bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular Effects of Increasing Positive End-expiratory Pressure in a Model of Left Ventricular Cardiogenic Shock in Female Pigs
Authors: Hørsdal Oskar Kjærgaard , Wethelund Kasper Lykke , Gopalasingam Nigopan , Lyhne Mads Dam , Ellegaard Mark Stoltenberg , Møller-Helgestad Ole Kristian , Ravn Hanne Berg , Wiggers Henrik , Christensen Steffen , Berg-Hansen Kristoffer
Published: August 2024

Background:

Cardiogenic shock (CS) presents a medical challenge with limited treatment options. Positive end-expiratory pressure (PEEP) during mechanical ventilation has been linked with clinical benefits in patients with CS. This study investigated whether increasing PEEP levels could unload the left ventricle (LV) in CS in a large animal model of LV-CS.

Methods:

Left ventricle cardiogenic shock was induced in 26 female pigs (60 kg) by microsphere injections into the left main coronary artery. In one study, protocol PEEP was increased (5, 10, and 15 cm H2O) and then reverted (15, 10, and 5 cm H2O) in 3-min intervals. In another protocol, PEEP increments with higher granularity were conducted through 3-min intervals (5, 8, 10, 13, and 15 cm H2O). Hemodynamic measurements were performed at all PEEP levels during a healthy state and in LV-CS with LV pressure–volume loops. The primary endpoint was pressure–volume area. Secondary endpoints included other mechanoenergetic parameters and estimates of LV preload and afterload.

Results:

Cardiac output (CO) decreased significantly in LV-CS from 4.5 ± 1.0 to 3.1 ± 0.9 l/min (P < 0.001). Increasing PEEP resulted in lower pressure–volume area, demonstrating a 36 ± 3% decrease in the healthy state (P < 0.001) and 18 ± 3% in LV-CS (P < 0.001) at PEEP 15 cm H2O. These effects were highly reversible when PEEP was returned to 5 cm H2O. Although mean arterial pressure declined with higher PEEP, CO remained preserved during LV-CS (P = 0.339). Increasing PEEP caused reductions in key measures of LV preload and afterload during LV-CS. The right ventricular stroke work index was decreased with increased PEEP. Despite a minor increase in heart rate at PEEP levels of 15 cm H2O (71 beats/min vs. 75 beats/min, P < 0.05), total mechanical power expenditure (pressure–volume area normalized to heart rate) decreased at higher PEEP.

Conclusions:

Applying higher PEEP levels reduced pressure–volume area, preserving CO while decreasing mean arterial pressure. Positive end-expiratory pressure could be a viable LV unloading strategy if titrated optimally during LV-CS.
Activation of α7 Nicotinic Acetylcholine Receptors Inhibits Hepatic Necroptosis and Ameliorates Acute Liver Injury in Mice
Authors: Xu Fang-Fang , Li Zi-Chen , Zhang Wen-Jing , Li Qiao , Li Dong-Jie , Meng Hong-Bo , Shen Fu-Ming , Fu Hui
Published: August 2024

Background:

Acute liver injury is a disease characterized by severe liver dysfunction, caused by significant infiltration of immune cells and extensive cell death with a high mortality. Previous studies demonstrated that the α7 nicotinic acetylcholine receptor (α7nAChR) played a crucial role in various liver diseases. The hypothesis of this study was that activating α7nAChR could alleviate acute liver injury and investigate its possible mechanisms.

Methods:

Acute liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal) in wild type, α7nAChR knockout (α7nAChR-/-) and stimulator of interferon gene (STING) mutation (Sting

gt

/gt
) mice in the presence or absence of a pharmacologic selective α7nAChR agonist (PNU-282987). The effects of α7nAChR on hepatic injury, inflammatory response, mitochondrial damage, necroptosis, and infiltration of immune cells during acute liver injury were assessed.

Results:

The expression of α7nAChR in liver tissue was increased in LPS/D-Gal–induced acute liver injury mice. Compared to the age-matched wild-type mice, α7nAChR deficiency decreased the survival rate, exacerbated the hepatic injury accompanied with enhanced inflammatory response and oxidative stress, and aggravated hepatic mitochondrial damage and necroptosis. Conversely, pharmacologic activation of α7nAChR by PNU-282987 displayed the opposite trends. Furthermore, PNU-282987 significantly reduced the proportion of infiltrating monocyte-derived macrophages (CD45+CD11bhiF4/80int), M1 macrophages (CD45+CD11b+F4/80+CD86hiCD163low), and Ly6Chi monocytes (CD45+CD11b+MHC [major histocompatibility complex] ⅡlowLy6Chi), but increased the resident Kupffer cells (CD45+CD11bintF4/80hiTIM4hi) in the damaged hepatic tissues caused by LPS/D-Gal. Interestingly, α7nAChR deficiency promoted the STING signaling pathway under LPS/D-Gal stimulation, while PNU-282987 treatment significantly prevented its activation. Finally, it was found that Sting mutation abolished the protective effects against hepatic injury by activating α7nAChR.

Conclusions:

The authors' study revealed that activating α7nAChR could protect against LPS/D-Gal–induced acute liver injury by inhibiting hepatic inflammation and necroptosis possibly via regulating immune cells infiltration and inhibiting STING signaling pathway.
Association Between IV Contrast Media Exposure and Acute Kidney Injury in Patients Requiring Emergency Admission: A Nationwide Observational Study in Japan
Authors: Hisamune Ryo , Yamakawa Kazuma , Umemura Yutaka , Ushio Noritaka , Mochizuki Katsunori , Inokuchi Ryota , Doi Kent , Takasu Akira
Published: August 2024

OBJECTIVE:

This study aimed to elucidate the association between IV contrast media CT and acute kidney injury (AKI) and in-hospital mortality among patients requiring emergency admission.

DESIGN:

In this retrospective observational study, we examined AKI within 48 hours after CT, renal replacement therapy (RRT) dependence at discharge, and in-hospital mortality in patients undergoing contrast-enhanced CT or nonenhanced CT. We performed 1:1 propensity score matching to adjust for confounders in the association between IV contrast media use and outcomes. Subgroup analyses were performed according to age, sex, diagnosis at admission, ICU admission, and preexisting chronic kidney disease (CKD).

SETTING AND PATIENTS:

This study used the Medical Data Vision database between 2008 and 2019. This database is Japan’s largest commercially available hospital-based claims database, covering about 45% of acute-care hospitals in Japan, and it also records laboratory results.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

The study included 144,149 patients with (49,057) and without (95,092) contrast media exposure, from which 43,367 propensity score-matched pairs were generated. Between the propensity score-matched groups of overall patients, exposure to contrast media showed no significant risk of AKI (4.6% vs. 5.1%; odds ratio [OR], 0.899; 95% CI, 0.845–0.958) or significant risk of RRT dependence (0.6% vs. 0.4%; OR, 1.297; 95% CI, 1.070–1.574) and significant benefit for in-hospital mortality (5.4% vs. 6.5%; OR, 0.821; 95% CI, 0.775–0.869). In subgroup analyses regarding preexisting CKD, exposure to contrast media was a significant risk for AKI in patients with CKD but not in those without CKD.

CONCLUSIONS:

In this large-scale observational study, IV contrast media was not associated with an increased risk of AKI but concurrently showed beneficial effects on in-hospital mortality among patients requiring emergency admission.
Treatment satisfaction, unmet needs, and new treatment expectations for vasomotor symptoms due to menopause: women's and physicians' opinions
Authors: DePree Barbara J. , Shiozawa Aki , Kim Janet , Wang Yao , Yang Hongbo , Mancuso Shayna
Published: August 2024

Objective

To assess treatment satisfaction, unmet treatment needs, and new vasomotor symptom (VMS) treatment expectations among women with moderate to severe VMS and physicians treating women with VMS.

Methods

This noninterventional, nonrandomized survey included qualitative interviews and quantitative surveys of women and physicians in the US. Participating women had moderate to severe VMS in the past year and received ≥1 hormone therapy (HT), non-HT, or over-the-counter (OTC) treatment for VMS in the past 3 months. Participating physicians were obstetrician-gynecologists (OB-GYNs) and primary care physicians (PCPs) who treated ≥15 women with VMS in the past 3 months. Two online survey questionnaires were developed using insights from literature, qualitative interviews, and clinical experts. Menopause Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) measured treatment satisfaction. Results were summarized descriptively.

Results

Questionnaires were completed by 401 women with VMS and 207 physicians treating VMS. Among women, mean total MS-TSQ score ranges were 62.8-67.3 for HT, 59.8-69.7 for non-HT, and 58.0-64.9 for OTC treatments. Among physicians, mean total MS-TSQ scores were considerably higher for HT than for non-HT and OTC treatments (HT: 73.4-75.6; non-HT: 55.6-62.1; OTC: 49.2-54.7). Women reported “lack of effectiveness” (41.2%), and physicians reported “long-term safety concerns” (56.5%) as main features that do not meet their current treatment expectations. The majority of women and physicians would consider trying a new non-HT treatment for VMS (75.8 and 75.9%, respectively).

Conclusions

Treatment satisfaction and new treatment expectations were similar but with some differences between women and physicians; the need for additional treatments for VMS was identified.
A Systematic Review of the Completion of Cardiac Rehabilitation Programs for Adults Aged 18-50 Years
Authors: Jansson Anna K. , Schumacher Tracy L. , Kocanda Lucy , Whatnall Megan , Fenwick Matthew , Betts Dimity , Bauman Adrian , Kerr Jane , Duncan Mitch J. , Collins Clare E. , Boyle Andrew , Inder Kerry J. , Plotnikoff Ronald C.
Published: August 2024

Objective:

To perform a systematic review of completion rates of cardiac rehabilitation (CR) in adults aged 18 to 50 yr and describe how core components were reported, measured, and tailored to those under 50 yr.

Review Methods:

Database search of MEDLINE, Embase, Emcare, PsycINFO, CINAHL, Scopus, and the Cochrane Library based on keywords, including articles from January 1, 1990. The last search was performed on April 21, 2023. Following the Preferred Reporting Items for Systematic Review and Meta-Analyses protocol, eligible articles contained adults (aged between 18 and 50 yr) who had participated in a CR program.

Out of the articles screened (n = 24,517), 33 reports across 31 independent studies were considered eligible (n = 1958 patients aged ≤50 yr). Cardiac rehabilitation completion rates ranged from 64% to 100%; however, only 5 studies presented a completion rate definition. The length of the program ranged from 7 d to 20 wk, with most (65%) ranging between 6 and 12 wk. While the studies included in this systematic review indicated relatively high rates of completing CR, these are likely to overrepresent the true completion rates as few definitions were provided that could be compared to completion rates used in clinical practice. This systematic review also found that all interventions prescribed exercise (eg, aerobic alone or combined with resistance training or yoga) but had very limited inclusion or description of other integral components of CR (eg, initial assessment and smoking cessation) or how they were assessed and individualized to meet the needs of younger attendees.
Association Between Exercise Systolic Blood Pressure and Risk of Stroke in Men With and Without Cardiovascular Disease
Authors: Jae Sae Young , Gwon Jun Gyo , Kurl Sudhir , Kunutsor Setor K. , Laukkanen Jari A.
Published: August 2024

Purpose:

We tested the hypothesis that an exaggerated exercise systolic blood pressure (ESBP) would be associated with the risk of stroke in men with and without a history of cardiovascular disease (CVD).

Methods:

An ESBP was defined as a maximal systolic blood pressure (SBP) ≥ 210 mmHg during graded exercise testing on a stationary bike until volitional fatigue in 2410 men aged 42 to 61 yr at baseline.

Results:

Over a median 27-yr follow-up, 419 incident stroke events occurred. In a multivariable adjusted model, men with an ESBP had a significantly increased risk of stroke in the entire cohort (HR = 1.41: 95% CI, 1.15-1.74). This association was still significant following further adjustment for resting SBP (HR = 1.25: 95% CI, 1.01-1.56). In subgroup analysis, ESBP was modestly associated with an increased risk of stroke in men with a history of CVD (HR = 1.37: 95% CI, 0.98-1.93), with no strong evidence of an association in men without a history of CVD (HR = 1.20: 95% CI, 0.90-1.60).

Conclusions:

These findings suggest that the heightened risk of stroke related to ESBP response in a general population-based sample of men may be primarily driven by a history of CVD. The results underscore the importance of considering exercise blood pressure response when interpreting stress tests, particularly in individuals with pre-existing CVD.
Generative Artificial Intelligence (AI) to Uncover Insights From Breast Cancer Patients’ Perceptions to Mindfulness-Based Stress Reduction (MBSR) Interventions
Authors: Chang Yun-Chen , Wu Chien-Hung , Lupo Roberto , Botti Stefano , Conte Luana , Vitone Marcello , Massafra Raffaella , De Nunzio Giorgio , Vitale Elsa
Published: August 2024

The study’s central objective is to harness the power of generative Artificial Intelligence (AI), in particular based on Large Language Models, as a valuable resource for delving deeper into the insights offered by patients with breast cancer (BC) who actively participated in a Mindfulness-Based Stress Reduction (MBSR) program. In a 6-week MBSR program, each session lasted 2 hours and encompassed a range of techniques, including sitting meditation, body scan, Hatha yoga, and walking meditation. A total of 25 participants were enrolled in the study. The majority of these participants reported a high level of satisfaction with the mindfulness course. The application of generative AI enabled a comprehensive analysis of the participants’ responses, revealing distinct subgroups among them. The MBSR program was found to be beneficial for most participants, serving as a valuable tool in managing the psychological stresses associated with BC.
Patient-reported outcome measures after laparoscopic totally extra-peritoneal versus open anterior repair of inguinal hernia
Authors: Bartolotta Vittorio , Cicconi Simone , Marziali Irene , Scalone Giancarla , Marilungo Fabio , Guercioni Gianluca , Catarci Marco
Published: August 2024

Background:

This prospective single-center case-control study evaluates the differences in patient-reported outcomes between endoscopic totally extraperitoneal (TEP) and open anterior repair (OR) of inguinal hernia.

Methods:

Seventy-two patients scheduled for elective inguinal hernia repair were divided into 2 groups: the OR group (35 patients) and the TEP group (37 patients). All but 1 patient filled out the questionnaire during their preoperative consultation and at 1–3–6–12 months postoperative follow-up.

Results:

A unilateral hernia was present in all the patients of the open group and in 10 patients (27%) of the TEP group (P < 0.001). At 1 and at 3 months, significantly more patients in the TEP group reported no pain (59.5% vs 29.5%, P = 0.03; 75.7% vs 47.1%, P = 0.02), did not have any groin problems interfering with work activity (67.6% vs 32.3%, P = 0.04; 78.4% vs 50.0%, P = 0.02), and felt very satisfied about surgery (78.4% vs 41.2%, P = 0.01; 83.8% vs 64.7%, P = 0.04). At 1 month, significantly more patients in the OR group cut down on the usual things (55.9% vs 5.4%, P < 0.001) and did not work (53% vs 8.1%, P < 0.001) for more than 21 days for their groin problems. At 1,3, 6 and 12 months follow-up, significantly more patients in the TEP group perceived that the operation helped them (86.5% vs 50%, P = 0.003; 94.6% vs 61.8%, P = 0.001; 91.9% vs 70.5%, P = 0.02; 91.9% vs 73.6%, P = 0.035).

Conclusions:

TEP is characterized by a significant improvement in patient-reported outcomes measures, with clear advantages regarding quality of life and recovery rate, in comparison with traditional OR.
The role of short-chain fatty acids in the regulation of osteoporosis: new perspectives from gut microbiota to bone health: A review
Authors: Feng Boyi , Lu Jingjing , Han Yanhua , Han Yaguang , Qiu Xiaokui , Zeng Zhuoying
Published: August 2024

Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration, resulting in increased fracture risk. With an aging population, osteoporosis imposes a heavy burden worldwide. Current pharmacotherapies such as bisphosphonates can reduce fracture risk but have limitations. Emerging research suggests that gut microbiota regulates bone metabolism through multiple mechanisms. Short-chain fatty acids (SCFAs) produced from microbial fermentation of dietary fiber beneficially impact bone health. Preclinical studies indicate that SCFAs such as butyrate and propionate prevent bone loss in osteoporosis models by inhibiting osteoclastogenesis and immune modulation. Early clinical data also suggest that SCFA supplementation may improve bone turnover markers in postmenopausal women. SCFAs likely act via inhibition of osteoclast differentiation, stimulation of osteoblast activity, regulation of T cells, and other pathways. However, optimal dosing, delivery methods, and long-term safety require further investigation. Modulating the gut-bone axis via supplementation, prebiotics/probiotics, diet, and lifestyle interventions represents an innovative therapeutic approach for osteoporosis. Harnessing the interplay between microbiome, metabolism, immunity, and bone may provide new directions for managing osteoporosis in the future.
The mitochondrial division inhibitor Mdivi-1 protected organ function and extended the treatment window in rats with uncontrolled haemorrhagic shock
Authors: Hu Yi , Fang He , Tan Lei , She Han , Du Yuanlin , Zhu Yu , Wu Yue , Liu Liangming , Li Tao
Published: August 2024

Aim

To elucidate whether the application of the mitochondrial division inhibitor Mdivi-1 can protect organ function and prolong the treatment window for traumatic hemorrhagic shock.

Methods

Before definitive haemostasis treatment, Mdivi-1 (0.25 mg/kg, 0.5 mg/kg and 1 mg/kg) was administered to uncontrolled haemorrhagic shock (UHS) model rats. Lactate Ringer’s solution plus hydroxyethyl starch (130/0.4) was used as a control. The effects of Mdivi-1 on blood loss, fluid demand, survival time, vital organ function, myocardial mitochondrial structure, and mitochondrial function of the heart, liver, kidney and intestine, and oxidative stress at 1 hour after hypotensive resuscitation (50–60 mmHg) were investigated. In addition, we investigated the effect of varying doses of Mdivi-1 on the maintenance time of hypotensive resuscitation without definitive haemostasis and the beneficial effect of Mdivi-1 after prolonging the duration of hypotensive resuscitation to 2 hours.

Results

Compared to conventional resuscitative fluid, Mdivi-1 significantly reduced blood loss and fluid demand, improved important organ functions during hypotensive resuscitation, improved animal survival and reduced the incidence of early death. Mdivi-1 significantly alleviated oxidative stress injury, reduced mitochondrial damage and restored myocardial mitochondrial structure and mitochondrial function of the heart, liver, kidney and intestine. In addition, Mdivi-1 increased the maintenance time of hypotensive resuscitation and improved rat survival after the duration of hypotensive resuscitation was prolonged to 2 h.

Conclusions

Mdivi-1 significantly prolonged the treatment window for traumatic hemorrhagic shock to 2 hours in UHS model rats. The underlying mechanism may be that Mdivi-1 inhibits excessive mitochondrial fission and oxidative stress and improves the structure and function of mitochondria.
Epileptiform Discharges Recorded as Monopoles and Dipoles in the EEG: A Practical Approach to Differentiate Tangential and Radial Generators Using Electrode Position Versus Voltage Graphs
Authors: Garcia-Losarcos Naiara , Hongxuyang Yu , Thyagaraj Suraj , Hampson Johnson P. , Lüders Hans
Published: August 2024

Differentiating dipoles (tangential generators) from monopoles (radial generators) in routine EEG reading can be difficult. The polarity of sharp waves seen on surface EEG will change depending on the generator being located at the wall of the sulcus versus the crown of a gyrus. In this article, the authors introduce visual rules that may be used to determine polarity and estimate the localization of potentials during analysis of the EEG. They also review a practical approach to differentiate monopoles (radial generators) from dipoles (tangential dipoles) in the surface EEG using “electrode position versus voltage graphs.” Finally, the authors illustrate examples of dipoles and monopoles with focal spikes located in the following locations: (1) bipolar spikes located in the anterior bank of the central sulcus, (2) bipolar spikes located in the posterior bank of the central sulcus, (3) monopolar spikes located in the crown of the precentral gyrus, (4) bipolar spikes with a vertically oriented dipole originated within the temporal (inferior) bank of the Sylvian fissure, and (5) monopolar spikes located in the convexity of a temporal gyrus. In summary, this article discusses electrographic features of spikes localized in various fissures and gyri and provides practical rules that permit the identification and location of dipoles and monopoles in standard scalp EEG recordings.
Rethinking HIV care for youth: Insights from qualitative research with youth in Chad
Authors: Bedingar Esias , Paningar Ferdinan , Bedingar Ngarossorang , Mbaidoum Eric , Ngaradoum Naortangar , Atun Rifat , Yousafzai Aisha K.
Published: August 2024

Youth ages 15-24 years are significantly impacted by the HIV/AIDS epidemic, representing approximately 37% of new infections globally. This demographic is especially vulnerable in sub-Saharan Africa, where over 80% of HIV-positive youth reside. In Chad, youth face significant barriers to effective HIV care, including high prevalence rates, particularly among young women, and substantial disparities across regions. Despite overall reductions in new HIV infections, youth remain disproportionately affected, necessitating targeted interventions to improve HIV care outcomes. This study employed thematic analysis to conduct a secondary data analysis of previously collected qualitative data. The analysis focused on understanding the pathways to care for youth living with HIV (YLHIV) in Chad, from diagnosis to antiretroviral therapy (ART) adherence. Data were collected through focus group discussions with 52 youth and 48 service providers, including healthcare workers and community actors. Grounded theory analysis was used to identify barriers and facilitators to HIV care, with data transcribed, translated, and analyzed assisted with ATLAS.ti software (Version 7.6.3). Youth reported significant barriers, including financial constraints, logistical challenges, and fear of stigma. Facilitators included supportive healthcare providers, peer support, and specialized HIV care facilities. Psychological barriers and lack of awareness were also critical factors influencing HIV testing and care engagement. The study highlighted the importance of tailored, youth-friendly services to improve care outcomes. To address the unique challenges faced by youth in Chad, healthcare services must be redesigned with active youth participation to be more adolescent-friendly and supportive. Interventions should focus on reducing stigma, improving accessibility, and providing continuous psychosocial support. By addressing these barriers, it is possible to enhance the HIV care continuum for youth, ultimately improving their health outcomes and contributing to the broader goal of ending the HIV epidemic.
High-Density Lipoprotein (HDL) Subtypes Adversely Alter Brain Structure in Mild Cognitive Impairment: A Tensor-Based Morphometry Analysis
Authors: Azargoonjahromi Ali , Ashrafi Mitra , Abroushan Donya , Ramezannezhad Elham , Sadeghi Mohammad , Pooresmaeil Niaki Seyede Roxane , Radmanesh Mehrsa , Haratian Amin , Taki Azin , Nekahi Negar , Moshiri Yeganeh , Rahimi Marzieh , Fadavian Heidar , Mousavi Seyede Maryam , Fard Atousa Moghadam , Mayeli Mahsa
Published: August 2024

High-density lipoprotein (HDL) cholesterol is typically protective for cognitive function due to its anti-inflammatory, antioxidant, and vascular health benefits. However, recent studies indicated that certain HDL subtypes might be associated with adverse brain structural changes, commonly seen in mild cognitive impairment (MCI). Thus, further research is needed to understand the intricate relationship between HDL levels and brain structure, potentially leading to more effective therapeutic strategies. The current study aimed to investigate the impact of HDL subtypes, such as XL_HDL_P, M_HDL_FC_PCT, M_HDL_P, M_HDL_C, and M_HDL_CE, as well as APOA1, on brain structure in individuals with MCI using tensor-based morphometry (TBM). The study analyzed ADNI data from subjects with at least two serial MRI scans, processed using the Mayo TBM-Symmetric Normalization (SyN) pipeline and SyN for longitudinal measures. The CDR and ADAS scores were used to assess the severity of cognitive impairment and disease progression in our study participants. Significant ROIs were identified from a Mayo Clinic training set, and TBM-SyN scores were computed. The significant correlation was considered with p-values less than 0.05. The study found significant negative effects of several lipoproteins on TBM scores in individuals with MCI. Specifically, XL_HDL_P, with an effect size of - 0.00145 (p=0.029), and M_HDL_FC_PCT, with an effect size of -0.00199 (p=0.0016), were linked to lower TBM scores. Similarly, M_HDL_P (−0.00138, p=0.028), M_HDL_C (−0.00140, p=0.025), M_HDL_CE (−0.00136, p=0.031), and APOA1 (−0.00149, p=0.017) also showed significant associations. These findings indicate that higher levels of HDL subtype cholesterol are significantly associated with reduced TBM scores, suggesting that elevated levels are linked to adverse structural brain changes, such as atrophy, in individuals with MCI, potentially contributing to cognitive decline.
Long-term Outcomes of Peripheral Artery Disease In Veterans: Analysis of the PEripheral ARtery Disease Long-term Survival Study (PEARLS)
Authors: Girotra Saket , Li Qiang , Vaughan-Sarrazin Mary , Lund Brian C. , Al-Garadi Mohammad , Beckman Joshua A. , Nathani Rohit , Hoffman Richard M. , Chan Paul S. , Banerjee Subhash , Tsai Shirling , Kumbhani Dharam J. , Minniefield-Young Nicole , Smolderen Kim G. , Arya Shipra , Nguyen Cathy , Matheny Michael E. , Gobbel Glenn T.
Published: August 2024

Background

Contemporary research in peripheral artery disease (PAD) remains limited due to lack of a national registry and low accuracy of diagnosis codes to identify PAD patients in electronic health records.

Methods & Results

Leveraging a novel natural language processing (NLP) system that identifies PAD with high accuracy using ankle brachial index (ABI) and toe-brachial index (TBI) values, we created a registry of 103,748 patients with new onset PAD patients in the Veterans Health Administration (VHA). Study endpoints include mortality, cardiovascular (hospitalization for acute myocardial infarction or stroke) and limb events (hospitalization for critical limb ischemia or major amputation) and were identified using VA and non-VA encounters. The mean age was 70.6 years; 97.3% were males, and 18.5% self-identified as Black race. The mean ABI value was 0.78 (SD: 0.26) and the mean TBI value was 0.51 (SD: 0.19). Nearly one-third (32.4%) patients were currently smoking and 35.4% formerly smoked. Prevalence of hypertension (86.6%), heart failure (22.7%), diabetes (54.8%), renal failure (23.6%), and chronic obstructive pulmonary disease (35.4%) was high. At 1-year, 9.4% of patients had died. The 1-year incidence of cardiovascular events was 5.6 per 100 patient-years and limb events was 4.5 per 100 patient-years.

Conclusions

We have successfully launched a registry of >100,000 patients with a new diagnosis of PAD in the VHA, the largest integrated health system in the U.S. The ncidence of death and clinical events in our cohort is high. Ongoing studies will yield important insights regarding improving care and outcomes in this high-risk group.
The microbiota affects stem cell decision making inHydra
Authors: He Jinru , Klimovich Alexander , Kock Sabine , Dahmke Linus , Franzenburg Sören , Bosch Thomas C.G.
Published: August 2024

Research on microbial communities colonizing animals has revealed that the microbiota, despite its typical containment to surfaces, influences virtually all organ systems of the host. In absence of a natural microbiota, the host’s development can be disturbed, but how developmental programs are affected by the microbiota is still poorly understood. Removing the microbiota fromHydra, a classic model animal in developmental biology, causes drastic developmental malformations and leads to polyps that temporarily lack the ability to bud. Recolonizing non-budding germfreeHydrawith bacteria reverses this budding inhibition. Single-cell RNA sequencing and trajectory-based differential expression analysis showed that epithelial stem cell decision making is disturbed in non-budding polyps, whereby key developmental regulators are not expressed. This process is reversible by adding back bacteria. Transcriptionally silencing of one of the genes that failed to be activated in non-budding animals, GAPR1, led to polyps that have a significantly reduced budding capacity. The results show that maintaining a species-specific microbiota may enable the animal host to maintain its developmental program.

Significance Statement

Animal developmental programs work within the context of coevolved associations with microbes. Here, we provide mechanistic evidence of the involvement of the microbiota in maintaining the pattern formation program ofHydrawith the asexual formation of buds in the lower part of the body column. We demonstrate that in the absence of bacteria key regulatory factors are not expressed, causing changes in stem cell trajectories that result in loss of budding capacity. This study provides a new perspective on the role that microbiota play during animal development and evolution.

One Sentence Summary

Microbiota interfere withHydra’s asexual reproduction via modulating its stem cell differentiation programs.
Bases for the selection of alternate foot placement during straight- and turning-gait
Authors: Kreter Nicholas , Fino Peter C.
Published: August 2024

Humans typically plan foot placement strategy multiple steps in advance when walking across complex terrain. Planning steps in advance is beneficial for both upright stability and forward progress, but one drawback is that new obstacles can make planned foot placement location unsafe between planning and execution, necessitating a rapid shift to foot placement that impacts stability and progress. This study investigates the bases for selection of alternate foot placement during both straight- and turning-gait. Thirteen healthy young adults walked along a virtually projected walkway with precision footholds oriented in either a straight line or with a single 60°, 90°, or 120° turn to the right. On a subset of trials, participants were required to rapidly avoid stepping on select footholds. We found stereotyped alternate foot placement strategies across turn angles that differed by turn strategy. Alternate foot placement for step turns supported the walker’s instantaneous kinematics but not the planned change in trajectory; whereas foot placement for disrupted spin turns supported the walker’s anticipated change in trajectory. We conclude that when humans are forced to rapidly alter previously developed motor plans for foot placement, they utilize a rapid stereotyped behavior that changes based on the demand of the turn.
AalpiRNA-18529 regulates vitellogenesis ofAedes albopictusvia theGadd45a-mediated JNK-dependent nurse cell apoptosis pathway
Authors: Yang Lu , Gao Yonghui , Chen Yulan , Ren Shuyi , Guo Yifan , Liu Peiwen , Batool Khadija , Tang Jianxia , Gu Jinbao
Published: August 2024

Aedes albopictusshows a rapid global expansion and dramatic vectorial capacity for various arboviruses. Mosquitoes display distinct sexual dimorphisms, only adult females consume blood meals to complete ovarian follicle development. Therefore, cyclic reproduction in female mosquitoes serves as a foundation for the transmission of numerous disease-causing pathogens. Aedes have an expansion of the piRNA biogenesis genes, indicated that piRNA may play multiple functional roles in mosquitoes. Although the antiviral function of piRNA pathway in mosquitoes has been extensively studied, the role of piRNAs in mosquito reproduction remain to be further understood. In the present study, we first profiled the characteristics of sex-biased piRNAs in adultAe.albopictus. Then, we identified a female biased piRNA (Aalpi18529) in adult females, that was highly expressed in ovaries at blood feeding-dependent termination, and depended on PIWI5 and ago3 mediated biogenesis. Aalpi18529 overexpression suppressed ovarian development, and reduced fertility and fecundity in adult females post-bloodmeal. Furthermore, we demonstrated that Aalpi18529 can effectively repress its direct target, growth arrest and DNA-damage-inducible protein 45a (GADD45A), and eventually regulates ovarian development via theGadd45a-mediated JNK-dependent nurse cell apoptosis pathway. Our study is the first to report an endogenous piRNA, which trigger silencing of an important protein-coding gene by posttranscriptional regulation in mosquitoes, expanding our current understanding of the important and multiple roles of piRNAs in biological processes inAe. albopictus.

Author Summary

Here, we conducted high throughput piRNA sequencing and comprehensive analysis of piRNA sex-based expression profiles in adult females and males of Aedes albopictus. Based on several established universal tools for research, we demonstrate an ovary-enriched endogenous piRNA, Aalpi-18529, is involved in the regulation of the apoptosis of nurse cells during vitellogenesis via the GADD45A/phosphorylated JNK (pJNK) axis and ultimately affects ovarian development. In general, uncovering the biological functions of sex-biased piRNAs in Aedes albopictus will enhance the understanding of piRNA roles in mosquito Sexual dimorphism (SD) and will provide provide more information about the high reproductive capacity of Aedes albopictus, which is essential to find alternative control strategies.

Classification:Research Reports
EEG Biomarkers of Age-Related Memory Change
Authors: Broitman Adam W. , Healey M. Karl , Kahana Michael J.
Published: August 2024

The current study investigates whether electroencephalographic (EEG) activity reflects age-related memory changes during encoding. We recorded scalp EEG in 151 young adults (aged 18-30) and 37 older adults (aged 60-85) as they memorized lists of words. Subjects studied the word lists either under full attention or while performing a secondary task that required them to make semantic judgments about each word. Although the secondary task reduced recall among all subjects, differences in recall performance between the age groups were smaller when participants performed a secondary task at encoding. Older adults also exhibited distinct neural subsequent memory effects, characterized by less negativity in the alpha frequencies compared to young adults. Multivariate classifiers trained on neural features successfully predicted subsequent memory at the trial level in both young and older adults, and captured the differential effects of task demands on memory performance between young and older adults. The findings indicate that neural biomarkers of successful memory vary with both cognitive aging and task demands.

Public significance

The current study investigates the EEG spectral biomarkers of memory encoding in young and older adults, and identifies key features of neural activity associated with age-related memory change. We further find that age-related memory differences are smaller when participants perform a semantic judgment task during encoding, and that multivariate classifiers trained on the EEG data predict these effects.
Evaluating the quality of prostate cancer diagnosis recording in routinely collected primary care data for observational research: A study using multiple linked English electronic health records databases
Authors: Somathilake Gayasha , Ford Elizabeth , Armes Jo , Moschoyiannis Sotiris , Collins Michelle , Francsics Patrick , Lemanska Agnieszka
Published: August 2024

Background

Primary care data in the UK are widely used for cancer research, but the reliability of recording key events such as diagnoses remains uncertain. Data linkage can mitigate these uncertainties; however, researchers may avoid linkage due to high costs, tight timelines, and sample size limitations. Hence, this study aimed to assess the quality of prostate cancer (PCa) diagnoses in primary care. We utilised Clinical Practice Research Datalink (CPRD) primary care data linked to National Cancer Registration and Analysis Service (NCRAS) and Hospital Episode Statistics (HES) in England. We compared accuracy, completeness, and timing of diagnosis recording between sources to facilitate decision-making regarding data source selection for future research.

Methods

Incident PCa diagnoses (2000-2016) for males aged ≥46 years recorded in at least one study data source were examined. The accuracy of a data source was estimated by the proportion of diagnoses recorded in the specific source that was also confirmed by any linked source. Completeness was estimated by identifying the proportion of all diagnoses in linked sources with a matching diagnosis in the specific source.

Results

The study included 51,487 PCa patients from either source. CPRD demonstrated 86.9% accuracy and 68.2% completeness against NCRAS and 75.1% accuracy and 61.1% completeness against HES. Overall, CPRD showed the highest accuracy (93%) but the lowest completeness (60.7%). Diagnosis dates in CPRD were more concordant with NCRAS (90.6% within 6 months) than with HES (61.2%). Over time, accuracy and completeness improved, especially after 2004. Discrepancies in diagnosis dates revealed a median delay of 2 weeks in CPRD than NCRAS and 1 week than HES. CPRD Aurum exhibited better quality compared to GOLD.

Conclusions

While the accuracy of PCa diagnoses in CPRD compared to linked sources was high, completeness was low. Therefore, linking to HES or NCRAS should be considered for improved case capture, acknowledging their inherent limitations.
Lateral hypothalamus drives early-onset sleep alterations in amyotrophic lateral sclerosis
Authors: Guillot Simon J. , Lang Christina , Simonot Marie , Knehr Antje , Stuart-Lopez Geoffrey , Weydt Patrick , Dorst Johannes , Kandler Katharina , Kassubek Jan , Wassermann Laura , Rouaux Caroline , Arthaud Sebastien , Luppi Pierre-Herve , Roselli Francesco , Ludolph Albert C. , Dupuis Luc , Bolborea Matei
Published: August 2024

Lateral hypothalamic neurons producing melanin-concentrating hormone (MCH) and orexin/hypocretin are involved in sleep regulation. Both MCH and orexin neurons are altered in amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease. However, sleep alterations are currently poorly characterized in ALS, and could represent either early symptoms or late consequences of disease progression. Here, we characterized sleep architecture using polysomnography in cohorts of both early ALS patients without respiratory impairment and presymptomatic carriers of mutations leading to familial ALS. We observed prominent sleep alterations, including increased wake and decreased deep sleep (non-rapid eye movement—NREM3) in both cohorts, which were replicated in two mouse models of familial ALS,Sod1G86RandFusΔNLS/+mice. Importantly, altered sleep structure in mice was fully rescued byper osadministration of a dual-orexin receptor antagonist, and partially rescued by intracerebroventricular MCH supplementation. Thus, our study shows the existence of a primary sleep alteration in ALS, driven by abnormal MCH and orexin signalling.

One Sentence Summary

Amyotrophic lateral sclerosis is a tragic uncurable motor neuron disease, in this study we decribed for the first time sleep alterations in symptomatic patients and healthy gene carrier which can be reverted byper osadministartion of a dual-orexin receptor antagonist in preclinical models.
aiHumanoid Simulations Uncover Dominant-Negative Effects in HNRNPH2-Related Neurodevelopmental Disorders
Authors: Danter WR
Published: August 2024

HNRNPH2-related neurodevelopmental disorders (NDDs) encompass a spectrum of cognitive, motor, and systemic impairments driven by mutations in the HNRNPH2 gene. While these disorders have been linked to both gain-of-function (GOF) and loss-of-function (LOF) mutations, the precise mechanisms underlying their varied phenotypic features remain unclear. In this study, we employed advanced aiHumanoid simulations to conduct a virtual longitudinal analysis of HNRNPH2 mutations, spanning from birth through young adulthood. Our findings reveal that LOF mutations, particularly severe missense, and nonsense/frameshift mutations, exert dominant-negative effects that significantly impair neurodevelopmental outcomes.

Through detailed comparison of mild versus severe mutations, we observed that severe LOF mutations lead to markedly worse cognitive, motor, and systemic deficits. These effects are compounded by the interference of mutant HNRNPH2 with the function of wild-type HNRNPH2 and potentially compensatory proteins such as HNRNPH1. Notably, our simulations indicate that the upregulation of HNRNPH1 observed in knockout models fails to compensate in the presence of dominant-negative mutations, highlighting a critical pathway disruption.

This study not only elucidates the mechanistic basis of dominant-negative effects in HNRNPH2-related NDDs but also suggests new therapeutic avenues, including the enhancement of compensatory mechanisms and targeted inhibition of mutant HNRNPH2. The use of aiHumanoid simulations offers a powerful tool for predicting long-term outcomes and testing potential interventions, providing a robust platform for advancing the understanding and treatment of HNRNPH2-NDDs.

Our findings underscore the importance of early diagnosis and intervention, particularly for patients with severe LOF mutations, and facilitate future research focused on mitigating the dominant-negative effects of these mutations.
Plasma triacylglycerol length and saturation level mark healthy aging groups in humans
Authors: Li Weisha , Schomakers Bauke V. , Weeghel Michel van , Grevendonk Lotte , Vaz Frédéric M. , Salomons Gajja S. , Schrauwen Patrick , Hoeks Joris , Gao Arwen W. , Houtkooper Riekelt H. , Janssens Georges E.
Published: August 2024

Complex lipids, essential components in biological processes, exhibit conserved age-related changes that alter membrane properties, cellular functions, and are implicated as biomarkers and contributors to longevity and age-related diseases. While physical activity alleviates age-related comorbidities and physical impairments, comprehensive exploration of the underlying biological mechanisms, particularly at the level of complex lipids, remains limited. However, clinical studies suggest that physical activity may counteract these age-related lipidomic changes, presenting a promising avenue for intervention. We performed lipidomic profiling of plasma from an extensively characterized cohort of young and aged individuals. Annotating 1446 unique lipid species across 24 lipid classes we found the most prominent difference in older adults was an accumulation of triacylglycerols (TGs), with lower physical activity levels associated with higher TG levels in plasma and reduced physical functionality. Remarkably, lipid species in the TG class did not accumulate uniformly. Rather, our study unveiled a negative correlation between higher physical activity levels and TGs with shorter chain length and more double bonds in this demographic. Overall, our research highlights that plasma TG length and saturation level can help mark healthy aging groups in humans. These findings deepen our understanding of how aging affects complex lipids, and the influence of physical activity on this process.
Predictingin vivoconcentrations of dietary hop phytoestrogens by physiologically based kinetic modeling
Authors: Stevanoska Maja , Beekmann Karsten , Punt Ans , Sturla Shana J. , Aichinger Georg
Published: August 2024

Hop extracts containing prenylated polyphenols such as 8-prenylnaringenin (8-PN) and its precursor isoxanthohumol (iXN) are popular among women seeking natural alternatives to hormone therapy for postmenopausal symptoms. Due to structural similarities with estrogens, these compounds act as estrogen receptor agonists. Especially 8-PN, described as the most potent phytoestrogen known to date, poses a potential risk for endocrine disruption. Therefore, its use as a hormone replacement raises concerns for human health. However, a significant challenge in assessing the potential endocrine-disruptive effects of hop polyphenols is the lack of data on their toxicokinetics. Particularly, information onin vivoconcentrations in target tissues is lacking. To address this gap, we developed a physiologically based kinetic (PBK) model tailored to female physiology. The model was used to predict the levels of hop polyphenols in human blood and target tissues under realistic exposure scenarios. The predictions suggest that iXN and 8-PN concentrations in target tissues reach the low nanomolar range after dietary supplementation. This study enhances our understanding of the safety profile of hop polyphenols and highlights the need for further research into their use as an alternative to hormone therapy in menopausal women.
The role of a non-native host plant in altering the seasonal dynamics of monarch development
Authors: DuBose James G. , Hoogshagen Mackenzie , de Roode Jacobus C.
Published: August 2024

The development and life history of many organisms have evolved to align with annual seasonal changes, but anthropogenic ecological changes have started to disrupt phenological dynamics. To understand the implications of these changes, tractable model systems are needed to identify the causes and consequences of phenological-seasonal asynchrony. Here, we investigate the potential of a non-native and tropical host plant whose phenology has been tuned to different seasonal dynamics to influence the seasonal developmental dynamics of the migratory monarch butterflyDanaus plexippus. Consistent with predictions, we found that the non-native host plant facilitated successful monarch development later into the fall and early winter, which is typically the season North American monarchs enter reproductive diapause and migrate to over-wintering locations. Furthermore, we found evidence that this success could partly be attributed to decreased thermal constraints on development experienced by monarchs reared onA. curassavica.