bluuebunny/crossref_metadata_2025 huggingface dataset:
Acceptors stability modulates the efficiency of post‐translational protein N‐glycosylation
Authors: Couto Paula M. , Guardia Carlos M. A. , Couto Facundo L. , Labriola Carlos A. , Labanda María S. , Caramelo Julio J.
Published: June 2024

N‐glycosylation is the most common protein modification in the eukaryotic secretory pathway. It involves the attachment a high mannose glycan to Asn residues in the context of Asn‐X‐Ser/Thr/Cys, a motif known as N‐glycosylation sequon. This process is mediated by STT3A and STT3B, the catalytic subunits of the oligosaccharyltransferase complexes. STT3A forms part of complexes associated with the SEC61 translocon and functions co‐translationally. Vacant sequons have another opportunity for glycosylation by complexes carrying STT3B. Local sequence information plays an important role in determining N‐glycosylation efficiency, but non‐local factors can also have a significant impact. For instance, certain proteins associated with human genetic diseases exhibit abnormal N‐glycosylation levels despite having wild‐type acceptor sites. Here, we investigated the effect of protein stability on this process. To this end, we generated a family of 40 N‐glycan acceptors based on superfolder GFP, and we measured their efficiency in HEK293 cells and in two derived cell lines lacking STT3B or STT3A. Sequon occupancy was highly dependent on protein stability, improving as the thermodynamic stability of the acceptor proteins decreases. This effect is mainly due to the activity of the STT3B‐based OST complex. These findings can be integrated into a simple kinetic model that distinguishes local information within sequons from global information of the acceptor proteins.
Development of a Situation-Specific Theory for the Transition of Survivors of Stroke With Dysphagia
Authors: Awamura Kenji , Sakashita Reiko
Published: June 2024

The process by which stroke survivors move toward health while facing various difficulties can be construed as a “transition.” Importantly, nurses need to understand and support this state of transition effectively. This study developed a situation-specific theory to explain post-stroke transition by integrating the findings of a qualitative study that explored the rehabilitation experiences of stroke survivors with dysphagia with a scoping review of qualitative studies using the theoretical framework of transition theory. This theory will help understand the transitions that stroke survivors with dysphagia undergo during recovery and provide a framework for exploring nursing care to support healthy transitions.
Tumor Deposits as an Adverse Prognostic Indicator in Stage III Colon Cancer: A Multicenter Database Study
Authors: Kim Jeeyou , Lee Dong Woon , Park Ji Won , Ryoo Seung-Bum , Oh Heung-Kwon , Shin Rumi , Choi Jin Sun , Kim Min Jung , Park Sung-Chan , Kim Duck-Woo , Heo Seung Chul , Kang Sung-Bum , Jeong Seung-Yong , Park Kyu Joo , Oh Jae Hwan ,   On Behalf of the Seoul Colorectal Research Group (SECOG)
Published: June 2024

Objective:

We explored the oncological impact of tumor deposits (TDs) on colon cancer and proposed optimal modifications to the current staging system.

Background:

In the existing American Joint Committee on Cancer colon cancer staging system, TDs are incorporated into the N category as N1c. When lymph node metastases (LNMs) are present, their number is considered to determine nodal stages, such as N1a/b or N2a/b, regardless of TDs.

Methods:

4212 patients with primary colon cancer who underwent surgical resection in the Seoul Colorectal Group (2010–2020) and 93,057 patients from the Surveillance, Epidemiology, and End Results*Stat database (2000–2017) were included in this study. Patients were classified according to the number of metastatic lymph nodes (LNs) (0/1–3/≥4) and the presence of TDs.

Results:

TDs were significantly associated with left colon cancer, a higher T category, and vascular/perineural invasion. Patients with TDs had higher recurrence rates (23.1 vs 7.5%, P < 0.001). The TD-positive patients had notably worse overall survival (OS) and recurrence-free survival rates. The survival outcomes of TD-positive patients without LNM were inferior to those of TD-negative patients with LN1–3 (5-year OS: 78.9 vs 87.8%, P = 0.04). The survival outcomes of TD-positive patients with LN1–3 were similar to those of TD-negative patients with LN ≥4 (5-year OS: 87.0 vs 77.1%, P = 0.11). Survival outcomes obtained using the Surveillance, Epidemiology, and End Results *Stat database yielded consistent results.

Conclusions:

TDs were associated with poor prognostic factors and had a significant impact on survival outcomes. The incorporation of tumor deposits into nodal classifications beyond the current N1c criteria may improve the staging system and more accurately reflect the recurrence and survival rates among patients with colon cancer. TD-positive in N1a or N1b could be categorized as N2.
High Levels of Triggering Receptor Expressed in Myeloid Cells-Like Transcript-1 Positive, but Not Glycoprotein 1b+, Microparticles Are Associated With Poor Outcomes in Acute Respiratory Distress Syndrome
Authors: Gibson Angelia D. , Bayrón-Marrero Zaida , Nieves-Lopez Benjamin , Maldonado-Martínez Gerónimo , Washington A. Valance
Published: June 2024

OBJECTIVES:

To identify triggering receptor expressed in myeloid cells-like transcript-1 positive (TLT-1+) microparticles (MPs) and evaluate if their presence is associated with clinical outcomes and/or disease severity in acute respiratory distress syndrome (ARDS).

DESIGN:

Retrospective cohort study.

SETTING:

ARDS Network clinical trials.

PATIENTS:

A total of 564 patients were diagnosed with ARDS.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Using flow cytometry, we demonstrated the presence of TLT-1+ platelet-derived microparticles (PMP) that bind fibrinogen in plasma samples from fresh donors. We retrospectively quantified TLT-1, glycoprotein (Gp) 1b, or αIIbβIIIa immunopositive microparticles in plasma samples from patients with ARDS enrolled in the ARMA, KARMA, and LARMA (Studies 01 and 03 lower versus higher tidal volume, ketoconazole treatment, and lisofylline treatment Clincial Trials) ARDS Network clinical trials and evaluated the relationship between these measures and clinical outcomes. No associations were found between Gp1b+ MPs and clinical outcomes for any of the cohorts. When stratified by quartile, associations were found for survival, ventilation-free breathing, and thrombocytopenia with αIIbβIIIa
+ and TLT-1+ MPs (χ2
p < 0.001). Notably, 63 of 64 patients in this study who failed to achieve unassisted breathing had TLT+ PMP in the 75th percentile. In all three cohorts, patients whose TLT+ MP counts were higher than the median had higher Acute Physiology and Chronic Health Evaluation III scores, were more likely to present with thrombocytopenia and were 3.7 times (p < 0.001) more likely to die than patients with lower TLT+ PMP after adjusting for other risk factors.

CONCLUSIONS:

Although both αIIbβIIIa
+ and TLT+ microparticles (αIIbβIIIa, TLT-1) were associated with mortality, TLT-1+ MPs demonstrated stronger correlations with Acute Physiology and Chronic Health Evaluation III scores, unassisted breathing, and multiple system organ failure. These findings warrant further exploration of the mechanistic role of TLT-1+ PMP in ARDS or acute lung injury progression.
Pulmonary comorbidities in people with HIV− the microbiome connection
Authors: Bai Xiangning , Nielsen Susanne Dam , Kunisaki Ken M. , Trøseid Marius
Published: June 2024

Purpose of review

To report recent evidence on associations between human microbiome, particularly airway and gut, and pulmonary comorbidities in people with HIV (PWH). Furthermore, we explore how changes in the microbiome may contribute to pulmonary immune dysregulation and higher rates of pulmonary comorbidities among PWH. Finally, we propose future directions in the field.

Recent findings

Increased risk of pulmonary comorbidities and rapid lung function decline have been reported in even well treated PWH. Altered microbiota profiles have been reported in PWH with pulmonary comorbidities and rapid lung function decline as compared to those without. The most consistent data have been the association between HIV-related pulmonary comorbidities, lung and oral microbiota dysbiosis, which has been also associated with distinct respiratory mucosal inflammatory profiles and short-term mortality. However, a possible causal link remains to be elucidated.

Associations between the lung and oral microbiome, HIV-associated pulmonary comorbidities and rapid lung function decline have been reported in recent studies. Yet the underlying mechanism underpinning the observed associations is largely unknown and substantial knowledge gaps remain. Future research is warranted to unveil the role and mechanism of human microbiome from different anatomical compartments in relation to pulmonary comorbidities in PWH.
Beyond the cuff: a consideration of factors that affect sexual function after benign hysterectomy
Authors: Cohen Natalie , Young Riley , Lin Emily , Chao Lisa
Published: June 2024

Purpose of review

Hysterectomy is the most common gynecologic surgical procedure performed on women in the United States. While there are data supporting that hysterectomy for benign indication often does not reduce sexual function and may in fact improve sexual function as fibroids and endometriosis are resected, it remains unclear if there are factors within the perioperative period that affect sexual function in the years following surgery. To date, there is no consensus on what factors can optimize patients’ sexual function after hysterectomy.

Recent findings

We present the current literature that assesses factors which may contribute to sexual function after hysterectomy. Preoperative demographic factors, including increasing age, pelvic pain, and preoperative sexual dysfunction, play a large role in postoperative sexual function. Perioperatively, there is a growing amount of data suggesting that premenopausal salpingo-oophorectomy at the time of hysterectomy may increase the risk of sexual dysfunction after hysterectomy, and no conclusive evidence that subtotal hysterectomy improves sexual function. The route of hysterectomy and technique of cuff closure can impact sexual function after hysterectomy due to the risk of shortening the vaginal length.

There is a lack of high-quality evidence that can provide a consensus on factors to optimize sexual function after hysterectomy. A growing area of research in the excision of endometriosis procedures is the consideration of nerve-sparing surgery. Considering the many variables that exist when counseling a patient on benign hysterectomy and its effects on sexual function, it is critical to understand the current research that exists with regards to these factors.
Can a Breast Augmentation Procedure Improve the Appearance of Pectus Excavatum Deformity in Female Patients? A Prospective Study
Authors: Keramidas Evangelos , Rodopoulou Stavroula , Gavala Maria-Ioanna
Published: June 2024

Background:

This study evaluates a specific breast augmentation (BA) technique in patients with pectus excavatum(PE) and its results in improving this deformity, augmenting the breasts, and correcting the concurrent breast asymmetry.

Methods:

Twenty-eight patients with PE were treated from 2017 to 2021. All patients who visited our private practice were aiming to augment their breasts, correct their breast asymmetry, and improve their PE. The mean age of the patients was 25 years. In most cases, the submuscular dual-plane technique was chosen. Patients’ quality of life regarding their chest wall deformity was assessed using the Single Step Questionnaire (SSQ). Subjects’ quality of life regarding general self-esteem, psychosocial well-being, and physical function were assessed at initial screening and 24-month follow-up using the BREAST-Q V2 questionnaire. Also, patients filled out a pain-evaluating questionnaire concerning the first 5 postoperative days to determine the recovery of this specific technique.

Results:

No complications were observed. The SSQ revealed high satisfaction (mean score=73) and significant (P = 0.001) improvement following the operation. The improvements regarding psychosocial well-being, sexual well-being, and satisfaction with the BREAST-Q were also equally high (P = 0.001). The pain was minimal during the first five postoperative days. This is the first prospective study that evaluates the quality of life using both the SSQ, the validated BREAST-Q, and the pain score when performing BA in patients with PE and breast asymmetry using breast silicone implants.

Conclusions:

BA is a procedure that can give excellent results both regarding chest wall deformity and BA in PE patients.
Hepatocyte-specific loss of DDB1 attenuates hepatic steatosis but aggravates liver inflammation and fibrosis in MASH
Authors: Gu Qiuxia , Chang Yushun , Jin Yan , Fang Jing , Ji Tong , Lin Jie , Zhu Xi , Dong Binzhi , Ying Hanning , Fan Xiaoxiao , Li Zheyong , Gao Zerui , Zhu Yongfen , Tong Yifan , Cai Xiujun
Published: June 2024

Background:

MASH is a common clinical disease that can lead to advanced liver conditions, but no approved pharmacotherapies are available due to an incomplete understanding of its pathogenesis. Damaged DNA binding protein 1 (DDB1) participates in lipid metabolism. Nevertheless, the function of DDB1 in MASH is unclear.

Methods:

Clinical liver samples were obtained from patients with MASH and control individuals by liver biopsy. Hepatocyte-specific Ddb1-knockout mice and liver Hmgb1 knockdown mice were fed with a methionine-and choline-deficient diet to induce MASH.

Results:

We found that the expression of DDB1 in the liver was significantly decreased in MASH models. Hepatocyte-specific ablation of DDB1 markedly alleviated methionine-and choline-deficient diet-induced liver steatosis but unexpectedly exacerbated inflammation and fibrosis. Mechanistically, DDB1 deficiency attenuated hepatic steatosis by downregulating the expression of lipid synthesis and uptake genes. We identified high-mobility group box 1 as a key candidate target for DDB1-mediated liver injury. DDB1 deficiency upregulated the expression and extracellular release of high-mobility group box 1, which further increased macrophage infiltration and activated HSCs, ultimately leading to the exacerbation of liver inflammation and fibrosis.

Conclusions:

These data demonstrate the independent regulation of hepatic steatosis and injury in MASH. These findings have considerable clinical implications for the development of therapeutic strategies for MASH.
How Do Occupational Physicians Address Employees’ Financial Problems? An Exploratory Interview Study Into Current Practice and Potential Improvements
Authors: Heezen Toine , van Berkel Jantien
Published: June 2024

Objective

Problematic debt poses a considerable challenge in the Netherlands, impacting health and work-related outcomes. Occupational physicians play a vital role in guiding absent employees and identifying work-related risk factors for illness. This study investigates how occupational physicians address financial issues among employees and proposes improvements.

Methods

Semistructured interviews were conducted with a diverse group of 12 occupational physicians and residents.

Results

Thematic content analysis revealed that while physicians do not routinely inquire about financial problems, they approach socioeconomic concerns cautiously and consider multiple (structural and individual) risk factors. Current interventions include budget coaching and lifestyle enhancements.

Conclusions

Despite awareness, current interventions focus on immediate advice targeting downstream factors (ie, social determinants at the individual level), thereby overlooking structural, upstream factors (ie, social determinants on a societal and systemic level) of employees’ financial problems. Exploring systems approaches, targeting both individual and structural factors, and more attention for this subject in occupational physicians education, are considered crucial for future effective approaches.
The performance of large language model-powered chatbots compared to oncology physicians on colorectal cancer queries
Authors: Zhou Shan , Luo Xiao , Chen Chan , Jiang Hong , Yang Chun , Ran Guanghui , Yu Juan , Yin Chengliang
Published: June 2024

Background:

Large language model (LLM)-powered chatbots have become increasingly prevalent in healthcare, while their capacity in oncology remains largely unknown. To evaluate the performance of LLM-powered chatbots compared to oncology physicians in addressing colorectal cancer queries.

Methods:

This study was conducted between August 13, 2023, and January 5, 2024. A total of 150 questions were designed, and each question was submitted three times to eight chatbots: ChatGPT-3.5, ChatGPT-4, ChatGPT-4 Turbo, Doctor GPT, Llama-2-70B, Mixtral-8x7B, Bard, and Claude 2.1. No feedback was provided to these chatbots. The questions were also answered by nine oncology physicians, including three residents, three fellows, and three attendings. Each answer was scored based on its consistency with guidelines, with a score of 1 for consistent answers and 0 for inconsistent answers. The total score for each question was based on the number of corrected answers, ranging from 0 to 3. The accuracy and scores of the chatbots were compared to those of the physicians.

Results:

Claude 2.1 demonstrated the highest accuracy, with an average accuracy of 82.67%, followed by Doctor GPT at 80.45%, ChatGPT-4 Turbo at 78.44%, ChatGPT-4 at 78%, Mixtral-8x7B at 73.33%, Bard at 70%, ChatGPT-3.5 at 64.89%, and Llama-2-70B at 61.78%. Claude 2.1 outperformed residents, fellows, and attendings. Doctor GPT outperformed residents and fellows. Additionally, Mixtral-8x7B outperformed residents. In terms of scores, Claude 2.1 outperformed residents and fellows. Doctor GPT, ChatGPT-4 Turbo, and ChatGPT-4 outperformed residents.

Conclusions:

This study shows that LLM-powered chatbots can provide more accurate medical information compared to oncology physicians.
Efficacy and safety of perioperative application of esketamine on postoperative depression: a meta-analysis of randomized controlled studies
Authors: Wen Yazhou , Mao Mingjie , Jiang Ming , Liu Qiaoqiao , Li Qian , Wang Xuan , Yuan Hongmei , Wang Xian , Feng Shanwu
Published: June 2024

Background:

Postoperative depression has a profound impact on patients’ postoperative rehabilitation and overall quality of life. Preventing postoperative depression is of significant value because conventional antidepressants have a slow onset of action. Esketamine showed prompt and sustained antidepressant efficacy. Nevertheless, the safety and effectiveness of perioperative esketamine in preventing postoperative depression are still unknown. The purpose of this meta-analysis was to assess the safety and effectiveness of perioperative intravenous esketamine in relation to its ability to prevent postoperative depression.

Materials and methods:

Randomized controlled trials were searched in the following databases: Web of Science, Cochrane Central Registry of Controlled Trials, PubMed, and Embase. The primary outcome assessed is the postoperative depression scores. Postoperative pain ratings and adverse effects constituted secondary outcomes. Subgroup analyses were carried out on the basis of multiple variables, including the absence or presence of preoperative depression, the mode of esketamine administration, the dosage of esketamine, and the type of anesthesia.

Results:

A total of 16 studies encompassed 1161 patients who received esketamine intervention, whereas 1106 patients served as controls. Esketamine was efficacious in reducing postoperative depression scores when administered perioperatively, and the esketamine group maintained a lower postoperative depression score than the control group more than 4 weeks after surgery. Esketamine effectively alleviated postoperative pain scores without increasing the occurrence of postoperative nausea and vomiting, dizziness, drowsiness, nightmares, and dissociation.

Conclusion:

The administration of esketamine during the perioperative has the potential to decrease postoperative depression and pain scores without increasing the incidence of adverse effects.
Effect of metformin on hepatocellular carcinoma patients with type II diabetes receiving transarterial chemoembolization: a multicenter retrospective cohort study
Authors: Chen Lei , Wu Linxia , Zhang Lijie , Sun Bo , Wu Wenlong , Lei Yu , Zhu Licheng , Sun Tao , Liang Bin , Zhao Huangxuan , Zheng Chuansheng
Published: June 2024

Background:

Diabetes is prevalent among patients with hepatocellular carcinoma (HCC) and is associated with a poor prognosis. Although the hypoglycemic drug metformin has shown antitumor effects, its potential positive effect on patients with HCC and diabetes undergoing transarterial chemoembolization (TACE) remains unclear. Therefore, this study aimed to investigate the efficacy and safety of metformin in patients with HCC and type II diabetes who are receiving TACE.

Materials and methods:

This retrospective study involved 372 consecutive patients with HCC and type II diabetes across three medical centers between January 2014 and June 2021. All patients underwent TACE. Propensity score matching (PSM) was used to reduce selection bias. Cox proportional hazards regression was employed to compare all-cause death between the metformin and nonmetformin groups while competing risk regression was performed to assess cancer-specific death.

Results:

Among 372 patients included in the study, 208 patients (177 male patients and 31 female patients) with a mean age of 59.6 (10.3) years received metformin, and 164 patients (139 male patients and 25 female patients) with a mean age of 60.3 (10.0) years did not. Before PSM, patients with metformin had significantly longer median overall survival (mOS) and median progression-free survival (mPFS) than those without metformin (mOS: 34 months, 95% CI: 25.6–42.4 vs. 20 months, 95% CI: 15.3–24.7; P<0.001; mPFS: 11 months, 95% CI: 9.3–12.7 vs. 8 months, 95% CI: 5.9–10.1; P<0.001). Similar results were observed after PSM. Multivariate regression analysis indicated that metformin was associated with a reduced risk of all-cause mortality (HR: 0.589, 95% CI: 0.454–0.763; P<0.001) and tumor progression (HR: 0.667, 95% CI: 0.526–0.845; P=0.001) before PSM. After excluding deaths related to other factors, metformin continued to demonstrate a reduction in cancer-specific mortality risk among the patients. Subgroup analysis further revealed that patients using metformin had lower all-cause mortality risk and tumor progression risk than those without metformin in most subgroups. Adverse event evaluation suggested that metformin could lead to elevated nausea incidence.

Conclusion:

Metformin may confer survival benefits to patients with HCC and type II diabetes undergoing TACE. Metformin may simultaneously address multiple aspects of treatment in these patients.
Favorable prostate-specific antigen levels correlate with a worse prognosis in high-grade prostate cancer: a population-based analysis
Authors: Liu Zenan , Hong Peng , He Jide , Li Ziang , Wu Jialong , Qiu Lei , Zhao Zhenkun , Lu Jian
Published: June 2024

Background:

To compare the association between prostate-specific antigen (PSA) levels and prostate cancer-specific mortality (PCSM) and the effectiveness of local treatment in patients with high-grade and low-grade prostate cancer (PCa).

Methods:

This retrospective cohort study enrolled patients diagnosed with clinically localized PCa (cT1-4N0M0) from January 2010 to December 2020 in the Surveillance, Epidemiology, and End Results (SEER) database. Fine-Gray competing risk regression analysis was conducted to generate cumulative incidence plots and estimate the hazard ratio (HR) and 95% CI of PCSM. Multivariable restricted cubic spline analysis was used to examine the nonlinear associations of continuous values of PSA levels with PCSM. Inverse probability of treatment weighting was employed to minimize imbalances in baseline characteristics between different local treatment cohorts.

Results:

A total of 392 083 eligible patients were included in the study, including 327 659 low-grade (Gleason score [GS]≤7) PCa and 64424 high-grade (GS≥8) PCa. In multivariate Fine-Gray competing risk regression analysis, using PSA levels of 4.1–10.0 ng/ml as the reference, the adjusted HR among high-grade patients with PSA levels ≤2.5 ng/ml, 2.6–4.0 ng/ml, 10.1–20.0 ng/ml and >20.0 ng/ml were 1.988 (95% CI: 1.677–2.358), 1.411 (95% CI: 1.194–1.668), 1.472 (95% CI: 1.351–1.603), and 2.506 (95% CI: 2.318–2.709), respectively. Among low-grade PCa, the adjusted HR were 0.985 (95% CI: 0.800–1.213), 0.727 (95% CI: 0.602–0.877), 1.844 (95% CI: 1.679–2.026), and 3.574 (95% CI: 3.220–3.966), respectively. Multivariable-adjusted restricted cubic spline analysis showed a U/J-shaped distribution relationship between PSA levels and PCSM in high-grade PCa, while there was a positive association between PSA levels and PCSM in low-grade PCa. As for local treatment effectiveness, radiation therapy (RT) provided better control of PCSM compared to radical prostatectomy (RP) and RP+RT in high-grade PCa, while RP provided better control of PCSM compared to RT and RP+RT in low-grade PCa.

Conclusion:

Low PSA level (≤2.5 ng/ml) is significantly associated with a very high-risk of PCSM in high-grade localized PCa but not in low-grade localized PCa. High-grade localized PCa patients benefit more from RT in terms of PCSM control, while low-grade localized PCa patients benefit more from RP. High-grade localized PCa with low PSA level may be a unique subgroup that could benefit from novel risk stratification strategies in PCa, which requires further studies to investigate the potential of developing novel therapeutic strategies, prognostic tools, and clinical management approaches.
Climate change, microplastics, and male infertility
Authors: Daniels Danesha , Berger Eberhardt Alexandra
Published: June 2024

Purpose of review

Semen quality is on the decline. While the etiology is unknown, recent literature suggests there may be a relationship between climate change, environmental toxins and male fertility. This review relays new information regarding associations between our environment and male infertility.

Recent Findings

Several recent studies have documented a negative association between heat stress and spermatogenesis, which suggests that climate change may be a factor in declining in sperm counts. The influence of particle pollution on spermatogenesis has also been recently investigated, with studies demonstrating a negative association. Another possible factor are microplastics, which have been posited to reduce sperm production. Recent animal studies have shown that microplastic exposure alters both adult sperm production and prenatal male genital development. The relationship between endocrine disrupting chemicals and male fertility remains an area of active study, with recent animal and human studies suggesting an association between these chemicals and male fertility.

The etiology of the decline in male fertility over the past decades is yet unknown. However, changes in our environment as seen with climate change and exposure to pollutants and endocrine disrupting chemicals are proposed mechanisms for this decline. Further studies are needed to investigate this association further.
Combining Brentuximab Vedotin With Dexamethasone, High-dose Cytarabine, and Cisplatin as Salvage Treatment in Pediatric Relapsed or Refractory Classic Hodgkin Lymphoma: Two Case Reports
Authors: Muggeo Paola , Sinisi Carmen , Angarano Rosa , Daniele Rosa Maria , Grassi Massimo , Ingravallo Giuseppe , Santoro Nicola
Published: June 2024

Hodgkin lymphoma (HL) is among the most commonly occurring malignancies in adolescents. For relapsed/refractory disease, many regimens have been proposed. Novel agents are increasingly used, like brentuximab vedotin (BV), an antiCD30 antibody-drug conjugate, used as a single agent or in combination with classic regimens mainly in adults, while limited is the experience in pediatrics. We report here on 2 boys with aggressive and high-risk relapsed HL, successfully treated with the BV plus dexamethasone, high-dose cytarabine, cisplatin regimen as induction salvage treatment. Our experience provides real-world evidence on the use of BV-dexamethasone, high-dose cytarabine, cisplatin as first-line salvage therapy for relapsed/refractory HL and expands the current therapeutic choices.
Absence of Neutropenia in Patients With Early Exon Nonsense Mutations in ELANE: Clinical Evidence to Support Gene Therapy Approaches for Severe Congenital Neutropenia
Authors: Joos Margret , Chang Timothy H. , Shimamura Akiko , Newburger Peter E.
Published: June 2024

Severe congenital neutropenia is an inherited bone marrow failure disorder characterized by profoundly low neutrophil counts and promyelocytic maturation arrest in bone marrow. Severe congenital neutropenia is most often caused by heterozygous ELANE mutations. In vitro and mouse xenograft studies using CRISPR/Cas9 have shown that introduction of frameshift/nonsense mutations in mutant ELANE may restore neutrophil counts, providing a model for gene therapy. Here, we present 2 children with inherited nonsense mutations in ELANE analogous to those proposed for gene therapy. Their normal peripheral blood neutrophil counts provide support for this approach through human “experiments of nature.”
Integrating Nurse-Led Interventions in Ophthalmology Care
Authors: Zhang Yufen , Cao Naiyue
Published: June 2024

Background:

Nurse-led interventions in ophthalmology care can enhance the overall patient experience while optimizing health care system efficiency.

Purpose:

The purpose of this study was to investigate the impact of nurse-led interventions in ophthalmology care.

Methods:

A comprehensive search was conducted across multiple databases for articles published from 2000 to 2023. Randomized controlled trials, quasi-experimental, and observational studies were included. Quality assessments were performed using the Cochrane Risk of Bias tool or Newcastle-Ottawa Scale, based on study design.

Results:

Nineteen studies were included. Nurse-led interventions positively impacted patient outcomes, improved efficiency and resource utilization, enhanced patient satisfaction and adherence, maintained safety and efficacy, and demonstrated notable diagnostic accuracy. Included studies originated from different countries and employed diverse methodologies, offering a global perspective on nurse-led interventions in ophthalmology care.

Conclusion:

The findings advocate for the integration of nurse-led strategies in routine practice to realize equitable, efficient, and patient-centered eye care.
The Rise of Congenital Syphilis as a Public Health Emergency
Authors: Allan-Blitz Lao-Tzu , Stafford Irene , Klausner Jeffrey D.
Published: June 2024

Even though affordable, safe, and effective tools for diagnosing and preventing congenital syphilis have been available for decades, in the past 10 years, the incidence of congenital syphilis has increased by more than 1,000% in the United States. Driven by a lack of access to equitable care—particularly for underserved communities—low clinician and patient awareness, and the unresolved national shortage of benzathine penicillin G, the dramatic rise in incidence of syphilis constitutes a public health emergency. Such a declaration would permit mobilization of the necessary resources to counteract the rising rates of congenital syphilis. It is essential that our political leadership act now, before countless families and communities are further affected.
Out-of-State Abortion Training Rotations for Residents in States With Limited Access
Authors: Turk Jema K. , Simonson Kristin , Claymore Emily , Dawoodbhoy Nafeesa , Steele Heather , Steinauer Jody E.
Published: June 2024

State laws that restrict abortion also impede abortion training, which is required by the Accreditation Council for Graduate Medical Education for obstetrics and gynecology programs. After the enactment of Texas Senate Bill 8 in September 2021 and 1 year after Dobbs v. Jackson Women's Health Organization, the Ryan Program facilitated partnerships between 13 obstetrics and gynecology residency programs in restrictive states and 13 programs in protective states for resident training. We describe the experiences of residents who traveled within these partnerships through postrotation surveys about training experiences, practice intentions, and alignment with the learning objectives. From April 2022 to August 2023, 60 residents traveled and 35 completed surveys (58.3%). Residents reported that the rotation met learning objectives, including extensive exposure to all abortion methods, and most intend to provide abortions in practice.
A Comprehensive Clinicopathologic and Molecular Reappraisal of GLI1-altered Mesenchymal Tumors with Pooled Outcome Analysis Showing Poor Survival in GLI1- amplified Versus GLI1-rearranged Tumors
Authors: Saoud Carla , Agaimy Abbas , Dermawan Josephine K. , Chen Jie-Fu , Rosenblum Marc K. , Dickson Brendan C. , Dashti Nooshin , Michal Michael , Kosemehmetoglu Kemal , Din Nasir Ud , Albritton Karen , Agaram Narasimhan P. , Antonescu Cristina R.
Published: June 2024

GLI1-altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1-altered mesenchymal neoplasms to date, including 23 GLI1-amplified and 15 GLI1-rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1-rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1-amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1-amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1-amplified tumors. GLI1-amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1-amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1-rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1-amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1-rearranged group. Despite comparable progression rates, GLI1-amplified tumors had a shorter median progression-free survival compared with GLI1-rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1-altered mesenchymal tumors.
PEComa With MITF Overexpression
Authors: Hanna John , Russell-Goldman Eleanor , Baranov Esther , Pissaloux Daniel , Li Yvonne Y. , Tirode Franck , de la Fouchardiere Arnaud , Fletcher Christopher D.M.
Published: June 2024

Perivascular epithelioid cell neoplasms (PEComas) are tumors of uncertain cell lineage that occur across a wide age range, at a variety of anatomic sites, and with a female predominance. Most PEComas are associated with dysregulation of the mTOR pathway, most commonly through inactivating mutations of TSC2 or TSC1. However, a small subset of PEComas are instead associated with TFE3 gene fusions. MITF is closely related to TFE3 and is frequently overexpressed in PEComas, often in a mutually exclusive manner with TFE3. Here we report the clinical, histopathologic, and molecular features of MITF-overexpressing PEComas in a series of 36 cases. The clinical and morphologic features were comparable to conventional PEComa, although the immunohistochemical profile was notable for the relatively limited expression of melanocytic markers, a surprising finding given that MITF is the master regulator of melanocytic differentiation. At the molecular level, 20 cases (56%) showed supernumerary copies of the MITF gene, suggesting a potential explanation for MITF overexpression. A putative genetic driver event within the mTOR pathway was identified in 11 of 15 cases (73%) analyzed by DNA or RNA sequencing. Interestingly, the malignant PEComas showed 2 distinguishing molecular features: they were associated with a complex chromosomal copy number profile, and they tended to show additional genetic changes, most commonly inactivating events involving TP53, RB1, and ATRX. These results elucidate key features of PEComas showing MITF overexpression, begin to explain the molecular basis for MITF overexpression in some PEComas and identify potential molecular correlates for malignancy that may be applicable to the broader PEComa family.
Incidental 68Ga-PSMA Uptake in the Benign Enchondroma—A Rare Finding on 68Ga-PSMA PET/CT
Authors: Singh Parneet , Kandula Keerthana Kiran , Patel Ranjan Kumar , Parida Girish Kumar , Agrawal Kanhaiyalal
Published: June 2024

68Ga-PSMA (prostate-specific membrane antigen)-HBED-CC (N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid) PET/CT is the new advancement in oncological imaging. However, false-positive uptake can be seen in benign lesions on 68Ga-PSMA PET/CT. We describe a rare case of intense 68Ga-PSMA uptake in an enchondroma confirmed on MRI.
Amygdala-predominant α-synuclein pathology exacerbates hippocampal neuron loss in Alzheimer’s disease
Authors: Gawor Klara , Tomé Sandra , Vandenberghe Rik , Van Damme Philip , Vandenbulcke Mathieu , Otto Markus , von Arnim Christine A.F. , Ghebremedhin Estifanos , Ronisz Alicja , Ospitalieri Simona , Blaschko Matthew , Thal Dietmar R.
Published: June 2024

Misfolded α-synuclein (αSyn) protein accumulates in 43-63% of individuals with symptomatic Alzheimer’s disease (AD). Two main patterns of co-morbid αSyn pathology have been identified: caudo-rostral and amygdala-predominant, with the latter being more common in AD. αSyn pathology has been shown to interact with DNA-binding protein 43 (TDP-43) and abnormally phosphorylated Tau protein (pTau). These proteins tend to accumulate in the amygdala, yet the specific role of amygdala-predominant αSyn pathology in the progression of AD and hippocampal degeneration remains unclear.

In this cross-sectional study, we analyzed 291 autopsy brains from both demented and non-demented elderly individuals neuropathologically. Neuronal density in the CA1 region of the hippocampus was assessed using hematoxylin-stained sections for all cases. We semi-quantitatively evaluated αSyn pathology severity in six brain regions and stratified the cases into the two spreading patterns. In 99 AD cases, we assessed limbic-predominant age-related TDP-43 neuropathological changes (LATE-NC), CA1 pTau density, and cerebral amyloid angiopathy (CAA). Structural equation modeling analysis was conducted based on the assessed pathological parameters in AD patients.

We identified an association between the amygdala-predominant αSyn pathology pattern and decreased neuronal density in the CA1 region. AD patients with an amygdala-predominant αSyn pattern exhibited the most severe pTDP-43 pathology among all groups, while those with the caudo-rostral pattern had the lowest severity of AD-related pathological changes including CAA type 1. Our model revealed that the relationship between αSyn pathology and CA1 neuron loss is mediated through pTau and LATE-NC.

Our results indicate that amygdala-predominant αSyn pathology, in contrast to αSyn pathology with a caudo-rostral pattern, significantly contributes to hippocampal neuron loss, potentially by accelerating TDP-43 and pTau pathologies. This finding, along with observed neuropathological differences between AD patients with these two αSyn spreading patterns, underscores the need for precise stratification of patients. The stratification should consider not only the molecular and morphological identity of co-pathologies but also the distribution pattern of the respective co-pathologies.
Recent neo-X and Y sex chromosomes in an ant cricket
Authors: Mérel Vincent , Vogel Simon , Lavanchy Guillaume , Dumas Zoé , Labédan Marjorie , Stalling Thomas , Schwander Tanja
Published: June 2024

In eukaryotes with separate sexes, sex determination often involves heteromorphic sex chromosomes which have diverged as a consequence of recombination suppression. In species with very old heteromorphic sex chromosomes, mechanisms such as dosage compensation and meiotic sex chromosome inactivation adjust for the fact that sex chromosomes occur as a single copy in the heterogametic sex. However, how such mechanisms evolve remains largely unknown because species with young sex chromosomes characterised by recent recombination suppression remain understudied. We discovered such young neo-sex chromosomes in the ant cricketMyrmecophilus myrmecophilus, which displays a neo-XY system. We generated a chromosomal-level assembly of the female genome and compared it to male genomic data and identified four evolutionary strata on the X, with varying degrees of Y chromosome degeneration. Phylogenetic studies and genomic comparisons with closely related species revealed two cases of taxonomic synonymies and that theMyrmecophilusneo-sex chromosomes likely evolved approximately 7 million years ago from an X-autosome fusion. The X strata subsequently emerged as a consequence of two localised events of recombination suppression. Ant crickets thus represent a promising new model for studying the early stages of sex chromosome degeneration and the establishment of processes such as dosage compensation or meiotic sex chromosome inactivation.
Fokker-Planck diffusion maps of multiple single cell microglial transcriptomes reveals radial differentiation into substates associated with Alzheimer’s pathology
Authors: Baumgartner Andrew , Robinson Max , Golde Todd , Jaydev Suman , Huang Sui , Hadlock Jennifer , Funk Cory
Published: June 2024

The identification of microglia subtypes is important for understanding the role of innate immunity in neu-rodegenerative diseases. Current methods of unsupervised cell type identification assume a small noise-to-signal ratio of transcriptome measurements that would produce well-separated cell clusters. However, identification of subtypes is obscured by gene expression noise, diminishing the distances in transcriptome space between distinct cell types and blurring boundaries. Here we use Fokker-Planck (FP) diffusion maps to model cellular differentiation as a stochastic process whereby cells settle into local minima, corresponding to cell subtypes, in a potential landscape constructed from transcriptome data using a nearest neighbor graph approach. By applying critical transition fields, we identify individual cells on the verge of transitioning between subtypes, revealing microglial cells in inactivated, homeostatic state before radially transitioning into various specialized subtypes. Specifically, we show that cells from Alzheimer’s disease patients are enriched in a microglia subtype associated to antigen presentation and T-cell recruitment.
The Hippo pathway effector YAP inhibits NF-kB signaling and ccRCC growth by opposing ZHX2
Authors: Li Xu , Cho Yong , Liu Yuchen , Yang Yingzi , Zhuo Shu , Jiang Jin , Han Yuhong , Zhou Mengmeng
Published: June 2024

The prevailing view in the cancer field is that Hippo signaling pathway functions as a tumor suppressor pathway by inhibiting the oncogenic potential of pathway effectors YAP/TAZ. However, YAP can also function as a context-dependent tumor suppressor in several types of cancer including clear cell renal cell carcinomas (ccRCC). Here we show that YAP blocks NF-kB signaling in ccRCC to inhibit cancer cell growth. Mechanistically, YAP inhibits the expression of ZHX2, a critical p65 co-factor in ccRCC. Furthermore, YAP competes with ZHX2 for binding to p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and p65, leading to diminished NF-kB target gene expression. Pharmacological inhibition of Hippo/MST1/2 blocked NF-κB transcriptional program and suppressed ccRCC cancer cell growth, which can be rescued by ZHX2/p65 overexpression. Our study uncovers a crosstalk between the Hippo and NF-kB/ZHX2 pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hippo pathway may provide a therapeutical opportunity for ccRCC treatment.
Glacier retreat decreases plant-pollinator network robustness over space-time
Authors: Conti Matteo , Cerretti Pierfilippo , Ferrari Andrea , Gabrieli Paolo , Paone Francesco , Polidori Carlo , Losapio Gianalberto
Published: June 2024

Glaciers are retreating worldwide at an ever-increasing rate, exposing new ice-free areas to ecological succession. This process leads to changes in biodiversity and potentially to species interactions. However, we still have a limited understanding of how glacier retreat influences species interaction networks, particularly the structure and robustness of mutualistic networks. After reconstructing plant-pollinator networks along a glacier foreland, we address the effects of glacier retreat on pollination network structure and robustness. Our results show that the prevalence of different network motifs changes over space-time. With glacier retreat, pollination networks shift from being highly connected with specialist interactions to loosely connected with generalist interactions. Furthermore, network robustness decreased with glacier retreat. Despite the turnover of plant species, we find that structural roles played by different plant species stay constant over space-time. Our findings suggest that glacier retreat pushes pollination networks towards a loss of specialist interactions and low robustness, leading to increased fragility in the long term. Monitoring network motifs may provide valuable insights into the ability of novel pollination networks to withstand disturbances and preserve functionality in the face of glacier extinction.