bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic analysis of fatty acid desaturases in breast invasive carcinoma: The prognosis, gene mutation, and tumor immune microenvironment
Authors: Wang Jie , Zhang Qian , Zhou Duanrui , Wang Yixuan , Che Huilian , Ge Yunjun , Zhong Zhangfeng , Wu Guosheng
Published: June 2024

Breast invasive carcinoma (BRCA) is one of the most common cancers in women, with its malignant progression significantly influenced by intracellular fatty acid (FA) desaturation. Stearoyl-coenzyme A desaturase (SCD) and fatty acid desaturase 2 (FADS2) are two key rate-limiting enzymes that catalyze the FA desaturation process and cooperate to accelerate lipid metabolic activities. In this study, we investigated the potential functions of SCD and FADS2 in BRCA using bioinformatic analysis and experimental validation. The gene expression profiling interactive analysis database showed that the expression of SCD or FADS2 genes was positively linked to worse overall survival and disease-free survival in the Cancer Genome Atlas database-BRCA. The University of Alabama at Birmingham cancer data analysis portal database indicates that the expression and methylation levels of SCD or FADS2 are associated with various clinicopathological factors in patients with BRCA. Moreover, the tumor immune estimation resource and TISCH databases showed a significant positive correlation between the expression of SCD and the abundance of CD8+ T cells and macrophage cell infiltration, while the expression of FADS2 was positively correlated with the abundance of B cells. Meanwhile, SCD or FADS2 had a higher expression in monocytes/macrophages analyzed the BRCA_GSE143423 and BRCA_GSE114727_inDrop datasets. Mechanistically, the Search Tool for the Retrieval of Distant Genes and CancerSEA databases showed that SCD and FADS2 were upregulated in several cell biology signaling pathways, particularly in inflammation, apoptosis, and DNA repair. Finally, SCD or FADS2 knockdown inhibited the proliferation of MCF-7 and MDA-MB-231 cells. In summary, SCD and FADS2 play significant roles in BRCA development, suggesting that they may serve as potential therapeutic targets for BRCA treatment.
The PAD-adapted 30-20-10 during Nordic walking: A new exercise training session in patients with symptomatic peripheral artery disease
Authors: Hagen Paolo , Malatesta Davide , Calanca Luca , Mazzolai Lucia , Lanzi Stefano
Published: June 2024

This study aimed to investigate the feasibility of a peripheral artery disease (PAD)-adapted 30-20-10 Nordic walking session in patients with symptomatic PAD and to compare the cardiovascular response of this new training session to a traditional walking (TW) and 4 × 4 minutes Nordic walking session. This is a prospective observational study. Patients with Fontaine stage II PAD were included. Patients participated in Nordic walking sessions, which were randomly assigned as TW, 4 × 4 minute intervals, and peripheral artery disease adapted 30-20-10 exercise session (PAD-adapted 30-20-10 sessions). PAD-adapted 30-20-10 and 4 × 4 minutes sessions consisted of 4 repetitions of 4 minutes of effort followed by 3 minutes of passive recovery. PAD-adapted 30-20-10 session was characterized by 4 continuous 1-min repetitions at 3 different walking speeds [high (30 seconds), moderate (20 seconds) and low (10 seconds)]. During the 4 × 4 minutes session, patients were asked to cover the maximal distance at a constant speed. During TW session, patients were asked to walk at a speed inducing moderate-to-severe claudication pain. Heart rate, rating of perceived exertion (RPE) and claudication pain intensity using a visual analog scale were assessed. The perceived enjoyment of each session was assessed using a visual analog scale ranging from 0 (not enjoyable) to 10 (very enjoyable). Eleven patients with chronic symptomatic PAD were included (62 ± 13 years; 54% women). The mean heart rate during the time of effort was significantly higher in PAD-adapted 30-20-10 group than in 4 × 4 minutes and TW groups (127 ± 12, 122 ± 12, 114 ± 11 bpm, respectively; P ≤ .001). The mean rating of perceived exertion (16 ± 1, 15 ± 1, 13 ± 1; P ≤ .001) and claudication pain intensity (8 ± 1, 7 ± 1; 7 ± 1 mm; P ≤ .019) were significantly higher during PAD-adapted 30-20-10 sessions than during 4 × 4 minutes and TW sessions. The perceived enjoyment was similar among sessions (8.7 ± 1.6 for TW, 8.6 ± 1.7 for 4 × 4 minutes, and 8.8 ± 1.8 mm for PAD-adapted 30-20-10 sessions; P = .935). The PAD-adapted 30-20-10 session is feasible and induces higher cardiovascular stimulation and claudication pain than 4 × 4 minutes and TW procedures in patients with symptomatic PAD. Despite these different responses, a similar perceived enjoyment among the sessions has been shown. Future investigations are needed to examine the effects of this new training session in these patients.
The relationship between dementia caregivers and quality of life in South Korean populations
Authors: Lee Sujin , Chung Jae Ho
Published: June 2024

The purpose of this study was to assess the relationship between quality of life and dementia caregivers. The 2019 Korean Community Health Survey participants were assessed using the Patient Health Questionnaire-9, subjective cognitive decline (SCD) and SCD-related functional limitation, and EuroQol 5-dimension (EQ-5D). Sociodemographic and psychosocial variables were evaluated and compared between participants with dementia caregivers (n = 37,614) and non-dementia caregivers (n = 140,518). The dementia caregivers group reported significantly higher rates of depression, SCD, SCD-related functional restriction, and mean EQ-5D compared to the non-dementia caregivers group (P < .001). After adjusting for multiple confoundings, the odds ratio (OR) for depression (Patient Health Questionnaire-9 ≥ 10), SCD, SCD-related functional limitation, and lowest quartile of the EQ-5D index scores in the dementia caregivers group were 1.43 (95% confidence interval [CI], 1.29–1.59), 1.30 (95% CI: 1.24–1.36), 1.26 (95% CI: 1.20–1.32), and 1.22 (95% CI: 1.16–1.29), respectively. Physical activity (OR: 1.47; 95% CI: 1.43–1.52), self-control (OR: 1.41; 95% CI: 1.35–1.47), daily activity (OR: 1.55; 95% CI: 1.50–1.60), pain (OR: 1.62; 95% CI: 1.58–1.67), and anxiety/depression (OR: 2.17; 95% CI: 2.10–2.24) were all more common among participants in the dementia caregivers group than in the non-dementia family caregivers group. Depression, SCD, and a lower quality of life are linked to dementia caregivers, especially if there is moderate to severe anxiety or depression.
Cardiac complications (arrhythmias and heart failure) in patients with ischemic stroke: A meta-analysis
Authors: Shah Sangam , Dahal Krishna , Subedi Prativa , Thapa Sangharsha , Mandal Prince , Kashyap Ashutosh , Bhattarai Himal Bikram , Gupta Ashwini , Dhakal Sarita , Singh Sweta , Chand Swati
Published: June 2024

Background:

In patients with ischemic stroke (pwIS), cardiac complications have been observed in observational studies. We conducted a systematic review and meta-analysis to investigate the arrhythmias and heart failure in pwIS.

Methods:

Up until September 2023, we searched for case-control, cross-sectional, or cohort studies in 4 databases. For case-control/cross-sectional studies, odds ratios (OR) were determined using a random-effects model meta-analysis, while hazard ratios (HR) were calculated for cohort studies, and 95% confidence intervals (CIs) were pooled in the meta-analysis.

Results:

In the meta-analysis, we incorporated 5 studies: 2 cohort studies, 2 case-control studies, and 1 cross-sectional study. In all, 81,181 controls and 25,544 pwIS were included in this investigation. The combined OR for case-control studies of arrhythmias was estimated to be 1.86 (95% CI: 0.70–4.94, P = .21), HR for cohort studies of arrhythmias to be 4.2 (95% CI: 1.49–12.01, P < .05), and for cohort studies of heart failure to be 2.9 (95% CI: 2.65–3.18, P < .05), suggesting that pwIS may be more likely to experience cardiac complications.

Conclusion:

Our results revealed that there is a comparatively higher risk of cardiac complications in pwIS; however, more research is needed to evaluate the risk of cardiac complications in pwIS.
Comparison of preemptive and non-preemptive kidney transplantation outcomes in children aged <6 years
Authors: Aoki Yujiro , Hamasaki Yuko , Hashimoto Junya , Zaitsu Ayuko , Suda Shiho , Itabashi Yoshihiro , Muramatsu Masaki , Kawamura Takeshi , Shishido Seiichiro , Sakai Ken
Published: June 2024

We aimed to compare the outcomes of pediatric kidney transplantation (KT) between preemptive KT (PEKT) and non-PEKT in children aged < 6 years. Seventy-four pediatric recipients aged < 6 years who underwent KT were divided into the PEKT and non-PEKT groups. They were retrospectively evaluated for patient and graft survival, graft function, growth, and cytomegalovirus (CMV) infection. Comparison of the groups (PEKT, n = 14; non-PEKT, n = 60) revealed no significant differences between them in terms of distribution of sex, age, weight, primary disease, or population of pre-transplant CMV immunoglobulin G-positive patients. The median estimated glomerular filtration rate before KT in the PEKT and non-PEKT groups was 11.4 and 7.3 (mL/min/1.73 m2) (P < .001), respectively, and the median duration of dialysis was 2.7 years in the non-PEKT group. Graft survival at 5 years was 100% and 95% in the PEKT and non-PEKT groups, respectively (P = .634). One patient in the non-PEKT group had vascular complications, with subsequent early graft loss. Incidence of CMV infection was significantly lower in the PEKT group (P = .044). There were no significant differences in post-transplant estimated glomerular filtration rate, acute rejection, or growth. The height standard deviation score showed catch-up growth after KT in both groups. There was no significant difference in transplant outcomes in recipients aged < 6 years, with or without pre-transplant dialysis, except for the incidence of CMV infection. Therefore, PEKT in younger children should be performed aggressively by experienced multi-disciplinary teams.
Palliative surgery versus non-surgery of the solitary metastatic lesion in De novo metastatic breast cancer: A SEER based study
Authors: Yue Jian , Wang Jing , Chen Wei , Yin Xuedong , Du Huimin , Wei Yuxian
Published: June 2024

This study aimed to evaluate whether palliative surgery for metastatic lesion could provide a survival benefit in metastatic breast cancer (MBC) patients with solitary metastasis. De novo MBC patients with solitary distant lesions were enrolled utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to form matched pairs of the surgery group and the non-surgery group. The breast cancer-specific survival (BCSS) and overall survival (OS) outcomes between the 2 groups were compared in the following 3 sample models: the entire cohort of MBC (7665 cases); subgroups of patients with different isolated metastatic organs; and subgroups of patients with different molecular subtypes for each isolated metastatic organ. Compared with the Non-surgery group, the surgery group showed better BCSS and OS before PSM (HR = 0.88, 95% CI = 0.79–0.99, P = .04 and HR = 0.85, 95% CI = 0.76–0.95, P = .006, respectively). After PSM, palliative surgery still provided an OS benefit in patients with brain metastasis and lung metastasis (HR = 0.59, 95% CI = 0.37–0.95, P = .01 and HR = 0.64, 95% CI = 0.45–0.90, P = .02, respectively). Likewise, a better BCSS benefit was also found in the subset of patients with brain metastasis (HR = 0.61, 95% CI = 0.38–1.00, P = .01). Further stratification analysis indicated that patients with the luminal A subtype with brain metastasis have a better BCSS (HR = 0.36, 95% CI = 0.16–0.79, P = .04) and OS (HR = 0.37, 95% CI = 0.18–0.75, P = .03) after undergoing palliative surgery than nonsurgical treatment. Our study originality showed that palliative surgery for metastatic lesion could improve survival prognosis in patients with special single-organ metastasis and specific molecular subtypes. More clinical studies are needed to determine whether palliative surgery should be performed in MBC patients.
Mutual effects of gestational diabetes and schizophrenia: how can one promote the other?: A review
Authors: Ghamri Kholoud A.
Published: June 2024

Although the physical complications of gestational diabetes mellitus (GDM) are well known, emerging evidence suggests a significant link with psychiatric conditions such as schizophrenia (SCZ). This review aimed to explore the extent, nature, and implications of the association between GDM and SCZ, exploring how the 2 conditions may reciprocally influence each other. We conducted a comprehensive literature review and, analyzed clinical and mechanistic evidence supporting the mutual effects of GDM and SCZ. This review examined factors such as neurodevelopment and the impact of antipsychotics. The study found that Maternal GDM increases the risk of SCZ in offspring. Conversely, women with SCZ were more prone to hyperglycemic pregnancies. The research highlights significant regional variations in GDM prevalence, with the highest rate in the Middle East, North Africa, and South-East Asia regions. These regional variations may have an impact on the epidemiology of SCZ. Furthermore, this review identifies the potential biological and environmental mechanisms underlying these associations. There is a bidirectional relationship between GDM and SCZ, with each disorder potentially exacerbating the others. This relationship has significant implications for maternal and offspring health, particularly in regions with high GDM prevalence. These findings underline the need for integrated care approaches for women with SCZ during pregnancy and the importance of monitoring and managing GDM to mitigate the risk of SCZ in the offspring. Notably, this study recognizes the need for further research to fully understand these complex interactions and their implications for healthcare.
Pes planus level affects counter movement jump performance: A study on amateur male and female volleyball players
Authors: Kurtoğlu Ahmet , Çar Bekir , Eken Özgür , Demir Gözde , Türkmen Musa , Setiawan Edi , Alotaibi Madawi H. , Elkholi Safaa Mostafa
Published: June 2024

The aim of this study was to investigate the effect of pes planus level on counter movement jump (CMJ) performance parameters in amateur female and male volleyball players. In this context, amateur volleyball players aged between 18 and 23 years actively playing in the university school volleyball team were included in the study. Pes planus levels of the participants were analyzed using the navicular drop test (NDT). My Jump Lab application was used for CMJ measurement. Within the scope of CMJ, the participants’ jump height, force, relative force, power, relative power, average speed, take-off speed, impulse, and flying time were analyzed. According to the linear regression results between NDT and CMJ parameters, force in males (t = 12.93, P = .049) and average speed in females (t = −3.52, P = .017) were significantly associated with NDT. NDT was similar in men and women (P > .05). However, all CMJ parameters were highly different between genders (P < .001). In the correlation analysis between sport age and physical characteristics and CMJ parameters; height (r = .386, P = .046), weight (r = .569, P = .002), leg length (r = .389, P = .045), foot length (r =. 558, P = .005), foot width (r = .478, P = .018), force (r = .407, P = .039), impulse (r = .460, P = .018) parameters, and sport age. The results suggest that the average speed in females and force in males both significantly influenced NDT, highlighting the significance of both factors in predicting NDT scores. Moreover, all CMJ measures showed significant variations between genders, although the NDT scores did not. Furthermore, the correlation analysis demonstrated a strong correlation between a number of physical attributes and CMJ parameters, highlighting the multifaceted nature of athletic performance and indicating the possible impact of these attributes on CMJ results.
Doxycycline Prophylaxis to Prevent Sexually Transmitted Infections in Women
Authors: Stewart Jenell , Oware Kevin , Donnell Deborah , Violette Lauren R. , Odoyo Josephine , Soge Olusegun O. , Scoville Caitlin W. , Omollo Victor , Mogaka Felix O. , Sesay Fredericka A. , McClelland R. Scott , Spinelli Matthew , Gandhi Monica , Bukusi Elizabeth A. , Baeten Jared M. ,   for the dPEP Kenya Study Team
Published: June 2024

(Abstracted from N Engl J Med 2024;389:2331–2340)

Around the globe, bacterial sexually transmitted infections (STIs) are increasing, with 374 million estimated annual infections of Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum. The burden of STI sequelae is disproportionately endured by women, with resulting effects such as chronic pain, pelvic inflammatory disease, ectopic pregnancy, infertility, pregnancy/fetal complications, and increased risk of human immunodeficiency virus (HIV) acquisition.
Comparison of Perioperative Adverse Events Following Suburethral Sling Placement Using Synthetic Mesh, Autologous Rectus Fascia, and Autologous Fascia Lata in a National Surgical Registry
Authors: Hong Christopher X. , Son Young , Patel Vaishnavi J. , Lince Kimberly , Gupta Priyanka
Published: June 2024

(Abstracted from Neurourol Urodyn 2024:1–10)

The involuntary loss of urine due to effort activities such as coughing, sneezing, or athletic exertion, better known as stress urinary incontinence (SUI), is common for adult women, with anywhere from 4% to 35% of the population being affected. Surgical placement of suburethral sling is a highly effective method of treatment, with up to an 89.2% success rate at 3 years.
The Use of Disposable Supplies: Measuring Suburethral Sling Surgical Waste by Cost and Weight
Authors: Melnyk Alexandra I. , Woods Noe , Bradley Megan S. , Moalli Pamela
Published: June 2024

(Abstracted from Urogynecology 2024;30:132–137)

Throughout the past decade, approximately 10% of total greenhouse gas emissions produced nationally in the United States have originated from the US health care system. Additionally, the carbon footprint of the health care system includes around 5 million tons of annual waste production (around 29 lb per hospital bed per day).
Efficacy and safety of tesamorelin in people with HIV on integrase inhibitors
Authors: Russo Samuel C. , Ockene Mollie W. , Arpante Allison K. , Johnson Julia E. , Lee Hang , Toribio Mabel , Stanley Takara L. , Hadigan Colleen M. , Grinspoon Steven K. , Erlandson Kristine M. , Fourman Lindsay T.
Published: June 2024

Objective:

Tesamorelin is the only FDA-approved therapy to treat abdominal fat accumulation in people with HIV (PWH). Phase III clinical trials were conducted prior to the introduction of integrase inhibitors (INSTIs), which are now a mainstay of HIV antiretroviral therapy.

Design:

We leveraged a randomized double-blind trial of 61 PWH and metabolic dysfunction-associated steatotic liver disease to evaluate the efficacy and safety of tesamorelin 2 mg once daily vs. identical placebo among participants on INSTI-based regimens at baseline.

Methods:

In the parent clinical trial, visceral fat cross-sectional area, hepatic fat fraction, and trunk-to-appendicular fat ratio were quantified using magnetic resonance imaging, proton magnetic resonance spectroscopy, and dual-energy x-ray absorptiometry, respectively, at baseline and 12 months. Metabolic and safety outcomes were compared between treatment arms.

Results:

Among 38 participants on INSTI-based regimens at baseline, 15 individuals on tesamorelin and 16 individuals on placebo completed the 12-month study. Tesamorelin led to significant declines in visceral fat (median [interquartile range]: −25 [−93, −2] vs. 14 [3, 41] cm2, P = 0.001), hepatic fat (−4.2% [−12.3%, −2.7%] vs. −0.5% [−3.9%, 2.7%], P = 0.01), and trunk-to-appendicular fat ratio (−0.1 [−0.3, 0.0] vs. 0.0 [−0.1, 0.1], P = 0.03). Tesamorelin was well tolerated with a similar frequency of adverse events, including hyperglycemia, between groups.

Conclusions:

The current analysis provides the first dedicated data on the efficacy and safety of tesamorelin among PWH on INSTI-based regimens. Despite the association of INSTI use with weight gain and adipose tissue dysfunction, tesamorelin had beneficial effects on body composition with no exacerbation of glycemic control.
COVID-19 Breakthrough Infections Among People With HIV: A Statewide Cohort Analysis
Authors: Yang Xueying , Zhang Jiajia , Chen Shujie , Liu Ziang , Poland Gregory A. , Olatosi Bankole , Weissman Sharon , Li Xiaoming
Published: June 2024

Objectives:

This study aims to identify COVID-19 breakthrough infections among people with HIV (PWH) across different phases of the pandemic and explore whether differential immune dysfunctions are associated with breakthrough infections.

Design and methods:

This retrospective population-based cohort study used data from an integrated electronic health record (EHR) database in South Carolina (SC). Breakthrough infection was defined as the first COVID-19 diagnosis documented in the state agency after the date an individual was fully vaccinated (ie, 2 doses of Pfizer/BNT162b2 or Moderna/mRNA-1273, or 1 dose of Janssen/Ad26.COV2.S) through June 14, 2022. We analyzed the risk and associated factors of the outcome using Cox proportional hazards models.

Results:

Among 7596 fully vaccinated PWH, the overall rate of breakthrough infections was 118.95 cases per 1000 person-years. When compared with the alpha-dominant period, the breakthrough infection rate was higher during both delta-dominant (HR: 1.50; 95% CI: 1.25 to 1.81) and omicron-dominant (HR: 2.86; 95% CI: 1.73 to 4.73) periods. Individuals who received a booster dose had a lower likelihood of breakthrough infections (HR: 0.19; 95% CI: 0.15 to 0.24). There was no association of breakthrough infections with degree of HIV viral suppression, but a higher CD4 count was significantly associated with fewer breakthroughs among PWH (>500 vs <200 cells/mm3: HR: 0.68; 95% CI: 0.49 to 0.94).

Conclusions:

In our PWH population, the incidence of breakthrough infections was high (during both delta-dominant and omicron-dominant periods) and mainly associated with the absence of a booster dose in patients older than 50 years, with comorbidities and low CD4 count.
Three Novel Patient-Reported Outcome Measures to Assess the Patient Experience With Daily and Weekly HIV Oral Antiretroviral Therapy
Authors: Bailey Julie R. , Fonseca Eileen , Borsa Alexander , Hawryluk Emily , Gubernick Steven I. , Motte Anna de la , Karantzoulis Stella , Reaney Matthew , Saretsky Todd L.
Published: June 2024

Background:

Patient-reported outcome measures (PROMs) can provide data on the barriers and facilitators of adherence to daily oral antiretroviral therapy (OART) regimens. We aimed to develop PROMs to understand the perspectives of people with HIV (PWH) on (1) facilitators/barriers to daily OART regimen adherence and (2) a hypothetical switch to a long-acting (LA)-OART regimen.

Methods:

Following the US food and drug administration patient-reported outcome guidance, targeted literature reviews and concept elicitation interviews with clinicians (n = 7) and PWH (n = 28) were conducted to develop conceptual models (CMs) of facilitators/barriers to OART regimen adherence. Three de novo PROMs were developed after an item-generation meeting. Three waves of cognitive debriefing interviews were conducted among PWH (n = 30) to demonstrate content validity and refine the PROMs.

Results:

The targeted literature review identified 25 facilitators/barriers; an additional 16 facilitators/barriers were added by clinicians and PWH and represented in 2 CMs. During the item-generation meeting, the CMs were used to develop 3 de novo PROMs: (1) HIV Patient Perspective of Regimen, (2) HIV Patient Perspective of Regimen Change, and (3) HIV Drivers of Adherence Questionnaire. In the cognitive debriefing interviews, PWH corroborated the relevancy of items in the PROMs, and minor adjustments were made for clarity.

Conclusion:

Three content-valid PROMs were developed to understand the treatment experience of PWH taking daily OART and how that experience may be altered upon a switch to weekly LA-OART. Data from future LA-OART clinical trials will help define a scoring guide and evaluate the structure and measurement properties of the PROMs.
IMPLICATIONS OF YWHAH GENE EXPRESSION IN THE EARLY DETECTION OF SEPSIS
Authors: Yao Hua , Zhou Yue , Geng Zhengguang , Gao Fei , Su De , Kang Yan , Fu Bao
Published: June 2024

Sepsis, a complex and multifaceted condition, is a common occurrence with serious implications for critically ill patients in the intensive care unit (ICU). The YWHAH gene encodes the 14-3-3n protein, a member of the 14-3-3 protein family. While existing research primarily focuses on the role of 14-3-3n in conditions such as schizophrenia and various cancers, our study revealed that the expression of the YWHAH gene remained relatively stable in both infected individuals and healthy controls. Through Venn plot analysis following weighted gene correlation network analysis, we observed a potential association between elevated YWHAH expression and the transition from infection to sepsis. In a comprehensive analysis of public single-cell transcriptome databases, the expression of YWHAH was found to be distinctive in cases of sepsis and infection. These findings were corroborated through an in vitro analysis utilizing real-time polymerase chain reaction. This study represents the initial identification of variations in YWHAH gene expression between patients with infection and sepsis, potentially offering insights for the development of early detection and treatment strategies for sepsis.
Long-term Outcomes After Kidney Transplantation From DBD Donors Aged 70 y and Older
Authors: Lindahl Jørn Petter , Åsberg Anders , Heldal Kristian , Jenssen Trond , Dörje Christina , Skauby Morten , Midtvedt Karsten
Published: June 2024

Background.

Transplantation of kidneys from elderly donations after brain death (DBD) donors has increased owing to organ shortages. We aimed to assess the impact on long-term kidney transplant outcomes from DBD donors aged 70 y and older compared with kidneys from younger donors.

Methods.

From 2007 to 2022, 2274 first single kidney transplantations from DBD donors were performed at our center. Data from 1417 kidney transplant recipients receiving a DBD organ were included and categorized into 3 groups according to donor age: 70 y and older (n = 444, median age 74 y), 60–69 y (n = 527, median age 64 y), and a reference group consisting of donors aged 45–54 y (n = 446, median age 50 y). Kaplan-Meier plots and multivariate Cox regression with correction for recipient, donor, and transplant characteristics were used to investigate patient and kidney graft survival outcomes.

Results.

The median patient follow-up time was 9.3 y (interquartile range, 5.3–13.1). The adjusted hazard ratios for patient death in recipients of kidneys from DBD donors aged 70 y and older compared with 60–69 y and 45–54 y were 1.12 (95% confidence interval [CI], 0.92-1.36; P = 0.26) and 1.62 (95% CI, 1.26-2.07; P < 0.001), respectively. Compared with recipients of donors aged 60–69 y and 45–54 y, the adjusted hazard ratios for kidney graft loss in recipients of donors aged 70 y and older were 1.23 (95% CI, 1.02-1.48; P = 0.029) and 1.94 (95% CI, 1.54-2.45; P < 0.001), respectively.

Conclusions.

Transplantation of kidneys from DBD donors aged 70 y and older resulted in acceptable long-term outcomes and is encouraging.
Hernia Correction After Liver Transplantation Using Nonvascularized Fascia
Authors: Justo Iago , Caso Oscar , Marcacuzco Alberto , Rodríguez-Gil Yolanda , Jiménez-Romero Carlos
Published: June 2024

Background.

Liver transplantation is an increasingly frequent surgical procedure, with elevated rates of postoperative incisional hernias ranging from 5% to 46%. There are numerous known risk factors for incisional hernia, including the type of incision, patient sex, and presence of comorbidities such as diabetes, ascites, older age, and the use of steroids. Most studies on the treatment of incisional hernias in patients who have undergone liver transplantation have shown consistently high rates of complications. Consequently, we propose the use of nonvascular fascia for the symptomatic treatment of incisional hernias in patients with concomitant liver transplantation.

Methods.

We performed our new technique on 8 patients, who had previously undergone liver transplantation, between January 2019 and January 2023. The patients were examined using imaging techniques during the follow-up period.

Results.

Of the 8 patients, 7 were liver transplant recipients and 1 was a combined liver-kidney transplant patient. The median donor age was 57 y (5–66 y), whereas the mean recipient age was 58 y (31–66 y). The median patient height and weight were 163 cm (117–185 cm) and 76 kg (17–104 kg), respectively. Immunosuppression did not change in fascia recipients. The median time between transplantation and hernia repair surgery was 41 mo (5–116 mo). The sizes of the aponeurotic defects varied from 6 × 6 to 25 × 20 cm. Two patients experienced complications: one experienced bulging that required reintervention and the other experienced surgical site seroma. There was no mortality related to the use of the technique, and none were reported during follow-up.

Conclusions.

With its promising results, nonvascularized fascial transplantation can be a successful treatment for incisional hernias in patients who had previously received a liver transplant.
Pharmacodynamic Effect of mTOR Inhibition-based Immunosuppressive Therapy on T- and B-cell Subsets After Renal Transplantation
Authors: Wei Xinyi , Weber Sabine , Yin Decheng , Allabauer Ida , Jobst-Schwan Tilman , Wiesener Michael , Schiffer Mario , Dudziak Diana , Lehmann Christian H. K. , Woelfle Joachim , Hoerning Andre
Published: June 2024

Background.

The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting PI3K-Akt-mTOR pathway blockade efficacy leading to potential under-or overimmunosuppression.

Methods.

In this cross-sectional study, phosphoflow cytometry was used to determine the efficacy of mTOR inhibition in peripheral T- and B-lymphocyte subsets by assessing p70S6 kinase (p70S6K) phosphorylation in renal transplant recipients upon treatment with a combination of either mTORi and calcineurin inhibitors (n = 18), or mTORi with mycophenolic acid (n = 9). Nine dialysis patients with end-stage renal disease and 17 healthy age-matched volunteers served as controls.

Results.

mTORi treatment reduced p70S6K phosphorylation in CD4+, CD8+ T, and CD19+ B cells compared with healthy controls (HCs). Subpopulation analysis of CD4+ T cells and CD19+ B cells revealed a significant reduction of p70S6K phosphorylation in CD4+CD45RA−CD25− Th cells (P < 0.05), CD24hiCD38hi transitional B cells (P < 0.001), CD24+CD38− memory B cells (P < 0.001), and CD24intCD38int-naive B cells (P < 0.05) upon mTORi treatment, whereas CD4+CD45RA−CD25++CD127− regulatory T cells and CD24−CD38hi plasmablasts were not affected. Compared with mTORi + mycophenolic acid therapy, mTORi + calcineurin inhibitor treatment exhibited an even stronger inhibition of p70S6K phosphorylation in CD4+CD45RA−CD25− Th cells and CD8+ T cells. However, trough levels of mTORi did not correlate with p70S6K phosphorylation.

Conclusions.

mTORi selectively inhibited p70S6K phosphorylation in select lymphocyte subtypes. Assessing p70S6K phosphorylation by phosphoflow cytometry may serve as an approach to understand cell subset specific effects of mTORi providing detailed pharmacodynamic information for individualizing immunosuppression.
Efficacy and outcomes of bempedoic acid versus placebo in patients with hypercholesterolemia: an updated systematic review and meta-analysis of randomized controlled trials
Authors: Goyal Aman , Shah Sangam , Dahal Krishna , Changez Mah I. Kan , Tariq Muhammad Daoud , Zuhair Varisha , Shamim Urooj , Abbasi Haleema Qayyum , Shrestha Abhigan Babu , Sah Ranjit , Sohail Amir Humza
Published: June 2024

Introduction

Bempedoic acid (BA) has shown varied efficacy in managing hyperlipidemia. We conducted the most extensive up-to-date meta-analysis, the first to include recent studies by Nissen et al., which boast the largest sample size.

Methods

Literature search was done on Medline, EMBASE, and Cochrane Library. The primary endpoint was a change in low-density lipoprotein-cholesterol (LDL-C) levels, while secondary endpoints encompassed changes in lipid parameters, clinical endpoints, and safety endpoints. The least-square mean (LSM) percent change was utilized for lipid changes, with statistical significance set at P < 0.05.

Results

This analysis included 12 randomized control trials with 22,249 participants. BA exhibited a substantial reduction in LDL-C levels [LSM % change, −24.34; 95% confidence interval (CI), −27.80 to −20.88; P < 0.0001], total cholesterol levels (LSM % change, −16.62; 95% CI, −21.70 to −11.54; P < 0.00001) and high-density lipoprotein-cholesterol (HDL-C) levels (LSM % change, −4.22; 95% CI, −5.51 to −2.92; P < 0.00001) compared to the placebo.

Conclusions

BA significantly lowers LDL-C, total cholesterol, HDL-C, non-HDL-C, high sensitivity C reactive protein, and apolipoprotein levels.
Major depression symptom severity associations with willingness to exert effort and patch foraging strategy
Authors: Bustamante Laura A. , Barch Deanna M. , Solis Johanne , Oshinowo Temitope , Grahek Ivan , Konova Anna B. , Daw Nathaniel D. , Cohen Jonathan D.
Published: June 2024

Background

Individuals with major depressive disorder (MDD) can experience reduced motivation and cognitive function, leading to challenges with goal-directed behavior. When selecting goals, people maximize ‘expected value’ by selecting actions that maximize potential reward while minimizing associated costs, including effort ‘costs’ and the opportunity cost of time. In MDD, differential weighing of costs and benefits are theorized mechanisms underlying changes in goal-directed cognition and may contribute to symptom heterogeneity.

Methods

We used the Effort Foraging Task to quantify cognitive and physical effort costs, and patch leaving thresholds in low effort conditions (reflecting perceived opportunity cost of time) and investigated their shared versus distinct relationships to clinical features in participants with MDD (N=52, 43 in-episode) and comparisons (N=27).

Results

Contrary to our predictions, none of the decision-making measures differed with MDD diagnosis. However, each of the measures were related to symptom severity, over and above effects of ability (i.e., performance). Greater anxiety symptoms were selectively associated withlowercognitive effort cost (i.e. greater willingness to exert effort). Anhedonia and behavioral apathy were associated with increased physical effort costs. Finally, greater overall depression was related to decreased patch leaving thresholds.

Conclusions

Markers of effort-based decision-making may inform understanding of MDD heterogeneity. Increased willingness to exert cognitive effort may contribute to anxiety symptoms such as worry. Decreased leaving thresholds associations with symptom severity is consistent with reward rate-based accounts of reduced vigor in MDD. Future research should address subtypes of depression with or without anxiety, which may relate differentially to cognitive effort decisions.
The Transdiagnostic Connectome Project: a richly phenotyped open dataset for advancing the study of brain-behavior relationships in psychiatry
Authors: Chopra Sidhant , Cocuzza Carrisa V. , Lawhead Connor , Ricard Jocelyn A. , Labache Loïc , Patrick Lauren M. , Kumar Poornima , Rubenstein Arielle , Moses Julia , Chen Lia , Blankenbaker Crystal , Gillis Bryce , Germine Laura T. , Harpaz-Rote Ilan , Yeo BT Thomas , Baker Justin T. , Holmes Avram J.
Published: June 2024

An important aim in psychiatry is the establishment of valid and reliable associations linking profiles of brain functioning to clinically relevant symptoms and behaviors across patient populations. To advance progress in this area, we introduce an open dataset containing behavioral and neuroimaging data from 241 individuals aged 18 to 70, comprising 148 individuals meeting diagnostic criteria for a broad range of psychiatric illnesses and a healthy comparison group of 93 individuals. These data include high-resolution anatomical scans, multiple resting-state, and task-based functional MRI runs. Additionally, participants completed over 50 psychological and cognitive assessments. Here, we detail available behavioral data as well as raw and processed MRI derivatives. Associations between data processing and quality metrics, such as head motion, are reported. Processed data exhibit classic task activation effects and canonical functional network organization. Overall, we provide a comprehensive and analysis-ready transdiagnostic dataset, which we hope will accelerate the identification of illness-relevant features of brain functioning, enabling future discoveries in basic and clinical neuroscience.
An iPSC-based model of Jacob Syndrome reveals a DNA methylation-independent transcriptional dysregulation shared with X aneuploid cells
Authors: Astro V. , Cardona-Londoño K. , Cortés-Medina L.V. , Alghamdi R. , Ramírez-Calderón G. , Kefalas F. , Dilmé-Capó J. , Radío S. , Adamo A.
Published: June 2024

Male sex chromosome aneuploidies are frequent genetic aberrations in humans characterized by additional Y or X chromosome complements. Jacob (JS) and Klinefelter syndromes (KS), carrying 47,XYY and 47,XXY chromosomes, respectively, share several clinical features, including sterility, hormonal deficits, neurocognitive delay, and skeletal-muscle defects. Despite the high incidence, a complete understanding of the molecular mechanisms underlying the clinical manifestations in sex aneuploid patients is still elusive. In this study, we generated and characterized the inaugural cohort of 47,XYY human induced pluripotent stem cells (iPSCs). We performed a comprehensive transcriptional analysis, including JS primary fibroblasts, iPSCs, and neural stem cells (NSCs) alongside KS cells. Our study revealed a transcriptional feedback mechanism tuning non-PAR X chromosome genes (NPX) homologs in Y supernumerary cells, a phenomenon not detected in X aneuploid iPSCs. By ectopically modulating the expression of selected NPY genes, we demonstrated a direct transcriptional link between the UTY-UTX gene pair. Furthermore, our analyses identified a shared transcriptomic signature between JS and KS, discernible already at the iPSC stage, with a notable enrichment for processes related to neurological functions. This transcriptomic convergence underscores potential commonalities in the molecular pathways underpinning the pathophysiology of male sex chromosome aneuploidies. Finally, through genome-wide DNA methylation profiling of JS iPSCs, we demonstrated that a supernumerary Y chromosome only minimally impacts the methylation status of 47,XYY cells at the pluripotent stage. Our work reveals critical transcriptional feedback mechanisms and shared gene expression signatures in male sex chromosome aneuploidies, paving the way for a better understanding of their common phenotypic features.
Human research islet cell culture outcomes at the Alberta Diabetes Institute IsletCore
Authors: Lyon James G , Carr Alice LJ , Smith Nancy P , Marfil-Garza Braulio , Spigelman Aliya F , Bautista Austin , O’Gorman Doug , Kin Tatsuya , Shapiro AM James , Senior Peter A , MacDonald Patrick E
Published: June 2024

Human islets from deceased organ donors have made important contributions to our understanding of pancreatic endocrine function and continue to be an important resource for research studies aimed at understanding, treating, and preventing diabetes. Understanding the impacts of isolation and culture upon the yield of human islets for research is important for planning research studies and islet distribution to distant laboratories. Here we examine islet isolation and cell culture outcomes at the Alberta Diabetes Institute (ADI) IsletCore (n=197). Research-focused isolations typically have a lower yield of islet equivalents (IEQ), with a median of 252,876 IEQ, but a higher purity (median 85%) than clinically-focused isolations before culture. The median recovery of IEQs after culture was 75%, suggesting some loss. This was associated with a shift towards smaller islet particles, indicating possible islet fragmentation, and occurred within 24 hours with no further loss after longer periods of culture (up to 136 hours). No overall change in stimulation index as a measure of islet function was seen with culture time. These findings were replicated in a representative cohort of clinical islet preparations from the Clinical Islet Transplant Program at the University of Alberta. Thus, loss of islets occurs within 24 hours of isolation and there is no further impact of extended culture prior to islet distribution for research.
No innocent bystanders: pertussis vaccination epitomizes evolutionary parallelisms betweenBordetella parapertussisandB. pertussis
Authors: Bouchez Valérie , Moreno-Mingorance Albert , Mir-Cros Alba , Landier Annie , Armatys Nathalie , Guillot Sophie , Martín-Gómez Maria Teresa , Rodrigues Carla , Toubiana Julie , Bento Ana I. , Weigand Michael R. , González-López Juan José , Brisse Sylvain
Published: June 2024

Pathogens adapting to the human host and to vaccination-induced immunity may follow parallel evolutionary paths.Bordetella parapertussis(Bpp) contributes significantly to the burden of whooping cough (pertussis), shares vaccine antigens withBordetella pertussis (Bp),and both pathogens are phylogenetically related and ecological competitors.Bpvaccine antigen-coding genes have accumulated variation, including pertactin disruptions, after introduction of acellular vaccines in the 1990s. We aimed to evaluate evolutionary parallelisms inBpp, even though pertussis vaccines were designed againstBp.

We investigated the temporal evolution ofBppsublineages, by sequencing 242Bppisolates collected in France, the USA and Spain between 1937 and 2019, spanning pre-vaccine and two vaccines eras.

We estimated the evolutionary rate ofBppat 2.12×10−7substitutions per site·year-1, with a most recent common ancestor of all sequenced isolates around year 1877, and found that pertactin deficiencyin Bppwas driven by 18 disruptive mutations, including deletionprn:ΔG-1895 estimated to have occurred around 1998 and observed in 73.8% (149/202) of post-2007 isolates. In addition, we detected two mutations in thebvgA-fhaBintergenic region (controlling expression of the master transcriptional regulator BvgA and the filamentous hemagglutinin), that became fixed in the early 1900s.

Our findings suggest early adaptation ofBppto humans through modulation of thebvgASregulon, and a rapid adaptation through the loss of pertactin expression, representing a late evolutionary parallelism concomitant with acellular vaccination against whooping cough.

IMPORTANCE

Vaccination againstBordetella pertussis(Bp) has strongly affected the recent evolution of this main agent of whooping cough. Whether it may have done so co-incidentally onBordetella parapertussis(Bpp), which is genetically and ecologically very similar toBp,has not been described in detail. Our findings show striking evolutionary parallelisms ofBppwithBp, including early changes in a critical regulatory region, and strong evidence of adaptation to vaccine-driven population immunity, even though whooping cough vaccines were not designed explicitly againstBpp. The rapid populational loss of pertactin in countries where acellular pertussis vaccines are used may also reduce protection by vaccination againstBpp, the second agent of whooping cough.
Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2’-deoxyguanosine and mutagenesis in lung epithelial cells
Authors: Ramirez D.C. , Gomez Mejiba S.E.
Published: June 2024

Irritation causes the recruitment and activation of neutrophils in the stressed airways. This process is known as neutrophilic inflammation. This process results in myeloperoxidase (MPO), an enzyme contained inside neutrophil azurophilic granules, being released as neutrophil extracellular traps (NETs), which also contain genomic DNA, modified histones, and other proteins. In the airways, released MPO can be taken up by bystander tissue epithelial cells. MPO is the only mammalian peroxidase enzyme that under physiological conditions produces hypochlorite (HOCl). Intracellularly produced HOCl may damage the cell genome, with the intermediacy of DNA-centered free radicals, which upon reaction with molecular oxygen decay to mutagenic end-oxidation products, such as 8-oxo-7,8-dihydro-2’ –deoxyguanosine (8-oxo-dGuo). Herein, we aimed to test whether HOCl-induced DNA-centered radicals precede the oxidation of DNA and mutagenesis in A549 human lung epithelial cells as anin vitromodel that resembles neutrophilic inflammation in irritated airways. Interestingly, by trapping HOCl-induced DNA-centered radicals, the nitrone spin trap 5,5-dimethyl-1-pyrrolineN-oxide (DMPO) blocks the formation of 8-oxo-dGuo and possibly other end-oxidation products, forming DNA-DMPO nitrone adducts, thus reducing mutagenesis in the hypoxanthine phosphoribosyl transferase (hrpt)gene, one of the most sensitive genes to oxidative damage. P53 is a transcription factor known as the master regulator of the cell response to genomic damage. By trapping DNA-centered radicals, DMPO also blocks the translocation of p53 to the cell nucleus, suggesting that by trapping DNA-centered radicals with DMPO, end-oxidation products are prevented, and the cell response to genomic damage is not sensed. DMPO traps DNA-centered radicals, reduces 8-oxo-dGuo accumulation, and blockshrptgene mutation. Trapping DNA-centered radicals to reduce the accumulation of HOCl-induced mutagenic end-oxidation products in the genome of bystander cells, which have taken MPO from the inflammatory milieu, will provide new therapeutic avenues to reduce genotoxic damage at sites of neutrophilic inflammation, such as in the irritated airways.