bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Drug Monitoring of Pazopanib in Renal Cell Carcinoma and Soft Tissue Sarcoma: A Systematic Review
Authors: Turjap Miroslav , Pelcová Marta , Gregorová Jana , Šmak Pavel , Martin Hiroko , Štingl Jan , Peš Ondřej , Juřica Jan
Published: May 2024

Background:

Pazopanib, an anti-angiogenic multitarget tyrosine kinase inhibitor, has been approved for the treatment of metastatic renal cell carcinoma and soft tissue sarcoma. However, its recommended dose does not always produce consistent outcomes, with some patients experiencing adverse effects or toxicity. This variability is due to differences in the systemic exposure to pazopanib. This review aimed to establish whether sufficient evidence exists for the routine or selective therapeutic drug monitoring of pazopanib in adult patients with approved indications.

Methods:

A systematic search of the PubMed and Web of Science databases using search terms related to pazopanib and therapeutic drug monitoring yielded 186 and 275 articles, respectively. Ten articles associated with treatment outcomes or toxicity due to drug exposure were selected for review.

Results:

The included studies were evaluated to determine the significance of the relationship between drug exposure/Ctrough and treatment outcomes and between drug exposure and toxicity. A relationship between exposure and treatment outcomes was observed in 5 studies, whereas the trend was nonsignificant in 4 studies. A relationship between exposure and toxicity was observed in 6 studies, whereas 2 studies did not find a significant relationship; significance was not reported in 3 studies.

Conclusions:

Sufficient evidence supports the therapeutic drug monitoring of pazopanib in adult patients to improve its efficacy and/or safety in the approved indications.
Optimizing the Pedicled Latissimus Dorsi Myocutaneous Flap in Breast Reconstruction: Lessons Learned from 110 Consecutive Flaps
Authors: Doan Leandra , Sam Andre-Philippe , Li Wai-Yee
Published: May 2024

Background:

The pedicled latissimus dorsi myocutaneous flap (LDMCF) in autologous breast reconstruction has been superseded by abdominal free tissue transfer. Common complaints of the LDMCF include the asymmetric back scar, need for prosthesis, and high seroma rates. We believe that the LDMCF remains versatile, with distinct advantages over other autologous options: the flap can be harvested unilaterally or bilaterally, not ‘burning any bridges’ for future reconstruction in unilateral breast reconstruction; the recovery is relatively easy, without complications such as risk of long-term abdominal wall weakness; and the aesthetic results are comparable, if not superior, leading to a more “youthful” result.

Methods:

We performed a retrospective review over an 8-year period.

Results:

A total of 106 patients underwent 110 breast reconstructions. Complications included four of 106 patients (3.8%) with seroma, three of 78 (3.8%) with periprosthetic implant infection, and one case of partial flap loss.

Conclusions:

We learned the following: (1) Direct-to-implant can be performed in most LDMCF patients, avoiding the use of tissue expanders; (2) High BMI patients may not require an implant; (3) Back donor site aesthetics can be improved using a “bra-line-back-lift” approach; (4) Use of liposomal bupivacaine intercostal blocks and modified enhanced recovery after surgery protocol can reduce length-of-stay to overnight; (5) We achieved low seroma rates using topical fibrin glue and closed suction drains; (6) Low and high BMI patients who may not qualify for free tissue transfer are usually still surgical candidates with LDMCF; and (7) Short and long-term recovery are faster than free tissue transfer, with minimal long-term deficit.
Small fibre neuropathy frequently underlies the painful long-COVID syndrome
Authors: Falco Pietro , Litewczuk Daniel , Di Stefano Giulia , Galosi Eleonora , Leone Caterina , De Stefano Gianfranco , Di Pietro Giuseppe , Tramontana Lorenzo , Ciardi Maria Rosa , Pasculli Patrizia , Zingaropoli Maria Antonella , Arendt-Nielsen Lars , Truini Andrea
Published: May 2024

Approximately 10% to 20% of individuals with previous SARS-CoV-2 infection may develop long-COVID syndrome, characterized by various physical and mental health issues, including pain. Previous studies suggested an association between small fibre neuropathy and pain in long-COVID cases. In this case–control study, our aim was to identify small fibre neuropathy in patients experiencing painful long-COVID syndrome. Clinical data, quantitative sensory testing, and skin biopsies were collected from 26 selected patients with painful long-COVID syndrome. We also examined 100 individuals with past COVID-19 infection, selecting 33 patients with painless long-COVID syndrome, characterized mainly by symptoms such as brain fog and fatigue, and 30 asymptomatic post–COVID-19 controls. Demographic and clinical variables were compared among these groups. Among the 26 patients with painful long-COVID syndrome, 12 had skin biopsy and/or quantitative sensory testing abnormalities compatible with small fibre neuropathy. Demographic and clinical data did not differ across patients with small fibre neuropathy, patients with painless long-COVID syndrome, and asymptomatic post–COVID-19 controls. This case–control study showed that approximately 50% of patients experiencing painful long-COVID syndrome had small fibre neuropathy. However, in our patient cohort, this specific post–COVID-19 complication was unrelated to demographic and COVID-19 clinical variables. Approximately half of our sample of patients with painful long-COVID symptoms met diagnostic criteria for small fibre neuropathy.
Inferior Long-Term Results of a Randomized Controlled Trial Initially Demonstrating Enhanced Sensory Nerve Recovery Using a Chitosan Nerve Tube
Authors: Aman Martin , Preisner Fabian , Mayrhofer- Schmid Maximilian , Eisa Amr , Schwarz Daniel , Kneser Ulrich , Harhaus Leila , Boecker Arne H.
Published: May 2024

Background:

Traumatic peripheral nerve injuries can result in significant functional impairments and long-term sequelae. This study evaluated the long-term outcomes of a chitosan tube implant to protect epineural coaptation after peripheral nerve injuries using 2 different tube versions (different wall thicknesses and resorption characteristics), compared with a control group. The study focused on pain levels, sensory function, and overall functional outcomes.

Methods:

Patients who received a tube implant around direct coaptation sites of digital nerves were randomized and compared with control patients with no additional tube protection. Pain levels, sensory function, grip force, and functional scores were assessed at time points ranging from 3 months to 5 years postoperatively. Tube biodegradation was measured using high-resolution magnetic resonance neurography and categorized.

Results:

Patients with the first tube version had higher pain levels compared with the control group after 5 years, and reported more symptoms of numbness and hypersensitivity. Patients with the second version exhibited higher pain levels at 3 months that did not persist at 6 months, but they showed compromised sensory function, with higher 2-point discrimination values compared with the first and control groups. No differences were found in grip force or functional scores between the groups. Magnetic resonance imaging displayed remnants of implants even at long-term follow-up.

Conclusions:

The findings suggest potential limitations attributable to increased pain and impaired sensory function associated with tube implantation in the long term. In the short term, however, the material seemed to have a protective effect (as published previously). The resorption process was not complete at the end of the 5-year observation period. This might explain the prolonged scarring and inferior long-term results. Future research should focus on improving tube materials and design to minimize adverse effects and enhance functional outcomes.
Brief Report: Veterans Aging Cohort Study Index 2.0 Shows Improved Discrimination of Neurocognitive Impairment and Frailty in People With HIV
Authors: Yan Cynthia Y. , Cooley Sarah A. , Ances Beau M.
Published: May 2024

Objective:

To examine whether the revised Veterans Aging Cohort Study (VACS2.0) index [including serum albumin, body mass index, and white blood cell count] had stronger correlations with cognitive function, brain volume, and frailty in persons with HIV (PWHs) ≥50 years compared with the VACS1.0.

Design and methods:

Neuropsychological performance (NP) Z-scores (learning, retention, executive functioning, psychomotor function/processing speed, language, and global cognition), and neuroimaging measures (brain volumetrics) were analyzed in PWHs (n = 162). A subset of the sample (n = 159) was defined as either frail (n = 18) or nonfrail (n = 141) according to the Fried phenotype criteria. Brain volumes, NP scores, and frailty subgroups were analyzed with VACS scores, albumin, body mass index, and white blood cell count using Pearson significance tests and independent T tests.

Results:

Higher VACS scores significantly correlated with lower brain volumes. Higher VACS2.0 scores were associated with lower NP in the executive functioning and psychomotor function/processing speed domains and were primarily driven by albumin. VACS1.0 scores did not correlate with cognition Z-scores. There was no relationship between frailty status and VACS1.0. PWHs who were frail had significantly greater VACS2.0 scores than nonfrail PWHs.

Conclusions:

The addition of albumin to the VACS index improved its correlations with NP and frailty in PWHs. While low albumin levels may contribute to cognitive decline or frailty, the reverse causality should also be considered. These findings suggest that the VACS2.0 index (especially albumin) is a valuable measure for clinicians to improve outcomes in PWHs.
Reconstruction of Squamous Cell Carcinoma on Oral Commissure With Hatchet-Shaped Flap
Authors: Ki Sae Hwi , Chung Do Hyuk , Park Tae Jun
Published: May 2024

The mouth is a unique and prominent element of the lower face. Given the complex anatomy, aesthetic appearance, and function of the oral commissure, its reconstruction due to various causes presents a significant challenge for surgeons. Squamous cell carcinoma (SCC) of the lip is the most common type of oral cancer, accounting for approximately 25% to 30% of all oral cancers. Wide excision is the treatment of choice, and the prognosis is generally favorable. We encountered a case of SCC of the right oral commissure in a 69-year-old man. We designed a hatchet-shaped flap to minimize anatomical disruption and, as a result, achieved satisfactory outcomes in terms of both functionality and aesthetics.
Prelaminated Nose Reconstruction: Comparison of Forehead and Radial Donor Site and Review of the Literature
Authors: Spyropoulou Georgia-Alexandra , Demiri Efterpi , Antoniades Kostantinos , Vahtsevanos Konstantinos , Triaridis Stefanos , Markou Konstantinos , Cohen Mimis
Published: May 2024

Introduction:

Total nose reconstruction is demanding as it is a 3-dimensional structure that needs lining, support and external coverage. Usually, several stages are needed to achieve a satisfactory result. The authors present 2 cases of prelaminated radial forearm and 2 prelaminated forehead nose reconstructions and compare both methods. According to our review of the literature, this is the first report of prelaminated forehead for total nose reconstruction.

Materials and Methods:

The last 5 years the authors have treated 4 patients with prelaminated flaps for total nose reconstruction. The age ranged from 50 to 75 years. There were 3 male patients and one female. Three patients underwent total nose amputation due to squamous cell carcinoma and one due to melanoma.

Results:

Two patients were treated with prelaminated radial forearm reconstruction and 2 with prelaminated forehead reconstruction. Both patients that were treated with prelaminated radial forearm reconstruction had the collapse of the nasal pyramid and had salvage procedures with replacement of the cartilaginous framework with iliac bone graft framework.

Conclusions:

Prelaminated nose reconstruction with either the radial forearm or forehead flap needs several stages. There is the possibility of infection-collapse of the cartilage framework, therefore, the authors recommend reconstruction of the nasal skeleton with an iliac bone graft. The flaps are stiff and difficult to handle. The authors don’t think that prelaminated nose reconstruction with the radial forearm flap has advantage compared with the classic several stages nose reconstruction with radial forearm flap. Possibly, prelaminated forehead reconstruction can be applied for aged patients who cannot undergo microsurgical reconstruction.
Turicibacter faecis sp. nov., isolated from faeces of heart failure mouse model
Authors: Imamura Yuko , Motooka Daisuke , Nakajima Yuri , Ito Shin , Kitakaze Masafumi , Iida Tetsuya , Nakamura Shota
Published: May 2024

Strain TC023T, a Gram-positive, long, rod-shaped, spore-forming anaerobe, was isolated from the faeces of a heart failure mouse model. The strain formed greyish-white coloured colonies with a convex elevation on brain–heart infusion medium supplemented with 0.1 % sodium taurocholate, incubated at 37 °C for 2 days. Taxonomic analysis based on the 16S rRNA gene sequence showed that TC023T belonged to the genus Turicibacter, and was closely related to Turicibacter bilis MMM721T (97.6 %) and Turicibacter sanguinis MOL361T (97.4 %). The whole genome of the strain has a G+C content of 37.3 mol%. The average nucleotide identity and genome-to-genome distance between TC023T and Turicibacter bilis MMM721T were 77.6 % and 24.3 %, respectively, and those with Turicibacter sanguinis MOL361T were 75.4 % and 24.3 %, respectively. These genotypic, phenotypic, and biochemical analyses indicated that the isolate represents a novel species in the genus Turicibacter, and the name Turicibacter faecis sp. nov. is proposed. The type strain is TC023T (RIMD 2002001T=TSD 372T).
Dengue: A review of laboratory diagnostics in the vaccine age
Authors: Frazer Jaimie L. , Norton Robert
Published: May 2024

Background. Dengue is an important arboviral infection of considerable public health significance. It occurs in a wide global belt within a variety of tropical regions. The timely laboratory diagnosis of Dengue infection is critical to inform both clinical management and an appropriate public health response. Vaccination against Dengue virus is being introduced in some areas.

Discussion. Appropriate diagnostic strategies will vary between laboratories depending on the available resources and skills. Diagnostic methods available include viral culture, the serological detection of Dengue-specific antibodies in using enzyme immunoassays (EIAs), microsphere immunoassays, haemagglutination inhibition or in lateral flow point of care tests. The results of antibody tests may be influenced by prior vaccination and exposure to other flaviviruses. The detection of non-structural protein 1 in serum (NS1) has improved the early diagnosis of Dengue and is available in point-of-care assays in addition to EIAs. Direct detection of viral RNA from blood by PCR is more sensitive than NS1 antigen detection but requires molecular skills and resources. An increasing variety of isothermal nucleic acid detection methods are in development. Timing of specimen collection and choice of test is critical to optimize diagnostic accuracy. Metagenomics and the direct detection by sequencing of viral RNA from blood offers the ability to rapidly type isolates for epidemiologic purposes.

Conclusion. The impact of vaccination on immune response must be recognized as it will impact test interpretation and diagnostic algorithms.
Concurrent validity, test-retest reliability, and normative properties of the Ignite app: a cognitive assessment for frontotemporal dementia
Authors: Convery Rhian S. , Adams-Carr Kerala , Nicholas Jennifer M. , Moore Katrina M. , Goldsmith Sophie , Bocchetta Martina , Russell Lucy L. , Rohrer Jonathan D.
Published: May 2024

Digital biomarkers can provide frequent, real-time monitoring of health-related behaviour and could play an important role in the assessment of cognition in frontotemporal dementia (FTD). However, the validity and reliability of digital biomarkers as measures of cognitive function must first be determined. The Ignite computerised cognitive app contains several iPad-based measures of executive function, social cognition, and other domains known to be affected in FTD. Here we describe the normative properties of the Ignite tests, evaluate the associations with gold-standard neuropsychology tests, and investigate test-retest reliability through two healthy controls studies. Over 2,000 cognitively normal adults aged 20-80 years (mean=55.2, standard deviation=15.8) were recruited to complete the Ignite app through a remote data collection study. Significant associations were found between age and performance on several Ignite measures of processing speed (r=0.42 to 0.56,p<0.001) and executive function (r=0.43 to 0.62,p<0.001), suggesting the tests are sensitive to cognitive decline observed in normal ageing. A separate cohort of 98 healthy controls were recruited to an observational study (mean age=51.2 years, standard deviation=17.3), completing Ignite at two timepoints (7 days apart), a gold-standard pen and paper neuropsychology battery of corresponding tests, and a user experience questionnaire (10-items). The Ignite tests demonstrated moderate to excellent test-retest reliability (ICCs=0.54 to 0.92) and significantly correlated with their pen and paper counterparts (r=0.25 to 0.72,p<0.05). The majority of participants (>90%) also rated the app favourably, stating it was enjoyable and easy to complete unsupervised. These findings suggest the Ignite tests are valid measures of cognitive processes, capture a stable picture of performance over time and are well accepted in healthy controls, speaking to the feasibility of administering the app remotely. Therefore, the results have important implications for the utility of Ignite as a cognitive endpoint in upcoming FTD clinical trials.
Development of a comprehensive genome-wide cardiovascular disease genetic risk assessment test
Authors: Amendola Laura M , Coffey Alison J , Lowry Josh , Avecilla James , Malhotra Alka , Chawla Aditi , Thacker Stetson , Taylor Julie P , Rajkumar Revathi , Brown Carolyn M , Golden-Grant Katie , Hejja Rueben , Lee Jennifer A , Medrano Phillip , Milewski Becky , Mullen Felipe , Walker Andrew , Huertez-Vasquez Adriana , Longoni Mauro , Perry Denise L , Hostin Damon , Ajay Subramanian S , Kesari Akanchha , Strom Samuel P , Margulies Elliott , Belmont John , Lanfear David E , Taft Ryan J
Published: May 2024

Background: Despite monogenic and polygenic contributions to cardiovascular disease (CVD), genetic testing is not widely adopted, and current tests are limited by the breadth of surveyed conditions and interpretation burden. Methods: We developed a comprehensive clinical genome CVD test with semi-automated interpretation. Monogenic conditions and risk alleles were selected based on systematic assessment of the strength of disease association and evidence for increased disease risk, respectively. Non-CVD secondary finding genes, pharmacogenomic (PGx) variants and CVD polygenic risk scores (PRS) were also assessed for inclusion. Test performance was modeled using 2,594 genomes from the 1000 Genomes Project, and further investigated in 20 previously tested individuals. Results: The CVD genome test is composed of a panel of 215 CVD gene-disease pairs, 35 non-CVD secondary findings genes, 4 risk alleles or genotypes, 10 PGx genes and a PRS for coronary artery disease. Modeling of test performance from samples in the 1000 Genomes Project revealed ~6% of individuals with a monogenic finding in a CVD-associated gene, 6% with a risk allele finding, 0.9% with a non-CVD secondary finding, and 93% with CVD-associated PGx variants. Assessment of blinded clinical samples showed complete concordance with prior testing. An average of 4 variants were reviewed per case, with interpretation and reporting time ranging from 9-96 min. Conclusions: A genome sequencing based CVD genetic risk assessment can provide comprehensive genetic disease and genetic risk information to patients with CVD. The semi-automated and limited interpretation burden suggest that this testing approach could be scaled to support population-level initiatives.
Single Cell Sequencing of Human Langerhans Cells Identifies Altered Gene Expression Profiles in Patients with Atopic Dermatitis
Authors: Tamminga Sara M. , van der Wal M. Marlot , Saager Elise S. , van der Gang Lian F. , Boesjes Celeste M. , Hendriks Astrid , Pannekoek Yvonne , de Bruin Marjolein S. , van Wijk Femke , van Sorge Nina M.
Published: May 2024

Atopic dermatitis (AD) is characterized by dysregulated T cell immunity and skin microbiome dysbiosis with predominance ofStaphylococcus aureus(S. aureus). Emerging evidence suggests a role forS. aureusin exacerbating AD skin inflammation. We have previously shown that specific glycosylation ofS. aureuscell wall structures amplifies skin inflammation through interaction with Langerhans cells (LCs). However, the role of LCs in AD remains poorly characterized. Here, we performed single cell RNA-sequencing of primary epidermal LCs and dermal T cells isolated from skin biopsies of AD patients and healthy controls, alongside specific glycoanalysis ofS. aureusstrains isolated from the AD lesions. Our findings reveal four LC subpopulations, including two steady-state clusters (LC1 and LC1H) and two pro-inflammatory/matured subsets (LC2 and migratory LCs). The latter two subsets were enriched in AD skin. AD LCs showed enhanced expression of C-type lectin receptors, the high-affinity IgE receptor (FcεR1), and activation of prostaglandin and leukotrienes biosynthesis pathways, as well as upregulated transcriptional signatures related to T cell activation pathways and increased expression of CCL17 (specifically LC2) compared to healthy LCs. Correspondingly, T helper 2 and regulatory T cell populations were increased in AD lesions. Our study provides proof-of-concept for a role of LCs in connecting theS. aureus-T cell axis in the AD inflammatory cycle.
Probing intratumoral metabolic compartmentalisation in fumarate hydratase-deficient renal cancer using clinical hyperpolarised13C-MRI and mass spectrometry imaging
Authors: Horvat-Menih Ines , Casey Ruth , Denholm James , Hamm Gregory , Hulme Heather , Gallon John , Khan Alixander S , Kaggie Joshua , Gill Andrew B , Priest Andrew N , Duarte Joao A G , Yong Cissy , Brodie Cara , Whitworth James , Barry Simon T , Goodwin Richard J A , Anand Shubha , Dodd Marc , Honan Katherine , Welsh Sarah J , Warren Anne Y , Aho Tevita , Stewart Grant D , Mitchell Thomas J , McLean Mary A , Gallagher Ferdia A
Published: May 2024

Background

Fumarate hydratase-deficient renal cell carcinoma (FHd-RCC) is a rare and aggressive renal cancer subtype characterised by increased fumarate accumulation and upregulated lactate production. Renal tumours demonstrate significant intratumoral metabolic heterogeneity, which may contribute to treatment failure. Emerging non-invasive metabolic imaging techniques have clinical potential to more accurately phenotype tumour metabolism and its heterogeneity.

Methods

Here we have used hyperpolarised13C-pyruvate MRI (HP13C-MRI) to assess13C-lactate generation in a patient with an organ-confined FHd-RCC. Post-operative tissue samples were co-registered with imaging and underwent sequencing, IHC staining, and mass spectrometry imaging (MSI).

Results

HP13C-MRI revealed two metabolically distinct tumour regions. The13C-lactate-rich region showed a high lactate/pyruvate ratio and slightly lower fumarate on MSI compared to the other tumour region, as well as increased CD8+ T cell infiltration, and genetic dedifferentiation. Compared to the normal kidney, vascularity in tumour was decreased, while immune cell fraction was markedly higher.

Conclusions

This study shows the potential of metabolic HP13C-MRI to characterise FHd-RCC and how targeting of biopsies to regions of metabolic dysregulation could be used to obtain the tumour samples of greatest clinical significance, which in turn can inform on early and successful response to treatment.
Effects of HMGCR deficiency on skeletal muscle development
Authors: Gunasekaran Mekala , Littel Hannah R. , Wells Natalya M. , Turner Johnnie , Campos Gloriana , Venigalla Sree , Estrella Elicia A. , Ghosh Partha S. , Daugherty Audrey L. , Stafki Seth A. , Kunkel Louis M. , Foley A. Reghan , Donkervoort Sandra , Bönnemann Carsten G. , Toledo-Bravo de Laguna Laura , Nascimento Andres , Benito Daniel Natera-de , Draper Isabelle , Bruels Christine C. , Pacak Christina A. , Kang Peter B.
Published: May 2024

Pathogenic variants inHMGCRwere recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. The mechanism linking pathogenic variants inHMGCRwith skeletal muscle dysfunction is unclear. We knocked downHmgcrin mouse skeletal myoblasts, knocked downhmgcrin Drosophila, and expressed three pathogenicHMGCRvariants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) inHmgcrknockdown mouse myoblasts.Hmgcrdeficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing ofHmgcrknockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown ofhmgcrin Drosophila led to lethality. Overexpression of referenceHMGCRcDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants ofHMGCRcDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.
Two-brain microstates: A novel hyperscanning-EEG method for quantifying task-driven inter-brain asymmetry
Authors: Li Qianliang , Zimmermann Marius , Konvalinka Ivana
Published: May 2024

Background: The neural mechanisms underlying real-time social interaction remain poorly understood. While hyperscanning has emerged as a popular method to better understand inter-brain mechanisms, inter-brain methods remain underdeveloped, and primarily focused on inter-brain synchronization (IBS). New method: We developed a novel approach employing two-brain EEG microstates, to investigate neural mechanisms during symmetric and asymmetric interactive tasks. Microstates are quasi-stable configurations of brain activity that have been proposed to represent basic building blocks for mental processing. Expanding the microstate methodology to dyads of interacting participants enables us to investigate quasi-stable moments of inter-brain synchronous and asymmetric activity. Results: Conventional microstates fitted to individuals were not related to the different interactive conditions. However, two-brain microstates were modulated in the observer-actor condition, compared to all other conditions where participants had more symmetric task demands, and the same trend was observed for the follower-leader condition. This indicates differences in resting state default-mode network activity during interactions with asymmetric tasks. Comparison with existing methods Hyperscanning studies have primarily estimated IBS based on functional connectivity measures. However, localized connections are often hard to interpret on a larger scale when multiple connections across brains are found to be important. Two-brain microstates offer an alternative approach to evaluate neural activity from a large-scale global network perspective, by quantifying task-driven asymmetric neural states between interacting individuals. Conclusions: We present a novel method using two-brain microstates, including open-source code, which expands the current hyperscanning-EEG methodology to measure and potentially identify both synchronous and asymmetric inter-brain states during real-time social interaction.
The Brain Computes Dynamic Facial Movements for Emotion Categorization Using a Third Pathway
Authors: Yan Yuening , Zhan Jiayu , Garrod Oliver G. , Chen Chaona , Ince Robin A.A. , Jack Rachael E. , Schyns Philippe G.
Published: May 2024

Recent theories suggest a new brain pathway dedicated to processing social movement is involved in understanding emotions from biological motion, beyond the well-known ventral and dorsal pathways. However, how this social pathway functions as a network that computes dynamic biological motion signals for perceptual behavior is unchartered. Here, we used a generative model of important facial movements that participants (N = 10) categorized as “happy,” “surprise,” “fear,” “anger,” “disgust,” “sad” while we recorded their MEG brain responses. Using new representational interaction measures (between facial features, MEGtsource, and behavioral responses), we reveal per participant a functional social pathway extending from occipital cortex to superior temporal gyrus. Its MEG sources selectively represent, communicate and compose facial movements to disambiguate emotion categorization behavior, while occipital cortex swiftly filters out task-irrelevant identity-defining face shape features. Our findings revealhowsocial pathway selectively computes complex dynamic social signals to categorize emotions in individual participants.
Circulating mitochondrial bioenergetics as fingerprint of the hepatic one: how to monitor genetic MASLD
Authors: Paolini Erika , Longo Miriam , Meroni Marica , Podini Paola , Maggioni Marco , Quattrini Angelo , Fracanzani Anna Ludovica , Dongiovanni Paola
Published: May 2024

Background & Aims

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) pathogenesis is shaped by genetics and mitochondrial dysfunction. Recently, we demonstrated that the co-presence of patatin- like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2) and membrane bound o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms predisposes to disease progression in MASLD patients and that their deletion contributes to mitochondrial (mt) maladaptation in anin- vitromodel. In this work we deepened the impact of genes silencing on mitochondrial dynamism. Then we restored TM6SF2 and/or MBOAT7 wild-type (WT) proteins in thein-vitromodel to evaluate the rescue of organelles’ morphology/function. Finally, we compared hepatic and peripheral mt-bioenrgetics in MASLD patients carrying PNPLA3, MBOAT7 and/or TM6SF2 loss-of-function variations.

Methods

WT proteins were overexpressed through lentiviral transfection, mt-respiration was assessed by Seahorse.

Results

The restore of MBOAT7 and/or TM6SF2 wild-type proteins resulted in the assembly ofspaghetti- shaped mitochondria with improved OXPHOS capacity. Mitochondrial activity was assessed in liver biopsies and peripheral blood mononuclear cells of biopsy-proven (n=44;Discovery cohort) and noninvasively assessed (n=45;Fibroscan-MASLD cohort) MASLD patients stratified according to the presence of the 3 at-risk variants alongside in unrelated liver disease patients (n=45;Unrelated liver disease cohort). In the Discovery cohort, the hepatic bioenergetic profile fully reflecting the circulating one, was impaired in carriers of the risk variants, more so when in combination. We confirmed the lowered serum respirometry in the Fibroscan-MASLD cohort. Finally, the circulating respiration did not change in unrelated liver disease patients, thus demonstrating that it was specifically impaired in MASLD.

Conclusions

These results boosted the relevance of mitochondrial circulating respirometry to outline genetically-based MASLD.
Estimating effective population size trajectories from time-series Identity-by-Descent (IBD) segments
Authors: Huang Yilei , Carmi Shai , Ringbauer Harald
Published: May 2024

Long, identical haplotypes shared between pairs of individuals, known as identity-by-descent (IBD) segments, result from recently shared co-ancestry. Various methods have been developed to utilize IBD sharing for demographic inference in contemporary DNA data. Recent methodological advances have enabled the screening for IBD in ancient DNA (aDNA) data, making demographic inference based on IBD also possible for aDNA. However, aDNA data typically have varying sampling times, but most demographic inference methods designed for modern data assume that sampling is contemporaneous. Here, we present TTNE (Time-Transect Ne), which models time-transect sampling to improve inference of recent effective population size trajectories. Using simulations, we show that utilizing IBD sharing in time series has increased resolution to infer recent fluctuations in effective population sizes compared to methods that only use contemporaneous samples. Finally, we developed an approach for estimating and modeling IBD detection errors in empirical IBD analysis. To showcase the practical utility of TTNE, we applied it to two time transects of ancient genomes, individuals associated with the Corded Ware Culture (CWC) and Medieval England. In both cases, we found evidence of a growing population, a signal consistent with archaeological records.
Proteomic and Lipidomic Plasma Evaluations Reveal Biomarkers for Domoic Acid Toxicosis in California Sea Lions
Authors: Solosky Amie M. , Claudio Iliana M. , Chappel Jessie R. , Kirkwood-Donelson Kaylie I. , Janech Michael G. , Bland Alison M. , Gulland Frances M.D. , Neely Benjamin A. , Baker Erin S.
Published: May 2024

Domoic acid is a neurotoxin secreted by the marine diatom genus,Pseudo-nitzschia, during toxic algal bloom events. California sea lions (Zalophus californianus) are exposed to domoic acid through ingestion of fish that feed on toxic diatoms, resulting in a domoic acid toxicosis (DAT), which can vary from mild to fatal. Sea lions with mild disease can be treated if toxicosis is detected early after exposure, therefore, rapid diagnosis of DAT is essential but also challenging. In this work, we performed multi-omics analyses, specifically proteomic and lipidomic, on blood samples from 31 California sea lions. Fourteen sea lions were diagnosed with DAT based on clinical signs and postmortem histological examination of brain tissue, and 17 had no evidence of DAT. Proteomic analyses revealed three apolipoproteins with statistically significant lower abundance in the DAT individuals compared to the non-DAT individuals. These proteins are known to transport lipids in the blood. Lipidomic analyses highlighted 29 lipid levels that were statistically different in the DAT versus non-DAT comparison, 28 of which were downregulated while only one was upregulated. Furthermore, of the 28 downregulated lipids, 15 were triglycerides, illustrating their connection with the perturbed apolipoproteins and showing their potential for use in rapid DAT diagnoses.

SYNOPSIS

Multi-omics evaluations reveal blood apolipoproteins and triglycerides are altered in domoic acid toxicosis in California sea lions.

GRAPHIC ABSTRACT
Flp-recombinase mouse line for genetic manipulation of ipRGCs
Authors: Contreras E , Liang C , Mahoney HL , Javier JL , Luce ML , Labastida Medina K , Bozza T , Schmidt TM
Published: May 2024

Light has myriad impacts on behavior, health, and physiology. These signals originate in the retina and are relayed to the brain by more than 40 types of retinal ganglion cells (RGCs). Despite a growing appreciation for the diversity of RGCs, how these diverse channels of light information are ultimately integrated by the ∼50 retinorecipient brain targets to drive these light-evoked effects is a major open question. This gap in understanding primarily stems from a lack of genetic tools that specifically label, manipulate, or ablate specific RGC types. Here, we report the generation and characterization of a new mouse line (Opn4FlpO), in which FlpO is expressed from theOpn4locus, to manipulate the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells. We find that the Opn4FlpOline, when crossed to multiple reporters, drives expression that is confined to ipRGCs and primarily labels the M1-M3 subtypes. Labeled cells in this mouse line show the expected intrinsic, melanopsin-based light response and morphological features consistent with the M1-M3 subtypes. In alignment with the morphological and physiological findings, we see strong innervation of non-image forming brain targets by ipRGC axons, and weaker innervation of image forming targets in Opn4FlpOmice labeled using AAV-based and FlpO-reporter lines. Consistent with the FlpO insertion disrupting the endogenous Opn4 transcript, we find that Opn4FlpO/FlpOmice show deficits in the pupillary light reflex, demonstrating their utility for behavioral research in future experiments. Overall, the Opn4FlpOmouse line drives Flp-recombinase expression that is confined to ipRGCs and most effectively drives recombination in M1-M3 ipRGCs. This mouse line will be of broad use to those interested in manipulating ipRGCs through a Flp-based recombinase for intersectional studies or in combination with other, non-Opn4 Cre driver lines.
Multivalent modulation of endothelial LRP1 induces fast neurovascular amyloid-β clearance and cognitive function improvement in Alzheimer’s disease models
Authors: Chen Junyang , Xiang Pan , Duro-Castano Aroa , Cai Huawei , Guo Bin , Liu Xiqin , Yu Yifan , Lui Su , Luo Kui , Ke Bowen , Ruiz Perez Lorena , Wei Xiawei , Gong Qiyong , Tian Xiaohe , Battaglia Giuseppe
Published: May 2024

The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer’s disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques. We propose an AD therapeutic strategy targeting the BBB low-density lipoprotein receptor-related protein 1 (LRP1). We show that a multivalent scaffold with LRP1-specific peptide modulates the Aβ transport at the BBB. We show via detailed experimentation on AD model mice that this intervention markedly reduces Aβ deposits and prevents cognitive decline. This study marks a new approach to drug design, combining multivalent targeting with the regulation of membrane trafficking through advanced molecular engineering. Crucially, the therapeutic effects emerge from the multivalent nature of our proposed system. Furthermore, our findings underscore the paramount significance of the BBB in AD pathogenesis, particularly emphasizing the critical role of LRP1-mediated Aβ clearance in mitigating disease progression.
Altered markers of brain metabolism and excitability are associated with executive functioning in young children exposed to alcoholin utero
Authors: Perdue Meaghan V. , Ghasoub Mohammad , Long Madison , DeMayo Marilena M. , Bell Tiffany K. , McMorris Carly A. , Dewey Deborah , Gibbard W. Ben , Tortorelli Christina , Harris Ashley D. , Lebel Catherine
Published: May 2024

Prenatal alcohol exposure (PAE) is the leading known cause of birth defects and cognitive disabilities, with impacts on brain development and executive functioning. Abnormalities in structural and functional brain features are well-documented in children with PAE, but the effects of PAE on brain metabolism in children have received less attention. Levels of brain metabolites can be measured non-invasively using magnetic resonance spectroscopy (MRS). Here, we present the first study of PAE-related brain metabolite differences in early childhood (ages 3-8 years) and their associations with cognitive performance, including executive functioning (EF) and pre-reading skills. We measured metabolites in two cohorts of children with PAE and unexposed children using MRS in the anterior cingulate cortex (ACC; cohort 1) and left temporo-parietal cortex (LTP; cohort 2). Total choline (tCho), a marker of membrane/myelin metabolism, was elevated in both regions in children with PAE compared to unexposed children, and glutamate+glutamine (Glx), a marker of excitability, was elevated in the ACC. The PAE group exhibited more difficulties with EF, and higher tCho was associated with better EF in both PAE and unexposed groups. In addition, elevated Glx in the ACC was associated with poorer inhibitory control within the PAE group only. LTP metabolites were not significantly associated with pre-reading skills in PAE or unexposed groups. Together, these findings point to altered membrane metabolism and excitability in young children with PAE. These findings provide new insight to potential mechanisms by which PAE disrupts brain development and cognitive functioning in early childhood.
Dynamic Overrepresentation of Accumbal Cues in Food- and Opioid-Seeking Rats after Prenatal THC Exposure
Authors: Luján Miguel Á. , Young-Morrison Reana , Aroni Sonia , Katona István , Melis Miriam , Cheer Joseph F.
Published: May 2024

The increasing prevalence of cannabis use during pregnancy has raised significant medical concerns, primarily related to the presence of Δ9-tetrahydrocannabinol (THC), which readily crosses the placenta and impacts fetal brain development. Previous research has identified midbrain dopaminergic neuronal alterations related to maternal THC consumption. However, the enduring consequences that prenatal cannabis exposure (PCE) has on striatum-based processing during voluntary reward pursuit have not been specifically determined. Here, we characterize PCE rats during food (palatable pellets) or opioid (remifentanyl)-maintained reward seeking. We find that the supra motivational phenotype of PCE rats is independent of value-based processing and is instead related to augmented reinforcing efficiency of opioid rewards. Our findings reveal that in utero THC exposure leads to increased cue-evoked dopamine release responses and an overrepresentation of cue-aligned, effort-driven striatal patterns of encoding. Recapitulating findings in humans, drug-related neurobiological adaptations of PCE were more pronounced in males, who similarly showed increased vulnerability for relapse. Collectively, these findings indicate that prenatal THC exposure in male rats engenders a pronounced neurodevelopmental susceptibility to addiction-like disorders later in life.
Consensus Guideline for the Management of Colorectal Cancer with Peritoneal Metastases
Authors:   PSM Writing Group,   PSM Consortium Group, Turaga Kiran K.
Published: May 2024

Background

The peritoneum is a common site of metastases from colorectal cancer (CRC), yet controversy exists regarding optimal treatment strategies. These guidelines describe the results of a national consensus addressing the management of CRC with peritoneal metastases (CRC-PM).

Methods

An update of the 2018 Chicago Consensus Guidelines was conducted using a modified Delphi technique. Two rounds of voting were performed to assess agreement levels on two clinical management pathways regarding synchronous and metachronous CRC-PM. Supporting evidence was evaluated via rapid literature reviews.

Results

The overall level of evidence was low in existing literature. Of 145 participants in the first round, 136 (96.8%) responded in the second round. Over 90% consensus was achieved in most pathway blocks. For both pathways, early referral to a peritoneal surface malignancy (PSM) center should be made for patients with CRC-PM. For the synchronous pathway, upfront cytoreductive surgery was de-emphasized in favor of systemic therapy. For the metachronous pathway, risk stratification via clinical and pathologic features was revised. For both pathways, surveillance strategies were added, including only a weak recommendation for circulating tumor DNA (ctDNA) testing given limited evidence of its utility in detecting and monitoring PM.

Conclusion

The consensus-driven clinical pathways provide valuable guidance for the management of CRC-PM. There remains a need for high-quality evidence and prospective multicenter trials in this domain.

SYNOPSIS

We developed two consensus-driven clinical pathways for the management of colorectal cancer with peritoneal metastases (CRC-PM), using a modified Delphi approach. Rapid reviews evaluating the optimal systemic therapy and the role of plasma-based liquid-biopsy for CRC-PM were conducted.
A QUANTITATIVE ASSESSMENT OF VISUAL FUNCTION FOR YOUNG AND MEDICALLY COMPLEX CHILDREN WITH CEREBRAL VISUAL IMPAIRMENT: DEVELOPMENT AND INTER-RATER RELIABILITY
Authors: Weden Kathleen M. , Barstow Elizabeth A. , Oster Robert A. , DeCarlo Dawn K.
Published: May 2024

Background

Cerebral Visual Impairment (CVI) is the most common cause of low vision in children. Standardized, quantifiable measures of visual function are needed.

Objective

This study developed and evaluated a new method for quantifying visual function in young and medically complex children with CVI using remote videoconferencing.

Methods

Children diagnosed with CVI who had been unable to complete clinic-based recognition acuity tests were recruited from a low-vision rehabilitation clinic(n=22)Video-based Visual Function Assessment (VFA) was implemented using videoconference technology. Three low-vision rehabilitation clinicians independently scored recordings of each child’s VFA. Interclass correlations for inter-rater reliability was analyzed using intraclass correlations (ICC). Correlations were estimated between the video-based VFA scores and both clinically obtained acuity measures and children’s cognitive age equivalence.

Results

Inter-rater reliability was analyzed using intraclass correlations (ICC). Correlations were estimated between the VFA scores, clinically obtained acuity measures, and cognitive age equivalence. ICCs showed good agreement (ICC and 95% CI 0.835 (0.701-0.916)) on VFA scores across raters and agreement was comparable to that from previous, similar studies. VFA scores strongly correlated (r= -0.706, p=0.002) with clinically obtained acuity measures. VFA scores and the cognitive age equivalence were moderately correlated (r= 0.518, p=0.005), with notable variation in VFA scores for participants below a ten month cognitive age-equivalence. The variability in VFA scores among children with lowest cognitive age-equivalence may have been an artifact of the study’s scoring method, or may represent existent variability in visual function for children with the lowest cognitive age-equivalence.

Conclusions

Our new VFA is a reliable, quantitative measure of visual function for young and medically complex children with CVI. Future study of the VFA intrarater reliability and validity is warranted.