bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurodevelopmentally rooted epicenters in schizophrenia:
sensorimotor-association spatial axis of cortical thickness alterations
Authors: Fan Yun-Shuang , Xu Yong , Hettwer Meike Dorothee , Yang Pengfei , Sheng Wei , Wang Chong , Yang Mi , Kirschner Matthias , Valk Sofie Louise , Chen Huafu
Published: March 2024

Pathologic perturbations in schizophrenia have been suggested to propagate
via the functional and structural connectome across the lifespan. Yet how the
connectome guides early cortical reorganization of developing schizophrenia
remains unknown. Here, we used early-onset schizophrenia (EOS) as a
neurodevelopmental disease model to investigate putative early pathologic
origins that propagate through the functional and structural connectome. We
compared 95 patients with antipsychotic-naïve first-episode EOS and 99 typically
developing controls (7–17 years of age, 120 females). Whereas patients showed
widespread cortical thickness reductions, thickness increases were observed in
primary cortical areas. Using normative connectomics models, we found that
epicenters of thickness reductions were situated in association regions linked
to language, affective, and cognitive functions, while epicenters of increased
thickness in EOS were located in sensorimotor regions subserving visual,
somatosensory, and motor functions. Using post-mortem transcriptomic data of six
donors, we observed that the epicenter map differentiated
oligodendrocyte-related transcriptional changes at its sensory apex and the
association end was related to expression of excitatory/inhibitory neurons. More
generally, we observed that the epicenter map was associated with
neurodevelopmental disease gene dysregulation and human accelerated region
genes, suggesting potential shared genetic determinants across various
neurodevelopmental disorders. Taken together, our results underscore the
developmentally rooted pathologic origins of schizophrenia and their
transcriptomic overlap with other neurodevelopmental diseases.
Identification and characterization of human GDF15 knockouts
Authors: Gurtan Allan M. , Khalid Shareef , Koch Christopher , Khan Maleeha Zaman , Lamarche Lindsey B. , Dolan Elizabeth , Carrion Ana M. , Zessis Richard , Clement Matthew E. , Chen Zhiping , Lindsley Loren D. , Chiu Yu-Hsin , Streeper Ryan S. , Denning Daniel P. , Goldfine Allison B. , Doyon Brian , Abbasi Ali , Harrow Jennifer L. , Tsunoyama Kazuhisa , Asaumi Makoto , Kou Ikuyo , Shuldiner Alan R. , Rodriguez-Flores Juan L. , Rasheed Asif , Jahanzaib Muhammad , Mian Muhammad Rehan , Liaqat Muhammad Bilal , Raza Syed Shahzaib , Sultana Riffat , Jalal Anjum , Saeed Muhammad Hamid , Abbas Shahid , Memon Fazal Rehman , Ishaq Muhammad , Dominy John E. , Saleheen Danish
Published: March 2024

Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight, and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans caused nausea without accompanying weight loss2, and the effect of GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3–7. Here, we characterize GDF15 loss-of-function carriers (LOF), including 5 homozygous null carriers (“knockouts”) from 75,018 participants enrolled in the Pakistan Genomic Resource (PGR)8,9. We tested for the association of GDF15 LOF with 97 quantitative traits and binary outcomes. Further, 3 additional knockouts and 59 heterozygous carriers were identified in recall-by-genotype (RBG) studies accompanied by recruitment of family members. GDF15 knockouts ranged in age from 31 to 75 years, were fertile, and showed no consistent overt metabolic dysfunction. Collectively, our data indicate that (i) complete GDF15 loss is compatible with life and fertility, (ii) chronic therapeutic inhibition of GDF15 may be tolerated, and (iii) GDF15 modulation may not significantly impact body weight or metabolic syndrome.
Closing the gap: Solving complex medically relevant genes at scale
Authors: Mahmoud Medhat , Harting John , Corbitt Holly , Chen Xiao , Jhangiani Shalini , Doddapaneni Harsha , Meng Qingchang , Lambert Christine , Zhang Siyuan , Baybayan Primo , Henno Geoff , Han Tina , Yi Han , Riegler Casey , Metcalf Ginger , Ivan Chinn K , Eberle Michael A , Kingan Sarah , Farinholt Tim , Claudia Carvalho , Gibbs Richard A , Kronenberg Zev , Muzny Donna , Sedlazeck Fritz J
Published: March 2024

Comprehending the mechanism behind human diseases with an established heritable component represents the forefront of personalized medicine. Nevertheless, numerous medically important genes are inaccurately represented in short-read sequencing data analysis due to their complexity and repetitiveness or the so-called "dark regions" of the human genome. The advent of PacBio as a long-read platform has provided new insights, yet HiFi whole-genome sequencing (WGS) cost remains frequently prohibitive. We introduce a targeted sequencing and analysis framework, Twist Alliance Dark Genes Panel (TADGP), designed to offer phased variants across 389 medically important yet complex autosomal genes. We highlight TADGP accuracy across eleven control samples and compare it to WGS. This demonstrates that TADGP achieves variant calling accuracy comparable to HiFi-WGS data, but at a fraction of the cost. Thus, enabling scalability and broad applicability for studying rare diseases or complementing previously sequenced samples to gain insights into these complex genes. TADGP revealed several candidate variants across all cases and provided insight into LPA diversity when tested on samples from rare disease and cardiovascular disease cohorts. In both cohorts, we identified novel variants affecting individual disease-associated genes (e.g., IKZF1, KCNE1). Nevertheless, the annotation of the variants across these 389 medically important genes remains challenging due to their underrepresentation in ClinVar and gnomAD. Consequently, we also offer an annotation resource to enhance the evaluation and prioritization of these variants. Overall, we can demonstrate that TADGP offers a cost-efficient and scalable approach to routinely assess the dark regions of the human genome with clinical relevance.
Comparative Effectiveness of Traditional Chinese Medicine vs. Losartan on Blood Pressure: Real-World Insights from RCT-Eligible Populations
Authors: Jiang Kuan , Lai Xinxing , Yang Shu , Gao Ying , Zhou Xiaohua
Published: March 2024

When evaluating the effectiveness of a drug, a Randomized Controlled Trial (RCT) is often considered the gold standard due to its perfect randomization. While RCT assures strong internal validity, its restricted external validity poses challenges in extending treatment effects to the broader real-world population due to possible heterogeneity in covariates. In this study, we employed the augmented inverse probability of sampling weighted (AIPSW) estimator to generalize findings from an RCT comparing the efficacy of Songling Xuemaikang Capsule (SXC) -- a traditional Chinese medicine (TCM) and Losartan on hypertension reduction to a real-world trial-eligible population. Additionally, we conducted sensitivity analyses to assess the robustness of the AIPSW estimation against unmeasured confounders. The generalization results indicated that although SXC is less effective in lowering blood pressure than Losartan on week 2, week 4, and week 6, there is no statistically significant difference among the trial-eligible population at week 8, and the generalization is robust against potential unmeasured confounders.
Impaired functional brain-heart interplay sustains emotion dysregulation in depressed individuals
Authors: Catrambone Vincenzo , Mura Francesca , Patron Elisabetta , Gentili Claudio , Valenza Gaetano
Published: March 2024

Depression is a leading worldwide cause of mental disorders and disability, strongly affecting emotional processing and regulation. Its dysfunctional psycho-physiological dynamics may be part of the a nervous-system-wise symptomatology, impacting not only patients’ psyche but also significantly influencing functional cardiovascular dynamics. Therefore, depression serves as an exemplary pathological manifestation of the dysfunctional interaction between the central and autonomic nervous systems. While recent literature has been developing specific techniques to quantify such interactions, often referred to as functional Brain-Heart Interplay (BHI), the quantitative role of BHI dynamics in depression is largely unknown. This study aims to experimentally unveil BHI patterns specific to emotional regulation and processing in subjects exhibiting depressive symptoms compared to healthy controls. Results were gathered from a cohort of 72 individuals and indicate that depressive symptoms are associated with a continuous efferent central-to-peripheral hyperactivity and an afferent peripheral-to-central hypoactivity. This hypoactivity appears to be specific to negative emotional processing. This study offers novel insights into the systemic investigation of the neuro-physiological bases of depression.
Parent attention-orienting behavior is associated with neural entropy in infancy
Authors: Williams Cabell L. , Belkowitz Allison R. , Nance Madelyn G. , Mortman Emily T. , Bae Soni , Ahmed Sheher-Bano , Puglia Meghan H.
Published: March 2024

Parents play a significant role in directing infant’s attention to environmental stimuli via joint attention. We hypothesized that infants whose parents provide more bids for joint attention will display a more complex neural response when viewing social scenes. Sixty-one 8-month-old infants underwent electroencephalography (EEG) while viewing videos of joint-and parallel-play and participated in a parent-infant free play interaction. EEG data was analyzed using multiscale entropy, which quantifies moment-to-moment neural variability. Free play interactions were coded for parent alternating gaze, a behavioral mechanism for directing attention to environmental cues. We found a significant positive association between parent alternating gaze and neural entropy in frontal and central brain regions. These results suggest a relationship between parent behavior and infant neural mechanisms that regulate social attention, underlying the importance of parent cues in the formation of neural networks in infancy.
New implementation of data standards for AI in oncology. Experience from the EuCanImage project
Authors: García-Lezana Teresa , Bobowicz Maciej , Frid Santiago , Rutherford Michael , Recuero Mikel , Riklund Katrine , Cabrelles Aldar , Rygusik Marlena , Fromont Lauren , Francischello Roberto , Neri Emanuele , Capella Salvador , Navarro Arcadi , Prior Fred , Bona Jonathan , Nicolas Pilar , Starmans Martijn P. A. , Lekadir Karim , Rambla Jordi ,   EuCanImage Consortium
Published: March 2024

Background

An unprecedented amount of personal health data, with the potential to revolutionise precision medicine, is generated at healthcare institutions worldwide. The exploitation of such data using artificial intelligence relies on the ability to combine heterogeneous, multicentric, multimodal and multiparametric data, as well as thoughtful representation of knowledge and data availability. Despite these possibilities, significant methodological challenges and ethico-legal constraints still impede the real-world implementation of data models.

Technical details

The EuCanImage is an international consortium aimed at developing AI algorithms for precision medicine in oncology and enabling secondary use of the data based on necessary ethical approvals. The use of well-defined clinical data standards to allow interoperability was a central element within the initiative. The consortium is focused on three different cancer types and addresses seven unmet clinical needs. We have conceived and implemented an innovative process to capture clinical data from hospitals, transform it into the newly developed EuCanImage data models and then store the standardised data in permanent repositories. This new workflow combines recognized software (REDCap for data capture), data standards (FHIR for data structuring) and an existing repository (EGA for permanent data storage and sharing), with newly developed custom tools for data transformation and quality control purposes (ETL pipeline, QC scripts) to complement the gaps.

Conclusion

This article synthesises our experience and procedures for healthcare data interoperability, standardisation and reproducibility.
Ambulatory Blood Pressure and Number of Subclinical Target Organ Injury Markers in Youth: The SHIP AHOY Study
Authors: Hamdani Gilad , Urbina Elaine M. , Daniels Stephen R. , Falkner Bonita E. , Ferguson Michael A. , Flynn Joseph T. , Hanevold Coral D. , Ingelfinger Julie R. , Khoury Philip R. , Lande Marc B. , Meyers Kevin E. , Samuels Joshua , Mitsnefes Mark
Published: March 2024

Background

Hypertension in adolescence is associated with subclinical target organ injury (TOI). We aimed to determine whether different blood pressure (BP) thresholds were associated with increasing number of TOI markers in healthy adolescents.

Methods

244 participants (mean age 15.5±1.8 years, 60.1% male) were studied. Participants were divided based on both systolic clinic and ambulatory BP (ABP), into low- (<75thpercentile), mid- (75th-90thpercentile) and high-risk (>90thpercentile) groups. TOI assessments included left ventricular mass, systolic and diastolic function, and vascular stiffness. The number of TOI markers for each participant was calculated. A multivariable general linear model was constructed to evaluate the association of different participant characteristics with higher numbers of TOI markers.

Results

47.5% of participants had at least one TOI marker: 31.2% had one, 11.9% two, 3.7% three, and 0.8% four. The number of TOI markers increased according to the BP risk groups: the percentage of participants with more than one TOI in the low-, mid-, and high groups based on clinic BP was 6.7%, 19.1%, and 21.8% (p=0.02), and based on ABP was 9.6%, 15.8%, and 32.2% (p<0.001). In a multivariable regression analysis, both clinic BP percentile and ambulatory SBP index were independently associated with the number of TOI markers. When both clinic and ABP were included in the model, only the ambulatory SBP index was significantly associated with the number of markers.

Conclusion

High SBP, especially when assessed by ABPM, was associated with an increasing number of subclinical cardiovascular injury markers in adolescents.
The impact of a conditional financial incentive on linkage to HIV care: Findings from the HITS cluster randomized clinical trial in rural South Africa
Authors: Kim Hae-Young , Inghels Maxime , Mathenjwa Thulile , Shahmanesh Maryam , Seeley Janet , Matthews Phillippa , McGrath Nuala , Adeagbo Oluwafemi , Gareta Dickman , Yapa H. Manisha , Zuma Thembelihle , Dobra Adrian , Bärnighausen Till , Tanser Frank
Published: March 2024

Introduction

HIV elimination requires innovative approaches to ensure testing and immediate treatment provision. We investigated the effectiveness of conditional financial incentives on increasing linkage to HIV care in a 2×2 factorial cluster randomized controlled trial-Home-Based Intervention to Test and Start (HITS) - in rural South Africa.

Methods

Of 45 communities in uMkhanyakude, KwaZulu-Natal, 16 communities were randomly assigned to the arms to receive financial incentives for home-based HIV counseling and testing (HBHCT) and linkage to care within 6 weeks (R50 [US$3] food voucher each) and 29 communities to the arms without financial incentives. We examined linkage to care (i.e., initiation or resumption of antiretroviral therapy after >3 months of care interruption) at local clinics within 6 weeks of a home visit, the eligibility period to receive the second financial incentive. Linkage to care was ascertained from individual clinical records. Intention-to-treat analysis (ITT) was performed using modified Poisson regression with adjustment for receiving another intervention (i.e., male-targeted HIV-specific decision support app) and clustering of standard errors at the community level.

Results

Among 13,894 eligible men (i.e., ≥15 years and resident in the 45 communities), 20.7% received HBHCT, which resulted in 122 HIV-positive tests. Of these, 27 linked to care within 6 weeks of HBHCT. Additionally, of eligible men who did not receive HBHCT, 66 linked to care. In the ITT analysis, the proportion of linkage to care among men did not differ in the arms which received financial incentives and those without financial incentives (adjusted Risk Ratio [aRR]=0.78, 95% CI: 0.51-1.21). Among 19,884 eligible women, 29.1% received HBHCT, which resulted in 375 HIV-positive tests. Of these, 75 linked to care. Among eligible women who did not receive HBHCT, 121 linked to care within 6 weeks. Women in the financial incentive arms had a significantly higher probability of linkage to care, compared to those in the arms without financial incentives (aRR=1.50; 95% CI: 1.03-2.21).

Conclusion

While a small once-off financial incentive did not increase linkage to care among men during the eligibility period of 6 weeks, it significantly improved linkage to care among women over the same period.

Clinical Trial Number:ClinicalTrials.gov#NCT03757104
Accelerating precision medicine: a proposed framework for large-scale multiomics data integrity, interoperability, analysis, and collaboration in biomedical discovery
Authors: Sriram Vivek , Conard Ashley Mae , Rosenberg Ilyana , Kim Dokyoon , Hall Amanda K
Published: March 2024

Objective

To identify and define a process and framework for biomedical discovery research. Our study aim was to characterize the biomedical discovery lifecycle across data modalities and professional stakeholders involved in biomedical research to address the multiomics data challenges of precision medicine.

Materials and Methods

We recruited fifteen professionals from various biomedical roles and industries to participate in 60-minute semi-structured interviews, which involved an assessment of common challenges, needs, tasks, and data management methods and a brainstorm exercise to validate each professional’s biomedical research process. We applied a qualitative analysis of individual interviews using a constant comparative approach for emerging themes.

Results

We found a general process of biomedical discovery across all participants that consisted of four key stages: data plan, data integrity, data analysis, and data-driven discovery. Within each stage of the process, participants highlighted their challenges and needs and emphasized the importance of data integrity and interoperability, particularly during data hand-offs. The process extends across three general levels of data, including non-human, non-clinical human, and clinical human data, to define an overarching framework for biomedical discovery research.

Conclusions

The proposed framework provides researchers with an opportunity to align workstreams and converge on a single process to conduct biomedical research across stakeholders and data types. Key opportunities were found that can be explored in the health technology space, including generative artificial intelligence, to help tackle multiomics data challenges to advance precision medicine.
Postpartum suicidal ideation in Austria and Germany during the COVID-19 pandemic
Authors: Florea C. , Preiß J. , Angerer M. , Schabus M.
Published: March 2024

Introduction

Postpartum suicidal ideation is a significant concern, as it poses a risk for future suicide attempts, particularly in high income countries, where suicide ranks among the leading causes of death for postpartum mothers. The literature indicates a global average prevalence of postpartum suicidal ideation of approximately 7%, but for Austria and Germany there are few studies on this subject.

Methods

In a web-based survey for Austrian and German mothers of children born during the COVID-19 pandemic, several measures of mental health (depression, stress), social support and other parenting and pandemic-related questions were assessed in 1964 mothers. Based on the answers for the last item of the Edinburgh Postpartum Depression Scale, the suicidality risk and the presence or absence of suicidal ideation were computed. Furthermore, possible risk or protective factors for suicidality were investigated.

Results

The prevalence of suicidal ideation was 7.3%, which is in the range of the global prevalence reported in the literature, but two times higher than previous reports on German mothers. The three strongest risk factors for suicidal ideation were (i) high levels of stress (increased risk by 350%), (ii) a lack of perceived social support (increased risk by 265%), and (iii) a perceived negative effect of the pandemic on the relationship with the partner (increased risk by 223%). Not receiving help from family and friends, having a lower income, and feeling negatively impacted by the pandemic also significantly increased the risk of suicidal ideation.

Discussion and conclusion

The results indicate a higher prevalence of suicidality than previously reported in German mothers, and confirm the risk factors previously associated with depression and suicidality. These risk and protective factors could be targets of social and public health policies, while the first step should be a general screening program for suicidality in this population group.
Smad4and TGF-β1 dependent gene expression biomarkers in conditional intestinal adenoma, organoids and colorectal cancer
Authors: Surakhy Mirvat , Matheson Julia , Barnes David , Carter Emma J. , Hughes Jennifer , Bühnemann Claudia , Sanegre Sabina , Morreau Hans , Metz Paul , Imianowski Charlotte J. , Hassan A. Bassim
Published: March 2024

TGF-β ligand activation suppresses cell growth yet can paradoxically and potently promote cancer invasion and metastasis depending on downstream pathway mutational context. Here, we evaluated the basis of this observation in conditional murine intestinal adenoma models with and without loss of Mothers against decapentaplegic homolog 4 (Smad4), with the aim of identifying TGF-β-BMP-SMAD4 pathway dependent gene expression biomarkers for translational application. ConditionalLgr5-CreERT2activation inApcfl/flSmad4fl/flresulted in adenoma formation with recombined homozygote floxed alleles(ApcΔ/ΔSmad4Δ/Δ). The adenoma phenotype was discordant, with a reduced small intestinal adenoma burden yet development of large non-metastatic caecal adenoma with nuclear localisation of phospho-Smad2/3. DerivedApcΔ/ΔSmad4Δ/Δadenoma organoids resisted TGF-β1 dose dependent growth arrest and cell death (IC50534pM) compared toApcΔ/ΔSmad4+/+(IC 24pM). TGF-β1 (390pM) modified adenoma mRNA expression (bulk RNA-Seq) most significantly forId1lowandSpp1highinApcΔ/ΔSmad4Δ/Δ. Single cell RNAseq of caecal adenoma identified expansion ofLgr5low, Pak3highandId1lowprogenitor populations inApcΔ/ΔSmad4Δ/Δ. Of the 76Smad4and TGF-β1 dependent genes identified in adenoma organoids, 7 human equivalent genes were also significantly differentially expressed in colorectal cancer, includingID1low,SPP1highandPAK3highthat also correlated with poorer survival (TCGA cohorts). Murine conditional models identifiedSmad4loss of function mRNA expression biomarkers that require further evaluation as functional classifiers of colorectal cancer subtypes.
The Origin of Movement Biases During Reaching
Authors: Wang Tianhe , Morehead Ryan J. , Tsay Jonathan S. , Ivry Richard B.
Published: March 2024

Goal-directed movements can fail due to errors in our perceptual and motor systems. While these errors may arise from random noise within these sources, they also reflect systematic motor biases that vary with the location of the target. The origin of these systematic biases remains controversial. Drawing on data from an extensive array of reaching tasks conducted over the past 30 years, we evaluated the merits of various computational models regarding the origin of motor biases. Contrary to previous theories, we show that motor biases do not arise from systematic errors associated with the sensed hand position during motor planning or from the biomechanical constraints imposed during motor execution. Rather, motor biases are primarily caused by a misalignment between eye-centric and the body-centric representations of position. This model can account for motor biases across a wide range of contexts, encompassing movements with the right versus left hand, proximal and distal effectors, visible and occluded starting positions, as well as before and after sensorimotor adaptation.
Splice site andde novomutations can cause mixed dominant negative/gain of functionPLCG2-associated immune dysregulation with cold urticaria (CU-PLAID)
Authors: Chou Sophia R. , Bailey Alexis C. , Baysac Kathleen , Oler Andrew J. , Milner Joshua D. , Ombrello Michael J.
Published: March 2024

Background

Phospholipase Cγ2 (PLCγ2) is an important signaling molecule that receives and transmits signals from various cell surface receptors in most hematopoietic lineages. Variants ofPLCG2cause PLCγ2-associated immune dysregulation (PLAID), a family of conditions that are classified by mutational effect. PLAID with cold urticaria (CU-PLAID) is caused by in-frame deletions ofPLCG2that are dominant negative at physiologic temperatures but become spontaneously active at sub-physiologic temperatures.

Objective

To identify genetic lesions that cause PLAID by combining RNA sequencing of full-lengthPLCG2with whole genome sequencing.

Methods

We studied nine probands with antibody deficiency and a positive evaporative cooling test, together with two known CU-PLAID patients and three healthy subjects. Illumina sequencing was performed on full-lengthPLCG2cDNA synthesized from peripheral blood mononuclear cell RNA and whole genome sequencing was used to identify genetic lesions. Novel alternate transcripts were overexpressed in thePlcg2-deficient DT40 cell overexpression system. ERK phosphorylation was quantified by flow cytometry with and without BCR crosslinking.

Results

Two probands expressed novel alternative transcripts ofPLCG2with in-frame deletions. The first, expressingPLCG2without exons 18-19, carried a splice site mutation in intron 19. The second, expressingPLCG2without exons 19-22, carried a 14kbde novodeletion ofPLCG2. DT40 cells overexpressing the exon 18-19 or exon 19-22 deletions failed to phosphorylate ERK in response to BCR crosslinking.

Conclusion

In addition to autosomal dominant genomic deletions,de novodeletions and splice site mutations ofPLCG2can also cause CU-PLAID. All of these can be identified by cDNA-based sequencing.

Capsule Summary

By identifying both the firstde novoand splice site variants to causePLCG2-associated immune dysregulation with cold urticaria (CU-PLAID), we demonstrate the diagnostic utility ofPLCG2-specific RNA-sequencing.
Reporting of Fairness Metrics in Clinical Risk Prediction Models: A Call for Change
Authors: Rountree Lillian , Lin Yi-Ting , Liu Chuyu , Salvatore Maxwell , Admon Andrew , Nallamothu Brahmajee K , Singh Karandeep , Basu Anirban , Mukherjee Bhramar
Published: March 2024

Clinical risk prediction models integrated in digitized healthcare systems hold promise for personalized primary prevention and care. Fairness metrics are important tools for evaluating potential disparities across sensitive features in the field of prediction modeling. In this paper, we seek to assess the uptake of fairness metrics in clinical risk prediction modeling by conducting a scoping literature review of recent high impact publications in the areas of cardiovascular disease and COVID-19. Our review shows that fairness metrics have rarely been used in clinical risk prediction modeling despite their ability to identify inequality and flag potential discrimination. We also find that the data used in clinical risk prediction models remain largely demographically homogeneous, demonstrating an urgent need for collecting and using data from diverse populations. To address these issues, we suggest specific strategies for increasing the use of fairness metrics while developing clinical risk prediction models.
Macular Structure Characteristics in Unilateral Idiopathic Full-Thickness Macular Hole and the Healthy Fellow Eyes
Authors: Hou Yi-Ting , Yang Chung-May , Hsieh Yi-Ting
Published: March 2024

Aims

To investigate the characteristics of the macular structure and foveal pit in eyes with lesions and healthy fellow eyes of patients with unilateral full-thickness macular holes (FTMH).

Methods

Patients with unilateral FTMH were retrospectively enrolled as the study group, and their age- and sex-matched individuals with no vitreomacular diseases as the control group in a medical center. FTMHs were classified as FTMH with lamellar hole-associated epiretinal proliferation (LHEP), FTMH without LHEP or FTMH without vitreomacular separation. Macular structure parameters, including foveal base width (FBW), central foveolar thickness (CFT), central subfield thickness (CST), central subfield volume (CSV), and retinal artery trajectory (RAT), were measured using optical coherence tomography and fundus photography. These parameters were compared among different FTMH groups.

Results

A total of 68 patients (39 women) with unilateral FTMH and 68 healthy controls were enrolled. The RAT of the lesioned eyes (0.19±0.06) and the healthy fellow eyes (0.14±0.04) were both smaller than those of the normal controls (0.37±0.14) (P<0.001 for both). The FBW of the healthy fellow eyes (446.8±98.2 µm) were significantly larger than those in the control group (338.4±80.6 µm,P<0.001). No significant differences in any macular parameters were noted among the three different types of FTMH.

Conclusions

Patients with unilateral FTMH had a wider RAT in both the lesioned and healthy eyes, and a wider foveal base in their healthy fellow eyes than in normal controls. Such macular structure characteristics may be prone to macular hole formation.
A Survey on Optimization and Machine Learning-Based Fair Decision Making in Healthcare
Authors: Chen Zequn , Marrero Wesley J.
Published: March 2024

The unintended biases introduced by optimization and machine learning (ML) models are a topic of great interest to medical professionals. Bias in healthcare decisions can cause patients from vulnerable populations (e.g., racially minoritized, low-income, or living in rural areas) to have lower access to resources and inferior outcomes, thus exacerbating societal unfairness. In this systematic literature review, we present a structured overview of the literature regarding fair decision making in healthcare until April 2024. After screening 782 unique references, we identified 103 articles within the scope of our review. We categorize the identified articles into the following three sections: algorithmic bias, fairness metrics, and bias mitigation techniques. Specifically, we identify examples of algorithmic, data, and publication bias as they are typically encountered in research and practice. Subsequently, we define and discuss the fairness metrics previously considered in the literature, including notions of fairness through unawareness, demographic parity, equal opportunity, and equal odds. Lastly, we summarize the bias mitigation techniques available in the optimization and ML literature by classifying them into pre-processing, in-processing, and post-processing approaches. Fairness in decision making is an emerging field, poised to substantially reduce social inequities and improve the overall well-being of underrepresented groups. Our review aims to increase awareness of fairness in healthcare decision making and facilitate the selection of appropriate approaches under varying scenarios.
A brain-to-text framework of decoding natural tonal sentences
Authors: Zhang Daohan , Wang Zhenjie , Qian Youkun , Zhao Zehao , Liu Yan , Hao Xiaotao , Li Wanxin , Lu Shuo , Zhu Honglin , Chen Luyao , Xu Kunyu , Li Yuanning , Lu Junfeng
Published: March 2024

Speech brain-computer interfaces (BCIs) directly translate brain activity into speech sound and text, yet decoding tonal languages like Mandarin Chinese poses a significant, unexplored challenge. Despite successful cases in non-tonal languages, the complexities of Mandarin, with its distinct syllabic structures and pivotal lexical information conveyed through tonal nuances, present challenges in BCI decoding. Here we designed a brain-to-text framework to decode Mandarin tonal sentences from invasive neural recordings. Our modular approach dissects speech onset, base syllables, and lexical tones, integrating them with contextual information through Bayesian likelihood and the Viterbi decoder. The results demonstrate accurate tone and syllable decoding under variances in continuous naturalistic speech production, surpassing previous intracranial Mandarin tonal syllable decoders in decoding accuracy. We also verified the robustness of our decoding framework and showed that the model hyperparameters can be generalized across participants of varied gender, age, education backgrounds, pronunciation behaviors, and coverage of electrodes. Our pilot study shed lights on the feasibility of more generalizable brain-to-text decoding of natural tonal sentences from patients with high heterogeneities.
Expanded T cell clones with lymphoma driver somatic mutations in refractory celiac disease
Authors: Singh Mandeep , Louie Raymond H. Y. , Samir Jerome , Field Matthew A. , Milthorpe Claire , Aldiriki Thiruni , Mackie Joseph , Roper Ellise , Faulks Megan , Jackson Katherine J. L. , Calcino Andrew , Hardy Melinda Y. , Blombery Piers , Amos Timothy G. , Deveson Ira W. , Read Scott A. , Shek Dmitri , Guerin Antoine , Ma Cindy S , Tangye Stuart G. , Sabatino Antonio Di , Lenti Marco V. , Pasini Alessandra , Ciccocioppo Rachele , Ahlenstiel Golo , Suan Dan , Tye-Din Jason A. , Goodnow Christopher C. , Luciani Fabio
Published: March 2024

Intestinal inflammation continues in a subset of celiac disease (CD) patients despite a gluten-free diet. Here, by applying multiomic single cell analysis to duodenal biopsies, we find low-grade malignancies with lymphoma driver mutations in refractory CD type 2 (RCD2) patients comprise surface CD3 negative (sCD3-) lymphocytes stalled at an innate lymphoid cell (ILC) - progenitor T cell stage undergoing extensiveTCRrecombination. In people with refractory CD type 1 (RCD1), who currently lack explanation, we discover sCD3+ T cells with lymphoma driver mutations forming large clones displaying inflammatory and cytotoxic molecular profiles in 6 of 10 individuals, and a single small clone in 1 of 4 active recently diagnosed CD cases. Accumulation of driver-mutated T cells and their sCD3-progenitors may explain chronic, non-responsive autoimmunity.

One-Sentence Summary

Treatment refractory autoimmunity in celiac disease may be explained by dysregulated T cells and progenitors that have acquired lymphoma-driver mutations.
Patient-specific compliant simulation framework informed by 4DMRI-extracted Pulse Wave Velocity: Application post-TEVAR
Authors: Girardin Louis , Lind Niklas , von Tengg-Kobligk Hendrik , Balabani Stavroula , Díaz-Zuccarini Vanessa
Published: March 2024

We introduce a new computational framework that makes use of the Pulse Wave Velocity (PWV) extracted exclusively from 4D flow MRI (4DMRI) to inform patient-specific compliant computational fluid dynamics (CFD) simulations of a Type-B aortic dissection (TBAD), post-thoracic endovascular aortic repair (TEVAR). From 4DMRI and brachial pressure, a 3D inlet velocity profile (IVP), dynamic outlet boundary, and reconstructed thoracic aortic geometry are obtained. A moving boundary method (MBM) is applied to simulate aortic wall displacement. The aortic wall stiffness was estimated through two methods: one relying on area-based distensibility and the other utilising regional pulse wave velocity (RPWV) distensibility, further fine-tuned to align within vivovalues. Predicted pressures and outlet flow rates were within 2.3% of target values. RPWV-based simulations were more accurate in replicatingin vivohemodynamic compared to the area-based ones. RPWVs were closely predicted in most regions, with the exception being the endograft, and systolic flow reversal ratios (SFRR) were accurately captured, while a difference of above 60% on in-plane rotational flow (IRF) between the simulations. Significant disparities between the wall shear stress (WSS)-based indices were observed between the two approaches, especially the endothelial cell activation potential (ECAP). At the isthmus, the RPWV-driven simulation indicated a mean ECAP>1.4Pa−1(critical threshold), indicating areas potentially prone to thrombosis. In contrast, the area-based simulation did not depict this. RPWV-driven simulation results agree well with 4DMRI measurements, emphasising that RPWV simulations are accurate in simulating haemodynamics, consequently facilitating a comprehensive assessment of surgery decision-making and potential complications, such as thrombosis and aortic growth.
Real-world Nuvaxovid COVID-19 vaccine safety profile after first 100,000 doses in Australia, 2022-2023
Authors: Clothier Hazel J , Parker Claire , Mallard John H , Effler Paul , Bloomfield Lauren , Carcione Dale , Buttery Jim P
Published: March 2024

Introduction Nuvaxovid became available in Australia from February 2022, a year later than the first COVID-19 vaccines were released. It was a much-anticipated alternative vaccine for people that had either suffered an adverse event to and/or were hesitant to receive one of the mRNA or adenovirus based COVID-19 vaccines. Although safety from clinical trials was reassuring, small trial population size, relatively low administration rates worldwide and limited post-licensure intelligence meant potential rare adverse events were underinformed. Methods We conducted a retrospective observational analysis of adverse events following immunisation (AEFI) spontaneously reported to SAFEVAC, the integrated vaccine safety surveillance system used by Victoria and Western Australia, Australia. Reports received from 14 Feb 2022 to 30 June 2023 were analysed by vaccinee demographics, reported reactions and COVID-19 vaccine dose received and compared as reporting rates (RR) per 100,000 doses administered. Results 356 AEFI reports were received, following 102,946 Nuvaxovid doses administered. Rates were higher post dose 1 than dose 2 (rate ratio 1.5, p=0.0008); primary series than booster (rate ratio 2.4, p<0.0001); in females than males (rate ratio 1.4, p<0.01), especially those aged 30-49 years (RR=1.6, p=0.002). Serious AEFI included 76 chest pain (RR=73.8), two myocarditis (RR=1.9) and 20 pericarditis (RR=19.4). No cases of Guillain Barre or thrombosis with thrombocytopaenia syndromes were reported and no deaths attributable to vaccination. Conclusion The shared SAFEVAC platform enables pooling of clinically reviewed data across jurisdictions, increasing the safety profile evidence base of novel vaccines like Nuvaxovid and improving the odds for identification and description of rare events across all vaccines.
Associations of cholecystectomy with the risk of gastroesophageal reflux disease: a Mendelian randomization study
Authors: Qian Jin , Xu Huawei , Liu Jun , Zheng Yihu
Published: March 2024

Background

Cholecystectomy is the standard surgery for patients with gallbladder disease, but the impact of cholecystectomy on gastroesophageal reflux (GERD) is not clear.

Methods

We obtained genetic variants associated with cholecystectomy at a genome-wide significant level (Pvalue < 5 × 10−8) as instrumental variables (IVs) and performed Mendelian randomization (MR) to explore the relationship with GERD.

Results

The Inverse Variance Weighted analysis (IVW) showed that the risk of GERD in patients after cholecystectomy increased (OR = 2.19; 95% CI: 1.18 – 4.09). At the same time, the analysis results of weighted median (OR = 2.30; 95% CI: 1.51 – 3.48) and weighted mode (OR = 2.21; 95% CI: 1.42 – 3.45) were also consistent with the direction of the IVW analysis and were statistically significant (P< 0.05).

Conclusions

This study shows that patients who have undergone cholecystectomy are a susceptible population of GERD.
Feasibility of individualized home exercise programs for patients with head and neck cancer – study protocol and first results of a multicentre single-arm intervention trial (OSHO #94)
Authors: Felser Sabine , Rogahn Julia , Glass Änne , Bonke Lars Arne , Strüder Daniel F. , Stolle Jana , Schulze Susann , Blaurock Markus , Kriesen Ursula , Junghanss Christian , Grosse-Thie Christina
Published: March 2024

Introduction

Patients with head and neck cancer (PwHNC) benefit from targeted exercise interventions: symptom relief, compensation for dysfunction, improvement in quality of life (QoL). Data on acceptance physical interventions in PwHNC are rare. The ‘OSHO #94’ trial investigates the short- and medium-term effects of individualized home exercise in PwHNC on QoL, physical activity and functionality. The study includes a feasibility phase in order to evaluate the acceptance (Phase A), followed by a consecutive QoL endpoint Phase B. Here we present the study protocol as well as the feasibility results.

Methods and analysis

This prospective, multicentre, single-arm intervention study includes PwHNC ≥18 years of age in aftercare or palliative care with stable remission under immunotherapy. The study opened in January 01, 2021, with estimated completion by December 31, 2024. The PwHNC receive an individualized home exercise program consisting of mobilization, coordination, strengthening and stretching exercises. This should be carried out at least three times a week over 12 weeks for 15 to 30 minutes, supplemented by aerobic training two to three times a week for 30 minutes (intervention). Once weekly telephone calls with a physiotherapist are performed. Subsequently, there is a 12-week follow-up (FU) without exercise specifications/contact. Outcomes are measured before and after the intervention and following the FU. Primary outcome of the feasibility phase (Phase A, n = 25) was the determination of the dropout rate during the intervention with a termination cut off if more than 30% PwHNC withdrew premature. The primary outcome of phases A + B (N = 53) are the change in global QoL score from pre- to post-intervention (EORTC QLQ-C30). Secondary outcomes include clinical and patient-reported measures, training details as well as functional diagnostic data (e.g. level of physical activity, training frequency, flexibility, fall risk and aerobic performance).

Results

25 PwHNC were enrolled onto the feasibility cohort. Only16% (4/25 patients) did not complete the study. Therefore, individualized home exercise programs in PwHNC seem feasible recruitment of PwHNC for phase B continued. The dropout rate was adjusted from 30% (N = 60) to 20% (N = 53, calculated sample size n = 42 PwHNC and 20% (n = 11) to dropout).

Ethics and dissemination

The study protocol was approved by the Ethics Committee of the University of Rostock, University of Halle-Wittenberg and University of Greifswald. The findings will be disseminated in peer-reviewed journals and academic conferences.

Trial registrationGerman Registry of Clinical Trials DRKS00023883.
A preliminary study to evaluate the exposure of human fetus to heavy metals in the umbilical cord blood in Syria
Authors: Kabbaa Maryana , Fadel Ekbal , Mayhoub Flora
Published: March 2024

The environmental situation in Syria needs a comprehensive assessment, especially in light of the conditions it has been experiencing for thirteen years, which have exacerbated pollution with heavy metals (HM) in various regions, including the coastal one.

This preliminary and first survey in Syria aims to evaluate the exposure of human fetus in the population to HM by measuring the toxic metals spread in the coastal environment in the umbilical cord blood (UCB), which are lead (Pb), mercury (Hg), cadmium (Cd), arsenic (As), chromium (Cr) and nickel (Ni).

The study was conducted between May 2022 and April 2023 among healthy newborns of the National Maternity Hospital in the Mediterranean coastal city of Tartous. This study adopted the official method of the American Association for Analytical Chemistry (AOAC, 2002) in collecting, preserving and processing UCB samples, and the heavy metals were measured using an Atomic Absorption Spectrometer. The statistical study was carried out using SPSS Statistics 23.0 (Statistical Package for Social Sciences).

The lower and upper limits for the concentrations of the studied elements in UCB range between: Pb (6.18-17.60µg/L), Hg (1.05-7.62µg/L), Cd (0.01-0.67µg/L), As (0.30-5.70µg/L), Cr (0.02-0.43µg/L), Ni (0.01-0.94µg/L).

The concentrations of all HM measured in UCB are below the recommended international reference limits. This paper represents the first step in studying the assessment of fetal exposure to HM in our region. The current and future studies aim to expand the study area to include all of Syria, in addition to linking laboratory levels of HM with various sources of exposure and pregnancy outcomes observed at birth.
Analyzing the efficacy of a decade-long endeavor: extracurricular medical research training amidst the turmoil of Syria
Authors: Hanafi Ibrahem , Alsalkini Marah , Kheder Kheder , Al Nafouri Maarouf Gorra , Rahmeh Ahmad Rami , Sabouni Rami
Published: March 2024

Objectives

Medical research in Syria faced significant limitations due to inadequate human and financial resources, exacerbated by the ongoing war. Until recently, the curriculum did not incorporate sufficient training on research skills. Consequently, extracurricular workshops were initiated or utilized nationwide to acquire research-related expertise, aiming to bolster research output. This study aims to characterize and evaluate these training endeavors concerning research-related knowledge, attitudes, barriers, as well as research productivity.

Methods

This case-control study encompassed all training initiatives in Syria from 2011 to 2020, both on-site and online. Participants consisted of early career healthcare professionals affiliated with all Syrian universities and were recruited into four equal groups based on the quantity of research projects they undertook and published. Our participants reported and assessed individual extracurricular workshops regarding their gained knowledge, attitudes, and practical skills. These initiatives were compared to curricular training and practical peer-led support regarding these outcomes.

Results

The study included 53 on-site and 30 online workshops, displaying diverse distributions and features. Attendance of extracurricular workshops correlated with participants’ knowledge, attitudes, and research productivity (p<0.001). The most effective interventions were massive open online courses and workshops lasting over 12 hours. Extracurricular workshops and peer-led support has comparable effectiveness and associated with higher knowledge, attitudes, and practical skills of their beneficiaries in comparison to curricular training (adjusted p<0.05). Lastly, peer trainers in these workshops exhibited more publications and higher levels of knowledge and attitude than the rest of the sample (adjusted p<0.05).

Conclusions

Overall, extracurricular interventions and peer support demonstrated their superiority over curricular training. Despite the varied nature of these workshops and the absence of institutional organization, these approaches exhibited significant potential in enhancing research-related knowledge, promoting positive attitudes, and augmenting research productivity in resource-constrained settings such as Syria.