bluuebunny/crossref_metadata_2025 huggingface dataset:
Transforming steatotic liver disease management: The emerging role of GLP-1 receptor agonists
Authors: Jensen Ellen L. , Israelsen Mads , Krag Aleksander
Published: October 2024

Chronic liver disease is a major cause of mortality, with approximately 2 million deaths worldwide each year, and it poses a significant economic burden. The most common cause of chronic liver disease in the United States and Europe is steatotic liver disease (SLD), which includes metabolic dysfunction–associated SLD, metabolic dysfunction and alcohol-associated SLD, and alcohol-associated liver disease (ALD). Effective treatment of these conditions is essential to reduce the liver disease burden, with promising approaches including treating cardiometabolic risk factors and excessive alcohol intake. Glucagon-like peptide 1 receptor agonists, both as monotherapy and in combination with other drugs, are gaining attention for their beneficial impact on cardiometabolic risk factors and excessive alcohol intake. In this review, we examine the molecular and clinical effects of glucagon-like peptide 1 receptor agonists, focusing on their direct hepatic steatohepatitis and liver fibrosis but also the indirect influence on cardiometabolic risk factors and excessive alcohol intake as key features of SLD. We also explore the future implications of glucagon-like peptide 1 receptor agonists for treating metabolic dysfunction–associated SLD, metabolic dysfunction and alcohol-associated SLD, alcohol-associated liver disease, and the potential challenges.
Persistent Serous Choroidal and Retinal Detachment After Ab Interno Trabeculotomy for Glaucoma
Authors: Nakagawa Suguru , Ishii Kiyoshi
Published: October 2024

We describe a case of serous retinal detachment (SRD) with ciliochoroidal detachment (CCD) that persisted for 2 years and 7 months after minimally invasive glaucoma surgery (MIGS). A 71-year-old woman with primary open-angle glaucoma and cataracts had a central corneal thickness of 489 μm/492 μm and an ocular axis length of 24.05 mm/24.30 mm. She underwent phacoemulsification and intraocular lens implantation in the right eye (OD), along with goniosynechialysis and microhook ab interno trabeculotomy. Postoperative intraocular pressure was 4–6 mmHg in the OD. Five months later, SRD was observed temporally and inferiorly to the macula, with increased choroidal thickness. Best-corrected visual acuity at 5 months was (1.2)/(1.2) (right eye [OD]/left eye [OS]), and intraocular pressure was 6 mmHg/13 mmHg. CCD in the OD was accompanied by choroidal vessel dilation and choroidal vascular hyperpermeability. Two years and 7 months post-surgery, intraocular pressure spiked to 50–54 mmHg but settled at 12 mmHg 1 week later. CCD resolved, and choroidal folds and SRD disappeared, with decreased choroid thickness. Two years and 10 months postoperatively, there was no SRD recurrence at 10 mmHg on two antiglaucoma eye drops, and best-corrected visual acuity remained stable at (1.0)/(1.0). This case suggests that SRD may result from increased choroidal vessel permeability and retinal pigment epithelium dysfunction secondary to prolonged CCD/low IOP after MIGS. The prolonged disease course may be attributed to the balance between aqueous humor excretion and absorption, influenced by the limited size of the cyclodialysis cleft caused by MIGS.
Fluoxetine and Sertraline Inhibit Height Growth and Growth Hormone Signaling During Puberty
Authors: Calarge Chadi , Amushie Chima , Dinh Stephanie , Mills James A. , Devaraj Sridevi , Barba-Villalobos Griselda , Nguyen Jacqueline , Garcia Jose M. , Sisley Stephanie , Bacha Fida , Zemel Babette
Published: October 2024

Purpose

The aim of this study was to examine the effect of fluoxetine and sertraline on height growth and insulin-like growth factor-1 (IGF-1) during puberty.

Methods

In this 6-month cohort study, electronic medical records were used to identify 8- to 15-year-old participants, within 1 month of starting fluoxetine (n = 39) or sertraline (n = 27), and sexual maturation stages 2 to 4 were confirmed. Conditions that interfere with height growth led to exclusion. Participants underwent anthropometric assessments and phlebotomy. Healthy, unmedicated children (n = 36) also provided anthropometric data.

Results

After the baseline height Z-score, sex, Tanner stage, daily selective serotonin reuptake inhibitor (SSRI) dose, and time were accounted for, the interaction effect of dose by time was inversely associated with height Z-score in SSRI-treated participants (β = −0.18; 95% confidence interval [CI]: −0.35, −0.02). Sertraline and fluoxetine did not differ in their effect on height growth. Compared with being unmedicated, SSRI treatment was associated with a smaller growth in height (time × dose 2-way interaction effect β = −1.30; 95% CI: −2.52, −0.09). The interaction effect of dose by time was significant for body mass index Z-score (β = 0.35; 95% CI: 0.06, 0.64) but not weight Z-score (β = 0.24; 95% CI: −0.01, 0.49). Body mass index Z-score increased more with sertraline compared with fluoxetine (time × dose × SSRI type 3-way interaction effect P < 0.05). SSRI dose was inversely associated with IGF-1 (β = −63.5; 95% CI: −112.2, −14.7) but not insulin growth factor binding protein-3 concentration (β = −207.3; 95% CI: −536.2, 121.5).

Conclusions

Fluoxetine and sertraline reduce height gain and IGF-1 concentration, in a dose-dependent manner. Longer-term studies are necessary.
Incorporating the Pillars of Lifestyle Medicine into Physician Assistant/Associate Education: A Benefit for Patients, Physician Assistants/Associate Education, and Physician Assistants/Associates
Authors: Shehade Karen A. , Broughton Adam
Published: October 2024

Introduction

The value of using lifestyle medicine (LM) to prevent disease is well established, yet medical education about LM is inconsistent, for both physicians and physician assistants/associates (PAs). As medical providers, PAs are uniquely positioned, with careers in a variety of disciplines from primary care to intensive care, as well as an ability to move across disciplines throughout their career lifespan. Therefore, the addition of LM principles in PA education can affect patients across the lifespan and in a wide variety of clinical settings. In addition, with burnout prevalent among PA students, the addition of LM to PA education may be able to give these future clinicians the tools they need to manage stress and improve overall wellness. The purpose of this study was to share with PA educators the valuable lessons learned when introducing LM into PA curriculum in hopes of broader adoption.

Methods

The American College of Lifestyle Medicine (ACLM) provides modules for teaching LM to medical providers which was adopted into the Northeastern University PA Program's didactic curriculum in the summer of 2023. An online survey was administered to first-year PA students in July 2023 to evaluate the PA students' perspectives on the value of adding a LM curriculum as part of their education to care for patients and the content provided through ACLM and to determine their perceived value in using the information for themselves as part of preventing future provider burnout.

Results

Most respondents (91%) indicated that they were either “likely” or “very likely” to use the information learned in the LM modules as part of their future patient care, and 86.4% indicated that they would use the information as part of their own self-care.

Discussion

Most PA student respondents (88.6%) thought that the components of LM complemented the existing PA curriculum in primary care and (86.4%) indicated that they will use the information as part of their own self-care. However, given the intense volume of information provided to PA students for their general primary care education, it was suggested to pare down the volume of materials to streamline the curriculum. Overall, these PA students believe that LM should comprise a portion of their PA medical education curricula for their patients and for themselves.
Development of posttransplant diabetes mellitus in US recipients of liver transplant is influenced by OPTN region
Authors: Khan Mohammad Qasim , Watt Kymberly D. , Teasdale Chloe
Published: October 2024

Posttransplant diabetes mellitus (PTDM) is associated with significant morbidity and mortality in liver transplant recipients (LTRs). We used the Organ Procurement and Transplantation Network (OPTN) database to compare the incidence of developing PTDM across the United States and develop a risk prediction model for new-onset PTDM using OPTN region as well as donor-related, recipient-related, and transplant-related factors. All US adult, primary, deceased donor, LTRs between January 1, 2007, and December 31, 2016, with no prior history of diabetes noted, were identified. Kaplan-Meier estimators were used to calculate the cumulative incidence of PTDM, stratified by OPTN region. Multivariable Cox proportional hazards models were fitted to estimate hazards of PTDM in each OPTN region and build a risk prediction model, through backward selection. Cumulative incidence of PTDM at 1 year, 3 years, and 5 years after transplant was 12.0%, 16.1%, and 18.9%, respectively. Region 3, followed by regions 8, 2, and 9, had the highest adjusted hazards of developing PTDM. Inclusion of OPTN region in a risk prediction model for PTDM in LTRs (including recipient age, sex, race, education, insurance coverage, body mass index, primary liver disease, cold ischemia time, and donor history of diabetes) modestly improved performance (C-statistic = 0.60). In patients without pre-existing, confirmed diabetes mellitus, the incidence of PTDM in LTRs varied across OPTN regions, with the highest hazards in region 3, followed by regions 8, 2, and 9. The performance of a novel risk prediction model for PTDM in LTRs has improved performance with the inclusion of the OPTN region. Vigilance is recommended to centers in high-risk regions to identify PTDM and mitigate its development.
Examining Nursing Medical Malpractice Cases Related to Medications
Authors: Higden Julie , Folcarelli Patricia , Schaffer Adam
Published: October 2024

OBJECTIVE

The aim of this study was to analyze medication-related nursing medical malpractice cases to gain insights regarding how malpractice risk can be reduced.

BACKGROUND

The criminal prosecution and verdict of nurse RaDonda Vaught focused attention on the potential medicolegal risk for nurses related to medications.

METHODS

Medication-related medical malpractice cases involving nurses were obtained from a national database. Various attributes of these cases were examined, including contributing factors, injury severity, and case outcomes.

RESULTS

Authors identified 231 nursing medication-related medical malpractice cases closed from 2017 to 2021. The most frequent adverse events involved medication administration. Not following policies or protocols was the most common contributing factor. Opioids and epinephrine were the medications most frequently involved in the cases. Indemnity payments were made in 56.3% of the cases, with an average indemnity payment of $366 002.

CONCLUSIONS

Nursing medication-related medical malpractice cases are relatively uncommon, which may reassure nurses regarding medicolegal risk. Medications and contributing factors involved in the cases suggest patient safety interventions including education related to policies, procedures, and protocols.
Are Ameloblastic Fibroma-related Lesions True Tumors?
Authors: Guo Xiaowen , Xue Jiang , Sun Lisha , Li Tiejun
Published: October 2024

Ameloblastic fibroma (AF) and related lesions, namely ameloblastic fibrodentinoma (AFD) and ameloblastic fibro-odontoma (AFO), span a spectrum from true neoplasms to hamartomas. The 2017 World Health Organization classification proposes that AFD and AFO are precursors to odontomas, yet their precise nature remains uncertain. This study examined 19 AF cases, 4 AFD, 15 AFO, 19 odontomas (OD, 14 complex, 5 compound), and 2 ameloblastic fibrosarcomas (AFS), focusing on clinical characteristics, recurrence, and molecular profiles. AF primarily affected individuals under 20 years (60.0% of cases), mainly in the mandible (68.4%), with a recurrence rate of 21.1% in the followed cases. AFD and AFO appeared in younger patients (average age 15.7 y) without any recurrence observed. Notable differences in site and size distribution were observed between AF, its related lesions, and odontomas. Copy number alterations (CNAs) were detected in the mesenchymal component in 9 of 19 AF (47.4%), 2 of 4 AFD (50.0%), 6 of 14 AFO (42.9%), and 2 of 2 AFS (100%). In contrast, all odontomas exhibited normal CNAs, highlighting the specificity of CNAs in mesenchymal elements of AF and related lesions. BRAF p.V600E mutation was identified in the mesenchymal component in 13 of 19 AF (68.4%), 2 of 4 AFD (50.0%), 8 of 15 AFO (53.3%), and 2 of 2 AFS (100%), whereas all 19 odontomas were BRAF wild type. No mutations were found in the epithelial component. Our analysis reveals that AF and its related lesions present a spectrum of biological behaviors, from true neoplasms to hamartomas. The presence of BRAF p.V600E mutations and CNAs in their mesenchymal components, as opposed to odontomas, indicates potential neoplastic characteristics. Profiling copy number alterations in AF and related lesions emerge as a valuable tool for enhancing their differential diagnosis and facilitating the anticipation of disease progression. Our findings underscore the efficacy of copy number alteration analysis in determining the nature of lesions within AF and related lesions.
Physical, Cognitive, Emotional, and Social Health Outcomes of Children in the First 6 Months After Childhood Critical Illness: A Prospective Single-Center Study
Authors: Poh Pei-Fen , Lee Jan Hau , Sultana Rehena , Manning Joseph C. , Carey Matthew C. , Latour Jos M.
Published: October 2024

OBJECTIVES:

To describe physical, cognitive, emotional, and social health outcomes of children and their trajectory in the first 6 months after PICU discharge.

DESIGN:

Prospective, longitudinal observational cohort study.

SETTING:

PICU in a tertiary pediatric hospital in Singapore from January 2021 to June 2022.

PATIENTS:

One hundred thirty-five children (1 mo to 18 yr), admitted for greater than or equal to 48 hours with at least one organ dysfunction and received PICU therapy.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Serial self/parent proxy-reported assessments were obtained at: PICU admission, PICU discharge, and 1, 3, and 6 months after PICU discharge. The Pediatric Quality of Life Inventory (PedsQL) scale, Functional Status Scale (FSS), and measures of post-traumatic stress disorder (PTSD) using the Young Child PTSD Screen and the Child and Adolescent PTSD Screen-Parent Version were used. Trajectory groups were identified using group-based trajectory model. One hundred thirty-five children (mean [sd] age, 5.6 yr [5.5 yr]) were recruited. Seventy-eight (52%) were male. The mean (sd) Pediatric Index of Mortality III score was 3.2 (4.1) and PICU length of stay was 10.0 days (21.0 d). The mean (sd) PedsQL total scores were 66.5 (21.1) at baseline, 69.7 (21.4), 75.6 (19.7), and 78.4 (19.8) at 1, 3, and 6 months after PICU discharge, respectively. Overall, the PedsQL and FSS plateaued at 3 months. Our model revealed three distinct trajectory groups. Seventeen and 103 children in the mild and moderate trajectory groups, respectively, demonstrated recovery to baseline. Fifteen children in the severe trajectory group were older in age (mean [sd] 8.3 yr [6.4 yr]), with higher proportion (11/15) of preexisting illness. Five of 15 children in the severe group experienced posttraumatic stress syndrome (PTSS) at 6 months post-discharge.

CONCLUSIONS:

In our cohort of PICU patients, we found three unique trajectory groups. Children in the severe group were older, more likely to have preexisting conditions and at increased risk for PTSS. Early identification and intervention may improve recovery in patients with severe PICU trajectories.
The relationship between changes in inflammation and locomotor function in sensory phenotypes of central neuropathic pain after spinal cord injury
Authors: Avonts Brittany L. , Shen Quan , Wrobel Neal J. , Fessler Richard G. , David Brian T.
Published: October 2024

Introduction:

Central neuropathic pain (CNP) commonly develops in patients after spinal cord injury (SCI), causing debilitating symptoms and sensory abnormalities to mechanical and thermal stimuli. The biological variability of pain phenotypes in individuals has limited the number of positive outcomes. Thus, it is necessary to investigate the physiological processes contributing to sensory changes that develop over time.

Objective:

To investigate the physiological processes contributing to neuropathic pain sensory changes and locomotor impairments with sensory phenotypes that develop over time.

Methods:

Using the tail flick and von Frey tests, we performed hierarchical clustering to determine the subpopulation of rats that developed thermal and mechanical sensory abnormalities. To measure inflammation as a potential mediator of CNP phenotypes, we used flow cytometry and immunohistochemistry. Finally, to assess the secondary effects on locomotor recovery, up to 8 weeks after injury, we used the CatWalk test to assess multiple parameters of gait.

Results:

The von Frey test showed a subpopulation of SCI rats that were hyposensitive to mechanical stimuli from 6 to 8 weeks after injury. The tail flick test showed a subpopulation of SCI rats that were hypersensitive to thermal stimuli at 1 week and 3 to 8 weeks after injury. Although there were no differences in inflammatory cells between subpopulations, we did see significant changes in locomotor recovery between rats with and without sensory abnormalities.

Conclusion:

The myeloid cell population at large is not affected by mechanical or thermal phenotypes of pain in this model; however, locomotor recovery is impaired depending on the pain phenotype present. Further investigation into acute inflammatory cells may be insightful for predicting the development of pain phenotypes.
Opposite effects of isometric exercise on pain sensitivity of healthy individuals: the role of pain modulation
Authors: Liebermann Paz , Defrin Ruth
Published: October 2024

Introduction:

Exercise-induced hypoalgesia (EIHypo) among healthy individuals is well documented; however, the opposite effect of exercise, ie, exercise-induced hyperalgesia (EIHyper), has mainly been described in patients with chronic pain or after intense/painful exercise.

Objectives:

We investigated the extent to which EIHypo and/or EIHyper occur among healthy participants and whether these responses are associated with individuals' pain modulation capacity.

Methods:

Fifty-seven participants (mean age 29.20 ± 5.21 years) underwent testing of pressure pain threshold as an index of EIHypo/EIHyper: pain adaptation, offset analgesia (OA), and conditioned pain modulation as indices of pain modulation, prior to and immediately postsubmaximal isometric exercise (n = 40) or rest (n = 17, control group). Body awareness and exercise-evoked stress were also evaluated. Test–retest repeatability of the pain modulation indices was performed as well.

Results:

Twenty-four participants (60%) exhibited EIHypo, whereas 16 (40%) exhibited EIHyper. Pressure pain threshold did not change in the control group. Baseline (preexercise) OA efficacy predicted EIHypo/EIHyper. Furthermore, OA significantly decreased postexercise in the EIHyper subgroup and slightly increased in the EIHypo subgroup. Exercise-induced hypoalgesia was associated with magnitude of daily exercise while EIHyper was associated with increased exercise-evoked stress and body awareness.

Conclusion:

Submaximal isometric exercise can induce opposite effects on pain sensitivity among healthy participants—EIHypo or EIHyper. Descending pain inhibition pathways, and top-down influences over these pathways, seem to be involved in EIHypo/EIHyper effects. As such isometric exercise is often preferred in early stages of rehabilitation, preliminary screening individuals' vulnerability to this exercise is important; OA test may be used for this purpose.
Impact of Surgical Timing on Postoperative Complications Following Open Reduction Internal Fixation of Mandibular Fractures
Authors: Hassan Bashar A. , Resnick Eric , Er Seray , Pope Pharibe , Lamaris Gregory , Grant Michael P. , Pan Judy
Published: October 2024

Purpose:

The mandible is the second most fractured facial bone. The timing of open reduction internal fixation (ORIF) has been a subject of debate for decades. The authors sought to investigate the association between the timing of ORIF and the incidence of postoperative complications.

Methods:

The authors retrospectively reviewed adult trauma patients who underwent ORIF in 2018 and 2019. The authors excluded patients who underwent mandibulomaxillary fixation (MMF) only and those with postoperative follow-up <2 weeks. The duration between injury and ORIF was categorized into: <4, 4 to 7, and >7 days. The association between surgical timing categories and the incidence of postoperative complications was assessed using bivariate analyses and multivariable logistic regression.

Results:

Of 226 patients included, the median (interquartile range) age was 32 (25–42) years, and the median (interquartile range) follow-up was 49 (25–118) days. Most patients [207 (92%)] underwent both ORIF and MMF. Most patients had ORIF within 3 days of injury [168 (74%)]. Major postoperative complications included unplanned re-operation [n=25 (11.1%)], malocclusion [n=20 (8.8%)], and malunion [n=7 (3.1%)]. Minor postoperative complications included mental nerve paresthesia [n=79 (35%)], infection [n=30 (13.3%)], TMJ complications [n=17 (7.5%)], and wound dehiscence [n=14 (6.2%)]. Delayed ORIF >7 days of injury was associated with significantly greater odds of unplanned re-operation [adjusted odds ratio (aOR) 95% CI 10.43 (2.16–50.44), P=0.004], malocclusion [aOR (95% CI) 8.17 (1.31–51.03), P=0.025], and malunion [aOR (95% CI) 23.04 (1.18–>10), P=0.039].

Conclusion:

The authors recommend early ORIF in the management of mandibular fractures to minimize postoperative complications.
The Impact of Pudendal Nerve Injection in Vaginal Surgery: A Secondary Analysis
Authors: Le Neveu Margot , Sears Sarah , Rhodes Stephen , Slopnick Emily , Petrikovets Andrey , Mangel Jeffrey , Sheyn David
Published: October 2024

Importance

Evidence regarding the effect of pudendal nerve blockade during vaginal surgery is conflicting. Previous studies compared pudendal nerve blockade to either normal saline placebo injection or no injection, demonstrating small or no difference in pain outcomes. Studies investigating nerve blocks at the time of vaginal surgery have not evaluated the effect of infiltration of the space around the pudendal nerve.

Objective

The aim of the study was to determine whether intraoperative pudendal nerve injection (bupivacaine or normal saline) will result in improved pain scores and satisfaction compared with patients who receive no pudendal injection.

Study Design

We performed a secondary analysis of 2 randomized controlled trials investigating postoperative pain after vaginal reconstructive surgery, comparing the outcomes of the following 3 groups: control (no pudendal injection), intervention (bilateral pudendal nerve blockade), and placebo (bilateral normal saline pudendal injections). The primary outcome was postoperative pain scores. Secondary outcomes were opioid use, patient satisfaction, and postoperative complications. Linear mixed effects models were applied to outcomes, and treatment effects with 95% confidence intervals were estimated at each time point from the model.

Results

One hundred four patients who underwent vaginal surgery were included: 36 pudendal nerve block, 35 normal saline pudendal injection, and 33 no injection. The groups were well-matched. Linear mixed effects models demonstrated no significant differences between treatment groups for postoperative pain severity scores, opioid use, and patient-reported satisfaction at each time point.

Conclusions

Normal saline injection and no injection seem to have no clinically meaningful difference in effect, and either could reasonably serve as control for pudendal blockade during vaginal surgery.
Urogynecologic Care for Women Who Are Incarcerated
Authors: Clark Rachel A. , Landis Lewis Deborah , Hong Christopher X.
Published: October 2024

In the United States, approximately 180,700 women are incarcerated across jails and prisons, comprising a demographic with an aging population and a higher growth rate compared to men. Despite this demographic trend, research into urogynecologic care for women who are incarcerated is notably lacking, with few studies addressing pelvic floor disorders such as incontinence, and even fewer focusing on access to treatment options like vaginal pessaries or surgical interventions. Women who are incarcerated may face unique challenges in obtaining urogynecologic care, including limited access to medical evaluations, invasive search procedures affecting intravaginal device use, and inadequate hygiene resources, all of which hinder effective management strategies. Barriers to nonsurgical treatments like pelvic floor physical therapy are exacerbated by transportation logistics, while access to surgical interventions is impeded by complex approval processes within correctional facilities. In addition, managing incontinence with limited access to hygiene products and bathroom facilities further compromises the health and dignity of incarcerated women. Urgent attention and advocacy are needed to address disparities in research and clinical care for incarcerated populations. As a first step, we urge clinicians to acquaint themselves with the correctional facilities in their areas and the current health care pathways for women incarcerated in these facilities. It is our collective responsibility to ensure equitable and compassionate care for this vulnerable population.
Quantitative Electroencephalography Biomarkers in Patients With Anti-N-methyl-D-aspartate Receptor Encephalitis: A Case–Control Study
Authors: David Cancino César Alejandro , Trenado Carlos , Kaplan Peter W. , Gómez Ávila Felipe Alberto , Fernández González-Aragón María del Carmen , Moreno Avellán Álvaro José , Soto Rincón Carlos Alberto , Quiñones Pesqueira Gerardo Arturo , San-Juan Daniel
Published: October 2024

Purpose:

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune reaction involving Immunoglobulin G antibodies against GluN1 subunit of NMDAR. Absence of biomarkers for early diagnosis and prognosis poses a challenge. Several small case–control studies have emphasized the prospect of quantitative EEG measurements. This study aimed to analyze and identify novel scalp quantitative EEG biomarkers and their implications on outcome of NMDRA encephalitis compared with a control group.

Methods:

Retrospective (2012–2021) case–control study of patients with NMDRA encephalitis and with acute/subacute encephalitis from other causes. Clinical variables and outcomes were assessed with modified Rankin Scale at admission, discharge, and follow-up. All patients underwent extensive diagnostic workup, including scalp EEG within 72 hours of admission. Quantitative EEG was calculated for Renyi, Tsalis entropy, Hjorth complexity, mean energy, and spectral power of the following frequency bands and ratios: delta (0.5–4 Hz), theta (5–8 Hz), alpha (9–14 Hz), beta (15–30 Hz), gamma (31–45 Hz), gamma-beta, beta/alpha, beta/theta, and beta/delta. Descriptive statistics, power frequency bands, complexity measures, and Wilcoxon rank sum test were used.

Results:

Patients with anti-NMDAR encephalitis had significantly higher delta frequency peak power, higher beta/alpha and gamma/beta frequency ratios, lower alpha and beta peak power, and lower beta/delta frequency ratio than the control group. In patients with anti-NMDAR encephalitis, higher delta and alpha peak power had the worst clinical outcome, at discharge and follow-up, and patients with higher gamma peak power had better outcomes.

Conclusions:

Quantitative EEG is a valuable tool to differentiate anti-NMDAR encephalitis from other inflammatory encephalitis and predict outcomes in patients with anti-NMDAR encephalitis.
Emerging challenge of Linezolid and Vancomycin resistant Enterococci faecium:First case report from Northern Pakistan
Authors: Naeem Afnan , Furqan Warda , Satti Luqman , Usman Javaid , Wattoo Nasir Mehmud
Published: October 2024

Enterococcus faecium are among the most versatile pathogens found to infect hospitalized patients. Resistance against anti-enterococcal antibiotics is gaining access day to day and among them linezolid resistant vancomycin resistant Enterococcus faecium are a nightmare for the clinicians especially in a resource limited country.
A 72year old patient presented with collection of pus and necrosis around the head of pancreases. These pockets of pus resulted as acute postsurgical complication along with surgical site infection. Pus was processed according to clinical guidelines Enterococcus faecium was identified and confirmed by VITEK. Isolate was resistant to vancomycin and linezolid. Tigecyclin was the only option for this patient due to unavailability of quinupristin/dalfopristin as a treatment option. A regular follow up was done and patient was discharged after recovery.
LRVRE is the result of non-implementation of antimicrobial stewardship and it can be followed with further resistance in Enterococcus which can be havoc. Clinicians infection control team and microbiologist should work together to overcome antimicrobial resistance crises.
Microbiome-derived metabolite effects on intestinal barrier integrity and immune cell response to infection
Authors: Adams Lauren , Li Xiang , Burchmore Richard , Goodwin Richard J. A. , Wall Daniel M.
Published: October 2024

The gut microbiota exerts a significant influence on human health and disease. While compositional changes in the gut microbiota in specific diseases can easily be determined, we lack a detailed mechanistic understanding of how these changes exert effects at the cellular level. However, the putative local and systemic effects on human physiology that are attributed to the gut microbiota are clearly being mediated through molecular communication. Here, we determined the effects of gut microbiome-derived metabolites l-tryptophan, butyrate, trimethylamine (TMA), 3-methyl-4-(trimethylammonio)butanoate (3,4-TMAB), 4-(trimethylammonio)pentanoate (4-TMAP), ursodeoxycholic acid (UDCA), glycocholic acid (GCA) and benzoate on the first line of defence in the gut. Using in vitro models of intestinal barrier integrity and studying the interaction of macrophages with pathogenic and non-pathogenic bacteria, we could ascertain the influence of these metabolites at the cellular level at physiologically relevant concentrations. Nearly all metabolites exerted positive effects on barrier function, but butyrate prevented a reduction in transepithelial resistance in the presence of the pathogen Escherichia coli, despite inducing increased apoptosis and exerting increased cytotoxicity. Induction of IL-8 was unaffected by all metabolites, but GCA stimulated increased intra-macrophage growth of E. coli and tumour necrosis-alpha (TNF-α) release. Butyrate, 3,4-TMAB and benzoate all increased TNF-α release independent of bacterial replication. These findings reiterate the complexity of understanding microbiome effects on host physiology and underline that microbiome metabolites are crucial mediators of barrier function and the innate response to infection. Understanding these metabolites at the cellular level will allow us to move towards a better mechanistic understanding of microbiome influence over host physiology, a crucial step in advancing microbiome research.
Fronto-motor circuits linked to effort-based decision-making and apathy in healthy subjects
Authors: Derosiere Gerard , Vassiliadis Pierre , Dricot Laurence , Dessain Quentin , Delinte Nicolas , Zénon Alexandre , Duque Julie
Published: October 2024

Apathy is a syndrome characterized by a disruption in effort-reward decision-making, accompanied by structural and functional changes in a related fronto-basal ganglia (BG) network. While activity changes in the primary motor cortex (M1) during effort and reward valuation have been repeatedly observed, previous work on apathy has largely overlooked the connections between the fronto-BG network and M1, potentially missing key circuits in the apathy network. This study addresses this gap by investigating structural and effective connectivity in fronto-M1, fronto-BG-M1, and intra-M1 circuits in relation to apathy in 45 healthy subjects. Behavior was assessed using a battery of apathy-related questionnaires and computational modeling of effort and reward valuation in a decision-making task. Fronto-motor circuits were examined through a combination of MRI-derived tractography and paired-pulse transcranial magnetic stimulation, which probed structural and effective connectivity, respectively. The data reveal that apathy scores are associated with both structural and effective connectivity in fronto-M1 and fronto-BG-M1 circuits. Circuits originating from the supplementary motor area primarily index effort valuation, while connectivity in intra-M1 GABAergic circuits correlates exclusively with reward valuation. These findings suggest that distinct fronto-motor circuits are linked to different dimensions of motivated behavior and may constitute specific neuromodulation targets for patients suffering from apathy.
Controlling heterologous protein synthesis through a plant RNA ThermoSwitch
Authors: Lastovka Filip , Peyret Hadrien , Thomas Sherine Elizabeth , Lomonossoff George P. , Chung Betty Y.-W.
Published: October 2024

Plants have evolved sophisticated mechanisms to adapt to temperature fluctuations, including transcriptional, post-transcriptional, and post-translational processes. Recent discoveries highlight RNA ThermoSwitches, cis-acting elements in several plant mRNAs that regulate protein synthesis based on temperature changes. These mechanisms, first identified in Arabidopsis thaliana, offer a promising tool for biotechnology by enabling temperature-sensitive control of protein expression. This study demonstrates, for the first time, the feasibility the application of plant RNA ThermoSwitches in Agrobacterium-mediated transient expression systems, presenting a novel method for controlled gene expression in plants. This system is particularly advantageous due to its homogeneous nature and independence from chemical inducers or suppressors.
CONSTRUCT: an algorithmic tool for identifying functional or structurally important regions in protein tertiary structure
Authors: Chivot Lucas , Bridier-Nahmias Antoine , Favennec Loïc , Gelly Jean-Christophe , Clain Jérôme , Coppée Romain
Published: October 2024

In the realm of protein-coding genes, evolutionary rates show considerable variability. Essential or highly expressed proteins evolve more slowly, and within a protein, different amino acid sites evolve at different rates. Accurately modeling this variation is critical for identifying structurally or functionally important amino acid sites. Standard methods such as Rate4Site assume independent substitution rates across sites, and the most conserved ones are widely distributed in protein tertiary structure. This is biologically unrealistic because functional sites often cluster together. Here, we developed CONSTRUCT, an improved strategy for identifying functional and structurally important regions in protein tertiary structure. Given a set of orthologous sequences, CONSTRUCT first calculates site-specific substitution rates using the Rate4site model, which are then weighted by the rates of neighboring amino acid sites within a range of window sizes. The optimal window size is determined by the strongest spatial correlation, if present. This method can be analyzed using either Cα atoms or the center of mass of amino acid sites to account for side chain orientation. Validation on 14 functionally characterized proteins of different size, conservation level and kingdom/domain of species has demonstrated the relevance of CONSTRUCT.
Variation in precipitation drives differences in interactions and short-term transient instability between grassland functional groups: a stage-structured community approach
Authors: Gupta Aryaman , Gascoigne Samuel , Barabás György , Qi Man , Fenollosa Erola , Thornley Rachael , Hernandez Christina , Hector Andy , Salguero-Gómez Roberto
Published: October 2024

Climate change is expected to increase the frequency and severity of precipitation extremes, causing droughts and flooding. Consequently, grassland communities are forecasted to become increasingly unstable. To predict grassland responses, we need empirical information together with models that reliably extrapolate community dynamics from those observations. However, such prediction is challenging because community models typically simulate long-term (asymptotic) performance, and thus potentially neglect their short-term (transient) performance. Here, we use data from a precipitation experiment performed over eight years to model both short- and long-term responses of three functional groups – grasses, legumes, and non-leguminous forbs – to precipitation extremes. We use multi-functional-group Integral Projection Models and pseudospectral theory, to track grassland community dynamics. We show that the percentage-cover-stage-structure of functional groups shapes their transient instability, and that inter-functional-group interactions are competitive under increased precipitation but facilitative under decreased precipitation. IPMs and pseudospectra enable forecasting of how functional-group-stage-structure drives responses to climatic extremes.
LipiDetective a deep learning model for the identification of molecular lipid species in tandem mass spectra
Authors: Würf Vivian , Köhler Nikolai , Molnar Florian , Hahnefeld Lisa , Gurke Robert , Witting Michael , Pauling Josch K.
Published: October 2024

Lipids are involved in many vital processes within the cell, and alterations in lipid homeostasis have been associated with various diseases such as cancer or type 2 diabetes. Confidently identifying lipids in samples is a prerequisite for understanding the multiple functions lipids fulfill in health and disease. However, the accurate identification of molecular lipid species based on tandem mass spectrometry data is still a key challenge in lipidomics. Most current approaches rely on using a custom pipeline to process and match the measured spectra against an in-house spectra reference library, which hinders the comparability of results. To address this challenge, a transformer model called LipiDetective was developed and trained on a dataset composed of reference spectra measured from lipid standards, spectra from databases, and published experiments, utilizing both shotgun as well as liquid-chromatography mass spectrometry. LipiDetective demonstrates, for the first time, that artificial neural networks can learn the characteristic lipid fragmentation patterns to automatically and accurately annotate molecular lipids species in tandem mass spectra independently of the experimental setup. The model can even correctly predict lipid species for which it has never seen a spectrum before as it is able to generalize the learned lipid fragmentation patterns. Analysis of the integrated gradients reveals that LipiDetective focuses on relevant peaks that can be matched to known fragments and are thus humanly interpretable. Therefore, LipiDetective has the potential to be a valuable tool to aid in the lipid identification process and support the comparability of results from different sources. Aside from Lipidetective as a “ready-to-use” application, this work primarily offers a deeper understanding of how the model functions and how future deep learning models for lipid identification in mass spectra could be improved.
LPS binding caspase activation and recruitment domains (CARDs) are bipartite lipid binding modules
Authors: Cao Anh B. , Devant Pascal , Wang Chengliang , Sun Mengyu , Kennedy Stephanie N. , Ruan Jianbin , Kagan Jonathan C.
Published: October 2024

Caspase-11 is an innate immune pattern recognition receptor (PRR) that detects cytosolic bacterial lipopolysaccharides (LPS) through its caspase activation and recruitment domain (CARD), triggering inflammatory cell death known as pyroptosis. Caspase-11 also detects eukaryotic (i.e.self) lipids. This observation raises the question of whether common or distinct mechanisms govern the interactions with self and nonself lipids. In this study, using biochemical, computational, and cell-based assays, we report that the caspase-11 CARD functions as a bipartite lipid-binding module. Distinct regions within the CARD bind to phosphate groups and long acyl chains of self and nonself lipids. Self-lipid binding capability is conserved across numerous caspase-11 homologs and orthologs. The symmetry in self and nonself lipid detection mechanisms enabled us to engineer an LPS-binding domainde novo, using an ancestral CARD-like domain present in the fishAmphilophus citrinellus. These findings offer critical insights into the molecular basis of LPS recognition by caspase-11 and highlight the fundamental and likely inseparable relationship between self and nonself discrimination.
Investigating Brain and Biological Development in Children and Their Relationship with Physical, Mental, and Academic Outcomes
Authors: Chang Hansoo , Street Kevin , Ferariu Ana , Taylor Alexei , Kounios John , Zhang Fengqing
Published: October 2024

Brain age and biological age, estimated using machine learning models with brain imaging and biological features, have emerged as promising biomarkers for predicting a broad range of health outcomes in adults. However, very few studies have examined the counterpart of brain age and biological age in children, that is Brain Development Index (BRDI) and Biological Development Index (BIDI). Existing studies on BRDI and BIDI are largely cross-sectional and do not provide adequate information on their temporal trajectory and predictive power for future health outcomes in children. Additionally, the interconnectedness of BRDI and BIDI across multiple health domains, especially child-specific developmental outcomes, remains underexplored. Our study utilized brain imaging features and blood-based biomarkers from the Adolescent Brain and Child Development (ABCD) study to assess the trajectory of BRDI and BIDI over multiple time points. We examined their relationships with physical, mental, and academic health outcomes.

Lastly, we utilize Bayesian network analysis to examine the relationship between the two indexes and their subcomponents. We found that delayed BRDI and BIDI were significantly associated with adverse future health outcomes across several domains. In addition, Bayesian network analysis revealed BRDI and BIDI subcomponents influence one another across different organ systems. Additionally, males exhibited more advanced BRDI, while females showed more advanced BIDI, revealing important sex differences in adolescent development. This research provides the first comprehensive analysis of BRDI and BIDI trajectories, revealing their predictive power for future health outcomes and offering new insights into the interconnected development of brain and biological systems in children.
Longitudinal multi-omics reveals pathogenicTSC2variants disrupt developmental trajectories of human cortical organoids derived from Tuberous Sclerosis Complex
Authors: Niu Weibo , Yu Shaojun , Li Xiangru , Wang Zhen , Chen Rui , Michalski Christina , Jahangiri Arman , Zohdy Youssef , Chern Joshua J , Whitworth Ted J , Wang Jianjun , Xu Jie , Zhou Ying , Qin Zhaohui , Li Bingshan , Gambello Michael J , Peng Junmin , Wen Zhexing
Published: October 2024

Tuberous Sclerosis Complex (TSC), an autosomal dominant condition, is caused by heterozygous mutations in either theTSC1orTSC2genes, manifesting in systemic growth of benign tumors. In addition to brain lesions, neurologic sequelae represent the greatest morbidity in TSC patients. Investigations utilizingTSC1/2-knockout animal or human stem cell models suggest that TSC deficiency-causing hyper-activation of mTOR signaling might precipitate anomalous neurodevelopmental processes. However, how the pathogenic variants ofTSC1/2genes affect the longitudinal trajectory of human brain development remains largely unexplored. Here, we employed 3-dimensional cortical organoids derived from induced pluripotent stem cells (iPSCs) from TSC patients harboringTSC2variants, alongside organoids from age- and sex-matched healthy individuals as controls. Through comprehensively longitudinal molecular and cellular analyses of TSC organoids, we found thatTSC2pathogenic variants dysregulate neurogenesis, synaptogenesis, and gliogenesis, particularly for reactive astrogliosis. The altered developmental trajectory of TSC organoids significantly resembles the molecular signatures of neuropsychiatric disorders, including autism spectrum disorders, epilepsy, and intellectual disability. Intriguingly, single cell transcriptomic analyses on TSC organoids revealed thatTSC2pathogenic variants disrupt the neuron/reactive astrocyte crosstalk within the NLGN-NRXN signaling network. Furthermore, cellular and electrophysiological assessments of TSC cortical organoids, along with proteomic analyses of synaptosomes, demonstrated that theTSC2variants precipitate perturbations in synaptic transmission, neuronal network activity, mitochondrial translational integrity, and neurofilament formation. Notably, similar perturbations were observed in surgically resected cortical specimens from TSC patients. Collectively, our study illustrates that disease-associatedTSC2variants disrupt the neurodevelopmental trajectories through perturbations of gene regulatory networks during early cortical development, leading to mitochondrial dysfunction, aberrant neurofilament formation, impaired synaptic formation and neuronal network activity.
The utility of single-cell RNA sequencing data in predicting plant metabolic pathway genes
Authors: Ma Jingwei , Zou Liting , Wang Zhenglin , Wang Xiaoxue , Zuo Xinyi , Wang Fei , Wang Zhiqing , Li Zhimei , Li Lin , Wang Peipei
Published: October 2024

It is an ever challenging task to make genome-wide predictions for plant metabolic pathway genes (MPGs) encoding enzymes that catalyze the biosynthesis of plant natural products.

Here, starting from 1,130 benchmark MPGs that have experimental evidence inArabidopsis thaliana, we investigate the utilities of single-cell RNA sequencing (scRNA-seq) data—a recently arisen omics data that has been used in several other fields—in predicting MPGs using four machine learning (ML) algorithms that support multi-label tasks.

Compared with traditional bulk RNA-seq data, scRNA-seq data lead to different and tighter co-expression networks among MPGs within metabolic classes, but relatively lower prediction accuracy of MPGs into classes. Splitting the scRNA-seq data into tissue-specific subsets can improve the gene co-expression network tightness and prediction accuracy of MPGs for some classes. Expression features from the same tissue types in bulk RNA-seq and scRNA-seq data have different contributions to the prediction of MPGs into classes. Models built using the ensemble algorithm AutoGluon outperforms those using other three classical ML algorithms.

Our results demonstrate the usefulness and characteristics of scRNA-seq data in predicting MPGs into metabolic classes, and propose that more effort is needed in the future to improve the model prediction performance.