagnostic challenge to pathologists and other clinicians due to their microscopic similarities. While RO is a benign renal neoplasm, ChRCC is considered malignant. Therefore, the differentiation between the two is crucial. In this study, we introduce an explainable framework to accurately differentiate ChRCC from RO, histologically. Our approach examined H&E-stained images of 656 ChRCC and 720 RO, and achieved a diagnostic accuracy of 88.2%, the sensitivity of 87%, and 100% specificity for explainable AI, which either outperforms or operate on par with convolutional neural network (CNN) models.

Besides, we enrolled 44 pathology experts (including pathologists and pathology trainees) to differentiate the two tumors. The average accuracy of pathologists was 73%, which is 15.2% lower than our framework.

These results indicate that the combination of human expert along with explainable AI achieve higher accuracy in differentiating the two tumors, while it reduces the workload of experts and offers the desired explainability for the medical experts.
Prognostic Significance of preoperative serum CA125, CA19-9, CA72-4, CEA, and AFP in Patients with Endometrial cancer
Authors: Wang Zi-hao , Zhang Yun-zheng , Ge Shu-wen , Luhe-Shan  , Wang Bo , Zhang Zi-yu , Wu Qi-jun , Ma Xiao-xin
Published: January 2024

Objective

To determine preoperative serum CA125, CA19-9, CA72-4, CEA, and AFP with prognostic value, and to establish a risk score based on CA125, CEA, AFP levels for predicting the overall survival (OS) and progression-free survival (PFS) of endometrial cancer (EC) patients.

Methods

A retrospective cohort study with 2081 EC patients was conducted at Shengjing Hospital of China Medical University. Patient baseline information, tumor characteristics, and data on five serum biomarkers (CA125, CA19-9, CA72-4, CEA, and AFP) were collected. Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined using univariate or multivariate Cox proportional hazard models. log-rank test and Kaplan-Meier analysis were used to compared survival, Data were randomly divided into a training cohort (50%, N = 1041) and an external validation cohort (50%, n = 1040). the least absolute shrinkage and selection operator (Lasso)-Cox regression model was used to screen the independent factors for establishing risk score. And develop nomograms for survival rate prediction.

Results

Multivariate analysis showed Elevated CA125 (P<0.0001) AFP (P <0.0001) and CEA(P=0.037) were identified as independent biomarkers for PFS. Increased CA125 (P = 0.003) AFP (P <0.0001) and CEA(P=0.014) were independent factors associated with OS. CA125, AFP and CEA were thus incorporated in an innovative Risk score (RS) by Lasso-Cox regression model, The RS was also an independent indicator for PFS (P<0.0001) and OS (P<0.0001). Furthermore, we developed and validated nomogram based on Cox regression models. The discriminative ability and calibration of the nomograms revealed good predictive ability, as indicated by the calibration plots.

Conclusion

This study suggests that the risk score based on preoperative serum levels of CA125, CEA, and AFP was prognostic biomarkers for predicting progression-free survival and overall survival for EC patients. Nomograms based on the RS and clinicopathological features accurately predict Prognosis of EC patients.
Methods to study xenografted human cancer in genetically diverse mice
Authors: Hasham Muneer G. , Sargent Jennifer K. , Warner Mark A. , Farley Shawnna R. , Hoffmann Brian R. , Stodola Timothy J. , Brunton Catherine J. , Munger Steven C.
Published: January 2024

Xenografting human cancer tissues into mice to test new cures against cancers is critical for understanding and treating the disease. However, only a few inbred strains of mice are used to study cancers, and derivatives of mainly one strain, mostly NOD/ShiLtJ, are used for therapy efficacy studies. As it has been demonstrated when human cancer cell lines or patient-derived tissues (PDX) are xenografted into mice, the neoplastic cells are human but the supporting cells that comprise the tumor (the stroma) are from the mouse. Therefore, results of studies of xenografted tissues are influenced by the host strain. We previously published that when the same neoplastic cells are xenografted into different mouse strains, the pattern of tumor growth, histology of the tumor, number of immune cells infiltrating the tumor, and types of circulating cytokines differ depending on the strain. Therefore, to better comprehend the behavior of cancerin vivo, one must xenograft multiple mouse strains. Here we describe and report a series of methods that we used to reveal the genes and proteins expressed when the same cancer cell line, MDA-MB-231, is xenografted in different hosts. First, using proteomic analysis, we show how to use the same cell linein vivoto reveal the protein changes in the neoplastic cell that help it adapt to its host. Then, we show how different hosts respond molecularly to the same cell line. We also find that using multiple strains can reveal a more suitable host than those traditionally used for a “difficult to xenograft” PDX. In addition, using complex trait genetics, we illustrate a feasible method for uncovering the alleles of the host that support tumor growth. Finally, we demonstrate that Diversity Outbred mice, the epitome of a model of mouse-strain genetic diversity, can be xenografted with human cell lines or PDX using 2-deoxy-D-glucose treatment.
A reduced vernalization requirement is a key component of the early-bolting trait in globe artichoke (Cynara cardunculusvar.scolymus)
Authors: Berentsen Rick , Benlloch Reyes , Visser Peter , Madueño Francisco , Balanzà Vicente
Published: January 2024

Early-bolting is a major breeding objective for globe artichoke (Cynara cardunculusvar.scolymusL.). It has been suggested that globe artichoke bolting time is linked to a vernalization requirement, although environmental conditions under which vernalized plants and controls have been grown may not always allow for proper comparison. Here, we defined morphological markers to monitor the vegetative-to- reproductive phase transition at the shoot apex and linked these to expression changes of homologues of key Arabidopsis flowering regulatorsSOC1,FUL, andAP1. Importantly, we developed an experimental setup where control and vernalized plants grow under comparable conditions. These tools together allowed for comparison of the vegetative-to-reproductive phase transition between early- and late-bolting genotypes and how they respond to vernalization. Our results show that vernalization requirement is significantly lower in early-bolting genotypes, supporting the view that the early-bolting trait is partly underlain by alterations in the network controlling vernalization response.
Regulatory genome annotation of 33 insect species
Authors: Asma Hasiba , Tieke Ellen , Deem Kevin D. , Rahmat Jabale , Dong Tiffany , Huang Xinbo , Tomoyasu Yoshinori , Halfon Marc S.
Published: January 2024

Annotation of newly-sequenced genomes frequently includes genes, but rarely covers important non-coding genomic features such as thecis-regulatory modules—e.g., enhancers and silencers—that regulate gene expression. Here, we begin to remedy this situation by developing a workflow for rapid initial annotation of insect regulatory sequences, and provide a searchable database resource with enhancer predictions for 33 genomes. Using our previously-developed SCRMshaw computational enhancer prediction method, we predict over 2.8 million regulatory sequences along with the tissues where they are expected to be active, in a set of insect species ranging over 360 million years of evolution. Extensive analysis and validation of the data provides several lines of evidence suggesting that we achieve a high true-positive rate for enhancer prediction. One, we show that our predictions target specific loci, rather than random genomic locations. Two, we predict enhancers in orthologous loci across a diverged set of species to a significantly higher degree than random expectation would allow. Three, we demonstrate that our predictions are highly enriched for regions of accessible chromatin. Four, we achieve a validation rate in excess of 70% using in vivo reporter gene assays. As we continue to annotate both new tissues and new species, our regulatory annotation resource will provide a rich source of data for the research community and will have utility for both small-scale (single gene, single species) and large-scale (many genes, many species) studies of gene regulation. In particular, the ability to search for functionally-related regulatory elements in orthologous loci should greatly facilitate studies of enhancer evolution even among distantly related species.
Linking phenotypic and genotypic variation: a relaxed phylogenetic approach using the probabilistic programming language Stan
Authors: Gemmell Patrick
Published: January 2024

PhyloG2P methods link genotype and phenotype by integrating evidence from across a phylogeny. I introduce a Bayesian approach to jointly modelling a continuous trait and a multiple sequence alignment, given a background tree and substitution rate matrix. The aim is to ask whether faster sequence evolution is linked to faster phenotypic evolution. Per-branch substitution rate multipliers (for the alignment) are linked to per-branch variance rates of a Brownian diffusion process (for the trait) via the flexible logistic function. The Brownian diffusion process can evolve on the same tree used to describe the alignment, or on a second tree, for example a tree with branch lengths in units of time. Simulation studies suggest the model can be well estimated using relatively short alignments and reasonably sized trees. An application of the model in both its one-tree and two-tree variants is provided as an example. Notably, the method is implemented concisely using the general-purpose probabilistic programming language Stan.
Declining reservoir elevations following a two-decade drought increase water temperatures and non-native fish passage facilitating a downstream invasion
Authors: Eppehimer D.E. , Yackulic C.B. , Bruckerhoff L.A. , Wang J. , Young K.L. , Bestgen K.R. , Mihalevich B.A. , Schmidt J.C.
Published: January 2024

River ecosystems are threatened by interactions among river regulation, non-native species, and climate change. Water use has exceeded supply for two decades in the USA’s Colorado River basin draining its two largest storage reservoirs (Lake Powell and Lake Mead). In 2022, after more than two decades of declining reservoir levels and warming downstream river water temperatures, Lake Powell began releasing water from its lower epilimnion into the Grand Canyon segment of the Colorado River. While managers were concerned about the risk of non-native, predatory smallmouth bass (Micropterus dolomieu) entrainment and reproduction, they lacked a quantitative tool to understand entrainment rates and population growth potential under different reservoir management strategies. To fill this void, we developed models in spring 2022 that: 1) predicted propagule pressure at different reservoir elevations, and 2) linked reservoir storage/operations, water temperatures, and smallmouth bass population dynamics to forecast population growth rates under different hydrologic and management scenarios. In the summers of 2022 and 2023, smallmouth bass were documented reproducing in the lower Colorado River for the first time. Our models accurately forecasted adult catch of smallmouth bass in 2022 and 2023 and forecasted that reproduction would occur in both years for the first time in the history of this river segment. Above average runoff in 2023 increased reservoir elevations, however the potential for smallmouth bass establishment remains high because of long-term forecasts of reduced reservoir inflows and lake levels significantly below full pool. Maintaining Lake Powell elevations above 1,088 m (3,570 ft) would likely minimize propagule pressure from the reservoir and would likely create downstream conditions that minimize smallmouth bass population growth.