bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of prenatal cocaine exposure on estrous cycle, and behavior and expression of estrogen receptor alpha and oxytocin during estrus and diestrus in mice offspring
Authors: Zheng Yanghui , Cheng Guangchao , Lin Xikai , Wang Jianli
Published: September 2024

Increasing evidence indicates that prenatal cocaine exposure may result in many developmental and long-lasting neurological and behavioral effects. The behaviors of female animals are strongly associated with the estrous cycle. Estrogen receptors and oxytocin are important neuroendocrine factors that regulate social behavior and are of special relevance to females. However, whether prenatal cocaine exposure induces estrous cycle changes in offspring and whether neurobehavioral changes in estrus and diestrus offspring differ remains unclear. On gestational day 12, mice were administered cocaine once daily for seven consecutive days, then the estrous cycle was examined in adult female offspring, as well as locomotion, anxiety level, and social behaviors, and the expression of estrogen receptor alpha-immunoreactive and oxytocin-immunoreactive neurons were compared between estrus and diestrus offspring. Prenatal cocaine exposure resulted in the shortening of proestrus and estrus in the offspring. During estrus and diestrus, prenatally cocaine-exposed offspring showed increased anxiety levels and changed partial social behaviors; their motility showed no significant differences in estrus, but declined in diestrus. Prenatal cocaine exposure reduced estrogen receptor alpha-immunoreactive expression in the medial preoptic area, ventromedial hypothalamic nucleus, and arcuate nucleus and oxytocin-immunoreactive expression in the paraventricular nucleus in estrus and diestrus offspring. These results suggest that prenatal cocaine exposure induces changes in the offspring’s estrous cycle and expression of estrogen receptor alpha and oxytocin in a brain region-specific manner and that prenatal cocaine exposure and the estrous cycle interactively change motility and partial social behavior. Estrogen receptor alpha and oxytocin signaling are likely to play important concerted roles in mediating the effects of prenatal cocaine exposure on the offspring.
Does the COVID-19 vaccine cause a disease flare in patients with primary Sjögren’s syndrome? A Cross-Sectional Study
Authors: Al Darwish Lama A. , Khalayli Naram M. , A. Almajzoub Rahaf , Kudsi Maysoun
Published: September 2024

Background:

Data regarding the efficacy of the COVID-19 (coronavirus disease) vaccine is limited in rheumatic disease patients. We aimed to study the post-COVID-19 vaccine disease exacerbation prevalence and characteristics in a sample of Primary Sjogren Syndrome (PSS) patients in Syria.

Patients and Methods:

We evaluated 32 PSS (Primary Sjogren Syndrome) patients. The pattern of vaccine received was evaluated, and the ESSDAI (Sjögren’s syndrome disease activity index). Activity score was used to assess the disease activity before and after vaccination. 32 patients had the first and second COVID-19 vaccine, 21 received a third dose, and 20 received the mRNA (Messenger ribonucleotide antibody vaccine) vaccine. The mean age of patients was 52 years, 22 patients were female, with a median disease duration of 7 years.

Results:

Respectively PSS flare was reported by 18 after the first vaccine dose, 15 after the second vaccine dose, and 13 after the third vaccine dose, typically appearing as musculoskeletal symptoms such as arthralgia/arthritis, without changing their medication. Eight patients discontinued the drug during vaccination. Seven patients used analgesics. Side effects were significantly higher in the mRNA vaccine group and in the first and second doses of the vaccine. There was no statistically significant difference in PSS exacerbation according to the pattern of vaccines.

Conclusion:

Our study highlights increased PSS flare risk post-COVID-19 vaccination, especially in high disease activity patients. Most flares were mild, mainly musculoskeletal symptoms. Side effects were higher with mRNA vaccines and initial doses. Despite risks, vaccination is recommended, prioritizing stable disease states for PSS patients.
Long-term impact of scheduled regular endoscopic interventions for patients with primary sclerosing cholangitis
Authors: Özdirik Burcin , Veltzke-Schlieker Wilfried , Nicklaus Jule Marie , Berger Hilmar , Schmidt Daniel , Leonhardt Silke , Penndorf Volker , Adler Andreas , Müller Tobias , Wree Alexander , Tacke Frank , Sigal Michael
Published: September 2024

Background:

Primary sclerosing cholangitis (PSC) is associated with biliary obstructions that can require endoscopic retrograde cholangiopancreatography (ERCP). While the beneficial effects of ERCP are well documented, follow-up interventional strategies are less defined, and their long-term impact is debated.

Methods:

We evaluated the outcome of a scheduled program of ERCP-guided interventions that have been developed and implemented at our tertiary liver center for more than 20 years. Within our center, follow-up ERCPs were performed at regular intervals to treat previously detected morphological stenosis independent of clinical symptoms. We calculated the transplant-free survival (TFS) of patients who were enrolled in the scheduled ERCP program and compared it to patients who received follow-up ERCPs only on clinical demand. Moreover, we documented the occurrence of hepatic decompensation, recurrent cholangitis episodes, hepatobiliary malignancies, and endoscopy-related adverse events.

Results:

In our retrospective study, we included 201 patients with PSC who all received an ERCP. In all, 133 patients received scheduled follow-up ERCPs and 68 received follow-up ERCPs only on demand. The rates of TFS since initial diagnosis (median TFS: 17 vs. 27 y;P= 0.020) and initial presentation (median TFS: 16 vs. 11 y;P= 0.002) were higher in patients receiving scheduled versus on-demand ERCP. Subgroup analysis revealed that progression in cholangiographic findings between the first and second ERCP was associated with a poorer outcome compared to patients without progression (17 y vs. undefined;P= 0.021).

Conclusion:

In conclusion, we report the outcome data of a scheduled follow-up ERCP program for patients with PSC in an experienced high-volume endoscopy center. Our data suggest the initiation of multicenter randomized controlled prospective trials to explore the full potential of regular endoscopic follow-up treatment as a strategy to prevent disease progression in patients with PSC.
The immune microenvironment of steatotic hepatocellular carcinoma: Current findings and future prospects
Authors: Cheu Jacinth Wing-Sum , Wong Carmen Chak-Lui
Published: September 2024

Hepatocellular carcinoma (HCC), the major type of primary liver cancer, is notorious for its resistance to systemic treatments. The field has made a great leap in the past decade, with the number of FDA-approved therapies for advanced HCC increasing from 1 to 9. Although tyrosine kinase inhibitors remain the most common first-line option as monotherapy treatment, the clinical success of immune checkpoint inhibitors, especially when used in combination with anti-VEGF/VEGFR in HCC will likely transform the treatment landscape. While immune checkpoint inhibitors represent an exciting therapeutic revenue for HCC, recent studies have revealed that nonviral HCC, which is primarily caused by metabolic dysfunction–associated steatotic hepatitis (MASH), has a distinct and less favorable response to the immune checkpoint inhibitors. MASH is the most rapidly increasing etiology for HCC. The immune microenvironment of MASH-HCC is greatly affected by the intertwined pathological processes of steatosis-induced iterative cycles between steatohepatitis and liver injury. Here, we present a timely summary of the immune microenvironment of MASH-HCC. We will delve into the use of cutting-edge technologies, such as single-cell RNA sequencing, spatial transcriptomics, and mass cytometry imaging, to deconvolute the complexity of the immune ecosystem in MASH-HCC. We will also discuss the novel therapeutic innovations for MASH-HCC in preclinical models, such as the metabolic inhibitor, epigenetic inhibitor, and immunomodulator. These inhibitors all have the ability to subvert the immune microenvironment of MASH-HCC, improving the efficiency of anti-PD-1. While awaiting new drugs to be tested in clinical trials, the knowledge gained from these investigations is crucial for the development of personalized and effective treatment strategies for MASH-HCC.
Treatment mechanism and outcome decoupling effects in cognitive therapy, mindfulness-based stress reduction, and behavior therapy for chronic pain
Authors: Gerhart James , Burns John W. , Thorn Beverly , Jensen Mark , Carmody James , Keefe Francis
Published: September 2024

Findings suggest that cognitive therapy (CT), mindfulness-based stress reduction (MBSR), and behavior therapy (BT) for chronic pain produce improvements through changes in putative mechanisms. Evidence supporting this notion is largely based on findings showing significant associations between treatment mechanism variables and outcomes. An alternative view is that treatments may work by reducing or decoupling the impact of changes in mechanism variables on changes in outcomes. We examined the degree to which relationships between previous changes in potential treatment mechanisms and subsequent changes in outcomes changed as treatment progressed and vice versa. Cognitive therapy, MBSR, BT, and treatment as usual (TAU) were compared in people with chronic low back pain (N = 521). Eight individual sessions were administered with weekly assessments of putative treatment mechanisms and outcomes. Lagged analyses revealed mechanism × session number interactions and outcome × session number interactions, such that associations between mechanism and outcome variables were strong and significant in the first third of treatment, but weakened over time and became nonsignificant by the last third of treatment. These effects were similar across treatment conditions but did not emerge among people undergoing TAU. Results suggest that during the course of CT, MBSR, and BT, the links between changes in treatment mechanism variables became decoupled from subsequent changes in outcomes and vice versa. Thus, starting by midtreatment and continuing into late treatment, participants may have learned through participation in the treatments that episodes of maladaptive pain-related thoughts and/or spikes in pain need not have detrimental consequences on their subsequent experience.
Implementation of a Novel Seizure Assessment Tool for Unified Seizure Evaluation Improves Nurse Response
Authors: Cubria Thanh , Nairon Emerson B. , Landers Jami , Joseph Sonia , Chandra Mishu , Denbow Maria E. , Hays Ryan , Olson DaiWai M.
Published: September 2024

BACKGROUND: Ictal and postictal testing is an essential aspect of clinical care when diagnosing and treating seizures. The epilepsy monitoring unit (EMU) has standard operating procedures for nursing care during and after seizure events, but there is limited interrater reliability. Streamlining ictal and postictal testing processes may enhance care consistency for patients in the EMU unit. The purpose of this study was to create an ictal and postictal seizure assessment tool that would increase the consistency of nursing assessment for EMU patients. METHODS: This prospective study had 4 phases: baseline assessment, instrument development, staff education, and field testing. During baseline assessment, an advanced practice provider and an epilepsy fellow graded nurse ictal and postictal assessment via survey questions. After instrument development, education, and implementation, the same survey was administered to determine if nursing consistency in assessing seizure events improved. The tool used in this study was created by a team of clinical experts to ensure consistency in the assessment of seizure patients. RESULTS: A total of 58 first seizure events were collected over a 6-month intervention period; 27 in the pretest and 31 in the posttest. Paired t test analyses revealed significant improvement in the clinical testing domains of verbal language function (P < .005), motor function (P < .0005), and item assessment order (P < .005) postintervention. There was nonsignificant improvement in the domains of responsiveness (feeling [P = .597], using a code word [P = .093]) and visual language function (P = .602). CONCLUSION: The data captured in this study support the need for this instrument. There is strong need to increase consistency in assessing seizure events and to promote continued collaboration among clinical teams to enhance care to EMU patients. Validation of this instrument will further improve team collaboration by allowing nurses to contribute to their fullest extent.
Effects of Ankle-Foot Orthoses on Gait Parameters in Children with Diplegic Cerebral Palsy Based on Kinect Analysis: A Preliminary Study
Authors: Suharti Amien , Yusviani Hafizia Asri , Alifprilia Savira Widha , Nadhif Muhammad Hanif , Utama Fakhri Rekha
Published: September 2024

Introduction

An objective, child-friendly tool is needed for physical rehabilitation intervention and evaluation of cerebral palsy children with permanent neuromotor disorders affecting movement and postures and causing gait deviation.

Materials and Methods

This study describes the feature of gait parameters in children with spastic cerebral palsy (SCP) using Microsoft Kinect and compares several spatiotemporal gait parameters before and after the use of ankle-foot orthoses (AFOs). The parameters measured were cadence and stride length. The types of orthotic devices used were hinged ankle-foot orthosis (HAFO) and supramalleolar orthosis (SMO).

Results

The gait analysis results showed different effects in stride length and cadence on each subject after using the orthotic devices. The effects also were significantly different between each patient (P < 0.050).

Conclusions

Kinect v2.0 may be more valid and comfortable for evaluating gait AFOs in cerebral palsy children.

Clinical Relevance

Improvement gait in cerebral palsy after use AFO could be evaluated by Kinect v2.0 as an objective tool and friendly for children.
Adverse effects of graft congestion and ameliorative effects of hepatocyte growth factor after liver transplantation in rats
Authors: Aoki Hikaru , Ito Takashi , Hirata Masaaki , Okumura Shinya , Masano Yuki , Ogawa Eri , Haga Hironori , Hatano Etsuro
Published: September 2024

Living donor liver transplantation (LT) and deceased donor split-LT often result in congestion within liver grafts. The regenerative process and function of congested areas, especially graft congestion associated with LT, are not well understood. Therefore, we created new rat models with congested areas in partially resected livers and orthotopically transplanted these livers into syngeneic rats to observe liver regeneration and function in congested areas. This study aimed to compare liver regeneration and the function of congested areas after liver resection and LT, and to explore a new approach to ameliorate the adverse effects of graft congestion. Although the congested areas after liver resection regenerated normally on postoperative day 7, the congested areas after LT had poor regeneration with abscess development on postoperative day 7. Necrotic areas in congested areas were larger after LT than after liver resection on postoperative days 1, 3, and 7 (p < 0.05, p < 0.05, and p < 0.01, respectively). Although congested areas after liver resection did not affect survival, in the LT model, the survival of rats with congested areas was significantly poorer even with larger grafts than that of rats with smaller noncongested grafts (p = 0.04). Hepatocyte growth factor administration improved the survival rate of rats with congested grafts from 41.7% to 100%, improved the regeneration of congested areas, and significantly reduced the size of necrotic areas (p < 0.05). Thus, congested areas in liver grafts may negatively impact recipients. Short-term administration of hepatocyte growth factor may improve postoperative outcomes of recipients with graft congestion and contribute to more effective use of liver grafts (approval number: MedKyo-23137, Institutional Ethics Committee/Kyoto University).
Tumor-informed circulating tumor DNA in urothelial carcinoma: a promising novel biomarker
Authors: Ben-David Reuben , Mehrazin Reza , Attalla Kyrollis , Wiklund Peter , Sfakianos John P.
Published: September 2024

Purpose of review

Tumor-informed circulating tumor DNA (ctDNA) is an emerging biomarker in urothelial carcinoma. Recent clinical trials have investigated the integration of ctDNA into clinical decision-making in patients with muscle-invasive bladder cancer, their findings suggest that ctDNA may potentially revolutionize the way we stratify patients to different treatment modalities.

Recent findings

ctDNA informed from TURBT specimens was found to be prognostic of disease outcomes among patients with localized nonmetastatic bladder cancer. Detectable precystectomy ctDNA status was associated with worse survival outcomes. Additionally, ctDNA status was predictive of adverse disease on radical cystectomy, including the likelihood of disease upstaging, lymph node involvement, and having a locally advanced disease (≥pT3a). In the postcystectomy minimal residual disease (MRD) period, ctDNA status may refine patient selection to adjuvant therapy, and if validated by ongoing clinical trials, patients with undetectable postcystectomy ctDNA status may forgo adjuvant treatment, regardless of pathological stage. On the contrary, patients with pre or postcystectomy detectable ctDNA status may benefit from treatment intensification.

The integration of ctDNA in clinical decision-making has the potential to revolutionize the way we manage urothelial carcinoma by refining patient selection to different treatment modalities. This approach could ultimately lead to personalization of oncological care, with the potential to reduce both treatment-related and financial toxicity.
HER2 Status in Low-grade Serous Ovarian Tumors
Authors: Němejcová Kristýna , Šafanda Adam , Kendall Bártů Michaela , Hájková Nikola , Drozenová Jana , Fabian Pavel , Laco Jan , Matěj Radoslav , Méhes Gábor , Škapa Petr , Stružinská Ivana , Dundr Pavel
Published: September 2024

Using immunohistochemistry, we examined a large cohort of 135 ovarian tumors, made up of 96 low-grade serous carcinomas (LGSCs) and 39 serous borderline tumors (micropapillary variant, mSBT), with the aim of exploring their HER2 status (overexpression). We followed with comprehensive genomic analyses on this sample set from our previous study, which revealed HER2 mutation in 5% (4/75) of LGSC and 10% (3/29) of mSBT. No cases were evaluated as HER2-positive, but 6 LGSCs and 1 mSBT were scored as HER2 1+, and 2 LGSCs and 1 mSBT showed the so-called HER2 “ultra-low” phenotype. This could be of clinical value as a potential therapeutical target concerning emerging therapeutic treatments (antibody conjugates). However, the clinical significance of this expression still needs to be established.
Belatacept Versus Tacrolimus for Kidney Transplant Recipients of Deceased Donors With Acute Kidney Injury: US National Database Study
Authors: Yamauchi Junji , Raghavan Divya , Jweehan Duha , Oygen Suayp , Marineci Silviana , Hall Isaac E. , Molnar Miklos Z.
Published: September 2024

Background.

It is unclear whether kidney grafts from deceased donors with acute kidney injury (AKI) are more vulnerable to calcineurin inhibitor nephrotoxicity, and whether de novo use of belatacept is more beneficial than tacrolimus for recipients of these types of kidney transplants.

Methods.

In this retrospective cohort study using the US Organ Procurement and Transplantation Network database, we created 1:4 matches with highly similar characteristics for recipients of AKI-donor kidneys receiving belatacept versus tacrolimus for initial maintenance immunosuppression and compared outcomes for graft function, patient and graft survival, and rejection.

Results.

The matched cohort consisted of 567 and 2268 recipients administered belatacept and tacrolimus, respectively. Posttransplant estimated glomerular filtration rate was significantly higher in the belatacept group at 6 mo (58.2 ± 24.2 versus 54.6 ± 21.6 mL/min/1.73 m2, P < 0.001); however, the between-group difference did not reach statistical significance at 12 mo (57.2 ± 24.3 versus 55.7 ± 22.2 mL/min/1.73 m2, P = 0.057). Median follow-up periods were 3.2 and 3.1 y for patient and graft survival, respectively. There were no significant differences between belatacept versus tacrolimus for mortality (hazard ratio 1.18 [95% confidence interval, 0.95-1.47], P = 0.14) or death-censored graft failure (hazard ratio 1.17 [0.85-1.61], P = 0.33). Rejection rate within 12 mo was significantly higher in the belatacept group (13% versus 7%, P < 0.001).

Conclusions.

In this matched cohort study, initial use of belatacept for AKI-donor kidney recipients was associated with small benefits in early graft function when compared with tacrolimus. Although rejection risk was significantly higher in recipients administered belatacept, patient and graft survival were not significantly different between groups.
A Third COVID-19 Vaccine Dose in Kidney Transplant Recipients Induces Antibody Response to Vaccine and Omicron Variants but Shows Limited Ig Subclass Switching
Authors: Lee Jenny M. , Sachithanandham Jaiprasath , Lee John S. , Shapiro Janna R. , Li Maggie , Sitaris Ioannis , Peralta Stephanie R. , Wouters Camille , Cox Andrea L. , Segev Dorry L. , Durand Christine M. , Robien Mark , Tobian Aaron A.R. , Karaba Andrew H. , Blankson Joel N. , Werbel William A. , Pekosz Andrew , Klein Sabra L.
Published: September 2024

Solid organ transplant recipients (SOTRs) suffer more frequent and more severe infections due to their compromised immune responses resulting from immunosuppressive treatments designed to prevent organ rejection. Pharmacological immunosuppression can adversely affect immune responses to vaccination. A cohort of kidney transplant recipients (KTRs) received their third dose of ancestral, monovalent COVID-19 vaccine in the context of a clinical trial and antibody responses to the vaccine strain, as well as to Omicron variants BA.1 and BA.5 were investigated and compared with healthy controls. Total IgG and live virus neutralizing antibody titers were reduced in KTRs compared to controls for all variants. KTRs displayed altered IgG subclass switching, with significantly lower IgG3 antibodies. Responses in KTRs were also very heterogeneous, with some individuals showing strong responses but a significant number showing no Omicron-specific neutralizing antibodies. Taken together, immune responses after COVID-19 vaccination in KTRs were not only lower than healthy controls but highly variable, indicating that simply increasing the number of vaccine doses alone may not be sufficient to provide greater protection in this population.

Importance

This study addresses the challenges faced by kidney transplant recipients (KTRs) in mounting effective immune responses against COVID-19. By evaluating the antibody responses to a third dose of monovalent mRNA COVID-19 vaccine and its effectiveness against Omicron subvariants (BA.1 and BA.5), this study reveals significant reductions in both binding and neutralizing antibodies in KTRs compared to healthy controls. The research highlights altered IgG subclass switching and heterogeneous responses within the KTR population. Reduced recognition of variants, coupled with differences in IgG subclasses, decreases both the quality and quantity of protective antibodies after vaccination in KTRs. These findings underscore the need for tailored vaccination strategies for immunosuppressed populations such as KTRs. Alternative formulations and doses of COVID-19 vaccines should be considered for people with severely compromised immune systems, as more frequent vaccinations may not significantly improve the response, especially regarding neutralizing antibodies.
The influence of visual attention on letter recognition and reading acquisition in Arabic
Authors: Ghandour Alaa , Trouche Emmanuel , Guillo Dominique , Valdois Sylviane
Published: September 2024

The present study sets out to explore the cognitive underpinnings of reading acquisition in Arabic. Previous studies have identified phonological awareness and rapid automatized naming as early predictors. However, the graphic complexity of Arabic letters imposes particular constraints on the visual system, which should mobilize visual attention. To test this hypothesis, 101 Arabic-speaking children who just began their formal reading instruction in Arabic were administered tests of syllable and word reading. Their nonverbal reasoning, vocabulary, phonological awareness, rapid automatized naming and letter knowledge were measured. Their visual attention was estimated through tasks of visual attention span. We found that phonological awareness, visual attention span and letter knowledge were associated with reading outcomes. However, regression analyses showed that the relationship between visual attention span and reading disappeared when letter knowledge was taken-into-account. We used structural equation modeling to examine the direct and indirect effects of visual attention span to reading. Results showed that phonological awareness and letter knowledge were significant and independent predictors of reading while visual attention span contributed only indirectly through its influence on letter knowledge. Our findings suggest that beginning readers rely on visual attention to identify and discriminate visually-complex Arabic letters. In turn, more efficient letter identification in children with higher visual attention facilitates reading acquisition. These findings support the cognitive models of word recognition that include visual attention as a component of the reading system. They open new perspectives for cross-language studies, suggesting that visual attention might contribute differently to reading depending on the orthographic system. They also provide a foundation for innovative teaching methodologies in Arabic language education.
In vivoImaging and Pharmacokinetics of Percutaneously Injected Ultrasound and X-ray Imageable Thermosensitive Hydrogel loaded with Doxorubicin versus Free Drug in Swine
Authors: Delgado Jose F. , Negussie Ayele H. , Varble Nicole A. , Mikhail Andrew S. , Arrichiello Antonio , Borde Tabea , Saccenti Laetitia , Bakhutashvili Ivane , Owen Joshua W. , Morhard Robert , Karanian John W. , Pritchard William F. , Wood Bradford J.
Published: September 2024

Intratumoral injections often lack visibility, leading to unpredictable outcomes such as incomplete tumor coverage, off-target drug delivery and systemic toxicities. This study investigated an ultrasound (US) and x-ray imageable thermosensitive hydrogel based on poloxamer 407 (POL) percutaneously delivered in a healthy swine model. The primary objective was to assess the 2D and 3D distribution of the hydrogel within tissue across three different needle devices and injection sites: liver, kidney, and intercostal muscle region.

Secondly, pharmacokinetics of POL loaded with doxorubicin (POLDOX) were evaluated and compared to free doxorubicin injection (DOXSoln) with a Single End Hole Needle. Utilizing 2D and 3D morphometrics from US and x-ray imaging techniques such as Computed Tomography (CT) and Cone Beam CT (CBCT), we monitored the localization and leakage of POLDOX over time. Relative iodine concentrations measured with CBCT following incorporation of an iodinated contrast agent in POL indicated potential drug diffusion and advection transport. Furthermore, US imaging revealed temporal changes, suggesting variations in acoustic intensity, heterogeneity, and echotextures. Notably, 3D reconstruction of the distribution of POL and POLDOX from 2D ultrasound frames was achieved and morphometric data obtained. Pharmacokinetic analysis revealed lower systemic exposure of the drug in various organs with POLDOX formulation compared to DOXSoln formulation. This was demonstrated by a lower area under the curve (852.1 ± 409.1 ng/mL·h vs 2283.4 ± 377.2 ng/mL·h) in the plasma profile, suggesting a potential reduction in systemic toxicity. Overall, the use of POL formulation offers a promising strategy for precise and localized drug delivery, that may minimize adverse effects. Dual modality POL imaging enabled analysis of patterns of gel distribution and morphology, alongside of pharmacokinetics of local delivery. Incorporating hydrogels into drug delivery systems holds significant promise for improving the predictability of the delivered drug and enhancing spatial conformability. These advancements can potentially enhance the safety and precision of anticancer therapy.
Incidence of postoperative acute kidney injury is higher in men than women after colorectal surgery – PROSACC: a posthoc analysis of a global, multicenter, randomized controlled trial
Authors: Frithiof Robert , Enlund Mats , Franzén Stephanie
Published: September 2024

Postoperative acute kidney injury (AKI) is a common postoperative complication. Approximately 7% of the general, elective, non-cardiac surgical population develop AKI after surgery. The female sex was previously believed to be associated with higher incidence of AKI however more recent literature implies that men have higher risk for AKI. Estrogen has been suggested to have renoprotective properties. We therefore aimed to analyze AKI incidence after colorectal cancer resection surgery in men and women on a global, multicenter, level.

In Sweden and China, a total pf 3255 patients were included in this posthoc analysis based on the CAN-trial (Cancer and Anesthesia: Survival After Radical Surgery - a Comparison Between Propofol or Sevoflurane Anesthesia). Presence of AKI was defined according to KDIGO (Kidney Disease: Improving Global Outcome) criteria for changes in plasma creatinine compared with preoperative values.

After colorectal surgery, 8% of the patients had developed AKI within 10 postoperative days. Within the 4–10-day postoperative timeframe, twice as many men as women (8% vs 4%) had developed AKI and women had a significantly lower likelihood of developing AKI (OR 0.4 [0.2-0.8], p=0.009). In general, the cumulative proportion of developing AKI within 10 days postoperatively was significantly higher in men than women (p=0.037). Moreover, older patients (60+ years) had significantly higher incidence of AKI than those younger than 60 years. This trend was evident in both men and women.

To our knowledge, this is the first ever global, multicenter, randomized controlled trial reporting a sex-difference in AKI incidence after colorectal surgery. Our posthoc analysis reinforces the notion that the male sex is a risk factor for postoperative AKI.
Lipid Aging Clocks as predictive and prognostic biomarker in cancer and inflammaging
Authors: Unfried Maximilian , Cazenave-Gassiot Amaury , Bischof Evelyne , Holcapek Michal , Scheibye-Knudsen Morten , Wenk Markus R. , Gruber Jan , Kennedy Brian K.
Published: September 2024

Lipids are a heterogenous class of molecules involved in signaling, cell structure and energy storage. Lipid metabolism is dysregulated in aging and aging-related diseases such as cancer, metabolic disorders, and neurodegeneration. In this study, we developed a biological age predictor – a Lipid Aging Clock - based on human serum lipidome data of pancreatic ductal adenocarcinoma (PDAC) patients, that has a Pearson correlation coefficient of 0.81 to chronological age with a median absolute error of 4.5 years. This shows that it is possible to build aging clocks measuring aging from pathological cohorts.

We find that LipidAgeAcceleration is increased in both PDAC and pancreatitis, indicating that these pancreatic conditions accelerate aging or that individuals with age acceleration or more likely to acquire them (or both). Furthermore, the lipid age clock is predictive of PDAC survival, where positive accelerated Lipid Age is associated with an 86% higher mortality risk. Among the lipid species associated with LipidAgeAcceleration, Ceramides, Sphingomyelins and Glycerophosphocholines, have statistically significant hazard ratios, and directly impact increased mortality. Pathway analysis of lipid species selected by the lipid clock further identifies age-dependent dysregulation of specific lipid pathways, including Sphingolipid, Glycerolipid, Glycerophospholipid metabolism, and steroid biosynthesis. Sphingolipid metabolism is significantly dysregulated in both aging and PDAC, connecting aging dynamics and cancer mortality. Moreover, sphingolipids are involved in inflammatory processes, and therefore the lipid aging clock could be, at least in part, reflecting inflammaging and is likely influenced by age-related alterations to the immune system. In summary, our work shows that lipid alterations are a robust biological age predictor with utility in cancer and aging research, as well as in predicting disease-associated outcomes.
A Machine Learning Approach to Predict Cognitive Decline in Alzheimer’s Disease Clinical Trials
Authors: Nallapu Bhargav T. , Petersen Kellen K. , Qian Tianchen , Demirsoy Idris , Ghanbarian Elham , Davatzikos Christos , Lipton Richard B. , Ezzati Ali ,   Alzheimer’s Disease Neuroimaging Initiative
Published: September 2024

Background

Of persons randomized to the placebo arm of Alzheimer’s Disease (AD) treatment trials, 40% do not show cognitive decline over 80 weeks of follow-up. Identifying and excluding these individuals from both arms of randomized clinical trials (RCTs) of AD has the potential to increase power to detect treatment effects.

Objectives

We aimed to develop machine learning-based predictive models to identify persons unlikely to show decline on placebo treatment over 80 weeks.

Method

We used the data from 1072 patients with mild dementia and biomarker evidence of amyloid burden from the placebo arm of EXPEDITION3 trial. Participants were identified as those who demonstrated Clinically Meaningful Cognitive Decline (CMCD, change in ADAS-Cog≥3) or Cognitive Stable (CS, change in ADAS-Cog<3) at final visit of the trial (week 80). Machine learning-based classifiers were trained to classify participants into CMCD vs. CS groups using combinations of demographics, neuropsychological tests (NP) and biomarkers, including APOE4 genotype and volumetric MRI. The results were developed in 70% of the EXPEDITION3 placebo sample (EXPtrain) using 5-fold cross-validation. Trained models were then used to classify the participants in an internal validation sample (EXPvalid)and an external matched sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.

Result

Participants selected from the EXPEDITION3 trial were on average 72.7(±7.7) years old, 59% were female. CMCD was observed in 55.8% of participants of EXPEDITION3 at final visit. In the independent validation sample within the EXPEDITION3 data, all the models showed high sensitivity and modest specificity. Positive predictive values (PPVs) of models were at least 11% higher than base prevalence of CMCD observed at the end of the trial. The subset of matched ADNI participants (ADNIAD) were on average 74.5(±6.4) years old and 46% female. The models that were validated in ADNIADalso showed high sensitivity, modest specificity and PPVs of at least 15% higher than the base prevalence in ADNIAD.

Conclusion

Our results indicate that predictive models have the potential to improve the design of AD trials through selective inclusion criteria for participants expected to decline and exclusion of those expected to remain stable.
Oxidative stress and PARP activation in the lungs is an early event in COVID-19 pneumonia
Authors: Juhász Péter , Bohus Péter , Sipos Adrienn , Curtin Nicola , Méhes Gábor , Bai Péter
Published: September 2024

Oxidative stress and poly(ADP-ribosyl)ation (PARylation) leads to tissue damage and inflammation in multiple lung diseases, likely in COVID-19. In a previous study we evidenced PARylation in multiple pulmonary cell types in patients who died of COVID-19, but not in patients who died of non-COVID-19 causes. We extended these observations in this retrospective immunohistochemical study by enlarging and stratifying the study population. We showed that pulmonary PARylation and oxidative stress peaked in the exudative and then decreased in the proliferative phase. Pulmonary oxidative stress and PARylation correlated with the serum markers of liver and kidney damage, oxygen transport, tissue hypoxia, lymphocytopenia, blood clotting and disseminated intravascular coagulation. Most correlations between PARylation and serum chemistry readouts were identified in the exudative phase. PARylation correlated with viral load and with the oxidative stress in the tissues, however, correlation between viral load and oxidative stress was marginal suggesting that oxidative stress and the presence of SARS-CoV-2 can independently induce PARylation. In males the time of hospitalization (time to death) was inversely correlated with pulmonary PARylation. Furthermore, males, died of COVID-19, were ∼15 years younger than females, however, there was no difference in pulmonary oxidative stress and PARylation between genders at death. Taken together, pulmonary PARylation and oxidative stress manifests early, in the exudative phase of COVID-19 and PARylation contributes to worse clinical outcome for males. These results suggest repurposing pharmacological PARP inhibitors for acute COVID-19 to counteract tissue damage.
Advancing Early Warning Systems for Malaria: Progress, Challenges, and Future Directions - A Scoping Review
Authors: Mategula Donnie , Gichuki Judy , Barnes Karen I , Giorgi Emanuele , Terlouw Dianne Jannete
Published: September 2024

Background

Malaria Early Warning Systems(EWS) are predictive tools that often use climatic and environmental variables to forecast malaria risk and trigger timely interventions. Despite their potential benefits, the development and implementation of malaria EWS face significant challenges and limitations. We reviewed the current evidence on malaria EWS, including their settings, methods, performance, actions, and evaluation.

Methods

We conducted a comprehensive literature search using keywords related to EWS and malaria in various databases and registers. We included primary research and programmatic reports focused on developing and implementing Malaria EWS. We extracted and synthesized data on the characteristics, outcomes, and experiences of Malaria EWS.

Results

After reviewing 5,535 records, we identified 30 studies from 16 countries that met our inclusion criteria. The studies varied in their transmission settings, from pre-elimination to high burden, and their purposes, ranging from outbreak detection to resource allocation. The studies employed various statistical and machine-learning models to forecast malaria cases, often incorporating environmental covariates such as rainfall and temperature. The most common mode used is the time series model. The performance of the models was assessed using measures such as the Akaike Information Criterion( AIC), Root Mean Square Error (RMSE), and adjusted R squared(R2). The studies reported actions and responses triggered by EWS predictions, such as vector control, case management, and health education. The lack of standardized criteria and methodologies limited the evaluation of EWS impact.

Conclusions

This review provides a comprehensive overview of the current status of Malaria EWS, highlighting the progress, challenges, and gaps in the field. The review informs and guides policymakers, researchers, and practitioners in enhancing EWS and malaria control strategies. The review also underscores the need for further research on the integration, sustainability, and evaluation of Malaria EWS usage and harmonized methods to ease review.
Population genomics ofMacrophominaspp. reveals cryptic host specialization and evidence for meiotic recombination
Authors: Pennerman K.K. , Goldman P. , Dilla-Ermita C.J. , Ramos G. , Jaime J.H. , Lopez-Hernandez J. , Ramos J. , Aviles M. , Borrero C. , Gomez A.O. , Neal J.M. , Chilvers M. , Ortiz V. , Stukenbrock E.H. , Goldman G.H. , Mengitsu A. , Lopez-Nicora H.D. , Sacher G.O. , Vaghefi N. , Kiss L. , Benz J.P. , Machado A.R. , Seijo T.E. , Peres N.A. , Martin F.N. , Broome J.C. , Ivors K. , Cole G. , Knapp S. , McFarlane D.J. , Mattner S.W. , Gambardella M. , Henry P.M.
Published: September 2024

Knowledge of the factors structuring populations of pathogenic fungi is fundamental to disease management efforts and basic biology. High-quality short-read sequence data were obtained for 463Macrophominaspp. isolates collected from 91 host plant species and soil in 23 countries. Analyses revealed high diversity, admixture, and equal mating type ratios suggesting on-going recombination. Although most tested isolates could asymptomatically colonize strawberry, only isolates from a single phylogroup caused disease. In addition to strawberry, evidence for host specialization was discovered for soybean, demonstrating this broad host range pathogen contains phylogroups with cryptic specialization. Geography × isolate genotype associations were weak, suggesting these species were frequently trafficked between regions. Re-analysis using genomic data supported current species boundaries, and new molecular markers were designed to specifically identify each species. Contrary to expectations,M. phaseolinashould be considered a species with both specialist and generalist populations for which meiosis can increase genetic diversity.
Revealing the co-existence of written and spoken language coding neural populations in the left-ventral occipitotemporal cortex
Authors: Wang Shuai , Dubarry Anne-Sophie , Chanoine Valérie , Sein Julien , Anton Jean-Luc , Nazarian Bruno , Mercier Manuel R. , Trébuchon Agnès , Pattamadilok Chotiga
Published: September 2024

Reading relies on the ability to map written symbols with speech sounds. The left ventral occipitotemporal cortex (left-vOT) plays a crucial role in this process. Through the automatization of the mapping ability, this specific part of the ventral visual pathway (a.k.a., the Visual Word Form Area) progressively becomes specialized in written word recognition. Yet, despite its key role in reading, the area also responds to speech. This observation raises questions about the actual nature of neural representations encoded in the left-vOT and, therefore, the underlying mechanism of the cross-modal responses. Here, we addressed this issue by applying fine-grained analyses of within- and cross-modal repetition suppression effects (RSEs) and Multi-Voxel Pattern Analyses in fMRI and sEEG experiments. Convergent evidence across analysis methods and protocols showed significant RSEs and successful decoding in both within-modal visual and auditory conditions suggesting that subpopulations of neurons within the left-vOT distinctly encode written and spoken language inputs. This functional organization of neural populations enables the area to respond to speech input directly and indirectly, i.e., after speech sounds are converted to orthographic representations. The finding opens further discussions on how the human brain may be prepared and adapted for an acquisition of a complex ability such as reading.

Significance Statement

Learning to read generates new functional responses in neurons in the left ventral visual pathway. Soon after reading acquisition, these neurons become specialized in processing known scripts, thus leading to the functional designation of the “Visual Word Form Area” (VWFA). However, controversies remain regarding the nature of neural representations encoded in this “reading” region, as its activation to speech is also reported. We investigate the neural mechanism(s) underlying these bimodal responses using within and cross-modal repetition suppression and decoding protocols. fMRI and sEEG experiments provided converging evidence indicating that, despite its specialization in reading, VWFA also contained subpopulations of neurons that encode speech. This functional organization could reveal why neurons at this anatomical location are ideal for reading acquisition.
Identification of M-Sec as a unique cellular regulator of CSF-1 receptor activation
Authors: Abdelnaser Randa A. , Hiyoshi Masateru , Takahashi Naofumi , Eltalkhawy Youssef M. , Mizuno Hidenobu , Kimura Shunsuke , Hase Koji , Ohno Hiroshi , Monde Kazuaki , Ono Akira , Suzu Shinya
Published: September 2024

Fms, the CSF-1 receptor encoding tyrosine kinase, is essential for tissue macrophage development, and the therapeutic target for many tumors. However, it is not completely understood how Fms activation is regulated. Here, we identify the cellular protein M-Sec as a unique regulator of Fms. In macrophages, Fms forms large aggregates via unknown mechanisms. We found that the inhibition or knockdown of reduced Fms aggregate formation and functional response of macrophages to CSF-1, which was consistent with reduced Fms activation after CSF-1 stimulation. When expressed in 293 cells, M-Sec augmented Fms aggregate formation and CSF-1-induced Fms activation. CSF-1 and M-Sec bind the cellular phosphatidylinositol 4,5-biphosphate (PIP2). The removal of PIP2-binding motif of Fms or M-Sec, or the depletion of cellular PIP2 reduced Fms aggregate formation. Moreover, M-Sec altered cellular distribution of PIP2. Since CSF-1-induced dimerization of Fms is critical for its activation, our findings suggest that M-Sec augments large Fms aggregate formation via PIP2, which brings Fms monomers close to each other and enables the efficient dimerization and activation of Fms in response to CSF-1.
Physical mechanism reveals bacterial slowdown above a critical number of flagella
Authors: Tătulea-Codrean Maria , Lauga Eric
Published: September 2024

Numerous studies have explored the link between bacterial swimming and the number of flagella, a distinguishing feature of motile multiflagellated bacteria. We revisit this open question using augmented slender-body theory simulations, in which we resolve the full hydrodynamic interactions within a bundle of helical filaments rotating and translating in synchrony. Unlike previous studies, our model considers the full torque-speed relationship of the bacterial flagellar motor, revealing its significant impact on multiflagellated swimming. Because the viscous load per motor decreases with flagellar number, the bacterial flagellar motor (BFM) transitions from the high-load to the low-load regime at a critical number of filaments, leading to bacterial slowdown as further flagella are added to the bundle. We explain the physical mechanism behind the observed slowdown as an interplay between the load-dependent generation of torque by the motor, and the load-reducing cooperativity between flagella, which consists of both hydrodynamic and non-hydrodynamic components. The theoretically predicted critical number of flagella is remarkably close to the values reported for the model organismEscherichia coli. Our model further predicts that the critical number of flagella increases with viscosity, suggesting that bacteria can enhance their swimming capacity by growing more flagella in more viscous environments, consistent with empirical observations.