bluuebunny/crossref_metadata_2025 huggingface dataset:
Inertial interface cavitation creates complex, flow-like structures within a soft solid
Authors: Yang Jin , McGhee Alexander , Tong Zixiang , Radtke Griffin , Rodriguez Mauro , Franck Christian
Published: February 2025

Inertial interface cavitation is a well-appreciated phenomenon in many natural, biological, and physical processes. The existence of impedance changes across an interface can generate complex fluid motion within a fluid but whether such motion persists, or is similar, within the adjacent solid has yet to be determined. Here, by leveraging recent technological advances in quantitative full-field imaging, deformation/motion characterization, and laser-based cavitation, we document the complex deformation fields that arise in a model soft solid of gelatin during interfacial cavitation. Specifically, we identify stagnation points, vortex pairs, and vortex ring-like structures as a function of the cavitation bubble standoff distance within the solid, for which we identify four distinct regimes. While two of the regimes have been previously studied, we show that the additional two regimes close to the interface generate most of the complex, fluid-like deformations within the gel. Finally, we quantify the associated material stresses and residual, permanent strains that can occur during such events providing both length and time scale estimates of the destructive power of cavitation.

Significance Statement

The study of interfacial cavitation dynamics has historically focused on resolving cavitation bubble morphology and surface deformations due to an inability to measure subsurface behavior. However, understanding the intricate dynamics of cavitation at these interfaces and below holds significant implications for engineering, medical, and life science applications. Leveraging recent technological advances, we provide the first, full-field sub-surface measurements during interfacial cavitation revealing complex, flow-like structures such as dynamically-evolving stagnation points and vortex pairs. Our results also provide insight into the unusual stresses and strains generated by the violent collapse of interfacial cavitation bubbles within the soft solid. These measurements provide an important first step in understanding how certain species in nature harness this power whereas others aim to mitigate it.
Targeted knockdown ofin vitrocandidates does not alterWolbachiadensityin vivo
Authors: Dainty Kimberley R. , Duyvestyn Johanna M. , Flores Heather A.
Published: February 2025

The bacterial endosymbiontWolbachiahas emerged as an effective biocontrol method to reduce arbovirus transmission. Transinfection ofwMelWolbachiafromDrosophila melanogastertoAedes aegyptiresults in the transfer of importantWolbachia-induced phenotypes including the reproductive modification, cytoplasmic incompatibility, and inhibition of viruses including dengue and chikungunya. However, the mechanisms underlying these critical traits as well otherWolbachia-host interactions are still not fully understood. Recently anin vitrogenome wide RNAi screen was performed onwMel-infected Drosophila S2 cells and identified large cohorts of host genes that alterwMel density when targeted. If these findings can be replicatedin vivo, this would provide a powerful tool for modulatingwMel density both systemically and in a tissue-specific manner allowing for interrogation ofwMel-host interactions. Here, we used the GAL4/UAS system to express RNAi molecules targeting host gene candidates previously identified to dysregulatewMel densityin vitro. We found systemic knockdown of two candidateD. melanogastergenes does not lead towMel density dysregulation. To explore the lack of consistency between our study and previous work, we also examined native tissue-specific density ofwMel inD. melanogaster. We show density is varied between tissues and find that individual tissue densities are not reliable linear predictors of other tissue densities. Our results demonstrate the complexities of implementingin vitrofindings in systemic applications.
Neural-physics adaptive reconstruction reveals 3D subcellular nanostructures over a large depth of field
Authors: Fu Shuang , Shi Wei , Fei Yue , Wang Ruixiong , Zhang Tianlun , Li Yiming
Published: February 2025

Achieving large depth-of-field super-resolution imaging deep inside samples is often hindered by unknown aberrations and overlapping molecular signals in 3D single-molecule localization microscopy. Here, we present LUNAR, a blind localization method that simultaneously resolves overlapping molecular signals and corrects for aberrations using a neural-physics model. Through self-supervised learning on single-molecule data without requiring prior knowledge or accurate calibration, LUNAR synergistically optimizes a physical model with a neural network to estimate key physical parameters (e.g., 3D positions, photons, aberrations) of molecules. Its hybrid Transformer network effectively handles PSFs of varying sizes, achieving theoretically maximum localization precision of consecutive blinking events. Extensive simulations and experiments demonstrate that LUNAR consistently outperforms current state-of-the-art methods, reducing localization error by up to sixfold in the presence of unknown aberrations and molecular overlaps, enabling high-fidelity whole-cell reconstruction of mitochondria, nucleus, and neuronal cytoskeleton at great depths.
Deciphering the Genetic Architecture of Parkinson’s Disease in India
Authors: Kishore Asha , Ashok Kumar Sreelatha Ashwin , Tenghe Amabel M. M. , Borgohain Rupam , Puthanveedu Divya Kalikavil , Rajan Roopa , Urulangodi Madhusoodanan , Gonzalez-Ricardo Luis-Giraldo , Pal Pramod Kumar , Kandadai Rukmini Mridula , Khodaee Saeideh , Yadav Ravi , Mehta Sahil , Kumar Hrishikesh , Kumar Niraj , Kukkle Prashanth Lingappa , Desai Soaham Dilip , Shetty Kuldeep , Wadia Pettarusp , Aggarwal Annu , Agarwal Pankaj , Abbas Mirza Masoom , Wali Gurusideshwar Mahadevappa , Krishnan Syam , Radhakrishnan Divya Madathiparambil , Kamble Nitish , Srivastava Achal Kumar , Lal Vivek , Ferreira Teresa Maria Costa , Chacko Manas , Raghavan Cibin Thoppil , Sarma Gangadhara , Solle Justin , Fiske Brian , Thalakkatttu Amiya , Garg Divyani , Krüger Jens , Lichtner Peter , Vitale Dan , Nalls Mike , Blauwendraat Cornelis , Singleton Andy , Debnath Monojit , Sarkar Swagata , Ansari Sabbir , Adukia Sachin , Vidyadharan Pravi , Kanthimathi R , Santhi CKV , Syed Tazeem Fathima , Mohareer Sindhuja ,   Global Parkinson’s Genetics program (GP2),   Lux-GIANT consortium, Sharma Manu
Published: February 2025

The genomic landscape of the Indian population, particularly for age-related disorders like Parkinson’s disease (PD) remains underrepresented in global research. Genetic variability in PD has been studied predominantly in European populations, offering limited insights into its role within the Indian population. To address this gap, we conducted the first pan-India genomic survey of PD involving 4,806 cases and 6,364 controls, complemented by a meta-analysis integrating summary statistics from a multi-ancestry PD meta-analysis (N=611,485). We further leveraged RNA-sequencing data from lymphoblastoid cell lines of 731 individuals from the 1000 Genomes project to evaluate the expression of key loci across global populations. Our findings reveal a higher genetic burden of PD in the Indian population compared to Europeans, accounting for ∼30% of the previously unexplained heritability. Thirteen genome-wide significant loci were identified, including two novel loci, with an additional three loci uncovered through meta-analysis. Polygenic risk score analysis showed moderate transferability from European populations. Our results highlight the importance of genetic loci in immune function, lipid metabolism andSNCAaggregation in PD pathogenesis, with gene expression variability emphasizing population-specific differences. We also established South Asia’s largest PD biobank, providing a foundation for patient-centric approaches to PD research and treatment in India.
Acute plasma VEGF-A levels are associated with raised intracranial pressure and chronic lesion volume after Traumatic Brain Injury
Authors: Li Lucia M. , Kodosaki Eleftheria , Heslegrave Amanda , Soreq Eyal , Nattino Giovanni , Garbero Elena , Zimmerman Karl A. , Graham Neil S.N. , Moro Federico , Novelli Deborah , Gradisek Primoz , Magnoni Sandra , Zetterberg Henrik , Bertolini Guido , Sharp David J
Published: February 2025

Background and Objectives

Severe Traumatic Brain Injury (TBI) is associated with secondary injury and poor outcomes, but the underlying mechanisms are poorly understood. Vascular mechanisms may be important. We aimed to characterise how blood vascular endothelial growth factor A (VEGF-A) levels are affected by TBI, and its associations with secondary injury and functional outcome.

Methods

We retrospectively analysed data from two multi-centre, international, prospective observational studies (CREACTIVE and BIO-AX-TBI) with follow-up of up to 1 year. These cohorts comprised adults with moderate-severe TBI (Mayo classification), recruited on admission to hospital (BIO-AX-TBI) and the intensive care unit (ICU) (CREACTIVE). Controls included non-TBI trauma (NTT) and uninjured adults. Plasma VEGF-A levels and TBI biomarkers (Neurofilament light [NFL], glial fibrillary acidic protein [GFAP], total Tau, UCH-L1, S100B) were measured on ICU admission and ∼5 days later (CREACTIVE), or at 5 timepoints from admission to 12 months post-TBI (BIO-AX-TBI), and compared to NTT and control groups. In BIO-AX-TBI, MRI assessment was performed at subacute and chronic timepoints. Functional outcomes (Glasgow Outcome Scale-Extended) were measured at 6 and 12 months. Plasma VEGF-A was measured using the OLINK® Target 96 Inflammatory platform, which reports in arbitrary standardised units (NPX), and TBI biomarkers were measured using Simoa® or Millipore platforms.

Results

Data was available from 195 TBI (21% female, mean age 45.30years), 24 NTT (8%, 43.98) and 89 CON (44%, 42.39) in BIO-AX-TBI, and 1146 TBI (25%, 56.29) in CREACTIVE. Plasma VEGF-A was elevated acutely after both TBI (estimated mean difference=0.45NPX, SE=0.09, p<0.001) and NTT (estimated mean difference=0.74NPX, SE=0.16, p<0.001), but remained raised after the initial timepoint only in TBI patients, peaking at day 16. Higher acute VEGF-A was associated with increased odds of refractory raised intracranial pressure (r-rICP) (maximum Odds Ratio for r-rICP=1.69, p=0.031), higher lesion volume (estimated increased lesion volume=20.14ml, SE=8.20ml, p=0.02), and worse functional outcomes (maximum Odds Ratio for worse outcome category=2.51, p<0.001).

Discussion

There is a sustained rise in plasma VEGF-A after TBI, which is associated with r-rICP and chronic injury markers, suggesting vascular pathophysiology is important after TBI. Further research is needed to explore mechanisms.
Longitudinal Validation of a Deep Learning Index for Aortic Stenosis Progression
Authors: Park Jiesuck , Kim Jiyeon , Yoon Yeonyee E. , Jeon Jaeik , Lee Seung-Ah , Choi Hong-Mi , Hwang In-Chang , Cho Goo-Yeong , Chang Hyuk-Jae , Park Jae-Hyeong
Published: February 2025

Aims

Aortic stenosis (AS) is a progressive disease requiring timely monitoring and intervention. Transthoracic echocardiography (TTE) remains the gold standard for AS assessment, while deep learning (DL)-based approaches have emerged as promising tools for enhanced evaluation. This study examined the longitudinal changes in a previously developed DL-derived index for AS continuum (DLi-ASc) and its association with AS progression. Additionally, we evaluated its utility in identifying high-risk patients prone to progression to severe AS.

Methods and Results

A total of 2,563 patients with follow-up TTE (8,053 TTEs) from two tertiary hospitals were included. DLi-ASc, generated from limited TTE views, was tracked over time. The longitudinal trends in AS severity showed a progressive shift toward advanced stages, with a corresponding increase in DLi-ASc (p for trend <0.001). DLi-ASc demonstrated positive correlations with conventional AS parameters, including AV maximal velocity (Vmax) (Pearson correlation coefficients [PCC] = 0.68) and mean pressure gradient (mPG) (PCC = 0.69). Higher baseline DLi-ASc was associated with a faster AS progression rate (p for trend <0.001). Furthermore, baseline DLi-ASc was an independent predictor of progression to severe AS, with area under the curve (AUC) values of 0.92, 0.88, and 0.87 within 1-, 2-, and 3-year follow-up windows, respectively. A DLi-ASc threshold of 50 was identified as a threshold for rapid progression to severe AS.

Conclusion

DLi-ASc increased in parallel with AS progression and independently predicted severe AS progression. These findings support its role as a non-invasive imaging-based digital marker for longitudinal AS monitoring and risk stratification.
Cefazolin versus Antistaphylococcal Penicillins for the Treatment of Methicillin-SusceptibleStaphylococcus aureusBacteremia: A Systematic Review and Meta-Analysis
Authors: Prosty Connor , Noutsios Dean , Lee Todd C. , Daneman Nick , Davis Joshua S. , Jager Nynke G. L. , Ghanem-Zoubi Nesrin , Goodman Anna L. , Kaasch Achim J. , Kouijzer Ilse , McMullan Brendan J. , McDonald Emily G. , Tong Steven Y. C. , Ong Sean W. X. ,   the Staphylococcus aureus Network Adaptive Platform MSSA/PSSA domain specific working group
Published: February 2025

Background

There is debate on whether cefazolin or antistaphylococcal penicillins should be the first-line treatment for methicillin-susceptibleStaphylococcus aureus(MSSA) bacteremia. Ongoing trials are investigating whether cefazolin is non-inferior to (flu)cloxacillin, but it remains uncertain whether these findings would apply to other antistaphylococcal penicillins.

Objective

We conducted a systematic review and meta-analysis comparing cefazolin to each of the individual antistaphylococcal penicillins for MSSA bacteremia.

Methods

Data Sources

We updated a 2019 systematic review but specifically focused on evaluating outcomes by individual antistaphylococcal penicillins.

Study Eligibility Criteria

Comparative observational studies.

Participants

Patients with MSSA bacteremia.

Interventions

Cefazolin versus the antistaphylococcal penicillins.

Assessment of Risk of Bias

The risk of bias in non-randomized studies of interventions tool.

Methods of Data Synthesis

The primary outcome was 30-day all-cause mortality, and we assessed for non-inferiority of cefazolin using a prespecified non-inferiority margin of a pooled odds ratio (OR) <1.2. Secondary outcomes were 90-day mortality, treatment-related adverse events (TRAEs), discontinuation due to toxicity, and nephrotoxicity.

Results

No randomized data have been published. 30 observational studies at moderate or high risk of bias were included, which comprised 3869 patients who received cefazolin and 11644 patients who received antistaphylococcal penicillins (flucloxacillin=6721, unspecified=2440, nafcillin=1305, cloxacillin=1258, and oxacillin=120). Cefazolin was associated with a reduced odds of 30-day all-cause mortality (OR=0.73, 95%CI=0.62-0.85) compared to antistaphylococcal penicillins, meeting pre-specified non-inferiority as well as superiority. This effect was consistent versus flucloxacillin (OR=0.92, 95%CI=0.73-1.16), nafcillin (OR=0.58, 95%CI=0.28-1.17), cloxacillin (OR=0.42, 95%CI=0.11-1.58), and oxacillin (OR=0.31, 95%CI=0.03-2.75). Point estimates favored cefazolin for 90-day mortality, TRAEs, nephrotoxicity, and discontinuation due to toxicity overall and in each comparison with individual antistaphylococcal penicillins, except for TRAEs versus cloxacillin.

Conclusions

In moderate to low quality observational data, cefazolin was associated with superior effectiveness and safety as compared to antistaphylococcal penicillins overall and individually.
Lipid Signature of Motile Human Sperm: Characterization of Sphingomyelin, Ceramide and Phospholipids with a Focus on Very Long Polyunsaturated Fatty Acid
Authors: Oresti Gerardo M. , Luquez Jessica M. , Belmonte Silvia A.
Published: February 2025

Sperm membrane lipids play a crucial role in male fertility, influencing sperm motility, viability, and functional competence. This study provides a comprehensive characterization of the phospholipid and sphingolipid composition in highly motile human spermatozoa obtained through the swim-up method, a widely used technique in assisted reproductive technology (ART). Using two-dimensional thin-layer chromatography and phosphorus analysis, we identified choline glycerophospholipids (CGP, 45%), ethanolamine glycerophospholipids (EGP, 26%), and sphingomyelin (SM, 17%) as predominant phospholipids, with minor components including cardiolipin, lysophospholipids, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and neutral lipids. Gas chromatography analysis of glycerophospholipids (GPL) revealed a high long chain (C20-C22) polyunsaturated fatty acid (PUFA) content (46.3%), particularly docosahexaenoic acid (DHA, 22:6n-3), which was more abundant in CGP (46%) than EGP (26%). Sphingolipid analysis indicated that ceramide (Cer) and SM shared similar fatty acid profiles due to their metabolic relationship, with very long-chain (VLC) PUFA (≥C26) being more prevalent in SM (10%) than in Cer (6%). Additionally, argentation chromatography allowed the identification of highly unsaturated VLCPUFA species in Cer, including 28:3n-6, 28:4n-6, and 30:4n-6, which had not been previously quantified in motile human spermatozoa. Given the essential function of sphingolipid metabolism in spermatogenesis, capacitation, and acrosomal exocytosis, our findings suggest that the balance of VLCPUFA-containing SM and Cer emerges as a key factor in sperm performance and fertilization potential. This study provides novel insights into the lipid signature of human sperm and highlights the relevance of membrane lipid remodeling for male fertility and ART outcomes.
Reactive Pericytes Lead to Microvascular Dysfunction and Cortical Neurodegeneration During Experimental Autoimmune Encephalomyelitis
Authors: Yousefi Mohammadreza , Özkan Ayşe , Özmen Kaan Kutay , Uysallı Yiğit , Mamipour Mina , Akkaya Nazan , Amandi Amir-Reza Dalal , Atbaşi Abdulsamet , Heidarzadeh Morteza , Erdener Şefik Evren , Kawakami Naoto , Kiraz Alper , Özdemir Yasemin Gürsoy , Vural Atay
Published: February 2025

The mechanisms underlying neurodegeneration in multiple sclerosis remain incompletely understood. In this study, we aimed to investigate the role of vascular dysfunction in cortical neurodegeneration using a chronic cranial window model of experimental autoimmune encephalomyelitis in mice. After the induction of experimental autoimmune encephalomyelitis with myelin oligodendrocyte glycoprotein peptides in C57BL/6J mice, we assessed cerebrovascular reactivity though a chronic cranial window using laser speckle contrast imaging and intrinsic optical signal imaging in awake animals. We observed a significant reduction in cortical cerebrovascular reactivity during peak inflammation in the EAE group, as detected by laser speckle contrast imaging after 5% hypercapnia (p=0.04) and optical signal imaging after whisker stimulation (p=0.008). Histological analysis revealed a diffuse increase in CD13+ pericyte coverage (p=0.001), accompanied by focal IgG deposition within the microvascular lumen (p=0.04) and increased amount of CD45+ leukocytes stalled in microvessels (p=0.03) in the cortex of experimental autoimmune encephalomyelitis mice. Microglial activation was also present in the cortex of experimental autoimmune encephalomyelitis mice (p=0.04) and was particularly evident around microvessels with IgG deposition. Subpial and intracortical foci exhibiting loss of NeuN reactivity (p=0.03) and axonal loss (p=0.007) were detected in experimental autoimmune encephalomyelitis, but not in control mice. Altogether, these results demonstrate that microvascular function and neurovascular unit elements are globally affected in the cortex during autoimmune neuroinflammation and is related to neurodegeneration.
Genome-wide cline analysis identifies new locus contributing to a barrier to gene flow across anAntirrhinumhybrid zone
Authors: Field David L , Stankowski Sean , Reiter Taylor , Polechova Jitka , Bradley Desmond , Richardson Daniel , Pal Arka , Shipilina Daria , Boell Louis , Pickup Melinda , Xue Yongbiao , Coen Enrico , Barton Nicholas
Published: February 2025

Identification of the genomic regions that contribute to reproductive isolation and how they interact is a major goal of evolutionary genetics. Much effort has focused on locating candidate genes and potential barrier loci by scanning genomes for regions of excess differentiation (FST). An alternative, and perhaps more robust approach, would be to scan for genomic regions exhibiting steep clines in allele frequency across a hybrid zone. Here we develop this approach and apply it to genomic data from across a hybrid zone between varieties ofAntirrhinum majussubspeciesmajuswith different flower colour patterns (A. m. mvar.pseudomajusandA. m. mvar.striatum). Most steep clines are clustered in seven genomic regions, only four of which were present fromFSTscans between all pair-wise comparisons. Six of these regions carry previously identified loci that influence flower colour in the hybrid zone. The seventh region harbours a novel locus, RUBIA, modifying magenta intensity. Clines atRUBIAapproached towards fixation on magenta side of the hybrid zone, whilst remaining polymorphic on the yellow side. This polymorphism on the yellow side may reflect a smaller phenotypic effect ofRUBIAin yellow compared to magenta genetic backgrounds. Our findings illustrate how whole-genome cline scans in hybrid zones can robustly detect genomic regions contributing to phenotypic differences and highlight how different reproductive barrier loci interact across the genome.
Boosting reliability when inferring interactions from time series data in gene regulatory networks
Authors: Greco Mattia , Tersenghi Federico Ricci , Martin Olivier C.
Published: February 2025

In the context of the dynGENIE3 [13] approach for inferring regulatory network interactions from time-series data, we show that it is possible to modify that algorithm to significantly enhance its prediction reliability. To quantify the level of reliability, we used ground-zero truths based on simulated datasets generated by the GeneNetWeaver [22] tool. Our work introduces novel methods leveraging time-lagged correlations and estimators of mRNA decay rates, leading to significantly improved driver-target inference. Additionally, a temperature-based rescaling of priors was developed to further enhance prediction reliability. Results demonstrate substantial improvements in performance with a particularly notable increase in AUPRC scores. These advances underscore the possible gains resulting from incorporating priors into gene regulatory network inference.
A temporary challenge by tumor cells can lead to a permanent partial-impairment of memory CD8 T cell function
Authors: Laubreton Daphné , Prieux Margaux , Djebali Sophia , Dubois Maxence , De Bernard Simon , Gandrillon Olivier , Arpin Christophe , Marvel Jacqueline
Published: February 2025

Memory CD8 T cells typically exhibit improved effector functions compared to their naive counterparts. However, under certain activation conditions, such as chronic viral infections or cancer, these cells may develop functional defects. In this study, we compared the functional quality of memory CD8 T cells generated following tumor rejection with those arising from an acute viral infection. We found that tumor-induced (Tum-CD8) memory cells exhibited a distinct phenotype and transcriptomic profile compared with viral-induced (Vir-CD8) memory cells. These memory cells are characterized by the expression of inhibitory receptors and displayed altered functions including reduced IFNγ and TNFα production as well as changes in integrin expression. Additionally, the protective capacity of Tum-CD8 memory cells was flawed relative to that of Vir-CD8 memory cells. Importantly, the functional defects of Tum-CD8 persisted upon viral recall. Together, these findings indicate that transient tumoral stimulation can imprint a stable partial exhaustion-like program on memory CD8 T cells.
Metabolically purified human stem cell-derived hepatocytes reveal distinct effects of Ebola and Lassa viruses
Authors: Prescott Joseph B. , Liu Kevin J. , Lander Angelika , Pek Nicole Min Qian , Jha Sawan Kumar , Bokelmann Marcel , Begur Manali , Koh Pang Wei , Yang Henry , Lim Bing , Red-Horse Kristy , Weissman Irving L. , Loh Kyle M. , Ang Lay Teng
Published: February 2025

Ebola and Lassa viruses require biosafety-level-4 (BSL4) containment, infect the liver, and cause deadly hemorrhagic fevers. The cellular effects of these viruses, and whether different families of hemorrhagic-fever viruses elicit similar effects, remain fundamental questions in BSL4 virology. Here, we introduce a new metabolic selection approach to create nearly-pure hepatocytes from human pluripotent stem cells, killing non-liver cells by withholding essential nutrients. Unexpectedly, Ebola and Lassa exerted starkly different effects on human hepatocytes. Ebola infection activated the integrated stress response (ISR) and WNT pathways in hepatocytes in vitro and killed them, whereas Lassa did not. Within non-human primates, Ebola likewise infected hepatocytes and activated ISR signalingin vivo. In summary, we present a single-cell transcriptional and chromatin accessibility roadmap of human hepatocyte differentiation, purification, and viral infection.
Development of an Australian Clinical Practice Guideline on methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy for Post-traumatic Stress Disorder
Authors: Jing Yong Alene Sze , Brennan Sue E , Bratuskins Suzie , Freeburn Aimée , Bedi Gillinder , Burke Rimona , Haines Terry , Hollick Mary , Jones Kimberley Ann , Lawrence Andrew J , Lee Yong Yi , McFarlane Alexander C , Parker Stephen , Procter Nicholas , Spicer Liam , Somogyi Andrew A. , Stafrace Simon , Watts Stacey , Walton Clare , Wilson Kay , Bell J Simon
Published: February 2025

Introduction

Despite recent clinical and research interest, medical use of psychedelics has not been legalised in most jurisdictions. The Australian Therapeutic Goods Administration rescheduled methylenedioxymethamphetamine (MDMA) in July 2023 to permit authorised prescribing of MDMA for Post-traumatic Stress Disorder (PTSD) outside of the clinical trial setting.

Objective

This manuscript describes the development of the Australian Clinical Practice Guideline on MDMA-assisted psychotherapy (MDMA-AP) for PTSD.

Methods

The Guideline will be developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) process. The Guideline will consider the benefits and harms of MDMA-AP compared to other treatments in people with PTSD. High quality systematic reviews identified via an overview of systematic reviews will be used as index and supplementary reviews. Using the GRADE Evidence-to-Decision framework, the multidisciplinary Guideline Development Group (GDG) will consider treatment benefits and harms, certainty of evidence, patient preferences and values, resources, equity, acceptability and feasibility. The GDG will be supported by a Stakeholder Group, Expert Group, Conflict of Interest Oversight Committee, and Evidence Review Team. The Guideline will be developed using an integrated knowledge translation approach, emphasising the co-production of knowledge through active participation and shared decision-making with end-users.

Conclusion

The Guideline will be published on the digital platform MAGICapp and disseminated in peer-reviewed publications, professional conferences and via specific stakeholder groups. A Companion Guide will be developed for people living with PTSD and their carers, family members, and supports.
STILLBIRTHS: PREVALENCE, RISKS AND CLINICAL INTERVENTIONS IMPACT AMONG WOMEN IN KWAHU GOVERNMENT HOSPITAL
Authors: Abdul-Salaam Gaddafi , Owusu-Adjei Michael , Ansong Kwakye , Opong Joseph Manasseh , Osei Nana , Seth Ampadu
Published: February 2025

Background

It is the expectation and joy of every expectant mother and her immediate family to welcome into their fold healthy newborn babies after each gestational period. Unfortunately, in most instances this expectation is marred by complications which ocassionally result in the death of the unborn/newborn child known as stillbirth. This anti-climax leads to unexpected periods of sadness for both mother and her immediate family members. The growing incidence of stillbirths is acknowledged worldwide and said to be associated with many factors both maternal and child health conditions. However, the key question is how many of these maternal and child conditions could have been anticipated and prevented. Addressing this challenge will require a review of specific instutional policy frameworks that deals with the incidence of stillbirths on a case by case basis. In this retrospective study, record of stillbirths over a 5-year period is examined to determine impact of clinical interventions on prevalence and risks among women within Kwahu West municipality in Ghana.

Method

A retrospective cross-sectional study to examine recorded cases of stillbirths over a 5-year period among women in Kwahu South Hospital to determine clinical intervention impact on prevalence, risks and control was undertaken. Using established clinical audit recommendations, this study examines the effectiveness of recommendations and its impact. Socio-demographic features such as age, educational level, gestational maturity, medical conditions of mother and child, delivery method, recorded stillbirth types, fetal sex and patient’s geographical location. All statistical analysis was performed using R programming tool.

Results

Clinical interventions and its impact show a reduction in stillbirth types from 4 to 2 from 2019-2023. However, macerated and fresh stillbirths remain the most dominant stillbirth types recorded with and without medical conditions in urban communities. Sustained decreases in the number of stillbirths across all years including the elimination of early neonatal deaths and intra-uterine fetal deaths from 2021-2023 is observed.

Conclusion

Established institutional clinical audit on each stillbirth occurrence provided in-depth analysis on case-by-case basis. This practice led to the use of clinically designed interventions resulting from audit reviews on specific cases to help address similar situations. Even though a reduction in the number of recorded stillbirths from 20.83 per 1000 live births in 2019 to 10.81 per 1000 live births in 2023 is noted, a staggering 76.88% share of stillbirths among patients and fetus with no medical condition presents a serious challenge to healthcare providers. Detailed review of all cases that excludes nothing irrespective of clinical presentation can provide important insight into the incidence of high stillbirth rates among women with such presentation.
A technology-based randomized controlled trial of self-affirmation and gain-framed health messaging to reduce sedentary behavior in older adults
Authors: Ai Meishan , Thovinakere Nagashree , Walker Caitlin S. , Ordway Cora , Quinoñez Elizabeth , Melsky Emily , D’Agostino Frank , Tobias Calvin , Whitfield-Gabrieli Susan , Phillips Siobhan M. , Pindus Dominika M. , Hilman Charles , Morris Timothy P. , Kramer Arthur F. , Geddes Maiya R.
Published: February 2025

Objective

Sedentary behavior significantly increases the risk for chronic diseases and cognitive decline in aging, underscoring the need for effective interventions. Older adults exhibit a ‘positivity effect’, whereby processing of positive information is prioritized over negative information. In addition, self-affirmation was shown to reduce sedentary behavior in younger adults, but its effects in older adults remain unknown. This study tested a novel, technology-based intervention combining daily self-affirmation and gain-framed health messages to reduce sedentary behavior in older adults.

Methods

In a 6-week randomized controlled trial (NCT0431536), 48 cognitively unimpaired, sedentary older adults were randomized into two groups: The intervention group (mean age=70.0±5.4years) completed daily self-affirmation based on their highest-ranked value, followed by gain-framed health messages. The active control group (mean age=68.4±5.0years) performed self-affirmation on their lowest-ranked value, followed by loss-framed messages. This was a single-blinded clinical trial that incorporated a hybrid efficacy and implementation design. Thus, information about intervention feasibility was examined. In addition, baseline motivational traits, including reward sensitivity, were assessed as moderators of behavior change. The neural basis of self-affirmation and gain-framed health messaging was examined at baseline using a task-based, event-related fMRI paradigm across groups, after randomization at the outset of the intervention.

Results

The intervention showed high adherence (0.92±0.08) and positive ease-of-use ratings. While the intervention did not significantly reduce sedentary behavior compared to the active control condition, increased reward sensitivity predicted reduced sedentary behavior across all participants. FMRI results showed increased ventral striatal activation in the intervention group, compared to the active control group during reading of gain-framed compared to neutral messages.

Conclusions

This study supports the feasibility of technology-based sedentary beahvior reduction interventions for older adults. While self-affirmation combined with gain-framed messaging did not significantly reduce sedentary behavior, gain-framed messages engaged the reward network, and reward sensitivity predicted future reduction in sedentary behavior.
Inflammatory profile changes in response to acute endurance exercise from NULISAseq-based detection of analytes in dried blood spot specimens from half marathon participants
Authors: Chen Robert , Garcia Karl , Tam Tsz H , Beer Joanne , Jhaveri Niyati , Arikatla Mohith , Joseph Brian , Kleinman Ashley , LeRoy Erik , Mahoney Max , Mathyk Begum , Omar Sara , Peralta Natalie , Proszynski Jacqueline , Sakharkar Anurag , Schweickart Annalise , Weiss Jordan , Krumsiek Jan , Mason Christopher E
Published: February 2025

Microsampling techniques, particularly dried blood spots (DBS), offer a minimally invasive alternative to venipuncture for biomarker profiling in endurance exercise. This study leverages NULISAseq, an ultra sensitive proteomics platform, to analyze inflammatory responses in athletes participating in a half–marathon. A cohort of six individuals (three endurance athletes and three sedentary controls) underwent longitudinal blood collection at five timepoints: pre run (R–7, R–1), mid–run (R), and post run (R+1, R+7). DBS samples were processed using the NULISAseq 250 plex Inflammation Panel to quantify inflammatory biomarkers. Principal component analysis revealed a significant inflammatory shift in athletes during the run, with a 3.9 fold greater proteomic change than controls. Enrichment analysis identified key inflammatory markers, including IL–6, TNFRSF8, and VEGFD, with individualized response patterns suggesting distinct recovery profiles. Furthermore, Inflammation Age increased transiently in athletes post run, indicating acute immune activation. These findings demonstrate the feasibility of field based proteomics using DBS and highlight potential biomarkers for exercise induced stress and recovery, which underscores the potential of high throughput proteomics in optimizing training and recovery strategies for athletes.
Harnessing Greater Statistical Power: Comprehensive Evaluation of Disease Modifying Treatment Effects Across All or Multiple Post-Baseline Visits Compared to the Last Visit for Alzheimer’s Disease Clinical Trials
Authors: Wang Guoqiao , Chen Tianle , O’Gorman John , Li Yan , Li Caiyan , Guizzetti Leonard , Mangal Brian , Wang Whedy , Wu Shuang , Inman Dave , McDade Eric , Bateman Randall J.
Published: February 2025

Background

In Alzheimer’s disease (AD) clinical trials, efficacy inference is traditionally based on the last visit (e.g., 18 months). However, recent studies suggest that disease-modifying treatment effects may emerge as early as 3 months post-baseline.

Objective

To explore this further, our study aimed to assess the increased statistical power achieved by incorporating all or multiple post-baseline visits to estimate treatment effect, compared to relying solely on the last visit.

Methods

We developed explicit formulas for the base functions of the natural cubic spline model, ensuring compatibility with standard SAS procedures. Through simulations using disease progression trajectories from ClarityAD and TRAILBLAZER-ALZ2 trials, we comprehensively evaluated various models in terms of power and type I error. Additionally, we offer SAS codes that to facilitate seamless implementation of different modeling approaches.

Results

Simulations based on ClarityAD and TRAILBLAZER-ALZ2 disease trajectories demonstrated that models incorporating multiple or all post-baseline visits yield greater power than those using only the last visit, while maintaining Type I error control. Furthermore, when three post-baseline visits were included, adding more visits resulted in minimal power gains.

Conclusions

Our findings support prioritizing statistical models that incorporate multiple or all post-baseline visits for treatment efficacy inference, as they offer greater efficiency than models relying solely on the last visit.
Potential and Limitations of the MinION Nanopore array for miRNA-Enabled Early Cancer Detection
Authors: Kanavarioti Anastassia , Rafiq Aleena
Published: February 2025

The 2024 Nobel Prize in Physiology or Medicine was awarded to the pioneers who reported that microRNAs (miRNAs) regulate and direct the switch between physiological and pathological pathways via their over- or under-expression. The discovery has not yielded any health benefit primarily due to raw data with no clear distinction between healthy and diseased blood samples. MiRNAs exist at femtomolar level in biological fluids, and typically quantified using amplification-based techniques. Experimental nanopores have illustrated potential for trace analysis including amplification-free miRNA quantification. We repurposed the MinION, the only commercially available nanopore-array device, and developed unique probes and protocols to quantify microRNAs in blood and urine. Our 2024 report revealed (i) miRNA copies are proportional to the total RNA isolated from the biospecimen, and (ii) several known miRNA cancer biomarkers were 1.8-fold overexpressed in blood samples from breast, prostate and pancreatic cancer patients compared to healthy. In contrast to literature reports sample variability was undetectable after normalization to the same RNA content. Here the earlier data were confirmed, and the conclusions extended to ovarian, lung, and colorectal cancer. The potential of the ready-to-use MinION/Yenos platform for multiple cancer early detection (MCED) using blood or urine is discussed.
Immunological and clinical markers of post-acute sequelae of COVID-19: Insights from mild and severe cases six months post-infection
Authors: Mouton William , Djebali Sophia , Villard Marine , Allatif Omran , Chauvel Cécile , Benezech Sarah , Vanhems Philippe , Marvel Jacqueline , Walzer Thierry , Trouillet-Assant Sophie
Published: February 2025

Post-acute sequelae of COVID-19 (PASC) is a complex and multifaceted clinical challenge requiring to emphasize its underlying pathophysiological mechanisms.

This study assessed hundreds of virological, serological, immunological, and tissue damage biomarkers in two patient cohorts who experienced mild (n=270) or severe (n=188) COVID-19, 6 to 9 months post-initial infection, and in which 40% and 57.4% of patients, respectively, developed PASC.

Blood analysis showed that mains differences observed in humoral, viral, and biological biomarkers were associated with the initial COVID-19 severity, rather than being specifically linked to PASC.

However, patients with PASC displayed altered CD4+and CD8+memory T-cell subsets, with higher cytokine-secreting cells and increased terminally differentiated CD45RA+effector memory T cells (TEMRA). Elevated SARS-CoV-2-specific T cells responsive to nucleocapsid/membrane proteins with a TEMRA phenotype were also observed. A random forest model identified these features and initial symptom duration as top variables discriminating PASC, achieving over 80% classification accuracy.

Highlights

Nine months post-initial SARS-CoV-2 infection, over 40% of patients developed PASC

Regardless of PASC, the initial disease form influenced the main immune differences

PASC led to altered memory T-cell subsets with elevated TEMRA phenotype

PASC presence is associated with disease form, initial symptom count and duration
Momentary Brain Imaging Assessment of Neuroplasticity in Psychiatric Illness: Protocol for Systematic Review
Authors: Brown A. , Upadhyay S. , Lloyd E. C.
Published: February 2025

Background

Neuroplasticity describes the brain’s ability to adapt in response to alterations in the environment, and is fundamental to learning. Reduced neuroplasticity has been proposed to underlie several psychiatric symptoms and disorders. Advances in neuroimaging have provided new methods for examining or indexing the potential for neuroplastic changes in-vivo. The proposed systematic review and meta-analysis will synthesize research utilizing neuroimaging assessments to compare the potential for rapid brain changes between individuals with commonly-studied psychiatric disorders relative to healthy control peers (HC).

Methods

This systematic review will include studies comparing the potential for neuroplastic changes between individuals with commonly-studied psychiatric disorders (mood, anxiety, compulsive, trauma-related, eating, and schizophrenia and other psychotic disorders). Included studies will assess neuroplasticity using established or putative neuroimaging biomarkers. Longitudinal studies, studies using non-neuroimaging methods to assess neuroplastic potential, and animal studies will be excluded. PubMed, Web of Science, Embase, and PsycINFO will be searched using predefined terms. Two independent reviewers will screen titles, abstracts, and full texts using Rayyan, with conflicts resolved by a third reviewer. Data including study and participant characteristics will be extracted. Summary statistics will be combined and analyzed using random-effects meta-analyses to estimate the average difference in neuroplasticity between groups. In the event of heterogeneity, subgroup analyses and meta-regression will explore potential moderators of the between-group difference. The extent to which publication bias is likely to impact the findings of the review will be assessed using Egger’s test.

Discussion

This review will summarize alterations in neuroplasticity, as indicated by momentary neuroimaging assessments, among individuals with major psychiatric disorders. As research increasingly links psychiatric conditions to neuroplasticity, this review will offer a valuable resource for understanding how neuroplasticity can be measured in-vivo to examine mechanisms of psychiatric illness.

Systematic review registration

This review is registered in PROSPERO (registration number: CRD42025630626)
Detecting Monogenic Obesity: A Systematic Exome-Wide Workup of Over 500 Individuals
Authors: Künzel Robert , Faust Helene , Bundalian Linnaeus , Blüher Matthias , Jasaszwili Mariami , Kirstein Anna , Kobelt Albrecht , Körner Antje , Popp Denny , Wenzel Eric , Abou Jamra Rami , Lemke Johannes R. , Schöneberg Torsten , Stein Robert , Garten Antje , Le Duc Diana
Published: February 2025

Background/Objectives

Obesity poses a major public health concern. Although BMI heritability is estimated at 40–80%, genetic diagnostics remain challenging. This study aims to (i) assess the diagnostic yield of monogenic obesity in a large patient sample using exome-wide data, (ii) identify predictors to improve genetic testing criteria, and (iii) evaluate whether the identified genes are included in public obesity gene panels.

Subjects/Methods

We reviewed the genetic test results of 521 patients with obesity. 84.7% underwent whole-exome analysis, 15.3% were analyzed using a multi-thousand gene panel.

Results

Monogenic obesity was diagnosed in 5.8% of patients, while 7.1% carried a potentially obesogenic variant. Diagnostic yield was higher in children (6.3%) and patients with syndromic obesity (7.0%). Surprisingly, diagnostic yield was lower in severe obesity cases. 40% of patients with monogenic obesity carried variants in genes not included in current obesity panels.

Conclusion

Overall, 12.9% of patients had monogenic obesity or a potentially obesogenic variant. These findings suggest that genetic testing should not be limited to patients with extreme obesity. Current obesity panels miss crucial syndromic genes, demonstrating a need for more comprehensive panels and the superiority of whole exome sequencing in obesity.
A Streamlined Point-of-Care CRISPR Test for Tuberculosis Detection Directly from Sputum
Authors: Dunkley Owen R. S. , Bell Alexandra G. , Modi Nisha H. , Huang Yujia , Tseng Soleil , Reiss Robert , Daivaa Naranjargal , Davis J. Lucian , Vargas Deninson Alejandro , Banada Padmapriya , Xie Yingda L. , Myhrvold Cameron
Published: February 2025

Mycobacterium tuberculosis(Mtb) is a major threat to global health and is responsible for over one million deaths each year. To stem the tide of cases and maximize opportunities for early interventions, there is an urgent need for affordable and simple means of tuberculosis diagnosis in under-resourced areas. We sought to develop a CRISPR-based isothermal assay coupled with a compatible, straightforward sample processing technique for point-of-care use. Here, we combine Recombinase Polymerase Amplification (RPA) with Cas13a and Cas12a, to create two parallelised one-pot assays that detect two conserved elements ofMtb(IS6110andIS1081) and an internal control targeting human DNA. These assays were shown to be compatible with lateral flow and can be readily lyophilized. Our finalized assay exhibited sensitivity over a wide range of bacterial loads (105to 102CFU/mL) in sputum. The limit of detection (LoD) of the assay was determined to be 69.0 (51.0 – 86.9) CFU/mL forMtbstrain H37Rv spiked in sputum and 80.5 (59.4 – 101.6) CFU/mL forM. bovisBCG. Our assay showed no cross reactivity against a wide range of bacterial/fungal isolates. Clinical tests on 13 blinded sputum samples revealed 100% (6/6) sensitivity and 100% (7/7) specificity compared to culture. Our assay exhibited comparable sensitivity in clinical samples to the microbiological gold standard, TB culture, and to the nucleic acid state-of-the-art, GeneXpert MTB/RIF Ultra. This technology streamlines TB diagnosis from sample extraction to assay readout in a rapid and robust format, making it the first test to combine amplification and detection while being compatible with both lateral flow and lyophilization.