bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Follow-Up Visit Timing After A Concussion and Subsequent Care Seeking in Children and Youth: A Population-Based Study in British Columbia
Authors: Ramsay Scott , Dahinten V. Susan , Ranger Manon , Babul Shelina , Saewyc Elizabeth
Published: November 2024

Objective:

To assess the relationship between follow-up visit timing and occurrence of the first subsequent health care seeking visit.

Setting:

The province of British Columbia, Canada.

Participants:

A total of 21 029 children and youth who were diagnosed with an initial concussion from January 1, 2016, to December 31, 2017. These data were obtained from Population Data BC.

Design:

A retrospective, descriptive correlational study.

Main Measures:

Follow-up timing was measured categorically as timely (4 weeks), delayed (1–3 months), or no follow-up; the occurrence of a subsequent health care visit beyond 3 months postinjury was measured up to 12 months at 3-month intervals (ie, 4-6, 7-9, and 10-12 months). These variables were measured using diagnostic codes for concussion, post-concussion syndrome, and the 17 concussion symptoms.

Results:

After controlling for sociodemographic characteristics, having a delayed follow-up, relative to timely follow-up, was associated with higher odds of a subsequent health care seeking visit at 4 to 6 months (odds ratio [OR] = 2.68; confidence interval [CI], 2.08-3.47), 7 to 9 months (OR = 1.71; CI, 1.21-2.40), and 10 to 12 months (OR = 1.67; CI, 1.13-2.48). In contrast to having a delayed follow-up, having no follow-up, relative to timely follow-up, was associated with not having a subsequent health care seeking visit at 4 to 6 months (OR = 0.57; CI, 0.48-0.67) and 7 to 9 months (OR = 0.79; CI, 0.66-0.96), respectively.

Conclusions:

Follow-up visit timing after a concussion in children and youth is associated with subsequent health care seeking. Greater efforts are needed to investigate the importance of initial follow-up visit timing, as they may play an integral role in injury prevention and symptom management following injury.
REAL-WORLD LONG-TERM OUTCOMES OF INTRAVITREAL FARICIMAB IN PREVIOUSLY TREATED CHRONIC NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
Authors: Ambati Naveen R. , Leone Adam , Brill Daniel , Sisk Robert A.
Published: November 2024

Purpose:

To study the real-world outcomes of intravitreal faricimab (IVF) in long-standing neovascular age-related macular degeneration (nAMD) over a 1-year study period.

Methods:

Retrospective single-center cohort study of patients with previously treated nAMD receiving IVF with at least 12 months of follow-up. Main outcome measures include injection intervals, visual acuity (VA), and optical coherence tomography features.

Results:

A total of 263 eyes from 217 patients received 6.4 ± 2.3 IVF injections over 1 year. Injection interval increased after switching to IVF (5.9 ± 1.8 vs. 7.6 ± 2.4 weeks) (P < 0.01). There was no improvement in VA after switching to IVF at any time period (P > 0.15). Average CST decreased after the first IVF injection and was sustained for 1 year (313.7 ± 96.0 vs. 288.2 ± 80.6 µm) (P < 0.01). There was a statistically significant resolution of subretinal fluid but not IRF at all time points (40.8%–50.4%; P < 0.01). Persistent fluid after the first IVF injection was resolved in 34.4% (n = 45) by 1 year. IVF was discontinued in 31 eyes (11.8%), four (1.6%) that experienced intraocular inflammation.

Conclusion:

Long-standing nAMD eyes switched to IVF experienced a significant extension in injection interval, stable visual acuity, improvement in CST, and resolution of fluid on OCT in many patients over 1 year.
Dupilumab-Associated Bilateral Conjunctival Papillomas and Corneal Perforation
Authors: Dewhurst Nicholas , Larney Conor , Jobson Dale , Nofal Nour , Chong Alvin , Chan Elsie
Published: November 2024

Purpose:

We report a unique case of significant human papillomavirus–associated conjunctival papillomas and severe corneal ulceration leading to corneal perforation in a patient treated with dupilumab for atopic dermatitis.

Methods:

This study is a case report and literature review of severe corneal side effects related to dupilumab.

Results:

A 27-year-old man with severe atopic dermatitis and no ocular history was administered dupilumab 300 mg via subcutaneous injections every 2 weeks with an excellent response. Following the onset of treatment, the patient developed conjunctivitis, conjunctival papillomas, and dry eyes, which were initially treated with lubricating eye drops. Fourteen months after commencing dupilumab, he had a rapid onset of painful visual loss in the OD accompanied by severe bilateral conjunctival injection and was found to have a central corneal ulcer and diffuse papillomas on the palpebral and bulbar conjunctiva. Despite management with intravenous methylprednisolone and topical dexamethasone, the patient's corneal ulcer progressed to a corneal melt, resulting in perforation 2 months after diagnosis, which necessitated a corneal graft.

Conclusions:

We present the third reported case of dupilumab-associated corneal perforation and the first case to our knowledge of dupilumab-associated conjunctival papillomas. As dupilumab usage increases, awareness of these potential complications among prescribers is essential.
Sex and Sexual Orientation as Potential Risk Factors for Coinfection With Sexually Transmitted Infections in Surabaya, Indonesia: A Single-Center Cross-Sectional Study
Authors: Dewi Arifiana Wungu Kartika , Hidayati Afif Nurul ,   Sawitri, Listiawan M. Yulianto , Ervianti Evy , Astari Linda , Utomo Budi
Published: November 2024

Objective:

Sexually transmitted diseases are infections transmitted from an infected person to an uninfected person through sexual contact. We conducted this study to evaluate the prevalence and the risk factors of coinfection because there has been few research that thoroughly demonstrates its occurrence in Indonesia, particularly in Surabaya.

Methods:

This research is a retrospective analytical study at Dr Soetomo General Academic Hospital in a period of 2019 to 2021, and primarily aimed to assess risk factors associated with coinfection events in patients with sexually transmitted infections. Patient’s data included sex, age, occupation, marital status, comorbid factors, number of sexual partners, sexual orientation, and patient’s nonsexual behavior were taken from the medical records for analysis. The chi-square test was used to analyze the correlations between variables.

Results:

There were 416 sexually transmitted infection patients between 2019 and 2021. Among them, 187 patients were proved to have coinfections, of which 184 patients had 2 coinfections and 3 patients had 3 coinfections. There was a statistically significant difference in the presence of coinfections according to sex and sexual orientation (both P < 0.001), however, there was no statistically significant association of age, patient’s occupation, marital status, comorbidity, and sexual partner with coinfection of patients with sexually transmitted infections.

Conclusion:

The incidence of coinfection is significantly associated with both sex and sexual orientation in Surabaya, Indonesia. The identified risk factors of coinfection should be considered in the development of local public health strategies to prevent and control sexually transmitted diseases.
Outcomes of Community-Acquired Acute Kidney Injury
Authors: Wang Virginia , Zepel Lindsay , Smith Valerie A. , Brookhart Maurice A. , Bowling Christopher B. , Maciejewski Matthew L. , Diamantidis Clarissa J.
Published: November 2024

Background:

Community-acquired acute kidney injury (CA-AKI) occurs outside of the hospital and is the most common form of AKI. CA-AKI is not well understood, which hinders efforts to prevent, identify, and manage CA-AKI.

Objective:

Examine 30-day outcomes following CA-AKI using national administrative and lab data from the Veterans Health Administration (VA).

Research Design:

Retrospective cohort study.

Subjects:

VA primary care patients with recorded outpatient serum creatinine (SCr) with observed CA-AKI (cases) and a standardized mortality ratio propensity-weighted 5% comparator sample without observed CA-AKI in 2013–2017.

Measures:

CA-AKI was defined as a ≥1.5-fold relative increase in outpatient SCr or inpatient SCr (≤24 h from admission) from a reference outpatient SCr ≤12 months prior. Outcomes were 30-day mortality and hospitalization and were assessed in separate weighted Cox regression models.

Results:

Among 220,777 CA-AKI events and 492,539 comparators without observed CA-AKI, CA-AKI was associated with a higher risk of 30-day all-cause mortality [hazard ratio (HR)=4.17, 95% CI: 3.74, 4.63] and hospitalization (HR=1.82, 95% CI: 1.74, 1.90) versus comparator. Risks increased with severity (mortality HR=3.02, 7.67, and 12.22 for AKI stages 1–3, respectively). Outpatient CA-AKI was associated with a high risk of mortality (HR=2.04, 95% CI: 1.83, 2.28) and even higher for inpatient CA-AKI, present [≤24 h from admission (HR=11.32, 95% CI: 10.16, 12.61)].

Conclusions:

In a national cohort of Veterans, CA-AKI was associated with a 2-fold increased risk of hospitalization and a 3–11-fold risk of mortality. Improving identification and management is critical to mitigate adverse outcomes of CA-AKI.
Assessment of Antibody Levels and Vaccine-induced Serologic Responses After Completion of Cancer Treatment in Pediatric Patients: A 6-Year Experience in Turkey on HAV, HBV, VZV, and MMR Vaccinations
Authors: Gundesli Sebiha S. , Celik Melda , Yalcin Siddika Songul , Aydin Guzide B. , Kurucu Nilgun , Yalcin Bilgehan , Varan Ali , Kutluk Tezer M.
Published: November 2024

Objective:

Childhood cancer treatment disrupts vaccination schedules and weakens or eliminates vaccine-induced immunity. In addition, post-treatment vaccine responses vary. This study aimed to assess post-treatment serum antibody levels and vaccine responses in children.

Methods:

Pediatric patients treated at Hacettepe University between years 2015 and 2020, achieved remission after chemotherapy for lymphoma and solid tumors were included. Post-treatment vaccination status, serum antibody levels for hepatitis A (HAV), hepatitis B (HBV), varicella-zoster (VZV), measles-mumps-rubella (MMR), and changes in vaccine responses were retrospectively analyzed.

Results:

The study included 533 patients. Post-treatment seronegativity rates were: measles (83.5%), HAV (64%), rubella (60.1%), HBV (48.5%), VZV (43.3%), and mumps (28%). Post-treatment antibody loss was observed for measles (47.1%), HAV (31.9%), HBV (31.4%), mumps (28.6%), VZV (21.7%), and rubella (11.4%). Seropositivity after 1 vaccine dose was seen with HAV (83.6%), rubella (82.9%), HBV (81.4%), VZV (63.5%), mumps (45.4%), and measles (33.3%). Seropositivity after 2 vaccine doses was achieved with HAV (98.8%), VZV (84.6%), rubella (80%), HBV (80%), measles (32.2%), and mumps (36.2%).

Conclusion:

Post-treatment serological vaccine responses in children were lower than anticipated despite multiple doses. Given the potential need for periodic serological assessments and booster vaccinations, long-term follow-ups are planned.
Case Report of Dinutuximab-induced Atypical Hemolytic Uremic Syndrome
Authors: Huang Letha , Miller Danielle , Hajjar Fouad
Published: November 2024

Limited evidence exists describing the relationship between the development of atypical hemolytic uremic syndrome (aHUS) and the administration of dinutuximab. This case report describes a 20-year-old male with neuroblastoma who experienced aHUS post-dinutuximab administration. The patient presented with uncontrolled hypertension and renal dysfunction, ultimately receiving a definitive diagnosis of aHUS through a renal biopsy. The patient required complement-directed therapy with eculizmab and later transitioned to ravulizumab. This case further describes a sequential relationship between dinutuximab administration and aHUS development.
Advancements in PNH treatment: crovalimab’s clinical efficacy
Authors: Shoaib Eisha , Imam Filzah , Khan Mahnoor , Jaber Amin Mohammed H.
Published: November 2024

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematologic disease that is characterized by the destruction of red blood cells, leading to a range of severe symptoms and complications. Recent advancements in drug therapies have significantly improved the prognosis for PNH patients. This editorial comprises the impact of PNH drugs, focusing on eculizumab and ravulizumab and comparing them to the recently approved complement inhibitor, crovalimab, which targets the complement system to prevent hemolysis. The discussion includes an analysis of clinical trial data and patient outcomes. The editorial mainly addresses emerging therapies, like crovalimab, that promise to offer more comprehensive, complete blockage of the complement system and low-dose solutions, reducing the treatment hassle while simultaneously appealing to a wider range of patients.
Summary of the best evidence for vocal rehabilitation training in adults with unilateral vocal fold paralysis
Authors: Tang Caihong , Zhang Xinxin , He Hong , Jing Lingling , Tuo Wangyang , Shi Yulan
Published: November 2024

Purpose:

To search, evaluate, and summarize the relevant evidence of voice rehabilitation training in adults with unilateral vocal fold paralysis (UVFP).

Methods:

Using the ‘6S’ model, the database of UpToDate, BMJ Best Practice, domestic and foreign guidelines, and voice rehabilitation training for adults with UVFP were systematically searched. The search includes clinical decisions, guidelines, systematic reviews, randomized controlled trials, and expert consensus. Data search since the establishment of the database to 27 November 2023. The quality evaluation of the literature methodology and the extraction and integration of evidence were carried out independently by two researchers.

Results:

A total of 12 literature were included, including 2 systematic reviews, 2 expert consensus, 4 guidelines, 2 clinical decisions, and 2 randomized controlled trials. Four categories of 16 pieces of evidence were summarized: evaluation of vocal cord paralysis, voice rehabilitation training, health education, joint decision-making, and multidisciplinary cooperation.

Conclusion:

This study summarized the best evidence of voice rehabilitation training for adults with UVFP and provided evidence-based summary for clinical staff to carry out relevant interventions.
Enhancing survival in cardiac arrest: the urgent need for optimized extracorporeal cardiopulmonary resuscitation implementation and protocols – editorial
Authors: Waheed Aiman , Gul Muhammad H. , Naeem Risha , Arshad Azam Raja Hafsa , Wardak Abdul B. , Khan Umer
Published: November 2024

Extracorporeal CPR (ECPR) involves venoarterial extracorporeal membrane oxygenation (VA-ECMO) in patients with sudden and unexpected pulse loss due to heart-stopping mechanical activity. ECPR in patients with cardiac arrest has been shown to significantly improve the prognosis. In emergency rooms, interdisciplinary coordination exists among emergency medicine, cardiology, critical care, and perfusion technology. However, some problems must be solved, such as excessive costs, resource allocation, and the need for specialized equipment. Resuscitation success and patient outcomes can be enhanced by combining ECPR and emergency care.
A rare case of left transverse testicular ectopia in an adult
Authors: Keshari Suraj , Pandey Archana , Subedi Abiral , Shrestha Rohit B. , Panta Priyanka , Aryal Manisha , Paudel Ishwor , Pandey Abhishek , Pande Prasamsa
Published: November 2024

Introduction and importance:

Transverse testicular ectopia (TTE) is a rare congenital anomaly in which both testes descend into the same inguinal canal and are located in the same hemiscrotum. Diagnosing TTE can be challenging due to its rarity and unusual presentation.

Case presentation:

The authors present a case of a male in his 50s who was diagnosed with left transverse testicular ectopia after presenting with an empty right hemiscrotum and two testes-like masses in the left hemiscrotum.

Clinical discussion:

TTE usually presents with a history of an inguinal hernia and a contralateral undescended testis. However, in our case, the patient had both testes in the left hemiscrotum without an inguinal hernia, making this case even rarer.

Conclusion:

Patients presenting with an empty hemiscrotum on one side and two testes-like masses on the other should be suspected of having TTE. In such cases, it is important to use imaging like USG or MRI, to identify and locate the ectopic site and assess the testicular morphology.
Evaluating Stigma Toward Individuals With Substance Use Disorder Among Prelicensure Nursing Students
Authors: Crook Jennifer I. , Giordano Nicholas A. , Mathias Joseph E. , Getz Tatiana , Febres-Cordero Sarah
Published: November 2024

Background:

Seventeen percent of individuals in the United States live with substance use disorder (SUD). Nursing curricula may not adequately address SUD, and stigma can impact care.

Purpose:

This project aimed to measure stigma toward people with SUD among nursing students.

Methods:

Surveys were administered to prelicensure nursing students. Stigma was measured using the Opening Minds Provider Attitudes Toward Opioid-Use Scale. Students were asked about personal experience with SUD and perceived adequacy of SUD-related curricula.

Results:

A total of 193 students participated. The mean stigma score was 31.35. Those with personal experience had lower stigma scores than those without ([95% CI 2.26-9.23]; P value = .0014). Most students (71.0%) desired to see content from individuals with lived experience incorporated into curriculum.

Conclusion:

Addressing stigma in SUD education is critical for improving future patient care. Nursing schools should consider incorporating stigma-reducing content, including perspectives from individuals with lived experiences, into SUD curricula.
Interprofessional Team Training
Authors: Shorten Allison , Bosworth Peter , Camp Shelly , House David , Somerall William , Watts Penni , Webb Tera , Shorten Brett
Published: November 2024

Background:

Interprofessional team training (IPTT) prepares students from health care professions for team-based care. Evaluating different learning environments to inform decisions about delivery format is timely and important.

Purpose:

To compare in-person and online IPTT learner outcomes.

Method:

Undergraduate and graduate students (n = 866) from 11 professions participated. Using retrospective pre-/post-methodology, 20 item Interprofessional Collaboration Competency Attainment Survey (ICCAS) scores were compared, and qualitative responses analyzed.

Results:

Mean ICCAS scores improved for in-person and online delivery (P < .0001) with large effect sizes (Cohen’s D = 0.94-1.86). In-person delivery resulted in greatest improvement (P = .038), offset by online logistical benefits. Qualitative themes highlighted impact on learning, importance of facilitator competence, and setting expectations.

Conclusion:

IPTT achieved learning consistent with competency development. Advantages from in-person delivery should be weighed against online logistical advantages.
Ischemia/Reperfusion Upregulates Genes Related to PANoptosis in Human Lung Transplants
Authors: Zhao Yajin , Liang Lubiao , Jeon Jamie E. , Keshavjee Shaf , Liu Mingyao
Published: November 2024

Background.

Activation of multiple programmed cell death (PCD) pathways has been reported in cellular and animal studies of ischemia/reperfusion injury in lung transplantation. However, the status of these pathways in human lung transplants remains unknown. This study investigates the involvement of PCD pathways and their relationship with inflammation and signaling pathways in human lung transplants.

Methods.

Transcriptomic analysis was conducted on 54 paired human lung tissue samples at the end of cold preservation time and 2 h after reperfusion, collected between 2008 and 2011. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA were used to examine the activation of genes in 6 PCD pathways. The relationships between PCD pathways and inflammation, as well as signaling pathways, were assessed via single-gene GSEA.

Results.

GSEA results indicated that apoptosis and necroptosis were significantly upregulated after reperfusion in human lung transplants, whereas the gene sets related to pyroptosis, ferroptosis, autophagy, and cuproptosis were not significantly upregulated. Notably, single-sample GSEA demonstrated an intricate interplay among pyroptosis, apoptosis, and necroptosis, collectively referred to as PANoptosis, which is further supported by enrichment of genes related to PANoptosome, inflammatory response, and nuclear factor-κB and interferon signaling pathways, via single-gene GSEA assays.

Conclusions.

This study demonstrated the genes of PANoptosis are upregulated in human lung grafts during reperfusion. The discovery of PANoptosis as an underlying mechanism of cell death in human lung grafts implies that effective therapeutics to prevent or reduce PANoptosis may alleviate ischemia/reperfusion injury and improve clinical lung transplant outcomes.
Exploring the Effect of Single-Session Transcranial Direct Current Stimulation on Attention, Verbal Fluency, and Working Memory in Patients With Alzheimer's Disease-Related Dementia
Authors: Can Kazım Cihan , Ozel-Kizil Erguvan Tugba , Onar Deha , Duman Berker , Kırıcı Sevinç , Baştuğ Gülbahar , Baştuğ Metin
Published: November 2024

Objectives

Alzheimer's disease (AD) is a leading cause of morbidity and mortality among the elderly. Transcranial direct current stimulation (tDCS) applies low-intensity currents to the brain, resulting in short-term neurocognitive effects and long-term neuroplasticity enhancement. Limited research reported on the impact of tDCS on cognitive functions in dementia due to AD. This study aims to compare changes in verbal fluency and working memory following a single tDCS application to the left dorsolateral prefrontal cortex (DLPFC) in AD patients.

Methods

Patients with mild dementia due to AD underwent cognitive assessment using the Standardized Mini-Mental Test, Clock Drawing Test, Rey Auditory Verbal Learning Test, Functional Activities Questionnaire, Informant Questionnaire on Cognitive Decline in the Elderly, and Montreal Cognitive Assessment Scale. A single-session tDCS was administered by applying anodal tDCS to the left DLPFC for a duration of 30 minutes. Verbal fluency and working memory were evaluated before and after tDCS using the WAIS-R Digit Span Test forward and backward subscales, Trail Making Test (TMT) A and B, and Verbal Fluency Test.

Results

Regarding cognitive test scores before and after tDCS application, there were statistically significant reductions in the durations of TMT-A and TMT-B. However, there were no significant differences observed for TMT B-A, VFT, DST-forward, and DST-backward performances.

Conclusions

The findings indicate that a single anodal tDCS targeting the left DLPFC enhances attention and processing speed in AD patients but has no effect on working memory or verbal fluency.
Electroconvulsive Therapy in a Left Ventricular Assist Device Recipient With Treatment-Resistant Depression
Authors: Nash Rebekah , Rosenkrans Daniel , Kolarczyk Lavinia , Khan Asif , Hatch Erica , Gala Gary , Laughon Sarah L. , McClure Robert K.
Published: November 2024

Depression and heart failure are highly comorbid, with up to 35% of heart failure patients suffering from comorbid depression. Left ventricular assist devices (LVADs) serve as a major lifeline for patients with heart failure; however, despite the drastic improvement in cardiac function following LVAD implantation, up to 24% of LVAD recipients suffer from depression. Depression management in LVAD recipients is often complicated by the recipient's increased risk for antidepressant side effects, adverse drug reactions, and inability to safely receive certain interventional psychiatry therapies, as the LVAD is either a relative or absolute contraindication. Electroconvulsive therapy (ECT) is highly effective for treatment-resistant depression; although it carries increased cardiovascular risks for the LVAD population (particularly bradycardia/hypotension and tachycardia/hypotension), these can be continuously monitored, along with LVAD function, such that with the close cooperation of a multidisciplinary team, the risks of ECT can be minimized. To our knowledge, there is only one published case report of ECT in an LVAD recipient. We present a case of an LVAD recipient with treatment-resistant depression who was successfully treated with ECT. Our case describes an approach by which ECT can be safely delivered to LVAD recipients with a collaborative multidisciplinary team approach.
Molecular characteristics of CTX-M β-lactamase-producing and quinolone-resistant Escherichia coli among deer in a popular tourist spot in Japan
Authors: Ikushima Shiori , Sugiyama Michiyo , Asai Tetsuo
Published: November 2024

Introduction. Antimicrobial resistance (AMR) is a growing global concern. Clonal lineages of CTX-M β-lactamase-producing Escherichia coli (CTXE) and quinolone-resistant E. coli (QREC) were disseminated among the deer population in a famous tourist destination (Nara Park; NP) in Japan.

Hypothesis/gap statement. The molecular characteristics of CTXE or QREC isolates, which could pose a threat to public health, have not been elucidated.

Aim. This study aimed to characterize the genetic traits of CTXE and QREC isolates derived from NP deer and compare them with lineages prevalent worldwide.

Methodology. Sixteen CTXE and three QREC isolates recovered from NP deer faeces between 2018 and 2020 were analysed using whole-genome sequencing (WGS). For endemic lineages, phylogenetic trees were constructed against the isolates registered in the EnteroBase database using the core genome SNP scheme.

Results. The most prevalent lineage in NP deer was ST3580. Several pandemic lineages, such as sequence type (ST) 38, ST58 and ST117, were included. The QREC lineages prevalent among deer were designated as extra-intestinal pathogenic E. coli or uropathogenic E. coli (UPEC). Thirteen of the 24 antimicrobial resistance genes (ARGs) were considered high-risk ARG families. Chromosomal integration of bla
CTX-M-15 was observed in all plasmid-negative isolates. Phylogenetic analysis suggested relationships between NP isolates and isolates sourced from the environment or poultry.

Conclusion. ST3580 has a high potential for clonal dissemination. Furthermore, multiple clinically relevant lineages of CTXE and QREC are endemic in NP deer; however, they could be less virulent than isolates belonging to the same lineages, which could cause severe infectious diseases. Further studies are required to investigate the relationship between chromosomal integration of plasmid-encoded genes and the stable propagation of AMR bacteria in wildlife and the environment.
Inhibition of serine and arginine-rich splicing factor 3 induces epidermal differentiation and decreases cutaneous squamous cell carcinoma risk
Authors: Donohue Isoline M. , He Haiyin , Nguyen Audrey , Hui Gavin , Muralidharan Jananee , Pike William C. , Jackson Michael L. , Ko Christine , Srivastava Ankit , Lee Carolyn S.
Published: November 2024

Serine/Arginine-rich splicing factor 3 (SRSF3) is one of 12 SRSFs that regulate gene expression via alternative splicing. SRSF3 is upregulated in cutaneous squamous cell carcinoma (cSCC) and several squamous cancer cell lines in relation to normal keratinocytes. We suppressed SRSF3 with a specific inhibitor, SFI003, and observed an increase in epidermal differentiation. Our data suggests that in cSCC, SRSF3 overexpression suppresses cellular differentiation to enable cancer progression. In a clinical setting, patients taking known SRSF3 inhibitors digoxin and amiodarone exhibited higher cSCC-free survival compared to a propensity score-matched cohort treated with beta blockers. Thus, SRSF3 upregulation may be a novel therapeutic target in cSCC that can improve patient prognoses.
Moderate Static Magnetic Fields Prevent Estrogen Deficiency-Induced Bone Loss: Evidence from Ovariectomized Mouse Model and Small Sample Size Randomized Controlled Clinical Trial
Authors: Wang Shenghang , Yang Jiancheng , Wei Yunpeng , Cai Chao , Chen Shuai , Wu Youde , Li Xiao , Sun Lilei , Li Xianglin , Gong Ming , Zhou Jianhua , Hu Yawei , Zhang Wang , Guo Zengfeng , Liao Jiacheng , Luo Chunling , Bai Xiaosu , luo Xinle , Duan Liming , Huyan Ting , Yang Zhouqi , Wei Min , Fang Yanwen , Zhang Hao , Shang Peng
Published: November 2024

Background

Postmenopausal osteoporosis (PMOP) is the most common type of osteoporosis. Numerous studies have shown that static magnetic fields (SMFs) can inhibit bone loss by regulating bone remodeling. However, there are currently no clinical studies on the treatment of osteoporosis with SMFs. This study aims to investigate the clinical therapeutic effects of moderate static magnetic fields (MMFs) on PMOP.

Methods

In this paper, we constructed MMF device using neodymium-iron-boron (NdFeB) materials. At the animal level, the effect of MMF exposure for 8 weeks on estrogen deficiency-induced bone loss was investigated by evaluating bone microstructure, mechanical properties, and bone conversion using ovariectomized (OVX) mice. Clinically, a single-blind randomized controlled study in patients with PMOP was designed. PMOP patients aged 55-70 years were recruited and randomized into the control and MMF treatment groups. Clinical assessments of bone mineral density (BMD), bone turnover markers (BTMs) and VAS scores were performed at baseline and day 90, respectively.

Results

The results showed that MMF exposure significantly improved BMD, bone mineral content (BMC), bone microarchitecture and bone strength in OVX mice. For bone turnover, MMF increased the number of osteoblasts on the bone surface of OVX mice as well as the level of serum bone formation marker P1NP, while decreasing the number of osteoclasts and the level of serum bone resorption marker β-CTX. The clinical trial’s results showed that MMF treatment had a positive effect on the improvement of BMD in the lumbar spine and increased serum P1NP levels while decreased β-CTX levels. In addition, MMF treatment decreased participants’ VAS scores for low back pain.

Conclusions

The results of both animal and clinical studies demonstrated that MMF treatment improved bone turnover and have a positive effect on BMD improvement, as well as alleviated low back pain in PMOP patients. This study will promote the translational research and clinical application of SMF treatment for osteoporosis.

Trial registration

Intervention study of moderate static magnetic field on osteoporosis and iron metabolism in postmenopausal women, ChiCTR2100048604
Interferon-λ-Neutralizing Autoantibodies and Common Autoimmune Disease Autoantibodies in Pediatric Acute-Onset Neuropsychiatric Syndrome
Authors: Yin Xihui , Frankovich Jennifer , Kalaycioglu Muge , Choudhury Ananya , Burry Michael J. , Kwon Woo Joo , Ma Meiqian , Farhadian Bahare , Manko Cindy , Silverman Melissa , Xie Yuhuan , Tran Paula , Schlenk Noelle , Utz Paul J. , Prestwood Tyler R.
Published: November 2024

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by sudden onset obsessive-compulsive disorder (OCD) symptoms in conjunction with other neuropsychiatric manifestations including disturbances in sleep, urination, cognition, and behavior with increased emotional lability and irritability. Clinical observations, including physical exam and laboratory findings, show many similarities between PANS cases and pediatric autoimmune conditions. While published studies have suggested autoantibodies are common in PANS patients, the molecular targets of these autoantibodies (AAbs) remain poorly characterized. Here, we profile the AAbs in 225 plasma samples taken from 166 PANS patients during periods of active disease, or flares, in comparison with 83 pediatric healthy controls using custom Luminex microbead panels conjugated with highly curated antigens from common autoimmune diseases as well as cytokines and chemokines. We find that PANS patients exhibit increased prevalence of AAbs against autoantigens known to be targeted scleroderma and GI/endocrine autoimmune conditions, reflective of clinical observations. Remarkably, a subset of PANS patients exhibits AAbs against interferon-λ, which is an important line of defense against infections at anatomic barriers. Furthermore, 9 of the 11 patients with IFN-λ-binding AAbs were found to be exhibit neutralizing activity. Overall, these findings demonstrate an autoimmune component to PANS and provide insight into a potential disease mechanism mediated by immune deficits at barrier surfaces.
A Mouse-adapted SARS-CoV-2 Model for Investigating Post-acute Sequelae of COVID infection
Authors: Qiao Haowen , Qu Yafei , Qiu Lingxi , Chiu Yuanpu , He Xiao , Ge Tenghuan , Zhao Zhen , Yuan Weiming
Published: November 2024

The coronavirus disease of 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), remains a major health issue after nearly 7 millions of death toll in the last four years. As the world is recovering with improving vaccines and antiviral treatments, the alarming rate of long-COVID, or Post-acute Sequelae of COVID-19 (PASC), calls for further investigations. Among a list of symptoms associated with multi-organ dysfunctions, the neurological complications are particularly intriguing, yet the underlying mechanisms remain elusive. With the recently developed mouse adapted SARS-CoV-2 stain, we are now able to model the mild COVID infection in C57BL/6 mice and study the chronic immune responses and subsequent damages in different organs long after the viruses are clearly naturally in the body. More specifically, we found adult C57BL/6J mice developed neurological impairments, including behavior changes related to sensorimotor coordination, depression- and anxiety-like behaviors, and inflammation in multiple organs including lung, liver and brain, which persisted over at least 4 weeks in mice even with mild infection. Therefore, this model can be used to further explopred the mechanisms of PASC, as well as potential intervention or therapeutic approaches.
Independent and joint effects of genomic and exposomic loads for schizophrenia on distressing and persisting psychotic experiences in adolescence
Authors: Vincenzo Matteo Di , Prachason Thanavadee , Sampogna Gaia , Arias-Magnasco Angelo , Lin Bochao Danae , Pries Lotta-Katrin , van Os Jim , Rutten Bart P.F. , Barzilay Ran , Fiorillo Andrea , Guloksuz Sinan
Published: November 2024

To assess the longitudinal associations of genomic and exposomic liabilities for schizophrenia, both independently and jointly, with distressing psychotic experiences (PEs) and their persistence in early adolescence. The Adolescent Brain and Cognitive Development Study data from children with European ancestry were used (n=5,122). The primary outcome was past-month distressing PEs at 3-year follow-up. Secondary outcomes were lifetime distressing PEs defined at varying cutoffs of persistence (from ≥ 1-4 waves). Multilevel logistic regression models were used to test the independent and joint associations of the binary modes (risk-category defined as above 75th percentile) of polygenic risk score for schizophrenia (PRS-SCZ75) and exposome score for schizophrenia (ES-SCZ75) on the outcomes. The relative excess risk due to interaction (RERI) was determined using the delta method to indicate departure additive interaction. PRS-SCZ75was statistically significantly associated with lifetime distressing PEs (≥ 1 wave) (OR 1.29 [95% CI 1.08, 1.53]) and repeating distressing PEs ≥ 2 waves (OR 1.34 [95% CI 1.08, 1.65]) but not with past-month distressing PEs or repeating distressing PEs at a higher cutoff of persistence. ES-SCZ75was consistently associated with past-month and repeating distressing PEs at all cutoffs, with increasing strength of association as a function of PEs persistence (one wave: OR 2.77 [95% CI 2.31, 3.31]; two waves: OR 3.16 [95% CI 2.54, 3.93]; three waves: OR 3.93 [95% CI 2.86, 5.40]; four waves: OR 3.65 [95% CI 2.34, 5.70]). There was evidence for additive interaction between ES-SCZ75and PRS-SCZ75for lifetime distressing PEs (RERI=1.26 95%CI: 0.14, 2.38), and repeating distressing PEs ≥ 2 waves (RERI=1.79, 95%CI: 0.35, 3.23). Genomic and exposomic liabilities for schizophrenia were independently and jointly associated with distressing PEs, as well as their persistence in early adolescence.
The relationship between brain structure and reduced hand dexterity in older adults
Authors: Manelis Anna , Hu Hang , Satz Skye
Published: November 2024

Hand dexterity is affected by normal aging and neuroinflammatory processes in the brain. Understanding the relationship between hand dexterity and brain structure in neurotypical older adults may inform about prodromal pathological processes, thus providing an opportunity for earlier diagnosis and intervention to improve functional outcomes. This study investigates the associations between hand dexterity and brain measures in neurotypical older adults (≥65 years) using the Nine Hole Peg Test (9HPT) and magnetic resonance imaging (MRI). Elastic net regularized regression revealed that reduced hand dexterity in dominant and non-dominant hands was associated with enlarged volume of the left choroid plexus, the region implicated in neuroinflammatory and altered myelination processes, and reduced myelin content in the left frontal operculum, the region implicated in motor imagery, action production, and higher-order motor functions. Distinct neural mechanisms underlying hand dexterity in dominant and non-dominant hands included the differences in caudate and thalamic volumes as well as altered cortical myelin patterns in frontal, temporal, parietal, and occipital regions supporting sensorimotor and visual processing and integration, attentional control, and eye movements. Although elastic net identified more predictive features for the dominant vs. non-dominant hand, the feature stability was higher for the latter, thus indicating higher generalizability for the non-dominant hand model. Our findings suggest that the 9HPT for hand dexterity may serve as a cost-effective screening tool for early detection of neuroinflammatory and neurodegenerative processes. Longitudinal studies are needed to validate our findings in a larger sample and explore the potential of hand dexterity as an early clinical marker.
Potential Lives Saved Through Widespread Global Availability of GLP-1 Receptor Agonists: A Modeling Study
Authors: Brook David , Singer Peter A.
Published: November 2024

This model attempts to quantify the potential impact of GLP-1 receptor agonists (GLP-1) in reducing global mortality linked to obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD). Using global population data, T2DM and obesity prevalence, cardiovascular risk, and mortality reduction from GLP-1s, we estimate that ∼943,000 lives could be saved annually with widespread global access to GLP-1 receptor agonists for individuals with obesity and/or T2DM and CVD.
In vivoTreatment of a Severe Vascular Disease via a Bespoke CRISPR-Cas9 Base Editor
Authors: Alves Christiano R. R. , Das Sabyasachi , Krishnan Vijai , Ha Leillani L. , Fox Lauren R. , Stutzman Hannah E. , Shamber Claire E. , Kalailingam Pazhanichamy , McCarthy Siobhan , Cardenas Christian L. Lino , Fong Claire E. , Imai Takahiko , Mitra Sunayana , Yun Shuqi , Wood Rachael K , Benning Friederike M. C. , Lawton Joseph , Kim Nahye , Silverstein Rachel A. , Ferreira da Silva Joana , de la Cruz Demitri , Richa Rashmi , Malhotra Rajeev , Chung David Y. , Chao Luke H. , Tsai Shengdar Q. , Maguire Casey A. , Lindsay Mark E. , Kleinstiver Benjamin P. , Musolino Patricia L.
Published: November 2024

Genetic vascular disorders are prevalent diseases that have diverse etiologies and few treatment options. Pathogenic missense mutations in the alpha actin isotype 2 gene (ACTA2) primarily affect smooth muscle cell (SMC) function and cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection, and death in childhood. Here, we explored genome editing to correct the most common MSMDS-causative mutationACTA2R179H. In a first-in-kind approach, we performed mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the R179H sequence. To directly correct the R179H mutation, we screened dozens of configurations of base editors (comprised of Cas9 enzymes, deaminases, and gRNAs) to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We then created a murine model of MSMDS that exhibits phenotypes consistent with human patients, including vasculopathy and premature death, to explore thein vivotherapeutic potential of this base editing strategy. Delivery of the customized base editor via an engineered SMC-tropic adeno-associated virus (AAV-PR) vector substantially prolonged survival and rescued systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta, and brain. Together, our optimization of a customized base editor highlights how bespoke CRISPR-Cas enzymes can enhance on-target correction while minimizing bystander edits, culminating in a precise editing approach that may enable a long-lasting treatment for patients with MSMDS.
Modeling CAR Response at the Single-Cell Level Using Conditional Optimal Transport
Authors: Driessen Alice , Born Jannis , Castellanos Rueda Rocio , Reddy Sai T. , Rapsomaniki Marianna
Published: November 2024

Chimeric Antigen Receptor (CAR) T cell therapy is a promising area of cancer immunotherapy. However, many challenges such as loss of persistence, T cell exhaustion, and therapy associated toxicities hamper further advancement of CAR T cell therapy. Therefore, recent efforts have focused on designing improved CARs that show better therapeutic characteristics. However, it is unfeasible to test all CAR variants in lab-based assays as CARs consist of multiple intracellular signalling domains. This results in over 100’000 possible variants. We leverage computational modeling to navigate this vast combinatorial space by learning the relationship between CAR design and T cell functionality, thereby proposing promising CAR T cell designs. CAR T cells expressing different variants can be viewed as cells that underwent different perturbations. Neural Optimal Transport is an upcoming field that can model single cell perturbations and predict unseen cells and conditions. In this work we leverage the conditional Monge Gap to model the response to CAR expression at a single-cell level and generate gene expression of cells that express an unseen CAR design. We show that CAR OT (CAROT) significantly outperforms the baseline for gene expression prediction for in-distribution CAR variants, with distinct gene expression patterns per CAR that capture biological characteristics. When predicting unseen CAR variants, we demonstrate promising results in terms of gene expression prediction and show the model learns gene expression patterns linked to domains in the training set. This work demonstrates that optimal transport may support discovery and development of new CAR T cell designs.
DIA-BERT: pre-trained end-to-end transformer models for enhanced DIA proteomics data analysis
Authors: Liu Zhiwei , Liu Pu , Sun Yingying , Nie Zongxiang , Zhang Xiaofan , Zhang Yuqi , Chen Yi , Guo Tiannan
Published: November 2024

Data-independent acquisition mass spectrometry (DIA-MS) plays an increasingly important role in quantitative proteomics. Here, we introduce DIA-BERT, a software tool that leverages a transformer-based pre-trained artificial intelligence (AI) model for the analysis of DIA proteomics data. Over 276 million of high-quality peptide precursors extracted from existing DIA-MS files were used for training the identification model, while 34 million peptide precursors from synthetic DIA-MS files were used for training the quantification model. Compared to DIA-NN, DIA-BERT led to on average 54% more protein identifications and 37% more peptide precursors in five different human cancer (cervical cancer, pancreatic adenocarcinoma, myosarcoma, gallbladder cancer, and gastric carcinoma) sample sets with a high degree of quantitative accuracy. This study highlights the potential of utilizing pre-trained models and synthetic datasets to advance DIA proteomics analysis.
Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset acrossPSEN1,PSEN2andAPPcausal genes
Authors: Gutiérrez Fernández Sara , Gan Oria Cristina , Annaert Wim , Ringman John M. , Fox Nick C. , Ryan Natalie S. , Chávez-Gutiérrez Lucía
Published: November 2024

Autosomal Dominant Alzheimer’s Disease (ADAD), caused by mutations in Presenilins (PSEN1/2) and Amyloid Precursor Protein (APP) genes, typically manifests before age 65. Age at symptom onset (AAO) is relatively consistent among carriers of the samePSEN1mutation, but more variable forPSEN2andAPPvariants, with these mutations associated with later AAOs thanPSEN1. Understanding this clinical variability is crucial for developing predictive models and tailored interventions in ADAD.

Biochemicalin vitroassessment of γ-secretase function is valuable in evaluatingPSEN1variant pathogenicity, disease onset and progression. Here, we examined Aβ profiles’ relationships to AAO across causal genes. Our analysis showed linear correlations between mutation-induced shifts in Aβ profiles and AAO forPSEN2andAPPmutations. Integration withPSEN1data revealed parallel but shifted correlations, indicating a common pathogenic mechanism with gene-specific onset timing shifts.

Our data support a unified model of ADAD pathogenesis wherein γ-secretase dysfunction and shifts in Aβ profiles define disease onset. This biochemical analysis of ADAD causality and established quantitative relationships deepen our understanding of ADAD pathogenesis, offering potential for predictive AAO modelling with implications for clinical practice, genetic research and development of therapeutic strategies modulating γ-secretase across ADAD forms and potentially more broadly in AD.

We examined the relationships between (full) Aβ peptide profiles and age at symptom onset (AAO) across all Alzheimer’s disease causal genes. Our findings establish a quantitative framework for mutation’s pathogenicity assessment and AAO prediction; with implications for clinical practice, genetic counselling, fundamental and translational research.
Conformational changes, excess area, and elasticity of the Piezo protein-membrane nanodome from coarse-grained and atomistic simulations
Authors: Dixit Sneha , Noé Frank , Weikl Thomas R.
Published: November 2024

The mechanosensitive ion channels Piezo 1 and 2 induce a curved protein-membrane nanodome that flattens with increasing membrane tension γ. The tension-induced flattening of the nanodome is associated with Piezo activation and driven by the energy γΔAwhere ΔAis the excess area of the curved nanodome relative to its planar projected area. Based on extensive coarse-grained and atomistic simulations of membrane-embedded Piezo 1 and 2 proteins, we report here an an excess area ΔAfor the Piezo protein-membrane nanodome of about 40 nm2in tensionless membranes, and a half-maximal reduction of ΔAat tension values of about 3 to 4 mN/m, which is within the range of experimentally determined values for the half-maximal activation of Piezo 1. In line with recent experimental investigations of Piezo proteins in cell membranes and membrane vesicles, the membrane-embedded Piezo proteins adopt conformations in our simulations that are significantly less curved than the protein conformation in the detergent micelles of cryo-EM structures. An elasticity analysis of the nanodome shapes and protein conformations obtained from our simulations leads to an elastic model for Piezo activation that distinguishes the different energy components of the protein and the membrane in the tension-induced flattening of the nanodome.