bluuebunny/crossref_metadata_2025 huggingface dataset:
The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities
Authors: Zhang Xingyuan , Joseph Sayali , Wu Di , Bowser Jessica L , Vaziri Cyrus
Published: April 2024

Genome maintenance is an enabling characteristic that allows neoplastic cells to tolerate the inherent stresses of tumorigenesis and evade therapy-induced genotoxicity. Neoplastic cells also deploy many mis-expressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and survival. Here, we present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to conventional histological and molecular subtypes. We show endometrial serous carcinoma (ESC), an aggressive endometrial cancer subtype, is defined by gene expression signatures comprising members of the Replication Fork Protection Complex (RFPC) and Fanconi Anemia (FA) pathway and CTAs with mitotic functions. DDR and CTA-based profiling also defines a subset of highly aggressive endometrioid endometrial carcinomas (EEC) with poor clinical outcomes that share similar profiles to ESC yet have distinct characteristics based on conventional histological and genomic features. Using an unbiased CRISPR-based genetic screen and a candidate gene approach, we confirm that DDR and CTA genes that constitute the ESC and related EEC gene signatures are required for proliferation and therapy-resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and reveals new vulnerabilities of aggressive endometrial cancer where none currently exist.
TDP2 is a regulator of estrogen-responsive oncogene expression
Authors: Manguso Nicholas , Kim Minhyung , Joshi Neeraj , Al Mahmud Md Rasel , Aldaco Juan , Suzuki Ryusuke , Cortes-Ledesma Felipe , Cui Xiaojiang , Yamada Shintaro , Takeda Shunichi , Giuliano Armando , You Sungyong , Tanaka Hisashi
Published: April 2024

With its ligand estrogen, the estrogen receptor (ER) initiates a global transcriptional program, promoting cell growth. This process involves topoisomerase 2 (TOP2), a key protein in resolving topological issues during transcription by cleaving a DNA duplex, passing another duplex through the break, and repairing the break. Recent studies revealed the involvement of various DNA repair proteins in the repair of TOP2-induced breaks, suggesting potential alternative repair pathways in cases where TOP2 is halted after cleavage. However, the contribution of these proteins in ER-induced transcriptional regulation remains unclear. We investigated the role of tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme for the removal of halted TOP2 from the DNA ends, in the estrogen-induced transcriptome using both targeted and global transcription analyses. MYC activation by estrogen, a TOP2-dependent and transient event, became prolonged in the absence of TDP2 in both TDP2-deficient cells and mice. Bulk and single-cell RNA-seq analyses defined MYC and CCND1 as oncogenes whose estrogen response is tightly regulated by TDP2. These results suggest that TDP2 may inherently participate in the repair of estrogen-induced breaks at specific genomic loci, exerting precise control over oncogenic gene expression.
Antifungal Treatment Duration in Hematology Patients With Invasive Mold Infections: A Real-life Update
Authors: Portillo Vera , Ragozzino Silvio , Stavropoulou Elisavet , El-Khoury Celine , Bochud Pierre-Yves , Lamoth Frederic , Khanna Nina , Neofytos Dionysios
Published: April 2024

Background

Limited data exist on when and how to stop antifungal treatment (AFT) in patients with invasive mold infections (IMIs) who are immunocompromised.

Methods

This retrospective multicenter study included adult patients with acute myelogenous leukemia and proven/probable IMI (1 January 2010–31 December 2022) in 3 university hospitals. The primary objective was to describe AFT duration and adaptation. Secondary objectives were to investigate the reasons for AFT adjustments and prolongation.

Results

In total 71 patients with 73 IMIs were identified; 51 (71.8%) had an allogeneic hematopoietic cell transplant. Most infections were invasive aspergillosis (IA; 49/71, 69%), followed by mucormycosis (12, 16.9%) and other (12, 16.9%); there were 2 mixed infections. Median treatment duration was 227 days (IQR, 115.5–348.5). There was no difference in AFT duration between patients with IA and non-IA IMI (P = .85) or by center (P = .92). Treatment was longer in patients with an allogeneic hematopoietic cell transplant vs not (P = .004). Sixteen patients (22.5%) had no therapy modifications. In 55 patients (77.5%), a median 2 changes (IQR, 1–3; range, 1–8) were observed. There were 182 reasons leading to 165 changes, associated with clinical efficacy (82/182, 44.5%), toxicity (47, 25.8%), and logistical reasons (22, 12.1%); no reason was documented in 32 changes (18.8%). AFT was continued beyond days 90 and 180 in 59 (83%) and 39 (54.9%) patients, respectively, mostly due to persistence of immunosuppression.

Conclusions

AFT in patients with acute myelogenous leukemia and IMI is longer than that recommended by guidelines and is frequently associated with treatment adjustments due to variable reasons. More data and better guidance are required to optimize AFT duration and secondary prophylaxis administration according to immunosuppression.
TP53-specific mutations serve as a potential biomarker for homologous recombination deficiency in breast cancer: a clinical next-generation sequencing study
Authors: Huang Yongsheng , Ren Shuwei , Ding Linxiaoxiao , Jiang Yuanling , Luo Jiahuan , Huang Jinghua , Yin Xinke , Zhao Jianli , Fu Sha , Liao Jianwei
Published: April 2024

Background

TP53 mutations and homologous recombination deficiency (HRD) occur frequently in breast cancer. However, the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear.

Methods

Clinical next-generation sequencing (NGS) of both tumor and paired blood DNA from 119 breast cancer patients (BRCA-119 cohort) was performed with a 520-gene panel. Mutations, tumor mutation burden (TMB), and genomic HRD scores were assessed from NGS data. NGS data from 47 breast cancer patients in the HRD test cohort were analyzed for further verification.

Results

All TP53 pathogenic mutations in patients had somatic origin, which was associated with the protein expression of estrogen receptor and progestogen receptor. Compared to patients without TP53 pathologic mutations, patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic alterations. The frequency of TP53 pathologic mutation was higher in the HRD-high group (HRD score ≥ 42) relative to that in the HRD-low group (HRD score < 42). TP53 has different mutational characteristics between the HRD-low and HRD-high groups. TP53-specific mutation subgroups had diverse genomic features and TMB. Notably, TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an area under the curve (AUC) of 0.61. TP53-specific mutations, namely HRD-low mutation, HRD-high mutation, and HRD common mutation, predicted the HRD status of breast cancer patients with AUC values of 0.32, 0.72, and 0.58, respectively. Interestingly, TP53 HRD-high mutation and HRD common mutation combinations showed the highest AUC values (0.80) in predicting HRD status.

Conclusions

TP53-specific mutation combinations predict the HRD status of patients, indicating that TP53 pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase (PARP) inhibitors in breast cancer patients .
The CELL NUMBER REGULATOR FW2.2 protein regulates cell-to-cell communication in tomato by modulating callose deposition at plasmodesmata
Authors: Beauchet Arthur , Bollier Norbert , Grison Magali , Rofidal Valérie , Gévaudant Frédéric , Bayer Emmanuelle , Gonzalez Nathalie , Chevalier Christian
Published: April 2024

FW2.2 (standing for FRUIT WEIGHT 2.2), the founding member of the CELL NUMBER REGULATOR (CNR) gene family, was the first cloned gene underlying a quantitative trait locus (QTL) governing fruit size and weight in tomato (Solanum lycopersicum). However, despite this discovery over 20 yr ago, the molecular mechanisms by which FW2.2 negatively regulates cell division during fruit growth remain undeciphered. In the present study, we confirmed that FW2.2 is a membrane-anchored protein whose N- and C-terminal ends face the apoplast. We unexpectedly found that FW2.2 is located at plasmodesmata (PD). FW2.2 participates in the spatiotemporal regulation of callose deposition at PD and belongs to a protein complex which encompasses callose synthases. These results suggest that FW2.2 has a regulatory role in cell-to-cell communication by modulating PD transport capacity and trafficking of signaling molecules during fruit development.
Democratic Backsliding in the American States: The Case of Judicial Independence
Authors: Leonard Meghan E
Published: April 2024

With ever-increasing gridlock and polarization at the national level, many new policy changes in the United States have come at the state level. This includes legislation that restricts the right to vote, limits free speech and expression, and gerrymanders state legislative and congressional districts. A growing body of literature describes these changes, when taken together, as evidence of subnational democratic backsliding. Yet this literature largely ignores the effects of federalism on the structure of institutions within the states, particularly on judicial independence. In this article, I examine the relationship between measures of democracy and introduction of court-curbing legislation in the states. Focusing on instances of court packing, changing the methods of selection and retention, and impeachment, I show that heightened attacks on judicial independence are associated with other types of democratic backsliding.
Clinical phenotyping in patients with anti-synthetase antibodies using cluster analysis
Authors: Yamamoto Shintaro , Yoshida Akira , Okazaki Yuka , Gono Takahisa , Kuwana Masataka
Published: April 2024

Objectives

To characterize clinically distinct subgroups among unselected patients with anti-synthetase antibodies using cluster analysis.

Methods

This study evaluated patients with anti-synthetase antibodies registered to two independent cohorts; 106 consecutive patients from a prospective, single-centre cohort of the Scleroderma/Myositis Centre of Excellence (SMCE) were used as a derivation cohort and 125 patients from the Multicentre Retrospective Cohort of Japanese Patients with Myositis-Associated Interstitial Lung Disease (JAMI) were used as a validation cohort. Anti-synthetase antibodies were identified by RNA immunoprecipitation. A multiple correspondence analysis followed by hierarchical clustering was performed to aggregate the patients into homogeneous subgroups. Subsequently, a simple-to-use classification tree was generated using classification and regression tree analysis.

Results

Three clusters were identified in the SMCE cohort: cluster 1 (n = 48), the interstitial pneumonia with autoimmune features/amyopathic dermatomyositis cluster, associated with older age at diagnosis and a higher frequency of malignancy; cluster 2 (n = 46), the DM cluster, corresponded to a younger age at diagnosis with a higher prevalence of myositis, arthritis, DM pathognomonic rashes, mechanic’s hands and fever; and cluster 3 (n = 12), the SSc cluster, characterized by chronic interstitial lung disease. There was no significant difference in overall survival or progression-free survival between the clusters. A simple classification tree using myositis and RP was created in the SMCE cohort. Clusters 1 and 2 were successfully reproduced and the classification tree demonstrated favourable performance in the JAMI cohort.

Conclusion

Patients with anti-synthetase antibodies were classified into three distinct phenotypes, indicating substantial heterogeneity within this patient group.
A systematic review on the effects of non-pharmacological interventions for fatigue among people with upper and/or lower limb osteoarthritis
Authors: Fawole Henrietta O , Idowu Opeyemi A , Osadiaye Osaretin A , Akinrolie Olayinka , Ibekaku Michael , Ojo Mayowa , Kolawole Francis O , Adandom Israel I , Oyeyemi Adewale L , Useh Ushotanefe , Riskowski Jody
Published: April 2024

Objectives

To identify non-pharmacological fatigue interventions and determine the effectiveness of these non-pharmacological interventions in reducing fatigue immediately and over time in OA.

Methods

A review protocol (CRD42020163730) was developed and registered with the PROSPERO database. Included studies comprised peer-reviewed randomized controlled trials (RCTs) that examined the effects of conservative interventions on fatigue in people with upper and lower limb OA. Cochrane Collaboration’s tool for assessing the risk of bias (ROB-2) was used to assess the quality of evidence of studies. Narrative synthesis was used to summarize the effectiveness of identified fatigue interventions.

Results

Out of 2644 citations identified from databases, 32 reports were included after screening for titles, abstracts and full texts. Of these reports, 30 parallel RCTs, one cluster and one cross-over RCT were included. 13 RCTs were of low ROB, 6 had some concerns and 13 had high ROB. The narrative synthesis identified interventions for fatigue including exercise, activity pacing, cognitive behavioural therapy, telerehabilitation and complementary alternative therapies. Exercise interventions showed the most significant beneficial effects on fatigue.

Conclusions

Diverse interventions for fatigue management among individuals with upper and lower limb OA were identified. Of these, exercise interventions appear to be the most promising with the majority of these interventions favouring fatigue improvement. While cognitive behavioural therapy has limited evidence of beneficial effects, there is insufficient evidence regarding the effectiveness of other identified interventions, including complementary and alternative therapies, and telerehabilitation.
A practical guide to EEG hyperscanning in joint action research: from motivation to implementation
Authors: Zamm Anna , Loehr Janeen D , Vesper Cordula , Konvalinka Ivana , Kappel Simon L , Heggli Ole A , Vuust Peter , Keller Peter E
Published: April 2024

Developments in cognitive neuroscience have led to the emergence of hyperscanning, the simultaneous measurement of brain activity from multiple people. Hyperscanning is useful for investigating social cognition, including joint action, because of its ability to capture neural processes that occur within and between people as they coordinate actions toward a shared goal. Here, we provide a practical guide for researchers considering using hyperscanning to study joint action and seeking to avoid frequently raised concerns from hyperscanning skeptics. We focus specifically on Electroencephalography (EEG) hyperscanning, which is widely available and optimally suited for capturing fine-grained temporal dynamics of action coordination. Our guidelines cover questions that are likely to arise when planning a hyperscanning project, ranging from whether hyperscanning is appropriate for answering one’s research questions to considerations for study design, dependent variable selection, data analysis and visualization. By following clear guidelines that facilitate careful consideration of the theoretical implications of research design choices and other methodological decisions, joint action researchers can mitigate interpretability issues and maximize the benefits of hyperscanning paradigms.
A Rapid, Equipment-Free Method for Detecting Avirulence Genes of Pyricularia oryzae Using a Lateral Flow Strip-Based RPA Assay
Authors: Qi Zhongqiang , Ju Fangyi , Guo Yunxia , Du Yan , Yu Junjie , Zhang Rongsheng , Yu Mina , Cao Huijuan , Song Tianqiao , Pan Xiayan , Dai Tingting , Liu Yongfeng
Published: April 2024

Rice blast, caused by Pyricularia oryzae, is one of the most destructive rice diseases worldwide. Using resistant rice varieties is the most cost-effective way to control rice blast. Consequently, it is critical to monitor the distribution frequency of avirulence (Avr) genes in rice planting fields to facilitate the breeding of resistant rice varieties. In this study, we established a rapid recombinase polymerase amplification–lateral flow dipstick (RPA-LFD) detection system for the identification of AvrPik, Avr-Piz-t, and Avr-Pi9. The optimized reaction temperature and duration were 37°C and 20 min, indicating that the reaction system could be initiated by body temperature without relying on any precision instruments. Specificity analysis showed that the primer and probe combinations targeting the three Avr genes exhibited a remarkable specificity at genus-level detection. Under the optimized condition, the lower detected thresholds of AvrPik, Avr-Piz-t, and Avr-Pi9 were 10 fg/μl, 100 fg/μl, and 10 pg/μl, respectively. Notably, the detection sensitivity of the three Avr genes was much higher than that of PCR. In addition, we also successfully detected the presence of AvrPik, Avr-Piz-t, and Avr-Pi9 in the leaf and panicle blast lesions with the RPA-LFD detection system. In particular, the genomic DNA was extracted using the simpler PEG-NaOH rapid extraction method. In summary, we developed an RPA detection system for AvrPik, Avr-Pi9, and Avr-Piz-t, combined with the PEG-NaOH rapid DNA extraction method. The innovative approach achieved rapid, real-time, and accurate detection of the three Avr genes in the field, which is helpful to understand the distribution frequency of the three Avr genes in the field and provide theoretical reference for the scientific layout of resistant rice varieties.
A New Look at Resilience in Nursing Students: Stress, Social Media, and Student Athletes
Authors: Keating Sharon R. , Fairbanks Clarisse
Published: April 2024

Resilience in nursing students is important for academic and practice success and a necessary subcompetency in the American Association of Colleges of Nursing 2021 Essentials. This study examined levels of resilience and identified related factors in prelicensure nursing students. Data were collected via an online survey that included a descriptive questionnaire with resilience and stress scales. Significant findings include negative relationships between resilience and stress, and resilience and social media use; positive relationships between stress and social media use, specifically TikTok use; and high resilience levels in student athletes. Specific implications for nursing education and future research are discussed.
Nonmedical Use of Stimulants Among Students in Jordan: A Nationwide Study
Authors: Abdulfattah Sadan , Ahmad Ahmad R. , Kitaneh Razi , Alsharaydeh Toqa , Almudallal Farah , Alzoubi Raha , Abbadi Rama , Haddad Tala A. , Wazaify Mayyada , Alkayed Zaid , Bani Mustafa Radwan , Tetrault Jeanette M.
Published: April 2024

Objectives

Nonmedical use (NMU) of stimulants is an increasingly common phenomenon worldwide. Motivated by enhancing academic performance, peer pressure, and seeking pleasure, students in the Middle East are thought to be a high-risk population. This is especially important in times when the political instability in the region facilitates the production and trafficking of such substances. This study aimed to unveil the burden of NMU of stimulants and examine associated correlates among senior high school and university students in Jordan.

Methods

We describe a cross-sectional study of senior high school and university students in Jordan assessing NMU of stimulants. Data were collected between January and April of 2022 through a survey, which was distributed online leading to a google forms page. The survey queried sociodemographic characteristics, history of NMU of stimulants, use of other illicit substances, attitudes toward NMU of stimulants, as well as a mental health assessment.

Results

A total of 8739 students completed the survey (mean age of 20.40 ± 2.45 years), of which 5.1% reported a lifetime NMU of stimulants. Fenethylline (Captagon) was the most widely reported stimulant (2.6%). Living in the southern region, being diagnosed with a personality disorder, and using concomitant illicit substances were associated with the NMU of stimulants.

Conclusions

The NMU of CNS stimulants, especially fenethylline, is prevalent in Jordan. More surveillance ought to be heeded toward the southern borders of Jordan. Students who use stimulants for academic reasons must be made aware of the potential consequences of the NMU of stimulants.
A Prospective Comparison of 180 Versus 360-Degree Gonioscopy-Assisted Transluminal Trabeculotomy Outcomes in Pseudoexfoliation Glaucoma
Authors: Gunay Murat , Cigiltepe Irem Berfu , Turk Adem , Uzlu Dilek , Kose Busra
Published: April 2024

Précis:

Analysis of surgical success and intraocular pressure (IOP), best-corrected visual acuity (BCVA), and antiglaucomatous medication (AGM) changes between segmental 180-degree and 360-degree gonioscopy-assisted transluminal trabeculectomy (GATT) in patients with pseudoexfoliation glaucoma (PEXG) showed no significant difference.

Objective:

To compare surgical outcomes of segmental 180-degree and 360-degree GATT in patients with PEXG.

Materials and Methods:

Prospective, comparative study of 65 PEXG eyes, who underwent segmental 180-degree GATT (GATT 180-degree group, 31 eyes) and 360-degree GATT (GATT 360-degree group, 34 eyes) in a tertiary academic center over a 12-month of follow-up. Primary outcome was qualified and complete surgical success rates for criterion A (IOP <18 mm Hg and >30% reduction) and criterion B (IOP <15 mm Hg and >30% reduction). Secondary outcome measures included IOP reduction, BCVA change, AGM use, and postoperative complications.

Results:

The probabilities of qualified and complete success rates both for criteria A and B did not significantly differ between the groups (P > 0.05). IOP and BCVA levels were similar at each time point (P > 0.05). IOP reduction was 59.3 ± 9.5% in the GATT 180-degree group and 55.8 ± 18.1% in the GATT 360-degree group (P = 0.33). No significant difference in the mean number of AGM was present at the 12-month visit (1.2 ± 1.1 in GATT 180-degree group vs 1.5 ± 1.2 in GATT 360-degree group, P = 0.25). Significantly higher incidences of postoperative hyphema and IOP spikes were observed in the GATT 360-degree group (P = 0.01 and P = 0.008, respectively).

Conclusion:

Both segmental 180-degree and 360-degree GATT similarly reduced IOP and AGM with comparable surgical success rates in patients with PEXG at the end of 12 months. Postoperative hyphema and IOP spike rates were significantly higher after 360-degree GATT. Segmental 180-degree GATT may be sufficient to adequately modulate IOP with a lower incidence of postoperative complications in PEXG.
Ultrasound for fillers: a preprocedural and postprocedural tool
Authors: Zhou Christina , Watts Andrew , Kong Wendy , Chang Jennifer , Wortsman Ximena , Staggert Madison , Pyles Clare , Bafuma Patrick
Published: April 2024

Ultrasound is a powerful imaging modality that assesses vascular and musculoskeletal structures. In the context of filler application, live visualization with ultrasound can be utilized pre and postprocedurally to evaluate critical anatomic points, detect filler remnants, mitigate vaso-occlusive crises, and guide corrective therapies. As ultrasound utilization gains traction in aesthetic dermatology, this article aims to increase knowledge of how injectors can benefit from this evaluation tool.
Steady Flow Left Ventricle Unloading Is Superior to Pulsatile Pressure Augmentation Venting During Venoarterial Extracorporeal Membrane Oxygenation Support
Authors: Goffer Efrat M. , Lamberti Kimberly K. , Spognardi Anna-Maria , Edelman Elazer R. , Keller Steven P.
Published: April 2024

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) shunts venous blood to the systemic arterial circulation to provide end-organ perfusion while increasing afterload that may impede left ventricle (LV) ejection and impair cardiac recovery. To maintain flow across the aortic valve and reduce risk of lethal clot formation, secondary mechanical circulatory support (MCS) devices are increasingly used despite limited understanding of their effects on cardiac function. This study sought to quantify the effects of VA-ECMO and combined with either intraaortic balloon pump (IABP) or percutaneous ventricular assist device (pVAD) on LV physiologic state and perfusion metrics in a porcine model of acute cardiogenic shock. Shock was induced through serial left anterior descending artery microbead embolization followed by initiation of VA-ECMO support and then placement of either IABP or pVAD. Hemodynamic measurements, LV pressure-volume loops, and carotid artery blood flow were evaluated before and after institution of combined MCS. The IABP decreased LV end-diastolic pressure by a peak of 15% while slightly increasing LV stroke work compared with decreases of more than 60% and 50% with the pVAD, respectively. The pVAD also demonstrated increased coronary perfusion and systemic pressure gradients in comparison to the IABP. Combined support with VA-ECMO and pVAD improves cardiovascular state in comparison to IABP.
Sex-Related Differences in Utilization and Outcomes of Extracorporeal Cardio-Pulmonary Resuscitation for Refractory Cardiac Arrest
Authors: Balucani Clotilde , Canner Joseph K. , Tonna Joseph E. , Dalton Heidi , Bianchi Riccardo , Al-Kawaz Mais N.G. , Choi Chun Woo , Etchill Eric , Kim Bo Soo , Whitman Glenn J. , Cho Sung-Min
Published: April 2024

Sparse data exist on sex-related differences in extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest (rCA). We explored the role of sex on the utilization and outcomes of ECPR for rCA by retrospective analysis of the Extracorporeal Life Support Organization (ELSO) International Registry. The primary outcome was in-hospital mortality. Exploratory outcomes were discharge disposition and occurrence of any specific extracorporeal membrane oxygenation (ECMO) complications. From 1992 to 2020, a total of 7,460 adults with ECPR were identified: 30.5% women; 69.5% men; 55.9% Whites, 23.7% Asians, 8.9% Blacks, and 3.8% Hispanics. Women’s age was 50.4 ± 16.9 years (mean ± standard deviation) and men’s 54.7 ± 14.1 (p < 0.001). Ischemic heart disease occurred in 14.6% women vs. 18.5% men (p < 0.001). Overall, 28.5% survived at discharge, 30% women vs. 27.8% men (p = 0.138). In the adjusted analysis, sex was not associated with in-hospital mortality (odds ratio [OR] = 0.93 [confidence interval {CI} = 0.80–1.08]; p = 0.374). Female sex was associated with decreased odds of neurologic, cardiovascular, and renal complications. Despite being younger and having fewer complications during ECMO, women had in-hospital mortality similar to men. Whether these findings are driven by biologic factors or disparities in health care warrants further investigation.
Is there a role for metastasis-directed therapy in bladder cancer?
Authors: Abufaraj Mohammad , Al Karmi Joud , Bdeir Adan
Published: April 2024

Purpose of review

This article aims to comprehensively review and critique the existing literature on the role of metastatic-directed therapy in patients with metastatic bladder cancer, particularly in oligometastatic disease state.

Recent findings

The role of metastasectomy in metastatic bladder cancer is still controversial. Several studies have demonstrated improved outcomes, particularly in a highly selected patients with small metastatic lesions or with lung or brain metastases, whereas others show no significant survival benefit. Combining metastasectomy with systemic therapies, such as immunotherapy and chemotherapy, has also shown benefits. Metastasis-directed radiotherapy is evolving as a potentially effective approach with minimal toxicity in achieving local control and improving survival, particularly in patients with oligometastatic disease. The evidence regarding the impact of several factors such as performance status, metastatic burden, and the presence of visceral metastases on outcomes is mixed. Concurrent treatment with systemic therapy may potentiate the effectiveness of metastasis-directed therapy.

In patients with metastatic deposits amenable to surgical resection, metastasectomy stands as a promising avenue. Metastatic-directed radiotherapy has demonstrated local control and improved survival in the evolving landscape of oligometastatic bladder cancer management. Further, well designed multicenter prospective studies are needed to support these findings and better understand the synergy between radiotherapy and systemic treatments, especially immunotherapy.
Role of cytoreductive radical prostatectomy in men with oligometastatic prostate cancer on molecular imaging
Authors: Robesti Daniele , Gallina Andrea , Montorsi Francesco , Briganti Alberto , Fossati Nicola
Published: April 2024

Purpose of review

The implementation of PET with prostate-specific membrane antigen (PSMA) tracer as primary staging tool occurred recently. Since its introduction, a novel category of patients emerged, with negative staging at conventional imaging, and positive molecular imaging. Local treatment in these patients might be associated with improved oncological outcomes when combined with systemic therapy. However, its impact on oligometastatic prostate cancer (omPCa) remains unknown. In this review, we aimed at investigating the role of cytoreductive radical prostatectomy (cRP) in oligometastatic disease at molecular imaging.

Recent findings

After comprehensive review of literature, two retrospective studies highlighted the feasibility, safety, and potential benefits of surgery in omPCA patients at molecular imaging. They showed that 72% of patients achieved PSA less than 0.01 ng/ml following cRP as part of a multimodal approach, 17% experienced radiographic progression, and 7% died at 27-month median follow-up. Moreover, complications postcRP after PSMA PET were modest, with a 40% rate of any adverse event, and 5% of grade more than 3. The 1-year urinary continence after cRP rate was 82%. The oncological, functional outcomes and the complication rate aligned with those observed in series of cRP after conventional imaging.

cRP is feasible, well tolerated, and effective in selected patients with omPCa at PSMA PET.
Predictors of Clinically Important Neuroimaging Findings in Children Presenting Pediatric Emergency Department
Authors: Gungor Emre , Haliloglu Goknur , Yalnizoglu Dilek , Oguz Kader Karli , Teksam Ozlem
Published: April 2024

Objective

The aim of the study is to evaluate predictors of clinically important neuroimaging results, that is, computed tomography and magnetic resonance imaging in children in an academic pediatric emergency department (PED) from 2015 to 2019.

Methods

This study was conducted in an academic PED. The patient's demographic and clinical characteristics of PED visits and neuroimaging findings requested at the PED were recorded for January 1, 2015, to December 31, 2019. In addition, descriptive statistics and logistic regression analyses were conducted. We described and determined the predictors of clinically important neuroimaging findings in children.

Results

Clinically important neuroimaging findings were detected in patients with blurred vision (P = 0.001), ataxia (P = 0.003), unilateral weakness (P = 0.004), and altered level of consciousness (P = 0.026). Clinically important neuroimaging was found 9.4 times higher in patients with altered level of consciousness, 7.4 times higher in patients with focal weakness, 4.6 times higher in patients with blurred vision, and 3.5 times more in patients presenting with ataxia.

Conclusions

Advanced neuroimaging, especially for selected patients in PED, can improve the quality of health care for patients. On the other hand, irrelevant neuroimaging findings can lead physicians away from prompt diagnosis and accurate management. According to our study, advanced neuroimaging can be performed in the early period for both diagnosis and early treatment, especially in selected patients with ataxia, blurred vision, altered consciousness, and unilateral weakness. In other cases, clinicians may find more supporting evidence.
Do Sleep Problems Exacerbate the Mental Health Consequences of Discrimination Among Adults?
Authors: Fuller-Rowell Thomas E. , Zeringue Megan M. , Saini Ekjyot K. , Yip Tiffany , El-Sheikh Mona
Published: April 2024

Objective

An emerging literature suggests that sleep may play an important role in moderating the association between discrimination and mental health problems among adolescents. However, few if any studies have considered this topic among adults. Addressing this knowledge gap, the current study examined multiple sleep parameters as moderating variables in the association between discrimination and mental health problems among adults.

Methods

Participants were 874 adults residing in small towns and semirural contexts within the Southeastern region of the United States (M
age = 41 years, SD = 7; 57% female; 31% Black, 69% White; 52% income-to-needs < 2). Sleep duration and night-to-night variability in duration were assessed using wrist actigraphy. Established self-report measures were used to assess global sleep problems, experiences of discrimination, and mental health problems (anxiety, depression, and externalizing symptoms).

Results

Experiences of discrimination were associated with more depression, anxiety, and externalizing problems. Two out of three sleep parameters were found to moderate the effects of discrimination on mental health. The association between discrimination and externalizing problems (but not anxiety or depression) was attenuated among those with less night-to-night variability in sleep duration. The associations between discrimination and anxiety and externalizing problems (but not depression) were attenuated among those with fewer global sleep problems. Less variability in sleep duration and fewer global sleep problems were also directly associated with lower levels of depression, anxiety, and externalizing problems.

Conclusions

Greater consistency in sleep duration from night-to-night, and fewer overall sleep problems appear to mitigate risk of mental health problems among adults, particularly in contexts where discrimination is prevalent.
18F-MFBG PET/CT and MRI in Identifying Brain Metastases in a Posttreatment Neuroblastoma Patient
Authors: Wang Peipei , Li Tuo , Zhuang Hongming , Li Fang , Jing Hongli
Published: April 2024

A 7-year-old girl with known brain metastasis from neuroblastoma developed new onset of severe headache. A brain MRI confirmed known metastasis in the right frontal lobe of the brain without new abnormalities. The patient was enrolled in a clinical trial using 18F-MFBG PET/CT to evaluate patients with neuroblastoma. The images confirmed abnormal activity in the known lesion in the right frontal lobe. In addition, the PET showed additional foci of abnormal activity in the left cerebellopontine region. A follow-up brain MRI study acquired 4 months later revealed abnormal signals in the same region.
A Customizable Digital Cognitive Aid for Neonatal Resuscitation
Authors: Benguigui Laurie , Le Gouzouguec Solène , Balanca Baptiste , Ristovski Maud , Putet Guy , Butin Marine , Guillois Bernard , Beissel Anne
Published: April 2024

Objective

Adherence to the International Liaison Committee on Resuscitation (ILCOR) algorithm optimizes the initial management of critically ill neonates. In this randomized controlled trial, we assessed the impact of a customizable sequential digital cognitive aid (DCA), adapted from the 2020 ILCOR recommendations, compared with a poster cognitive aid (standard of care [SOC]), on technical and nontechnical performance of junior trainees during a simulated critical neonatal event at birth.

Methods

For this prospective, bicentric video-recorded study, students were recruited on a voluntary basis, and randomized into groups of 3 composed of a pediatric resident and two midwife students. They encountered a simulated cardiac arrest at birth either (1) with DCA use and ILCOR algorithm poster displayed on the wall (intervention group) or (2) with sole ILCOR algorithm poster (poster cognitive aid [SOC]). Technical and nontechnical skills (NTS) between the two groups were assessed using a standardized scoring of videotaped performances. A neonate specific NTS score was created from the adult Team score.

Results

108 students (36 groups of three) attended the study, 20 groups of 3 in the intervention group and 16 groups of 3 in the poster cognitive aid (SOC) group. The intervention group showed a significant improvement in the technical score (P < 0.001) with an average of 24/27 points (24.0 [23.5–25.0]) versus 20.8/27 (20.8 [19.9–22.5]) in poster cognitive aid (SOC) group. No nontechnical score difference was observed. Feedback on the application was positive.

Conclusions

During a simulated critical neonatal event, use of a DCA was associated with higher technical scores in junior trainees, compared with the sole use of ILCOR poster algorithm.
Early Immunomodulatory Program Triggered by Protolerogenic Bifidobacterium pseudolongum Drives Cardiac Transplant Outcomes
Authors: Gavzy Samuel J. , Kensiski Allison , Saxena Vikas , Lakhan Ram , Hittle Lauren , Wu Long , Iyyathurai Jegan , Dhakal Hima , Lee Zachariah L. , Li Lushen , Lee Young S. , Zhang Tianshu , Lwin Hnin Wai , Shirkey Marina W. , Paluskievicz Christina M. , Piao Wenji , Mongodin Emmanuel F. , Ma Bing , Bromberg Jonathan S.
Published: April 2024

Background.

Despite ongoing improvements to regimens preventing allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes.

Methods.

In this study, we further detailed the multifaceted immunomodulatory properties of protolerogenic and proinflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation.

Results.

In addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed that Bifidobacterium pseudolongum induced an early anti-inflammatory phenotype within 7 d, whereas Desulfovibrio desulfuricans resulted in a proinflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed, in vitro results showed that B pseudolongum and D desulfuricans acted directly on primary innate immune cells. However, by 40 d after treatment, these 2 bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation with B pseudolongum treatment.

Conclusions.

These dynamic effects suggest a critical role for early microbiota-triggered immunologic events such as innate immune cell engagement, T-cell differentiation, and LN architectural changes in the subsequent modulation of protolerant versus proinflammatory immune responses in organ transplant recipients.
Public health surveillance of new psychoactive substances: recent developments
Authors: Fitzgerald Nicole D. , Cottler Linda B. , Palamar Joseph J.
Published: April 2024

Purpose of review

New psychoactive substances (NPS) continue to emerge globally and present a threat to public health. This article summarizes the most recent literature on approaches for monitoring NPS use and adverse events related to use.

Recent findings

A variety of approaches have recently been employed for surveillance of NPS use and associated harms, including the use of toxicology testing of patients in emergency departments, surveys of sentinel populations, drug checking and syringe services programs, wastewater-based epidemiology, and retrospective analyses of clinical samples and toxicology reports. These studies cover a range of time periods and NPS examined across numerous countries.

Areas of particular interest for future research include the use of data from drug checking services to inform surveillance efforts of the illicit drug supply and the development of methods for wastewater-based monitoring of NPS. Studies that combine self-report data with toxicology testing in particular are important for capturing unintentional or unknown exposure to NPS including fentanyls and drugs like xylazine. Given the limitations associated with individual indicators of drug use and associated harms, the harmonization of multiple data sources can help present a more complete picture of both trends involving NPS to better inform public health responses.
Identification of anaerobic and aerobic bacteria that can be associated with DFI and their therapeutic in Elnaw teaching hospital
Authors: Ahmed Fathi Sharief , Ibrahim Hiba Siddig , Saeed Mohammed Ibrahim
Published: April 2024

Diabetic foot infection (DFI) is one of the commonest diabetic complications, which considered a major public health concern around the world, with the rising prevalence especially in developing countries. Globally, adults with diabetes accounted for 463 million in 2019 according to the International Diabetes Federation.
The aim of this study was to identify the anaerobic and aerobic bacteria that causing DFI and their therapeutic regimen on diabetic patients in diabetic clinic room in Elnaw teaching hospital - Khartoum state.
The study showed that there was no infection by anaerobic organism and the most frequently isolated organisms were  gram negative rods (70%)  which represents (65%) on diabetic patients.
The commonest isolated organism was S.aureus (30%) followed by E.coli (25%) in control group (non-diabetic), while Klebsiella.spp and S.aureus with (20%) for each; were isolated from the clinic room swabs.
Early diagnosis, optimal management and effective antibiotic therapy are necessary to prevent DFI and amputation.
How dietary landscapes impact food allergy
Authors: Ni Duan , Senior Alistair , Tan Jian , Macia Laurence , Nanan Ralph
Published: April 2024

Diets and environments are critical determinants for food allergy development. Harnessing unprecedented epidemiological and nutritional data, we examined the overall dietary environments for common food allergens and their intrinsic nutrient composition. We found that food and macronutrient supplies minimally impacted food allergy prevalence, but higher protein and glycine in food allergens correlated with less allergies. These findings offer new directions in food allergy research and management.
Mechanical causes and implications of repetitive DNA motifs
Authors: Torrillo Paul , Swigon David
Published: April 2024

Experimental research suggests that local patterns in DNA sequences can result in stiffer or more curved structures, potentially impacting chromatin formation, transcription regulation, and other processes. However, the effect of sequence variation on DNA geometry and mechanics remains relatively underexplored. Using rigid base pair models to aid rapid computation, we investigated the sample space of 100 bp DNA sequences to identify mechanical extrema based on metrics such as static persistence length, global bend, or angular deviation. Our results show that repetitive DNA motifs are overrepresented in these extrema. We identified specific extremal motifs and demonstrated that their geometric and mechanical properties significantly differ from standard DNA through hierarchical clustering. We provide a mathematical argument supporting the presence of DNA repeats in extremizing sequences. Finally, we find that repetitive DNA motifs with extreme mechanical properties are prevalent in genetic databases and hypothesize that their unique mechanical properties could contribute to this abundance.
Risks from Language Models for Automated Mental Healthcare: Ethics and Structure for Implementation
Authors: Grabb Declan , Lamparth Max , Vasan Nina
Published: April 2024

Amidst the growing interest in developing task-autonomous AI for automated mental health care, this paper addresses the ethical and practical challenges associated with the issue and proposes a structured framework that delineates levels of autonomy, outlines ethical requirements, and defines beneficial default behaviors for AI agents in the context of mental health support. We also evaluate ten state-of-the-art language models using 16 mental health-related questions designed to reflect various mental health conditions, such as psychosis, mania, depression, suicidal thoughts, and homicidal tendencies. The question design and response evaluations were conducted by mental health clinicians (M.D.s). We find that existing language models are insufficient to match the standard provided by human professionals who can navigate nuances and appreciate context. This is due to a range of issues, including overly cautious or sycophantic responses and the absence of necessary safeguards. Alarmingly, we find that most of the tested models could cause harm if accessed in mental health emergencies, failing to protect users and potentially exacerbating existing symptoms. We explore solutions to enhance the safety of current models. Before the release of increasingly task-autonomous AI systems in mental health, it is crucial to ensure that these models can reliably detect and manage symptoms of common psychiatric disorders to prevent harm to users. This involves aligning with the ethical framework and default behaviors outlined in our study. We contend that model developers are responsible for refining their systems per these guidelines to safeguard against the risks posed by current AI technologies to user mental health and safety.

Trigger warning

Contains and discusses examples of sensitive mental health topics, including suicide and self-harm.
Determinants in the HTLV-1 capsid major homology region that are critical for virus particle assembly
Authors: Yang Huixin , Arndt William G. , Zhang Wei , Mansky Louis M.
Published: April 2024

The Gag protein of retroviruses is the primary driver of virus particle assembly. Particle morphologies among retroviral genera are distinct, with intriguing differences observed relative to HIV-1, particularly that of human T-cell leukemia virus type 1 (HTLV-1). In contrast to HIV-1 and other retroviruses where the capsid (CA) carboxy-terminal domain (CTD) possesses the key amino acid determinants involved in driving Gag-Gag interactions, we have previously demonstrated that the amino-terminal domain (NTD) encodes the key residues crucial for Gag multimerization and immature particle production. Here in this study, we sought to thoroughly interrogate the conserved HTLV-1 major homology region (MHR) of the CACTDto determine whether this region harbors residues important for particle assembly. In particular, site-directed mutagenesis of the HTLV-1 MHR was conducted, and mutants were analyzed for their ability to impact Gag subcellular distribution, particle production and morphology, as well as the CA-CA assembly kinetics. Several key residues (i.e., Q138, E142, Y144, F147 and R150), were found to significantly impact Gag multimerization and particle assembly. Taken together, these observations imply that while the HTLV-1 CANTDacts as the major region involved in CA-CA interactions, residues in the MHR can impact Gag multimerization, particle assembly and morphology, and likely play an important role in the conformation the CACTDthat is required for CA-CA interactions.