bluuebunny/crossref_metadata_2025 huggingface dataset:
Staphylococcus simulans infections in a patient following high supracondylar osteotomy to treat osteoarthritis: a case report
Authors: Tan Lin , Wang Jian , Li Ming , Zhou Yadi , Xia Binyi , Zhang Minmin , Yang Chengli
Published: September 2024

Staphylococcus simulans (S. simulans) is a coagulase-negative staphylococcus that is commonly found in animal pathogens. S. simulans rarely causes infections in clinical practice due to its low pathogenic ability and opportunistic pathogen, which results in few relevant clinical reports. In this paper, the authors primarily report a patient infected with S. simulans after a high supracondylar osteotomy and the S. simulans was identified by the means of the next-generation sequencing technology. This case report provides new evidence for the further research of S. simulans and paves the way for its clinical therapy.
Protection of Omicron Bivalent Vaccine, Previous Infection, and Their Induced Neutralizing Antibodies Against Symptomatic Infection With Omicron XBB.1.16 and EG.5.1
Authors: Yamamoto Shohei , Matsuda Kouki , Maeda Kenji , Mizoue Tetsuya , Horii Kumi , Okudera Kaori , Tan Tomofumi , Oshiro Yusuke , Inamura Natsumi , Nemoto Takashi , S Takeuchi Junko , Konishi Maki , Sugiyama Haruhito , Aoyanagi Nobuyoshi , Sugiura Wataru , Ohmagari Norio
Published: September 2024

Background

Data are limited on the protective role of the Omicron BA bivalent vaccine, previous infection, and their induced neutralizing antibodies against Omicron XBB.1.16 and EG.5.1 infection.

Methods

We conducted a nested case-control analysis among tertiary hospital staff in Tokyo who had received ≥3 doses of COVID-19 vaccines and donated blood samples in June 2023 (1 month before the Omicron XBB.1.16 and EG.5.1 wave). We identified 206 symptomatic cases between June and September 2023 and selected their controls with 1:1 propensity score matching. We examined the association of vaccination, previous infection, and preinfection live virus neutralizing antibody titers against Omicron XBB.1.16 and EG.5.1 with the risk of COVID-19 infection.

Results

Previous infection during the Omicron BA- or XBB-dominant phase was associated with a significantly lower infection risk during the XBB.1.16 and EG.5.1–dominant phase than infection-naive status, with 70% and 100% protection, respectively, whereas Omicron BA bivalent vaccination showed no association. Preinfection neutralizing titers against XBB.1.16 and EG.5.1 were 39% (95% CI, 8%–60%) and 28% (95% CI, 8%–44%) lower in cases than matched controls. Neutralizing activity against XBB.1.16 and EG.5.1 was somewhat detectable in the sera of individuals with previous infection but barely detectable in those who were infection naive and received the Omicron bivalent vaccine.

Conclusions

In the era when the Omicron XBB vaccine was unavailable, the Omicron BA bivalent vaccine did not confer the neutralizing activity and protection against Omicron XBB.1.16 and EG.5.1 symptomatic infection. The previous infection afforded neutralizing titers and protection against symptomatic infection with these variants.
Hyaluronic acid and urology: a systematic review and meta-analysis
Authors: Roth Bradley J , Hammad Muhammed A M , Sultan Mark I , Abou Chawareb Elia , Banton Jasmin , Park Sean Sung Hun , Perito Paul E , Yafi Faysal A , Raheem Omer
Published: September 2024

Introduction

The use of hyaluronic acid as a nonsurgical treatment for various conditions within urology has been of great interest in recent literature.

Objectives

In this study, we aimed to provide an updated review and analysis of the current state of hyaluronic acid use in urology, characterize its adverse effects, and briefly discuss future directions of research for hyaluronic acid in urology.

Methods

PubMed searches were run utilizing multiple terms, including “hyaluronic acid,” “penile,” “augmentation,” “Peyronie disease,” “premature ejaculation,” and “cosmetic urology,” among other related iterations. Relevant data extracted included International Index of Erectile Function score, intravaginal ejaculatory latency, glans circumference, penile girth, and plaque size. We also included studies which reported on complications of hyaluronic acid injections. Aggregated analysis was performed on studies with complete pre and post injection data at time closest to 6 months postinjection.

Results

A total of 33 studies met our inclusion criteria. Studies had marked heterogeneity in design, but most reported positive results. A total of 16 studies were included in our analysis. Intravaginal ejaculatory latency, penile girth, glans circumference, and International Index of Erectile Function were all increased on a fixed-effects model. Reduction in plaque size was not significant (P = .069). Complications were rare.

Conclusion

Literature on hyaluronic acid for urologic issues demonstrates promising results; however, the quality of studies was variable. Our analysis of these studies largely corroborates these findings; however, the results are limited by the data available. Hyaluronic acid may be promising, but we highly implore standardization of study regimens in randomized controlled trials.
Pre-implementation planning to enhance integration of HIV and behavioral health care services at two Ryan White-funded HIV care centers
Authors: Hussen Sophia A , Byrd Rosalind N , Doraivelu Kamini , Moore Shamia J , Camp Daniel M , Wood-Palmer Drew , Kalokhe Ameeta S , Farber Eugene W , Ali Mohammed K
Published: September 2024

Behavioral health conditions are disproportionately experienced by people living with Human immunodeficiency virus (HIV), including young Black gay, bisexual, and other men who have sex with men (GBMSM). Left unaddressed, these symptoms can adversely impact HIV care outcomes. Improving the integration of behavioral health and HIV care services has been proposed as a strategy to address this challenge. To conduct a pre-implementation study exploring barriers and facilitators to improving HIV and behavioral health care integration at two HIV clinics in Atlanta, Georgia. We conducted a mixed-methods study guided by the Consolidated Framework for Implementation Research (CFIR). Sixty (60) HIV care providers, behavioral health care providers, and social service providers participated in cross-sectional surveys, and a subset of survey participants (15) also participated in a qualitative in-depth interview to explore CFIR constructs in greater depth. We focused on Intervention Characteristics, Outer Setting, and Inner Setting as the most relevant CFIR domains. Within each of these domains, we identified both facilitators and barriers to improving HIV and behavioral care integration in the two clinics. Participants agreed that enhancing integration would provide a relative advantage over current practice, would address young Black GBMSM and other patient needs, and would be compatible with the organizational mission. However, they also expressed concerns about complexity, resource availability, and priority relative to other clinic initiatives. Participants were enthusiastic about improving care integration but also invoked practical challenges to translating this idea into practice. Future research should test specific implementation strategies and their potential effectiveness for improving the integration of behavioral health and HIV care, as a strategy for improving well-being among young Black GBMSM and other people living with HIV.
Reports of Burnout Among Historically Marginalized and Female Graduating Medical Students During the COVID-19 Pandemic
Authors: Dyrbye Liselotte N. , Brushaber Danielle E. , West Colin P.
Published: September 2024

Purpose

To examine graduating medical student reports of burnout by sex, race and ethnicity, and sexual orientation and explore trends within intersectional demographic groups from 2019–2021 in a national sample.

Method

The authors obtained medical student responses to the 2019–2021 Association of American Medical Colleges (AAMC) Graduation Questionnaires (GQs) linked to data from other AAMC sources. The dataset included year of GQ completion, responses to a modified Oldenburg Burnout Inventory (exhaustion subscale range: 0–24; disengagement subscale range: 0–15), and demographics previously shown to relate to the risk of burnout in medical students, residents, or physicians. Multivariable linear regression analysis was performed to evaluate independent associations between demographics and burnout.

Results

Overall response rate was 80.7%. After controlling for other factors, mean exhaustion scores were higher among Asian (parameter estimate [PE] 0.38, 95% confidence interval [CI] 0.21, 0.54), bisexual (PE 0.97, 95% CI 0.76, 1.17), and gay or lesbian (PE 0.55, 95% CI 0.35, 0.75) students than those who did not identify with each of those respective groups. Mean disengagement scores were lower among female (PE −0.47, 95% CI −0.52, −0.42), Hispanic (PE −0.11, 95% CI −0.22, −0.01), and White (PE −0.10, 95% CI −0.19, 0.00) students and higher among Asian (PE 0.17, 95% CI 0.07, 0.27), Black or African American (PE 0.31, 95% CI 0.18, 0.44), bisexual (PE 0.54, 95% CI 0.41, 0.66), and gay or lesbian (PE 0.23, 95% CI 0.11, 0.35) students than those who did not identify with each of those respective groups. From 2019–2021, mean exhaustion and disengagement scores were relatively stable or improved across nearly all intersectional groups.

Conclusions

Male, Asian, Black or African American, and sexual minority students had a higher risk of burnout, while female, Hispanic, White, and heterosexual or straight students had a lower risk of burnout.
Lung-protective ventilation and postoperative pulmonary complications during pulmonary resection in children
Authors: Zhu Change , Zhang Mazhong , Zhang Saiji , Zhang Rufang , Wei Rong
Published: September 2024

BACKGROUND

Children are more susceptible to postoperative pulmonary complications (PPCs) due to their smaller functional residual capacity and higher closing volume; however, lung-protective ventilation (LPV) in children requiring one-lung ventilation (OLV) has been relatively underexplored.

OBJECTIVES

To evaluate the effects of LPV and driving pressure-guided ventilation on PPCs in children with OLV.

DESIGN

Randomised, controlled, double-blind study.

SETTING

Single-site tertiary hospital, 6 May 2022 to 31 August 2023.

PATIENTS

213 children aged < 6 years, planned for lung resection secondary to congenital cystic adenomatoid malformation.

INTERVENTIONS

Children were randomly assigned to LPV (n = 142) or control (n = 71) groups. Children in LPV group were randomly assigned to either driving pressure group (n = 70) receiving individualised positive end-expiratory pressure (PEEP) to deliver the lowest driving pressure or to conventional protective ventilation group (n = 72) with fixed PEEP of 5 cmH2O.

MAIN OUTCOME MEASURES

The primary outcome was the incidence of PPCs within 7 days after surgery. Secondary outcomes were pulmonary mechanics, oxygenation and mechanical power.

RESULTS

The incidence of PPCs did not differ between the LPV (24/142, 16.9%) and the control groups (15/71, 21.1%) (P = 0.45). The driving pressure was lower in the driving pressure group than in the 5 cmH2O PEEP group (15 vs. 17 cmH2O; P 
= 0.001). Lung compliance and oxygenation were higher while the dynamic component of mechanical power was lower in the driving pressure group than in the 5 cmH2O PEEP group. The incidence of PPCs did not differ between the driving pressure (11/70, 15.7%) and the 5 cmH2O PEEP groups (13/72, 18.1%) (P 
= 0.71).

CONCLUSIONS

LPV did not decrease the occurrence of PPCs compared to non-protective ventilation. Although lung compliance and oxygenation were higher in the driving pressure group than in the 5 cmH2O PEEP group, these benefits did not translate into significant reductions in PPCs. However, the study is limited by a small sample size, which may affect the interpretation of the results. Future research with larger sample sizes is necessary to confirm these findings.

TRIAL REGISTRATION

ChiCTR2200059270.
Population Pharmacokinetic Modeling of Pyrazinamide Among Chinese Patients With Drug-Sensitive or Multidrug-Resistant Tuberculosis
Authors: Chen Shuyan , Rao Weiqiao , Fu Liang , Liu Guohui , Zhang Jiancong , Liao Yunli , Lv Ning , Deng Guofang , Yang Shijin , Lin Liang , Li Lujin , Qu Jiuxin , Liu Siqi , Zou Jin
Published: September 2024

Background:

Pyrazinamide is used to treat drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB). This study aimed to characterize the factors associated with the pharmacokinetic parameters of pyrazinamide and evaluate the disposition of the current regimen, which could provide suggestions for adequate dosing strategies for therapeutic targets.

Methods:

A population pharmacokinetic model of pyrazinamide was developed based on the data from 499 plasma concentrations from 222 Chinese patients diagnosed with DS or MDR TB. Pyrazinamide exposure was best described using a one-compartment model.

Results:

No significant differences were observed in the pharmacokinetic parameters between DS and MDR TB. The final covariate model showed that total body weight was the only significant covariate for apparent clearance, which increased by 0.45 L/h with a 10 kg increase in body weight. A simulation showed that for typical subjects weighing 40–80 kg, a fixed dosage of 1500 mg daily had an area under the concentration–time curve from 0 to 24 hours (AUC0–24) of 389.9–716.0 mg·h/L and peak serum concentrations of the drug (Cmax) of 32.2–44.8 mg/L.

Conclusions:

Fixed pyrazinamide doses of 1500, 1750, and 2000 mg are recommended for patients weighing 40–70, 70–80, and 80–90 kg, respectively, to achieve the exposure targets of AUC0–24 > 363 mg·h/L or Cmax > 35 mg/L to attain efficacy.
Comparative Three-dimensional Analysis of Facial Lifting Effects across Five Aesthetic Units following Continuous Radiation 115-Watt 6.78-MHz Monopolar Radiofrequency Therapy
Authors: Kim JongSeo
Published: September 2024

Background:

Modern aesthetic trends favor noninvasive facelift procedures, shifting away from traditional surgery. This study explores the three-dimensional evaluation of facial lifting across aesthetic units using the VolNewMer (VNM) device after continuous 115-W 6.78-MHz monopolar radiofrequency (RF) therapy.

Methods:

A cohort of 30 Korean women underwent VNM treatment with a detailed protocol, including energy levels, cooling techniques, and stem cell media application. Lifting amount was analyzed using a three-dimensional scanner with computer program in five specific areas, including the forehead, lateral orbital rim, mid-face, low-face, and neck areas. The changes in Global Aesthetic Improvement Scale for skin texture, tightening, and lifting were surveyed.

Results:

Immediate and sustained improvement was observed in the mid-cheeks and lower face area. The lifting amount of facial mid-cheek areas was 1.88 ± 0.76 mm, whereas the lifting amount of lower face areas was 1.79 ± 0.91, lateral orbital rim areas was 1.62 ± 0.99, forehead areas was 1.46 ± 1.26, and neck areas was 2.66 ± 1.40 mm immediately after the procedure. The lifting amount of mid-cheek areas was 1.93 ± 0.90 mm, whereas lower face areas was 1.67 ± 1.04, lateral orbital rim areas was 1.58 ± .072, forehead areas was 1.31 ± 0.73, and neck areas was 2.80 ± 0.78 mm 1 month after the procedure.

Conclusions:

RF treatment is emerging as a recommended noninvasive procedure for facial lifting. VNM-RF treatment showed a significant lifting effect immediately after the procedure, and the lifting effect continued 1 month later (P < 0.05). Global Aesthetic Improvement Scale skin texture was more satisfying 1 month later than immediately after, suggesting a potential correlation with collagen regeneration, indicating a lasting effect over time.
Umbilical Lift: A Simple Effective Procedure to Rejuvenate the Umbilicus
Authors: Nassab Reza
Published: September 2024

The umbilical lift procedure is a useful technique for improving the skin laxity in the upper umbilicus, which is commonly seen in patients with umbilical piercings who have had children or with aging.
Duplication of the Lacrimal Sac With Three Canaliculi
Authors: Sinha Prerna , Ranjan Ashish , Ali Mohammad Javed
Published: September 2024

Complex congenital lacrimal drainage anomalies are known to be associated with several syndromes and present unique surgical challenges. Duplication of human body structures is uncommon and has been reported in the uterus (uterine didelphys), ureter (duplex ureter), duodenum, transverse colon, and nose. Lacrimal drainage anomalies have been reported in proboscis lateralis. To the best of the authors’ knowledge, there are no prior reports on duplication of the lacrimal sac. The present case reports a complex congenital nasolacrimal duct obstruction that was associated with duplication of the lacrimal sac and the presence of 3 canaliculi.
The Algorithmic Role of Critical Radiographic Features in the Treatment of Angioinvasive Fungal Sinusitis
Authors: Kassotis Alexis , Coombs Allison , Matari Nahill , Lignelli Angela , Kazim Michael
Published: September 2024

Introduction:

Angioinvasive fungal sinusitis (AIFS) is a rapidly progressive, highly morbid infection. It can be challenging to obtain an early diagnosis, but intervention in the acute period is crucial for prognosis. Previous literature has identified numerous radiographic features with high sensitivity and specificity for AIFS, even in early disease. Bedside nasal endoscopy can substantiate the diagnosis but can also yield false negative results. Initially, these patients may present to the ophthalmologist. Thus, to avoid visual and potentially life-threatening complications, subtle clinical signs in conjunction with suspicious radiographic features must be promptly recognized by the ophthalmologist and escalated appropriately. We review, for the benefit of the ophthalmic community, the salient radiographic features of AIFS and integrate them into a decision-making algorithm for diagnostic workup and management.

Methods:

A literature search was conducted using a comprehensive keyword search in the Pubmed and Embase databases. English studies from 1988 to 2022 describing the radiographic features of AIFS queried. Literature on the newly described entity, COVID-19 COVID-19-associated mucormycosis was included. The authors collected the most frequently reported indicators of AIFS.

Results:

The authors review 4 radiographic findings that are frequently associated with AIFS, including in the early stages of disease: 1) loss of contrast enhancement in the nasal turbinate and maxilla (i.e., “black turbinate and maxillary sign”), (2) periantral involvement seen as changes in density, fat stranding or obliteration of the anterior, retromaxillary, or retroantral fat planes on CT, (3) Tissue invasion without bony erosion, (4) Hypointense T2W sinonasal secretions on MRI in the setting of acute sinusitis. The authors additionally propose an algorithm that suggests surgical exploration for patients with clinical concern for AIFS and these radiographic features, even if bedside nasal endoscopy is inconsistent with AIFS.

Conclusion:

The radiographic signs highlighted herein should heighten suspicion for AIFS in the appropriate clinical setting, prompting urgent surgical exploration regardless of nasal endoscopy findings.
Usefulness of the Malyugin ring upside-down technique
Authors: Ichihara Kosuke , Masuda Yoichiro , Komatsu Koji , Ohira Ryo , Tachibana Sei , Iida Masanobu , Matsuda Hitomi , Mitooka Shingo , Nakano Tadashi
Published: September 2024

The use of the Malyugin ring involves inserting a folded ring inside an injector and then expanding and fixing the pupil with the 3 spiral fixation points. The typically recommended technique as provided by MicroSurgical Technology involves inserting the injector with the opening facing upward. However, this technique is often challenging in cases where 3-point fixation of the scrolls on the pupil with a 1-action insertion is difficult. To address these challenges, we have been using the upside-down technique, where the injector is inserted with the opening facing downward, to achieve a high success rate in 1-action 3-point fixation. This technique demonstrated a success rate of over 80% in achieving 1-action 3-point fixation. 1-action 3-point fixation tended to be easier in smaller horizontal pupils. The upside-down technique suggests the potential for achieving minimally invasive and efficient pupil expansion.
Prediction of Spread Through Air Spaces By Intraoperative Frozen Section for Patients With cT1N0M0 Invasive Lung Adenocarcinoma
Authors: Cao Hang , Zheng Qiang , Deng Chaoqiang , Fu Zichen , Shen Xuxia , Jin Yan , Yang Yongguo , Qian Bin , Yuan Chunyan , Wang Weihua , Zhang Lei , Song Qingping , Zuo Shuying , Ma Junjie , You Shuqing , Zheng Senzhong , Gao Qingli , Su Guangli , Zhang Yang , Chen Haiquan , Li Yuan
Published: September 2024

Objective:

To investigate the value of intraoperative assessment of spread through air spaces (STAS) on frozen sections (FS) in peripheral small-sized lung adenocarcinoma.

Background:

Surgical decision-making based on FS diagnosis of STAS may be useful to prevent local control failure after sublobar resection.

Methods:

We conducted a multicenter prospective observational study of consecutive patients with cT1N0M0 invasive lung adenocarcinoma to evaluate the accuracy of FS for the intraoperative detection of STAS. The final pathology (FP) diagnosis of STAS was based on corresponding permanent paraffin sections.

Results:

This study included 878 patients with cT1N0M0 invasive lung adenocarcinoma. A total of 833 cases (95%) were assessable for STAS on FS. In total, 26.4% of the cases evaluated positive for STAS on FP, whereas 18.2% on FS. The accuracy, sensitivity, and specificity of FS diagnosis of STAS were 85.1%, 56.4%, and 95.4%, respectively, with moderate agreement (κ=0.575). Interobserver agreement was substantial (κ=0.756) among the 3 pathologists. Subgroup analysis based on tumor size or consolidation-to-tumor ratio all showed moderate agreement for concordance. After rigorous reassessment of false-positive cases, the presence of artifacts may be the main cause of interpretation errors. In addition, true positive cases showed more high-grade histologic patterns and more advanced p-TNM stages than false negative cases.

Conclusions:

This is the largest prospective observational study to evaluate STAS on FS in patients with cT1N0M0 invasive lung adenocarcinoma. FS is highly specific with moderate agreement, but is not sensitive for STAS detection. While appropriately reporting STAS on FS may provide surgeons with valuable information for intraoperative decision-making, better approaches are needed.
Treatment escalation for people with anorexia nervosa: setting, therapies and nutritional interventions
Authors: Himmerich Hubertus , Keeler Johanna Louise , Tchanturia Kate , Treasure Janet
Published: September 2024

Purpose of review

Adult patients with severe anorexia nervosa often receive the same unsuccessful treatment without changes regarding the setting, the therapies, or nutritional interventions.

Recent findings

Settings where people with anorexia nervosa are treated include their general practitioner, an independent psychiatric practice, a community mental health team (CMHT), a specialized eating disorder outpatient service, eating disorder early intervention services, a highly intensive eating disorder outpatient or home treatment programme, eating disorder daycare, an inpatient eating disorder service, a general hospital or a general psychiatric hospital, or residential treatment. At a specialized eating disorder service, patients should be offered evidence-based psychotherapy for anorexia nervosa, dietary advice and physical health monitoring as a first step. Additionally, they may be allocated to a specific treatment pathway, family interventions and creative therapies. As a second step, clinicians may consider integrating interventions targeting psychiatric or physical comorbidities, medication for anorexia nervosa or noninvasive neurostimulation. After several years of futile treatment, deep brain stimulation (DBS) should be considered to prevent a chronic course of anorexia nervosa. Nutritional interventions can be escalated from nutritional counselling to nasogastric tube feeding. Patients who rely on nasogastric tube feeding might benefit from percutaneous endoscopic gastrostomy (PEG). Patients who vomit despite a nasogastric tube, might need nasojejunal tube feeding.

Treatment for people with anorexia nervosa should be regularly reviewed and, if necessary, escalated to avoid a chronic and longstanding disease course.
Altered intestinal Streptococcus anginosus and 5α-reductase gene levels in patients with hepatocellular carcinoma and elevated Bacteroides stercoris in atezolizumab/bevacizumab non-responders
Authors: Fujii Tadashi , Kuzuya Teiji , Kondo Nobuhiro , Funasaka Kohei , Ohno Eizaburo , Hirooka Yoshiki , Tochio Takumi
Published: September 2024

Introduction. Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide.

Gap statement. Monitoring of HCC and predicting its immunotherapy responses are challenging.

Aim. This study explored the potential of the gut microbiome for HCC monitoring and predicting HCC immunotherapy responses.

Methods. DNA samples were collected from the faeces of 22 patients with HCC treated with atezolizumab/bevacizumab (Atz/Bev) and 85 healthy controls. The gut microbiome was analysed using 16S rRNA next-generation sequencing and quantitative PCR (qPCR).

Results. The microbiomes of patients with HCC demonstrated significant enrichment of Lactobacillus, particularly Lactobacillus fermentum, and Streptococcus, notably Streptococcus anginosus. Comparative analysis between Atz/Bev responders (R) and non-responders (NR) revealed a higher abundance of Bacteroides stercoris in the NR group and Bacteroides coprocola in the R group. Using qPCR analysis, we observed elevated levels of S. anginosus and reduced levels of 5α-reductase genes, essential for the synthesis of isoallolithocholic acid, in HCC patients compared to controls. Additionally, the analysis confirmed a significantly lower abundance of B. stercoris in the Atz/Bev R group relative to the NR group.

Conclusions. The gut microbiome analysis and specific gene quantification via qPCR could provide a rapid, less invasive, and cost-effective approach for assessing the increased risk of HCC, monitoring patient status, and predicting immunotherapy responses.
Diurnal regulation of Acyl-CoA synthetase 3 (ACSF3) underlies daily mitochondrial lysine-malonylation and hepatic metabolism
Authors: Le Questel Enora , Besnard Charlène , Atger Florian , Foucher Yolène , Tollec Alwéna , Pakulska Victoria , Rodrigues Oliveira Arsênio , Clotteau Chloé , Gourdel Mathilde , Nemazanyy Ivan , Croyal Mikael , Coute Yohann , Jacobi David , Cariou Bertrand , Mauvoisin Daniel
Published: September 2024

Circadian rhythms are fundamental to maintaining health and are implicated in various diseases. In the liver, daily rhythms are coordinated via the interplay between feeding rhythms and the molecular circadian clock, ensuring metabolic homeostasis. Disruption of feeding rhythms can lead to circadian misalignment, contributing to metabolic disorders, yet the underlying molecular mechanisms remain unclear. Recent evidence suggests that post-translational modifications play a key role in regulating circadian functional output. In this framework, mitochondria serve as a convergence point, integrating rhythms in metabolism, feeding rhythms and the circadian clock. In the present study, we used a multi-omics approach to investigate the role of the Acyl-CoA synthetase 3 (ACSF3) in driving lysine-malonylation and in regulating daily hepatic metabolism. We found that ACSF3 expression and its mediated impact on lysine-malonylation are rhythmic and largely governed by feeding rhythms. While hepatic ACSF3 knockdown did not alter diet-induced metabolic abnormalities, our results demonstrate that ACSF3 plays a role in the diurnal regulation of liver glycogen storage,de novolipogenesis, and triglyceride synthesis.
Synchrotron Tomography-Based Finite Element Analysis of Vertebral Endplate Loading Reveals Functional Roles for Architectural Features
Authors: Chen Jishizhan , Parmenter Alissa L , Sharma Aikta , Newham Elis , Bele Eral , Marussi Sebastian , Pitsillides Andrew A , Terrill Nick J , Gupta Himadri S , Lee Peter D
Published: September 2024

Lower back pain is linked to vertebral biomechanics, with vertebral endplates (VEPs) playing a key role in vertebral load transfer and distribution. Synchrotron computed tomography (sCT) allows for detailed visualisation of the microstructure of intact VEPs under near-physiological loads and, when coupled with digital volume correlation (DVC), can be used to quantify three-dimensional (3D) strain fields with nanoscale resolution. Herein, we spatially couple DVC data and an image-based finite element model (FEM) to determine the material properties of murine VEPs. This model was then extended to investigate VEP biomechanics under different motions and disease conditions to reveal that VEP protrusions are important for load absorption and redistribution under different motions and predicted that abnormal intervertebral disc (IVD) stress may underpin osteoporosis-and pycnodysostosis-related IVD degeneration. Our study validates the efficacy of using DVC to increase the accuracy of FEM predictions and highlights that these methodologies may be scalable to large animals and humans.
Metabolomic and Lipidomic Analysis of Manganese-Associated Parkinsonism: a Case-Control Study in Brescia, Italy
Authors: Lewis Freeman , Shoieb Daniel , Azmoun Somaiyeh , Colicino Elena , Jin Yan , Chi Jinhua , Gu Haiwei , Placidi Donatella , Padovani Alessandro , Pilotto Andrea , Pepe Fulvio , Turla Marinella , Crippa Patrizia , Wang Xuexia , Lucchini Roberto G
Published: September 2024

Background and Objectives

Excessive Manganese (Mn) exposure is neurotoxic and can cause Mn-Induced Parkinsonism (MnIP), marked by cognitive and motor dysfunction. Although metabolomic and lipidomic research in Parkinsonism (PD) patients exists, it remains limited. This study hypothesizes distinct metabolomic and lipidomic profiles based on exposure status, disease diagnosis, and their interaction.

Methods

We used a case-control design with a 2×2 factorial framework to investigate the metabolomic and lipidomic alterations associated with Mn exposure and their link to PD. The study population of 97 individuals was divided into four groups: non-exposed controls (n=23), exposed controls (n=25), non-exposed with PD (n=26) and exposed with PD (n=23). Cases, defined by at least two cardinal PD features (excluding vascular, iatrogenic, and traumatic origins), were recruited from movement disorder clinics in four hospitals in Brescia, Northern Italy. Controls, free from neurological or psychiatric conditions, were selected from the same hospitals. Exposed subjects resided in metallurgic regions (Val Camonica and Bagnolo Mella) for at least 8 continuous years, while non-exposed subjects lived in low-exposure areas around Lake Garda and Brescia city. We conducted untargeted analyses of metabolites and lipids in whole blood samples using ultra-high-performance liquid chromatography (UHPLC) and mass spectrometry (MS), followed by statistical analyses including Principal Component Analysis (PCA), Partial Least Squares–Discriminant Analysis (PLS-DA), and Two-Way Analysis of Covariance (ANCOVA).

Results

Metabolomic analysis revealed modulation of alanine, aspartate, and glutamate metabolism (Impact=0.05, p=0.001) associated with disease effect; butanoate metabolism (Impact=0.03, p=0.004) with the exposure effect; and vitamin B6 metabolism (Impact=0.08, p=0.03) with the interaction effect. Differential relative abundances in 3- sulfoxy-L-Tyrosine (β=1.12, FDR p<0.001), glycocholic acid (β=0.48, FDR p=0.03), and palmitelaidic acid (β=0.30, FDR p<0.001) were linked to disease, exposure, and interaction effects, respectively. In the lipidome, ferroptosis (Pathway Lipids=11, FDR p=0.03) associated with the disease effect and sphingolipid signaling (Pathway Lipids=9, FDR p=0.04) associated with the interaction effect were significantly altered. Lipid classes triacylglycerols, ceramides, and phosphatidylethanolamines showed differential relative abundances associated with disease, exposure, and interaction effects, respectively.

Discussion

These findings suggest that PD and Mn exposure induce unique metabolomic and lipidomic changes, potentially serving as biomarkers for MnIP and warranting further study.
Changing dynamics ofAedes aegyptiinvasion and vector-borne disease risk for rural communities in the Peruvian Amazon
Authors: Fikrig Kara , Noriega Arnold O. , Rodriguez Rosa A. , Bardales John , Rivas José , Reyna Becker , Izquierdo Guido , Morrison Amy C. , Harrington Laura C.
Published: September 2024

Aedes aegypti,the primary vector of dengue virus, is predominantly considered an urban mosquito, especially in the Americas, where its reemergence began in cities after the end of continent-wide eradication campaigns. The results of our study diverge from this narrative, demonstrating the recent and widespread rural invasion ofAe. aegyptialong major shipping routes in the northern Peruvian Amazon between the major cities of Iquitos, Pucallpa, and Yurimaguas. We identifiedAe. aegyptipopulations in 29 of 30 sites surveyed across a rural to urban gradient and characterized mosquito larval habitats andAe. aegyptiadult metrics. Households, regardless of community size, were more likely to be positive forAe. aegyptiadult(s) and had a higher number ofAe. aegyptiadults if a mosquito larval habitat was identified on the property, compared to houses without a larval habitat. In multiple instances, adultAe. aegyptiindices in rural villages were equal to or greater than indices in dengue-endemic cities, suggesting the entomological risk level in some rural areas is sufficient to sustain dengue transmission. Fourteen rural sites were sampled in transects from the community river port into town. In seven of these sites, houses closer to the port were significantly more likely to be infested withAe. aegyptiadults than houses further from the ports, and four additional sites had a marginal relationship to the same effect. This pattern suggests that many rural sites are invaded via adultAe. aegyptidisembarking from boats at the port, finding nearby oviposition sites, and advancing stepwise into town. The existence of the pattern also suggests that many of the sites are still experiencing active invasion, with sections of towns stillAe. aegypti-free. Only one site shows a strong signal of invasion via the egg or larval stage, with a focus ofAe. aegyptifar removed from the port. The widespread infestation ofAe. aegyptiin rural areas is a major public health threat given the far distance of communities to hospital care. It is important to implement control measures now before the mosquito gains a stronger foothold in zones of active invasion.
Running against the clock: describing microbial diversity in an extremely endangered microbial oasis in the Chihuahuan desert
Authors: Rodriguez-Cruz Ulises E. , Ochoa-Sánchez Manuel , Eguiarte Luis E. , Souza Valeria
Published: September 2024

Cuatro cienegas Basin (CCB) is an extraordinary diverse oasis that is dying in front of our eyes. The Churince system disappeared completely in 2016 and the poza named for its amazing diversity, Archaean Domes, disappeared in 2023. However, there could be groundwater water connections between sites, allowing to dispersal of taxa as well as the survival of microbial lineages in the deep aquifer Herein, we explore whether there is microbial connectivity across sites in the oasis of CCB, located in the Chihuahuan Desert, in the Northern state of Coahuila in Mexico. We focused first on two distinct aquatic system within CCB that are ∼4700 meters apart on the Eastern lobe of the basin: Pozas Rojas –a preserved system characterized by several unique ponds surrounding a deep lagoon, and the now extinct Archean Domes (AD)--noted for its extreme salinity, as well as anoxic and methane-rich conditions. We sequenced the hypervariable V4 region of the 16S rRNA gene from samples of Pozas Rojas (PR), and of two different features in AD: orange circles (C) and dome-shaped structures (D). Additionally, we utilized whole-genome metagenomic data from different samples from AD site (from the years 2016 to 2023). Second, we compared metagenomes obtained from the now extinct Churince (samples from 2012 to 2014) in the West lobe of the basin, with the Easter side. Our results revealed taxa common to different sites, includingHalanaerobiumsp. andDesulfovermiculussp., that are prevalent across samples from PR and AD, and shared between AD and Churince, suggesting that those genera are core to the deep aquifer.

Moreover, during the eight years of sampling, AD exhibited a substantial decline in microbial diversity. Possibly, this decline, as well as Churince demise, is due to anthropogenic disturbances of the deep aquifer due to overexploitation for alfalfa irrigation. Diversity in metagenome-assembled genomes (MAGs) decreasing from 125 MAGs in 2016 to only 22 in 2023. Our study supports the hypothesis of the importance of groundwater as a fundamental microbial reservoir and connector among CCB ponds. Therefore, the regulation of extraction of such aquifer is paramount.
Bias from heritable confounding in Mendelian randomization studies
Authors: Sanderson Eleanor , Rosoff Dan , Palmer Tom , Tilling Kate , Smith George Davey , Hemani Gibran
Published: September 2024

Mendelian randomization (MR) is an approach to causal inference that utilises genetic variants to obtain estimates of the causal effect of an exposure on an outcome in the presence of unobserved confounding. MR relies on a set of assumptions to obtain unbiased effect estimates, one of these assumptions is that there is no pathway from the genetic variants to the outcome that does not act through the exposure. Increasing genome-wide association study (GWAS) sample sizes for the exposure enables discovery of instrumental variables with smaller effect sizes. We illustrate through simulations how smaller effect sizes could arise from genetic variants that act through traits that have greater liability to confound an exposure-outcome relationship. When such genetic variants are selected as instruments this can bias the MR effect estimate obtained from that instrument in the same direction as the confounded observational association but with larger magnitude. Through simulation we illustrate how the total bias of the MR estimates increases across a range of standard MR estimation methods increases as the proportion of the genetic instruments that are associated with the confounder increases. However, if such heritable confounders are known and can be instrumented, the confounder free effect estimate can be obtained through applying a pre-estimation filtering to standard MR methods, removing instruments that explain more variation in that confounder than the exposure, or by estimating effects through multivariable MR. We highlight the potential for SNPs identified in GWAS to be associated with potential confounders through examination of a recent GWAS of C-Reactive Protein. Finally, we illustrate our approach through estimation of the causal effect of age at menarche on type 2 diabetes, hypothesising that the MR effect estimate may be biased by confounding due to the inclusion of genetic variants associated with early life adiposity as instruments.
Methodological Challenges using Routine Clinical Care Data for Real-World Evidence: a Rapid Review utilizing a systematic literature search and focus group discussion
Authors: Pfaffenlehner Michelle , Behrens Max , Zöller Daniela , Ungethüm Kathrin , Günther Kai , Rücker Viktoria , Reese Jens-Peter , Heuschmann Peter , Kesselmeier Miriam , Remo Flavia , Scherag André , Binder Harald , Binder Nadine ,   the EVA4MII project
Published: September 2024

Background

The integration of real-world evidence (RWE) from real-world data (RWD) in clinical research is crucial for bridging the gap between clinical trial results and real-world outcomes. Analyzing routinely collected data to generate clinical evidence faces methodological concerns like confounding and bias, similar to prospectively documented observational studies. This study focuses on additional limitations frequently reported in the literature, providing an overview of the challenges and biases inherent to analyzing routine clinical care data, including health claims data (hereafter: routine data).

Methods

We conducted a literature search on routine data studies in four high-impact journals based on the Journal Citation Reports (JCR) category “Medicine, General & Internal” as of 2022 and three oncology journals, covering articles published from January 2018 to October 2023. Articles were screened and categorized into three scenarios based on their potential to provide meaningful RWE: (1) Burden of Disease, (2) Safety and Risk Group Analysis, and (3) Treatment Comparison. Limitations of this type of data cited in the discussion sections were extracted and classified according to different bias types: main bias categories in non-randomized studies (information bias, reporting bias, selection bias, confounding) and additional routine data-specific challenges (i.e., operationalization, coding, follow-up, missing data, validation, and data quality). These classifications were then ranked by relevance in a focus group meeting of methodological experts. The search was pre-specified and registered in PROSPERO (CRD42023477616).

Results

In October 2023, 227 articles were identified, 69 were assessed for eligibility, and 39 were included in the review: 11 on the burden of disease, 17 on safety and risk group analysis, and 11 on treatment comparison. Besides typical biases in observational studies, we identified additional challenges specific to RWE frequently mentioned in the discussion sections. The focus group had varied opinions on the limitations of Safety and Risk Group Analysis and Treatment Comparison but agreed on the essential limitations for the Burden of Disease category.

Conclusion

This review provides a comprehensive overview of potential limitations and biases in analyzing routine data reported in recent high-impact journals. We highlighted key challenges that have high potential to impact analysis results, emphasizing the need for thorough consideration and discussion for meaningful inferences.
Using TMS-EEG to study the intricate interplay between GABAergic inhibition and glutamatergic excitation during reactive and proactive motor inhibition
Authors: Zhu Tingting , Cao Chenglong , Coxon James , Sack Alexander T. , Leunissen Inge
Published: September 2024

Background

Combining Transcranial magnetic stimulation (TMS) with electroencephalography (EEG) enables assess TMS-evoked potentials (TEP) and estimate γ-aminobutyric acid (GABA) and glutamatergic neurotransmission across the entire motor inhibition network. The N45 and N100 TEP peaks are associated with GABAa and GABAb signaling, respectively, whereas the N15, P30 and P60 TEPs reflect glutamatergic neurotransmission. This study applied TMS-EEG to investigate modulation of TEP components during reactive and proactive inhibition and whether individual differences in GABA and glutamate signaling predict inhibitory performance.

Methods

Twenty-four healthy participants completed two TMS-EEG sessions, targeting either the left primary motor cortex (M1) or the pre-supplementary motor area (preSMA) at rest and during a stop-signal task. We compared TEP peak amplitudes across TMS (active/sham) and Trial Type (stop/go trials) and assessed their relationship with task performance.

Results

Participants with a higher N45 amplitude at rest over M1, reflecting increased GABAa signaling, demonstrated a faster stop-signal reaction time. TMS during motor inhibition revealed higher N15 amplitudes over preSMA, reflecting increased glutamatergic neurotransmission, for successful stops versus go trials. Similarly, N15 was higher for uncertain than certain go trials suggesting that an early excitatory signal from preSMA is crucial for both reactive and proactive motor inhibition.

Conclusion

Higher GABAa inhibitory signaling in M1 at rest is linked to faster reactive inhibition. The preSMA likely plays a key role in both reactive and proactive motor inhibition. Here we provide novel direct empirical insights into the underlying neurophysiological mechanisms, highlighting a functional relevance of early glutamatergic excitatory signals for successful motor inhibition.
Deciphering the nanoscale architecture of presynaptic actin using a micropatterned presynapse-on-glass model
Authors: Tumminia Sofia , Mezache Louisa , Wiesner Theresa , Vianay Benoit , Théry Manuel , Papandréou Marie-Jeanne , Leterrier Christophe
Published: September 2024

Chemical synapses are fundamental units for the transmission of information throughout the nervous system. The cyto-skeleton allows to build, maintain and transform both pre- and postsynaptic contacts, yet its organization and the role of its unique synaptic nanostructures are still poorly understood. Here we present a presynapse-on-glass model where presynaptic specializations are robustly induced along the axons of cultured neurons by micropatterned dots of neuroligin, allowing the controlled orientation and easy optical visualization of functional induced presynapses. We demonstrate the relevance and usefulness of this presynapse-on-glass model for the study of presynaptic actin architecture, showing that a majority of induced presynapses are enriched in actin, with this enrichment being correlated to higher synaptic cycling activity. We confirm our previous results on bead-induced presynapses by identifying the same distinct actin nanostructures with-in presynapses: corrals, rails and mesh. Furthermore, we leverage the controlled orientation of the presynapse-on-glass model, visualizing the arrangement of these actin structures relative to the active zone nanoclusters using multicolor 3D Single Molecule Localization Microscopy (SMLM), and relative to the sub-diffractive localization exocytic events using a correlative live-cell and SMLM approach.
STRUCTURE-BASED DESIGN OF PROTACS FOR THE DEGRADATION OF SOLUBLE EPOXIDE HYDROLASE
Authors: Schönfeld J. , Brunst S. , Ciomirtan L. , Liebisch N. , Kumar A. , Ehrler J. H. M. , Wintermeier L. , Heering J. , Brüggerhoff A. , Weizel L. , Kaiser A. , Schubert-Zsilavecz M. , Knapp S. , Fürst R. , Proschak E. , Hiesinger K.
Published: September 2024

Soluble epoxide hydrolase (sEH) represents a promising target for inflammation-related diseases as it hydrolyzes highly anti-inflammatory epoxy-fatty acids (EpFAs) to the less active corresponding diols.1sEH harbours two distinct catalytic domains, the C-terminal hydrolase domain and the N-terminal phosphatase domain which are connected by a proline-rich linker.2Although potent inhibitors of enzymatic activity are available for both domains, sEH-PROTACs offer the unique ability to simultaneously degrade both domains, mimicking the sEH knockout phenotype associated with beneficial effects as reducing inflammation, attenuating neuroinflammation, and delaying the progression of Alzheimer’s disease. Herein, we report the structure-based development of a potent sEH-PROTAC as a useful tool compound for the investigation of sEH. In order to facilitate a rapid testing of the synthesized compounds a cell-based sEH degradation assay was developed based on the HiBiT-technology. A structure-activity-relationship (SAR) investigation was performed, based on the crystal structure of previously published sEH inhibitor FL217 where we identified two possible exit vectors. We designed and synthesized a set of 24 PROTACs with varying linkers in a combinatorial manner. Furthermore, co-crystallization of sEH with two selected PROTACs allowed us to explore the binding mode and rationalize the appropriate linker length. After biological and physicochemical investigation, the most suitable PROTAC23was identified and applied to degrade sEH in primary human macrophages, marking the successful translation and applicability to non-artificial systems.