bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of nitrates and NO-donors as a transdermal therapy for erectile dysfunction: a comprehensive review
Authors: Khorasanian Fatemeh , Shami Maryam , Langarizadeh Mohammad Amin , Ranjbar Tavakoli Marziye , Rezaiezadeh Hojjat , Forootanfar Hamid
Published: January 2025

Introduction

Erectile dysfunction (ED) is among the most prevalent urologic issues affecting men globally, with a notably high incidence rate. It significantly impacts the quality of life of patients and their sexual partners.

Objectives

Given the increasing prevalence of ED among men in recent years, numerous pharmacotherapies have been developed to address these conditions. However, systemic drug therapies for ED are often associated with significant challenges, including drug interactions and contraindications across a wide range of medical conditions. This has prompted researchers to focus on designing drugs and dosage forms that maintain efficacy while reducing side effects, interactions, and contraindications.

Methods

Building on previous studies, this article investigates nitrates and NO-donors with a focus on their transdermal impact, strategies for enhancing therapeutic efficiency, potential local side effects, and the evaluation of various formulations.

Results

In this regard, organic nitrates such as nitroglycerin and isosorbide dinitrate and NO donors comprising volatile alkyl nitrites, linsidomine, sodium nitroprusside, and L-arginine are among good candidates for transdermal formulations of ED treatment. In the current article, the topical effects of these compounds, both alone and in combination with other drugs, have been thoroughly examined, including aspects such as their mechanism of action, effectiveness, side effects, and contraindications.

Conclusion

Based on these findings, it appears that novel formulations with enhanced absorption of these compounds could play a significant role in the treatment of ED, either as a standalone therapy or as an adjunctive treatment. Currently, most of the data are from preclinical studies and future clinical research can reveal the precise efficacy of such transdermal formulations.
mTOR Ser1261 is an AMPK‐dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity
Authors: Li Jingwen , Madsen Agnete B. , Knudsen Jonas R. , Henriquez‐Olguin Carlos , Persson Kaspar W. , Li Zhencheng , Raun Steffen H. , Li Tianjiao , Kiens Bente , Wojtaszewski Jørgen F. P. , Richter Erik A. , Nogara Leonardo , Blaauw Bert , Ogasawara Riki , Jensen Thomas E.
Published: January 2025

The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity‐dependent manner. Contraction‐stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2‐dependent phosphorylations were affected in muscle‐specific kinase‐dead AMPK mice with no detectable mTOR Ser1261 phosphorylation in skeletal muscle. Thus, mTOR Ser1261 is an exercise but not insulin‐responsive AMPK‐dependent phosphosite in human and murine skeletal muscle, playing an unclear role in mTORC1 regulation but clearly not required for mTORC2 activity.
Clinical Outcome of Endothelium-Outward Preloaded Descemet Membrane Endothelial Keratoplasty in Long-Term Dextran-Containing Transport Medium Preservation
Authors: Rickmann Annekatrin , Wahl Silke , Messias André , Trouvain André M. , Roberts Philipp K. , Boden Karl T. , Szurman Peter
Published: January 2025

Purpose:

To analyze the clinical outcome of organ-cultured endothelium-outward preloaded DMEK (pDMEK) using the RAPID cartridge.

Methods:

This prospective study included 80 eyes of 80 patients who received a pDMEK. Best-corrected visual acuity (BCVA), endothelial cell count (ECC), and central corneal thickness were measured preoperatively and 4 to 6 weeks, 3 months, 6 months, and 1 year postoperatively. The difficulty of graft preparation and implantation, rebubbling, and re-DMEK frequency were evaluated.

Results:

The graft preparation time was 5.3 ± 1.2 minutes on average. After preparation, the ECC before preloading was 2652 ± 180 cells/mm2 (P = 0.9, endothelial cell loss [ECL] = 0.8%). After pDMEK, the cornea started to clear up after 1.6 ± 1 day. Compared with the preoperative values, BCVA and central corneal thickness significantly improved during the postoperative course (P < 0.0001). At the first follow-up examination, the ECL was 43% (P < 0.0001) and remained stable throughout the follow-up period (all P > 0.5). Rebubbling was necessary in 39/80 patients (48.75%). One patient (1/80, 1.25%) required a re-DMEK after 1 year owing to secondary graft failure with insufficient ECC.

Conclusions:

The clinical results after endothelium-outward pDMEK showed a significant improvement in BCVA and corneal thickness over the 1-year follow-up period, but the relatively high rebubbling rate and ECL should be taken into account. Therefore, we recommend that further comparative clinical studies should be conducted.
Evaluation of the impact of refined nursing care on schizophrenia patients
Authors: Zhang Yuanling , Liang Wenbin , Gui Jiao
Published: January 2025

This study evaluates the impact of refined nursing interventions on patients with schizophrenia, focusing on disease severity, cognitive function, medication adherence, quality of life, and medication-related complications. The aim is to provide evidence for enhancing future clinical treatments. From January 2022 to January 2024, 201 schizophrenia patients were enrolled based on specific inclusion and exclusion criteria. Patients were allocated into 2 groups using propensity score matching: an experimental group that received refined nursing care and a control group that received routine care. Outcome measures included Positive and Negative Syndrome Scale scores, cognitive assessments (Mini-Mental State Examination and Nurses’ Observation Scale for Inpatient Evaluation), medication adherence, quality of life, relapse rates, and medication-related side effects. After propensity score matching, baseline characteristics of the experimental and control groups were comparable. Following nursing interventions, the experimental group demonstrated significant improvements in Positive and Negative Syndrome Scale scores, cognitive assessments (Mini-Mental State Examination and Nurses’ Observation Scale for Inpatient Evaluation), medication adherence, and quality of life compared to the control group. The experimental group also showed lower relapse rates and fewer medication side effects, confirming the enhanced effectiveness of refined nursing interventions. Refined nursing care significantly improved disease outcomes, cognitive function, medication adherence, and quality of life in schizophrenia patients, while reducing relapse rates and medication-related complications, highlighting its clinical value in psychiatric care.
The effect of enhanced recovery protocols on postoperative rehabilitation in orthopedic surgery patients
Authors: Cao Hui , Huang Zhaoxu , Yuan Hua , Hu Xuehui , Fu Zhanli , Song Xiaohuan , Zhang Meixia , Du Xia , Long Zhuoyu
Published: January 2025

Orthopedics is a critical hospital department that has experienced shifts in the spectrum of orthopedic conditions due to societal advancements in recent years. While surgical interventions are effective in restoring fracture function, perioperative care remains a key factor in optimizing patient recovery. This study aims to assess the impact of orthopedic rehabilitation care based on the enhanced recovery after surgery (ERAS) protocol on postoperative rehabilitation. A total of 836 patients who underwent orthopedic surgery from June 2023 to June 2024 were included in the study. They were divided into a control group, which received standard care, and an observation group, which received care interventions based on ERAS principles. Recovery outcomes were assessed by measuring hospital stay duration, fracture healing time, joint function recovery time, and the incidence of complications in both groups. The observation group showed significantly shorter hospital stays, faster fracture healing times, and quicker joint function recovery compared with the control group. Furthermore, the incidence of complications was notably lower in the observation group. Postoperative joint function recovery scores and patient satisfaction were also higher in the observation group, with statistically significant differences between the 2 groups (P < .05). ERAS-based care enhances orthopedic recovery by reducing hospital stays, accelerating functional recovery, lowering complications, and improving patient satisfaction, proving its effectiveness in perioperative cares, and should be widely implemented in orthopedic rehabilitation.
EBUS-guided Iodine-125 seed implantation in lymph node as a novel therapy for MCAO: A case report
Authors: Qian Huiwen , Jin Jianqiang , Wang Changguo , Wang Yuting , Ge Juxiang , Huang Jianan , Ji Cheng
Published: January 2025

Rationale:

We report here a case of using iodine-125 (125I) seed implantation via endobronchial ultrasound (EBUS) in the treatment of malignant central airway obstruction (MCAO) in a patient with lung adenocarcinoma.

Patient concerns:

The patient still experienced MCAO after conventional bronchoscopic interventional therapy.

Diagnoses:

The patient was diagnosed as lung adenocarcinoma stage IV (T4N2M1a).

Interventions:

She received implantation of radioactive 125I seeds in the lesion inside the right middle lobe bronchus and 12R lymph node via bronchoscopy and EBUS, in combination with chemotherapy and immunotherapy.

Outcomes:

The patient’s MCAO has been effectively controlled.

Lessons:

The success of this case suggests that EBUS-guided 125I seed implantation to lymph nodes is a safe and effective therapeutic option for MCAO.
Ferroptosis: a novel pathogenesis and therapeutic strategies for Parkinson disease: A review
Authors: Jiao Di , Yang Yang , Wang Kejing , Wang Yaomei
Published: January 2025

Parkinson disease (PD) is the second most common neurodegenerative disease, and its incidence is climbing every year, but there is still a lack of effective clinical treatments. In recent years, many studies have shown that ferroptosis plays a key role in the progression of PD. Most importantly, many cellular and animal studies and clinical trials have shown that episodes of PD can be alleviated by inhibiting the ferroptosis process, such as utilizing inhibitors, chelating agents, and others. Here, we review the role of ferroptosis, a new form of cell death, in the pathogenesis of PD, and summarize the therapeutic strategies for targeting ferroptosis in PD, hoping to provide new thinking for the study of PD pathogenesis and the development of therapeutic strategies.
Rheumatoid arthritis and the risk of fracture: A Mendelian randomization study
Authors: Zhang Yanyan , Weng Qin , Deng Zhibo , Zhang Huaizhi , Dai Jianhui , Chen Xu
Published: January 2025

Observational epidemiological studies indicate a higher fracture incidence in rheumatoid arthritis (RA) patients compared to the general population. However, the causal relationship between RA and fracture risk, particularly traumatic and osteoporotic fractures, is not well established. We performed Mendelian randomization (MR) analysis to evaluate the causal relationship between RA and fracture risk. We performed a MR analysis using summary statistics from genome-wide association studies to investigate the causal association between RA and the risk of traumatic fractures at 9 sites and 3 types of osteoporotic fractures. The primary analysis used inverse-variance weighting, supplemented by MR-Egger regression and other methods to assess causal relationships and sensitivity analyses, including heterogeneity and pleiotropy assessments, using R software with appropriate packages. The inverse-variance weighting results demonstrated a causal relationship between genetically predicted RA and an elevated risk of fractures, particularly traumatic fractures of the long bones and osteoporotic fractures, including fractures of shoulder and upper arm (odds ratio [OR] = 1.041, 95% confidence interval [CI]: 1.020–1.062, P = 9.06e-05), fractures of forearm (OR = 1.026, 95% CI: 1.007–1.044, P = .006), fracture of femur (OR = 1.036, 95% CI: 1.009–1.064, P = .009), fractures of lower leg, including joint (OR = 1.031, 95% CI: 1.016–1.047, P = 6.38e-05), fractures of rib(s), sternum, and thoracic vertebrae (OR = 1.041, 95% CI: 1.018–1.064, P = 4.08e-04), osteoporotic with pathological features (OR = 1.128, 95% CI: 1.071–1.188, P = 5.54e-06), postmenopausal osteoporotic with pathological features (OR = 1.060, 95% CI: 1.002–1.123, P = .044), and drug-induced osteoporotic with pathological features (OR = 1.255, 95% CI: 1.124–1.400, P = 5.02e-05). This study highlights the genetic causal link between RA and an increased risk of traumatic and osteoporotic fractures, presenting a new direction for future exploration of the mechanisms underlying RA-related fractures.
Efficacy and safety of ivermectin–albendazole combination versus ivermectin or albendazole monotherapy in soil-transmitted helminthiasis: A systematic review and meta-analysis
Authors: Malik Hurais , Din Muhammad Fazal Ud , Faizan Muhammad Aqib , Rehman Tooba , Hudaib Muhammad , Shah Syed Muhammad Abdullah , Khan Abdullah Abid , Amir Syeda Fatima , Fraz Musarrat , Khalid Maham , Anjum Muhammad Umair , Larik Muhammad Omar , Bhattarai Pratik
Published: January 2025

Background:

Soil-transmitted helminthiasis remains a daunting challenge to global health, exerting its greatest toll on resource-limited regions of the world. A dual drug approach using the co-administration of ivermectin and albendazole has shown promising results in comparison to the traditional monotherapy strategy. In light of this, a systematic review and meta-analysis of randomized controlled trials was conducted.

Methods:

Several electronic databases including PubMed, Cochrane Central, Google Scholar, and Embase were explored to search for relevant studies from inception to September 2023. The Cochrane Risk of Bias Tool for Randomized Controlled Studies was utilized to evaluate the quality of studies.

Results:

A total of 8 randomized controlled trials, reporting 10 patient populations, were included. The treatment of trichuriasis significantly favored the dual therapy regimen of ivermectin–albendazole over albendazole-only monotherapy (risk ratio [RR]: 2.86; 95% confidence interval [CI]: 1.66–4.93; P = .0002), with no significant differences observed for ascariasis and hookworm. The treatment of trichuriasis and hookworm significantly favored the dual therapy regimen of ivermectin–albendazole over ivermectin-only monotherapy (RR: 1.86; 95% CI: 1.56–2.21; P < .00001 and RR: 2.31; 95% CI: 1.23–4.31; P = .009, respectively). There were no statistically significant differences between dual therapy and monotherapy in terms of adverse effects.

Conclusion:

These findings highlight the nuanced effectiveness of combined therapy specific to certain helminth types, in addition to their comparable safety profiles, thereby providing pivotal insights that contribute to the evolving landscape of soil-transmitted helminth treatment strategies.
Alkaptonuria presenting as lumbar degenerative disease: A case report and literature review
Authors: Sang Peiming , Ma Yanyan , Yang Jun , He Fan , Chen Jingyan , Zhang Xie , Chen Binhui , Cai Ying , Chen Zhenjing
Published: January 2025

Rationale:

Alkaptonuria (AKU) is a rare, inherited metabolic disease caused by deficient activity of homogentisic acid oxidase, leading to the accumulation of homogentisic acid and its oxidized product, benzoquinone acetic acid. These compounds cause black discoloration of cartilage, degeneration, inflammation, and calcification of intervertebral disks and large joints, resulting in pain and impaired quality of life. Despite its debilitating effects, there are no curative treatments for AKU, and management remains supportive. This study aims to contribute to the limited literature on AKU-related spinal manifestations by reporting a case of lumbar degenerative disease in an AKU patient and highlighting surgical intervention as an effective treatment approach.

Patient concerns:

A 49-year-old woman presented with chronic lower back pain and the posterior side of right lower limb radiating pain for 1 year, worsening over the past week. Magnetic resonance imaging revealed lumbar spondylolisthesis at the L4/5 level and migrated lumbar disk herniation at the L5/S1 level.

Interventions:

The patient underwent transforaminal lumbar interbody fusion surgery at L4/5 and L5/S1. Intraoperatively, the resected disk material was black, with darkened intervertebral disks and cartilage endplates, distinct from the typical white appearance of degenerative disks. Surgical intervention included disk and cartilage endplate removal, insertion of cages with harvested autografts, and implantation of bilateral pedicle screws and rods.

Diagnosis:

AKU with lumbar degenerative disease.

Outcome:

The patient experienced resolution of pain postoperatively.

Lessons:

This case underscores the importance of recognizing AKU as a potential cause of lumbar degenerative disease and highlights transforaminal lumbar interbody fusion surgery as a viable treatment option for pain relief and improved functionality in affected individuals.
Retroperitoneal cystic mature teratoma in an adult male: A clinical report of one case and review of the literature
Authors: Zhang Zekai , Zhang Ling , Zhang Hua , Huo Xiaoguang , Xu Wenzhe , Zhang Yongting
Published: January 2025

Rationale:

A case of retroperitoneal cystic mature teratoma in an adult male. Retroperitoneal cystic mature teratoma is a type of teratoma. The disease has occult onset, does not have the typical characteristics of teratoma, and is difficult to distinguish from cystadenoma and other diseases. Cystic mature teratoma is benign, but it has a certain risk of malignant transformation. The purpose of this case report is to highlight the specificity of the case, collect and analyze the imaging features of the disease, and provide assistance for daily clinical diagnosis.

Patient concerns:

Adult extraglandular abdominopelvic teratoma is extremely rare, especially in men. These masses are most commonly found by chance and require surgical resection for diagnostic confirmation after a thorough examination.

Diagnoses:

We report a case of retroperitoneal cystic mature teratoma in an 86-year-old man. Abdominal ultrasound revealed a cystic mass in the abdominal cavity (possibly from the pancreas). Enhanced abdominal computed tomography showed a space-occupying lesion with a lack of blood supply in the hepatogastric space (above the pancreas), and the local boundary with the pancreas was unclear. The tumor was considered first, but pancreatic cystadenoma was not excluded.

Interventions:

Surgical resection is the most important treatment for retroperitoneal cystic teratoma, and the best adjuvant treatment needs further study.

Outcomes:

Postoperative pathological findings showed (retroperitoneal) mature cystic teratoma with lymphoid hyperplasia, lymphoid follicle formation, and mild to moderate atypical hyperplasia of squamous epithelium.

Lessons:

In conclusion, adult retroperitoneal cystic mature teratoma is a rare disease. This disease should be taken into account when we find a retroperitoneal cystic mass on our routine imaging. The shortcomings of this case report are mainly single case, small sample size, need to collect more cases, and long-term follow-up to summarize the characteristics of retroperitoneal cystic mature teratoma, in addition, this case did not undergo magnetic resonance imaging examination, magnetic resonance images cannot be analyzed.
The clinicopathologic features of uterine inflammatory myofibroblastic tumor: A case report
Authors: Pan Xiaoming , Zou Jian , Yang Shizhou , Wang Yuanhe , Luo Jie , Zhu Xiaojun
Published: January 2025

Rationale:

Inflammatory myofibroblastic tumor (IMT) is a rare soft tissue neoplasm with low malignant potential. These patients present with a certain probability of malignant potential. The management of IMT has not been standardized, especially for the patients with fertility needs.

Patient concerns and Diagnoses:

Thirteen patients with IMT who attended in the Department of Gynecology, Women’s Hospital, Zhejiang University School of Medicine were enrolled between 2019 and 2023. The data of the clinical and pathological features was analyzed.

Interventions and Outcomes:

The mean age of the patients was 45.31 ± 12.80 years. Seven of the 13 cases (53.85%) had abnormal uterine bleeding. Five of them (38.46%) had a rapidly growing mass, and 2 of them (15.38%) had no obvious symptoms. With regard to surgical strategies, 7 patients underwent hysterectomy, and 6 patients underwent mass resection only. All the patients were alive with no evidence of disease at an average of 9.58 months of follow-up. One of them gave birth to a full-term male infant at 40 weeks of gestation after hysteroscopic resection, without recurrence.

Lessons:

Uterine inflammatory myofibroblastic tumor can be diagnosed by the anaplastic lymphoma kinase overexpression. Complete excision under hysteroscopy or laparoscopy seems to be effective and safe. Because there is a certain risk of recurrence and metastasis, conservative surgery should be performed carefully to preserve fertility in patients who can undergo close follow-up.
Low-dose dasatinib-induced chylothorax, pulmonary hypertension, and pericardial effusion in a patient with chronic myeloid leukemia: A case report and literature review
Authors: Pai Ting-Wei , Huang Cheng-Wei
Published: January 2025

Rationale:

Chylothorax is a rare adverse effect that is associated with dasatinib, a tyrosine kinase inhibitor administered for chronic myeloid leukemia (CML) treatment. Most reported cases have described standard dosing. In this case report, we described a 43-year-old male patient with CML who developed chylothorax after 4 years of low-dose dasatinib therapy. To the best of our understanding, this is the first case to report the simultaneous development of pulmonary hypertension, pericardial effusion, and dasatinib-induced chylothorax.

Patient concerns:

A 43-year-old male patient with CML developed chylothorax after 4 years of low-dose dasatinib.

Diagnoses:

The patient also developed pulmonary hypertension and pericardial effusion at the same time.

Interventions:

Therapeutic interventions included thoracentesis, steroids, diuretics, and sildenafil. Dasatinib was discontinued and replaced with nilotinib, which resolved the chylothorax, pulmonary hypertension, and pericardial effusion.

Outcomes:

Chylothorax occurs with long-term and low-dose dasatinib administration. Concurrent pulmonary hypertension and pericardial effusion, although infrequent, may occur. Prompt recognition, dasatinib discontinuation, and therapeutic interventions are crucial for optimizing outcomes.

Lessons:

Close monitoring for these rare side effects is paramount even in patients on long-term or low-dose dasatinib.
Qualitative and quantitative analysis of reduced bed position acquisition time on FDG PET image quality
Authors: Ting Michael , McDermott Garry , Zarei Amir , Patel Chirag , Chowdhury Fahmid U. , Rodrigues Andreia , Scarsbrook Andrew F.
Published: January 2025

The study aim was to evaluate whether reducing bed position acquisition time would result in significant detriment to image quality. Secondary aims were to compare effect of time of flight (TOF) and Q.Clear reconstructions and patient BMI on image quality. Fluorodeoxyglucose PET-CT performed in 30 patients on a new scanner at our institution between March and May 2024 was retrospectively evaluated. Four PET reconstructions were performed: (a) 1 min 45 s TOF, (b) 2 min TOF, (c) 1 min 45 s Q.Clear, and (d) 2 min Q.Clear. For qualitative analysis, four maximum intensity projection images were evaluated side-by-sideusing a five-point visual score (1 = non-diagnostic, 5 = excellent). For quantitative analysis, liver signal-to-noise ratio (SNR) was calculated. A statistically significant reduction in visual score occurred when reducing bed position time from 2 min to 1 min 45 s (mean TOF scores 0.24 reduction, P = 0.0002; mean Q.Clear scores 0.04 reduction, P = 0.02. There was also a statistically significant difference in liver SNR when reducing bed position time. Deterioration in image quality was minimised when bed position acquisition time was reduced if Q.Clear construction was utilized. This could facilitate increased scanning capacity without clinical detriment.
Differences in lasers and laser technologies: what does a clinician need to know?
Authors: Morozov Andrey , Skossyrskiy Vladislav , Babaevskaya Diana , Gauhar Vineet , Enikeev Dmitry
Published: January 2025

Purpose of review

This review focuses on recent advancements in laser technologies used in urology, particularly in enucleation, vaporization, lithotripsy, and focal laser ablation (FLA). The growing use of the thulium fiber laser (TFL) and the development of pulsed thulium lasers (p-Tm:YAG) highlight the relevance of this review, as these innovations aim to improve precision and outcomes in urological procedures.

Recent findings

Recent studies have shown the advantages of TFL in achieving precise tissue ablation, reduced retropulsion offered by the Moses technology in holmium lasers, and the potential of pulsed thulium lasers for more precise control of the effects on tissues. Additionally, FLA is gaining traction for its ability to treat localized prostate cancer with minimal collateral damage. These technologies not only optimize procedural accuracy but also reduce complications, making them safer for high-risk patients, including those receiving anticoagulants.

The advancements in laser technology, including TFL, Moses technology, and pulsed thulium lasers, are improving outcomes in urological surgeries by increasing precision, reducing operative time, and minimizing complications. FLA represents a promising alternative for minimally invasive cancer treatments. Ongoing research should focus on optimizing laser parameters and exploring broader clinical applications.
En bloc resection of large bladder tumor: is it feasible and reasonable?
Authors: Babaevskaya Diana , Morozov Andrey , Fridman Eddie , Tsoy Larisa , Shariat Shahrokh F. , Molchanov Yossef , Yakimov Maxim , Compérat Eva , Herrmann Thomas R.W. , Enikeev Dmitry
Published: January 2025

Purpose of review

Transurethral resection of bladder tumor (TURBT) remains the basis of bladder tumor diagnosis and an effective means of treating nonmuscle invasive bladder cancer (NMIBC). There are several limitations to this procedure: TURBT may cause free floating of malignant cells in the bladder and as a result re-implantation and early recurrence. Also, it does not allow the pathologist to define the correct spatial orientation of the specimen. The development of en bloc resection of bladder tumor (ERBT) has helped overcome the abovementioned key disadvantages of TURBT. However, many urologists doubt whether this approach is feasible for treating larger tumors.

Recent findings

In this review, it is shown that ERBT of large bladder tumor (>3 cm) is in fact a feasible and well tolerated method. Although there is a lack of comparative data proving its advantages over TURBT, en bloc in large tumor seems to result in better local cancer control (due to higher prevalence of detrusor specimen, lower need for re-TURBT), lower rate of relapse outside the resection area (due to lower risk of tumor cells circulation), and higher quality of pathology specimen.

Despite the skepticism of some surgeons, potential difficulties caused by larger tumor size may be overcome easily, and most agree that tumor size should not limit the implementation of the method in their daily practice.
The McLean Screening Instrument for Borderline Personality Disorder: A Review
Authors: Semaan Farah , Croarkin Paul E.
Published: January 2025

Borderline personality disorder (BPD) poses significant challenges for early identification and diagnosis due to its intricate symptomatology that overlaps with other psychiatric illnesses. To address this challenge, the McLean Screening Instrument for BPD (MSI-BPD) was developed to identify individuals displaying potential BPD symptoms. This review aims to consolidate the current limited body of research on the MSI-BPD, delving into its origins, the rigor of its validation process, its practicality in clinical settings, and potential applications. By comprehensively examining these aspects, clinicians and researchers involved in BPD assessment and diagnosis can develop a deeper understanding of the instrument’s utility. The MSI-BPD’s development involved meticulous consideration of BPD diagnostic criteria, resulting in a tool tailored to effectively capture relevant symptoms. Validation studies have provided supportive evidence for its accuracy in identifying individuals at risk of BPD, thereby underlining its utility as a resource for early screening and intervention in clinical settings. However, it is essential to acknowledge that, while the MSI-BPD demonstrates satisfactory psychometric properties and utility as a screening tool for BPD, its diagnostic accuracy may vary across diverse populations. Consequently, clinicians and academics must judiciously consider sample characteristics and potential limitations when utilizing this instrument in both clinical and research contexts. Recognizing the advantages and potential applications of the MSI-BPD within a comprehensive approach to addressing BPD is important for professionals working in the field of BPD assessment and diagnosis. It is important to emphasize that the MSI-BPD is a screening tool and one data point in understanding patients presenting with complex symptomatology.
What Matters Most for Long-Acting Antiretroviral Therapy? A Best-Worst Scaling Discrete Choice Experiment
Authors: Fisk-Hoffman Rebecca J , Liu Yiyang , Somboonwit Charurut , Widmeyer Maya , Bilello Lori A , Cohen Colby , Leeman Robert F , Prosperi Mattia , Salloum Ramzi G , Cook Robert L
Published: January 2025

Introduction:

Florida remains a high-incidence, high-prevalence setting for HIV. Long-acting (LA) antiretroviral therapies (ART) could improve HIV-related outcomes and reduce transmission. This study identifies preferred LA ART characteristics and classes of preference among people with HIV (PWH) in Florida.

Methods:

The Florida Cohort enrolls adult PWH from six counties. In February 2023, a best-worst scaling discrete choice experiment (BWDCE) was added which included 12 tasks with three alternatives and an opt-out (i.e., their current regimen). Six attributes were included: treatment type (e.g., shot), long-term effects, side effects, location (e.g., at home), effectiveness, and frequency. A Hierarchical Bayes model was used to estimate level utilities, attribute importance was calculated, and a latent class model was run in Sawtooth Software.

Results:

Overall, 208 PWH participated (60% aged 50+, 49% non-Hispanic Black, 54% male). Treatment type had the greatest impact on preference [27.2% (95%CI 25.1-29.3)], followed by frequency [23.4% (95%CI 21.6-25.2)], and long-term effects [19.0% (95%CI 17.8-20.3)]. Within treatment type, LA pills were preferred over other options, including their current regimen. Less frequent administration was preferred, but only yearly administration was preferred over their current regimen. Within long-term effects, participants preferred no increase in risk. Two classes were identified where one class (27% of participants) preferred their current regimen and the other (73% of participants) preferred an alternative, placing greater importance on frequency.

Conclusion:

PWH preferred LA pills and less frequent administration, so future ART development could focus on options with these traits. Further exploration of user preference classes is needed.
Bi-allelic variants in the aminopeptidase XPNPEP3 cause mitochondrial disease with pediatric cardiomyopathy
Authors: Ruijmbeek Claudine W.B. , Ruizenaar Sjoerd , van der Linde Herma C. , Nollet Edgar E. , Doff Wouter A.S. , Bogaard Victoria C.S. , de Pee Marlène , Ferraro Federico , Rodenburg Richard J. , Schipper Henk S. , Hirsch Alexander , van Slegtenhorst Marjon A. , von der Thüsen Jan H. , Demmers Jeroen A.A. , van IJcken Wilfred F.J. , van Ham Tjakko J. , Verhagen Judith M. A.
Published: January 2025

Bi-allelic variants inXPNPEP3are known to cause nephronophthisis-like nephropathy-1. However, recent findings indicate XPNPEP3 deficiency causes a broader phenotypic spectrum encompassing extra-renal manifestations. XPNPEP3 is suggested to be the human ortholog of ICP55, a mitochondrial protein involved in the processing and maturation of mitochondrial proteins in plants and yeast.

Here, we present a family with two children affected by a homozygous splice variant inXPNPEP3. Both children exhibited early-onset renal insufficiency and progressive mixed hypertrophic and dilated cardiomyopathy, requiring cardiac transplantation during childhood. RNA and protein analysis of patient fibroblasts and cardiac tissue revealed loss of XPNPEP3 expression due to the splice variant. Assessment of explanted cardiac tissue confirmed mitochondrial dysfunction, indicated by decreased cytochrome c oxidase activity and changes in mitochondrial morphology.

Although the deficiency of Xpnpep3 in zebrafish did not result in noticeable phenotypic abnormalities during early larval stages, transcriptomic and proteomic analyses revealed mitochondrial alterations. Notably, proteomic profiling identified decreased abundance of mitochondrial proteins inxpnpep3Δ7/Δ7mutants as compared to wild-types, including those identified in our study as putative substrates of Xpnpep3. We hypothesize that impaired processing of these proteins plays a critical role in the early developmental molecular changes observed, potentially predisposing to disease and also underlies the clinical manifestations in affected children.

In summary, our study underscores that loss of XPNPEP3 causes a mitochondrial disorder with varied phenotypes, including cardiomyopathy, through a molecular mechanism likely involving abnormal processing and stabilization of mitochondrial precursor proteins. AddingXPNPEP3to cardiac and mitochondrial disease gene panels is essential for the accurate diagnosis and management of potential cardiac complications.
Circulating cytokine levels and 5-year vascular recurrence after stroke: a multicenter prospective cohort study
Authors: Zhang Lanyue , Antabi Mohamad Ali , Mattar Jana , Bounkari Omar El , Fang Rong , Waegemann Karin , Bode Felix J. , Stösser Sebastian , Hermann Peter , Liman Thomas G. , Nolte Christian H. , Ikenberg Benno , Bernkopf Kathleen , Glanz Wenzel , Janowitz Daniel , Spottke Annika , Görtler Michael , Wunderlich Silke , Zerr Inga , Petzold Gabor C. , Endres Matthias , Bernhagen Jürgen , Dichgans Martin , Georgakis Marios K.
Published: January 2025

Background

Anti-inflammatory therapies are tested in randomized trials for secondary stroke prevention. Detecting inflammatory biomarkers that predict vascular recurrence could optimize patient selection for these trials.

Methods

In a multicenter prospective cohort study, we measured plasma levels of 22 inflammatory cytokines in 486 acute stroke patients (median age 68 years, 34% female, median 3 days post-stroke onset). Patients were followed for over 5 years through telephone and in-person interviews to record the occurrence of the following outcomes: (1) recurrent stroke or transient ischemic attack (TIA; primary outcome); (2) a composite of recurrent vascular events (stroke, TIA, acute coronary syndrome, hospital admission due to heart failure, and death; secondary outcome). Associations between cytokine levels and these outcomes were analyzed using Cox proportional hazards models adjusted for demographic and vascular risk factors.

Results

During the 5-year follow-up period, 59 patients (12.1%) experienced recurrent stroke or TIA, and 118 (24.3%) experienced recurrent vascular events. After adjustments for demographic and vascular risk factors, and correction for multiple comparisons, higher plasma levels of CD62E (adjusted Hazard Ratio [aHR] per SD increment: 1.595, 95%CI, 1.186–2.145) and MIF (aHR: 1.581, 95%CI, 1.186–2.107) in the acute phase after stroke were statistically significantly associated with increased risk of recurrent stroke or TIA. The associations followed a dose-response pattern across quartiles of CD62E and MIF levels. Adding baseline CD62E and MIF levels to models including age, sex, vascular risk factors, and baseline C-reactive protein (CRP) levels led to significant improvements in the prediction of 5-year risk of recurrent stroke or TIA (ΔC-index 0.039 to 0.050).

Conclusions

Among stroke patients, higher baseline levels of CD62E and MIF improved prediction of 5-year risk of recurrent stroke or TIA on top of vascular risk factors and CRP levels. Whether assessment of these cytokines could improve patient selection for secondary prevention trials of anti-inflammatory treatments, should be explored in future studies.
Improving the Safety ofN,N-Dimethylacetamide (DMA) as a Potential Treatment for Preterm Birth in a Pregnant Mouse Model Using a Vaginal Nanoformulation
Authors: Mir Asad , Acosta Teeshavi , Concheiro-Guisan Marta , Yellon Steven M. , Patel Ketan , Reznik Sandra E.
Published: January 2025

Vaginal administration and the uterine first pass effect allow for preferential delivery of drugs to the reproductive tract. Dimethylacetamide has previously been shown to delay preterm birth in a pregnant mouse model when given intraperitoneally but the effectiveness of a vaginal nanoformulation of dimethylacetamide has yet to be tested. The purpose of this study was to compare the two formulations of dimethylacetamide for efficacy in rescuing pups from preterm birth in an inflammation-induced mouse model, effects on the maternal fetal interface, and pharmacokinetic profiles in maternal plasma. Timed pregnant CD1 mice were given a 1.56 mg/kg intraperitoneal dose of lipopolysaccharide followed by 3 doses of either vaginal dimethylacetamide or intraperitoneal dimethylacetamide. Mice were monitored for 48 hours and times of deliveries were recorded. Additionally, CD1 mice in late gestation were given a single dose of either vaginal or intraperitoneal dimethylacetamide and blood was drawn at 3 different time points following administration. Vaginal administration of dimethylacetamide had similar efficacy in delaying inflammation induced preterm birth as intraperitoneal administration but resulted in lower concentrations in the systemic circulation and decreased effects on the maternal fetal interface. Vaginal nanoformulations should be explored for their potential therapeutic value for the delay of preterm birth.
N,N-dimethylacetamide blocks inflammation-induced preterm birth and remediates maternal systemic immune responses
Authors: Reznik Sandra E. , Kashou Alexander , Ward Daylan , Yellon Steve M.
Published: January 2025

The common excipient, N,N-dimethylacetamide (DMA), prevents imminent endotoxin-induced preterm birth in mice. The present study hypothesized that DMA forestalls preterm birth to term (defined as day 18.5 or later) by attenuating bacterial endotoxin lipopolysaccharide (LPS)–induced maternal systemic inflammatory responses and cervix remodeling. Accordingly, LPS (i.p.) on day 15 postbreeding stimulated preterm delivery within 24 h while mice treated with DMA 2 h preceding and 9 h following LPS administration remained pregnant, comparable to saline and DMA controls, to deliver viable pups at term. Irrespective of LPS or DMA+LPS treatment, maternal plasma pro- and anti-inflammatory cytokines on day 15.5 (12 h post-LPS) increased 10-fold compared to baseline concentrations in controls. On day 16 of pregnancy, plasma concentrations of G-CSF and TNFα were reduced in the prepartum LPS+DMA group compared to those in postpartum mice given LPS. By day 18 of pregnancy, all cytokines returned to baseline - equivalent to low systemic levels throughout the study in saline and DMA controls that gave birth at term. In addition, maternal plasma progesterone declined within 12 h in prepartum LPS-treated mice to postpartum concentrations on day 16. Although a similar transient decrease occurred by 12 h in DMA+LPS mice, plasma progesterone returned to baseline concentrations in controls. Contemporaneously, the progression of prepartum cervix remodeling leading to preterm delivery was acutely forestalled by DMA without impeding birth at term. These findings support the hypothesis that DMA not only prevents inflammation-driven preterm birth, but rescues pregnancy for birth to occur at term. The results raise the possibility that maternal signals can forecast risk of preterm birth while selective suppression of systemic inflammation can mitigate adverse pregnancy outcomes.

DMA rescues pregnancy from inflammation-induced preterm birth through a progesterone-independent mechanism that involves multiple proinflammatory cytokines in maternal circulation.

Supported by NIH Grant 1R16GM145586 and the Ines Mandl Research Foundation
GLUT5 armouring enhances adoptive T cell therapy anti-tumour activity under glucose-limiting conditions
Authors: Page Robert , Martinez Olivier , Larcombe-Young Daniel , Bugallo-Blanco Eva , Papa Sophie , Perucha Esperanza
Published: January 2025

Cancer immunotherapy with engineered T cells has become a standard treatment for certain hematologic cancers. However, clinical trial outcomes for solid tumours are significantly lagging. A primary challenge in solid tumours is the lack of essential metabolites in the tumour microenvironment, such as glucose, due to poor vascularization and competition with tumour cells. To address this, we modified T cells to use fructose as an alternative energy source by introducing ectopic GLUT5 expression. We show that “GLUT5-armored” T cells, engineered with either chimeric antigen receptors (CARs) or an ectopic T cell receptor (TCR), achieve enhanced anti-tumour activity in low-glucose environments in bothin vitroandin vivomodels. This straightforward modification is compatible with current clinical approaches and may improve the efficacy of T cell therapies for solid tumours.

Graphical Abstract
Evolution of species’ range and niche in changing environments
Authors: Polechová Jitka
Published: January 2025

What determines the limits to adaptation and to a species’ range is a fundamental question, especially relevant in the context of current rapid environmental change. Yet, to date, no predictive theory incorporates the feedback between ecology and evolution while accounting for the evolution of genetic variance under selection, mutation, dispersal, and genetic drift. This study outlines a comprehensive theory showing that under joint evolutionary and population dynamics, the limits of adaptation are fundamentally determined by the three measurable parameters: i) the effective environmental gradient, ii) the effective rate of temporal change, and iii) the neighbourhood size, which represents the local population size accessible via dispersal. Dispersal across heterogeneous environments supports higher local genetic variance, facilitating adaptation to a faster temporal change. However, local diversity is depleted by genetic drift, which is measured by the inverse of neighbourhood size. Extending earlier predictions in stable environments, I use scaling arguments to derive a generalized expansion threshold – a tipping point where adaptation fails and the species’ range can no longer expand. Beyond this threshold, species’ ranges also tend to fragment, particularly when temporal change incurs a high fitness cost. The onset of fragmentation is rapid and associated with a loss of genetic variance. The theory not only identifies new phenomena but also establishes a fundamental relationship between these core measurable parameters. It provides a predictive framework for understanding species’ range and niche limits while advancing the theoretical foundations for assessing population resilience of spatially structured populations under unprecedented environmental change.
Reflection Knockoffs via Householder Reflection: Applications in Proteomics and Genetic Fine Mapping
Authors: Guan Yongtao , Levy Daniel
Published: January 2025

We present a novel knockoff construction method, and demonstrate its superior performance in two applications: identifying proteomic signatures of age and genetic fine mapping. Both applications involve datasets of highly correlated features, but they differ in the abundance of driver associations. Our primary contribution is the invention of the reflection knockoff, which is constructed from mirror images – obtained via Householder reflection – of the original features. The reflection knockoff substantially outperforms Fixed-X and Model-X knockoffs in feature selection, particularly when features are highly correlated. Our secondary contribution is a simple method to aggregate multiple sets of identically distributed knockoff statistics to improve the consistency of knockoff filters. In the study of proteomic signatures of age, single feature tests showed overly abundant proteomic association with age. However, knockoff filters using reflection knockoffs and aggregation revealed that a majority of these associations are hitchhikers. When applied to genetic fine mapping, knockoff filters using reflection knockoffs and aggregation outperform a state-of-the-art method. We discuss a promising application of reflection knockoffs: sharing genetic data without raising concerns about privacy and regulatory violations.
The inflammasome adaptor protein ASC triggers immunometabolic dysregulation induced by dysbiosis during obesity
Authors: Martinez-Garcia JJ , Rodríguez S , Guijarro A , Quevedo-Romero I , Mateo SV , Molina-López C , Hurtado-Navarro L , Baroja-Mazo A , Pelegrín P
Published: January 2025

The innate immune system oversees the response to danger signals. One of the most complexes organs that develops this response is the gut, which is extremely sensitive to the microbial changes in response to high saturated fat diets (HFD), leaving the space to be colonised by opportunistic bacteria, and triggering the innate immune response. Different evidence suggests the potential of the inflammasome in diet-induced inflammation, but little is known about its impact on the gut immunometabolic dysregulation. In this work, we report that the inflammasome adaptor apoptosis speck-like protein with a caspase activation domain (ASC) is essential for the development of obesity and insulin resistance during a high-fat diet (HFD). In ASC-deficient mice (Pycard-/-), lower weight gain and improved glucose tolerance were observed in comparison to wild type mice. Therefore, the absence of ASC reduces intestinal permeability and improves the benefitial effects of the gut microbiota, decreasing dysbiosis, making the intestinal environment healthier. Additionally,Pycard-/-mice presented an enhanced glycolysis and aerobic metabolism, contributing to reduced inflammation, fat accumulation in the liver and improved hepatic metabolic function. Developing therapies targeting ASC could be beneficial to treat obesity, type II diabetes, and metabolism-associated liver diseases.