bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of paediatric sialorrhea
Authors: Levi Eric , Alexander William , Cooper Monica S.
Published: October 2024

Purpose of review

To summarize current understanding of and recent literature on the management of sialorrhea in children.

Recent findings

Sialorrhea is a symptom of oropharyngeal dysphagia and reduced clearance. Sialorrhea can be anterior, with forward overflow of saliva, causing skin rash, social embarrassment and spillage on communication devices; or posterior, where there is pharyngeal pooling of saliva, which may cause aspiration.

Assessment of sialorrhea involves a clinical evaluation, focusing on the individual's age, development, underlying medical condition and whether the sialorrhea is anterior, posterior or both. Craniomaxillofacial structure, posture, airway patency, neuromotor control, level of social awareness, motivation and caregiver concerns are assessed. To manage sialorrhea, integration of multiple strategies is usually needed. There is good evidence for behavioral intervention, oral appliances, anticholinergic medications, botulinum toxin injection and surgery. The role of various options of surgery in providing a longer lasting effect is supported. Adjunctive airway and craniomaxillofacial surgery may be indicated.

Sialorrhea is a modifiable condition with multifactorial causes requiring multimodal therapy by an inter-disciplinary team. There is increasing evidence on the role of saliva surgery in improving the quality of life for the person with sialorrhea and their caregivers.
Advances in the Application of Microsurgical Techniques in Repairing Traumatic Auricular Defects
Authors: Wei Siming , Chen Yongjun , Dong Liwei
Published: October 2024

Objectives:

Auricular reconstruction is one of the most challenging procedures in plastic surgery. However, traumatic auricular defects present more uncertainty and complexity than congenital microtia with various surgical options in auricular reconstruction. The purpose of this article is to review advances in the use of microsurgical techniques for the treatment of traumatic ear defects.

Methods:

Three databases, PubMed, Web of Science, and Google Scholar, have been used to gather the most relevant papers discussing the topic. This paper searched for studies from 1980 to 2023: searching for a range of keywords such as “post-traumatic ear deformities,” “free flap,” and “free facial flap.” Using this method, studies related to free flaps in posttraumatic ear reconstruction were reviewed and discussed.

Results:

Fifty-four studies related to auricular reconstruction using different free flaps were obtained through screening.

Conclusion:

The microsurgical technique for auricular reconstruction requires both exceptional auricular reconstruction skills and microsurgical expertise due to its intricate nature. Nevertheless, microsurgical techniques remain a valuable avenue of investigation and can provide satisfactory surgical outcomes in appropriately selected patients.

Level of Evidence

Level V.
Modified Technique of Gummy Smile Treatment: Double M-V Plasty for Esthetic and Functional Lip Reposition Surgery
Authors: Pokrowiecki Rafal
Published: October 2024

Excessive gingival display is a common problem that results in an unaesthetic appearance while smiling. Lip reposition surgery is a powerful, noninvasive surgery approach for gummy smile treatment, frequently performed in outpatient oral and maxillofacial surgery units. The procedure as such, provides camouflage of the increased gingival display through re-attachment of the upper lip and limits the pull effect of the muscles by reducing the depth of the upper vestibule. Few techniques of surgical treatment of maxillary gingiva overexposure have been described so far. Proposed midline double V- plasty provides anatomic reposition of the frenulum, whereas bilateral vertical M-plasty enables wider excision of the mucosa than the conventional approach providing better adaption of the wound margins without residual dog-ear defects giving more functional, esthetic, and satisfactory effect to the patients. It can also be performed in patients who do not desire orthognathic surgery with good esthetic results.
Office-Based Digital Workflow for Managing Old Mandibular Fracture Malunion: Use of Short-Segment Drilling and Osteotomy Guides With Predictive Holes
Authors: Zhuang Hai , Wan Youjun , Zhang Tianyu , Bu Shoushan
Published: October 2024

Treating old mandibular fractures with malunion is challenging due to the need for osteotomy and interference between bone segments, complicating occlusal restoration. This technical note introduces a novel office-based digital workflow utilizing surgical guides. Preoperative computed tomography (CT) data were imported into MIMICS software for virtual surgical planning to precisely realign bone fragments based on anatomical and occlusal relationships. A pre-bent reconstruction plate was adapted to a 3-dimensional-printed mandible model, and cone beam CT scans captured detailed screw path data. This information was used in 3-matic software to design short-segment drilling guides (SSDGs), and osteotomy guides with predictive holes. These guides facilitated accurate bone osteotomy and realignment during surgery. This workflow addresses the limitations of previous SSDGs, offering a reliable solution for managing malunion in old mandibular fractures. The approach reduces surgical complexity, enhances precision, and streamlines treatment, providing an innovative method for challenging mandibular fractures.
Impact of 2023 Ventral Hernia Repair CPT Code Changes on Work Relative Value Units in a Tertiary Hernia Referral Center
Authors: DiPaola Blake C , Mooney Rachel E , Sairajeev Sasha V , Butler Lance , Plymale Margaret A , Davenport Daniel L , Roth J Scott
Published: October 2024

BACKGROUND:

CPT codes for ventral hernia repair (VHR) changed in January 2023 to address the heterogeneity of procedures with a concomitant shift from a 90- to 0-day global period. This study reviews a tertiary referral center’s experience with hernia coding comparing the work relative value units (wRVUs) generated for VHR pre-2023 compared with post-2023.

STUDY DESIGN:

CPT codes were analyzed for patients undergoing open or laparoscopic VHR before updates to the CPT hernia codes (January 2022 to September 2022) and after CPT change (January 2023 to September 2023). wRVU values were assigned based on nationally published values. CPT codes in 2022, CPT codes in 2023, 8 inpatient evaluation and management (E&M) codes, and 5 outpatient E&M codes were evaluated.

RESULTS:

A total of 299 patients underwent VHR, 143 in 2022 and 156 in 2023. Average procedural VHR wRVUs increased from 9.6 in 2022 to 11.6 in 2023 (p < 0.001). Procedures involving myofascial advancement flaps or component separation techniques (53.8% vs 48.7%, p = 0.419) and wRVUs for the component separation procedures were similar between 2022 and 2023, respectively, 17.7 vs 16.1 (p = 0.419). The wRVUs associated with adjunctive procedures (mesh removal or placement) decreased from 3.3 to 0.6 (p < 0.001) in the post-2023 era. Postoperative E&M wRVUs increased in 2023 for postoperative inpatient (0.48) and postoperative outpatient (0.39) services, compared with 0 wRVUs in 2022. Overall, the total management including follow-up clinic visit adjusted wRVUs for hernia repair was similar between 2022 and 2023, respectively 30.7 vs 29.2 (p = 0.409).

CONCLUSIONS:

Procedural wRVUs for anterior abdominal hernia repair increased from 2022 to 2023 (p < 0.001) at a tertiary referral medical center. However, total wRVUs, including the operation and postoperative visits, remained unchanged.
Stress produces negative judgement bias in cuttlefish
Authors: Giancola-Detmering Sarah E. , Crook Robyn J.
Published: October 2024

Judgement bias tasks (JBTs) are used to assess the emotional state and welfare of animals in zoos, farms and laboratories, based on the interpretation of an ambiguous or intermediate cue. Animals in positive affective states are more likely to interpret the ambiguous cue positively, whereas animals experiencing negative affect are more likely to interpret ambiguous cues pessimistically. Here, we developed a modified JBT assay for the stumpy-spined cuttlefish,
Sepia bandensis
, to determine whether cuttlefish exhibit negative affective states resulting from external stressors. Positive and neutral visual cues were presented twice daily until animals learned to associate food with the reinforced visual cue. After training, one treatment group was exposed to combined exposure and handling stress produced by 6 days of impoverished housing and simulated net capture. Our control group received no stress experience. In test trials performed after the stress experience, stressed animals showed higher latencies to approach ambiguous cues, spent significantly less time in rooms with ambiguous cues once they entered, and were less likely to enter first into the ambiguous cue-paired room compared with controls. These behaviours suggest that stress induces pessimistic judgement bias in cuttlefish, the first indication of this capacity in cephalopods.
Plasmodesmata act as unconventional membrane contact sites regulating inter-cellular molecular exchange in plants
Authors: Pérez-Sancho Jessica , Smokvarska Marija , Dubois Gwennogan , Glavier Marie , Sritharan Sujith , Moraes Tatiana Souza , Moreau Hortense , Dietrich Victor , Platre Matthieu Pierre , Paterlini Andrea , Li Ziqiang Patrick , Fouillen Laetitia , Grison Magali S. , Cana-Quijada Pepe , Immel Françoise , Wattelet Valerie , Ducros Mathieu , Brocard Lysiane , Chambaud Clément , Luo Yongming , Ramakrishna Priya , Bayle Vincent , Lefebvre-Legendre Linnka , Claverol Stéphane , Zabrady Matej , Busch Wolfgang , Barberon Marie , Tilsner Jens , Helariutta Yrjö , Russinova Eugenia , Taly Antoine , Jaillais Yvon , Bayer Emmanuelle M.
Published: October 2024

Membrane contact sites (MCS) are fundamental for intracellular communication, but their role in intercellular communication remains unexplored. We show that in plants, plasmodesmata communication bridges function as atypical endoplasmic reticulum (ER)-plasma membrane (PM) tubular MCS, operating at cell-cell interfaces. Similar to other MCS, ER-PM apposition is controlled by a protein-lipid tethering complex, but uniquely, this serves intercellular communication. Combining high-resolution microscopy, molecular dynamics, pharmacological and genetic approaches, we show that cell-cell trafficking is modulated through the combined action of Multiple C2 domains and transmembrane domain proteins (MCTP) 3, 4, and 6 ER-PM tethers, and phosphatidylinositol-4-phosphate (PI4P) lipid. Graded PI4P amounts regulate MCTP docking to the PM, their plasmodesmata localization and cell-cell permeability. SAC7, an ER-localized PI4P-phosphatase, regulates MCTP4 accumulation at plasmodesmata and modulates cell-cell trafficking capacity in a cell-type specific manner. Our findings expand MCS’s functions in information transmission, from intracellular to intercellular cellular activities.

In brief

Plant intercellular communication is regulated via tubular membrane contact through PI4P binding-ER-PM tether MCTP proteins

Highlights

Plasmodesmata are unconventional ER/PM tubular contact sites located at cell-cell interface

Plasmodesmata operate as control valves, modulating ER-PM contacts to regulate transport

MCTP3, MCTP4, MCTP6 and PI4P tethering elements act as valve regulators

SAC7 PI4P phosphatase controls plasmodesmata MCS in a cell-type-specific manner
Multi-ancestry GWAS of Long COVID identifies immune-related loci and etiological links to chronic fatigue syndrome, fibromyalgia and depression
Authors: Chaudhary Ninad S. , Weldon Catherine H. , Nandakumar Priyanka ,   23andMe Research Team, Holmes Michael V. , Aslibekyan Stella
Published: October 2024

The etiology of Long COVID is poorly understood despite its estimated global burden of 65 million cases. There exists a paucity of genetic studies that can shed light on potential mechanisms leading to Long COVID. Using consented and genotyped data from 23andMe adult research participants, we conducted the largest multi-ancestry meta-analysis of genome-wide association studies of Long COVID across European (42,899 cases, 94,721 controls), Latinx (8,631 cases, 20,351 controls), and African-American (2,234 cases, 5,596 controls) genetic ancestry groups. GWAS of Long COVID identified three genome-wide significant loci (HLA-DQA1–HLA-DQB, ABO, BPTF–KPAN2–C17orf58). Functional analysis of these genes points to underlying immune and thrombo-inflammatory mechanisms. We present evidence of shared genetic architecture (genetic correlation p-value < 0.001) of Long COVID with thirteen phenotypes of similar symptomatology or pathophysiology. We identified potential causal roles from liability to chronic fatigue (Mendelian randomization OR=1.59, 95% CI[1.51,1.66]), fibromyalgia (OR=1.54, 95% CI[1.49,1.60]), and depression (OR=1.53, 95% CI[1.46,1.61]) with Long COVID, which replicated in the COVID-19 Host Genetics Initiative data, and which are unlikely to originate from collider bias. These findings can help identify populations vulnerable to Long COVID and inform future therapeutic approaches.
The genetic interaction map of the human solute carrier superfamily
Authors: Wolf Gernot , Leippe Philipp , Onstein Svenja , Goldmann Ulrich , Frommelt Fabian , Teoh Shao Thing , Girardi Enrico , Wiedmer Tabea , Superti-Furga Giulio
Published: October 2024

Solute carriers (SLCs), the largest superfamily of transporter proteins in humans with about 450 members, control the movement of molecules across membranes. A typical human cell expresses over 200 different SLCs, yet their collective influence on cell phenotypes is not well understood due to overlapping substrate specificities and expression patterns. To address this, we performed systematic pairwise gene double knockouts using CRISPR-Cas12a and -Cas9 in human colon carcinoma cells. A total of 1,088,605 guide combinations were used to interrogate 35,421 SLC-SLC and SLC-enzyme double knockout combinations across multiple growth conditions, uncovering 1,236 genetic interactions with a growth phenotype. Further exploration of an interaction between the mitochondrial citrate/malate exchanger SLC25A1 and the zinc transporter SLC39A1 revealed an unexpected role for SLC39A1 in metabolic reprogramming and anti-apoptotic signaling. This full-scale genetic interaction map of human SLC transporters is the backbone for understanding the intricate functional network of SLCs in cellular systems and generates hypotheses for pharmacological target exploitation in cancer and other diseases. The results are available atwww.resolute.eu/dashboards/genomics.
Decoding the chemical language of RiPPs from the untapped Archaea domain
Authors: Song Zhi-Man , Cai Cunlei , Gao Ying , Lin Xiaoqian , Yang Qian , Zhang Dengwei , Wu Gengfan , Liang Haoyu , Zhuo Qianlin , Zhang Junliang , Cai Peiyan , Jiang Haibo , Liu Wenhua , Li Yong-Xin
Published: October 2024

Chemical communication is crucial in ecosystems with complex microbial communities. However, the difficulties inherent to the cultivation of archaea have led to a limited understanding of their chemical language, especially regarding the structure diversity and function of secondary or specialized metabolites (SMs). Our comprehensive investigation into the biosynthetic potential of archaea, combined with metabolic analyses and the first report of heterologous expression in archaea, has unveiled the previously unexplored biosynthetic capabilities and chemical diversity of archaeal ribosomally synthesized and post-translationally modified peptides (RiPPs). We have identified twenty-four new lanthipeptides of RiPPs exhibiting unique chemical characteristics, including a novel subfamily featuring an unexplored type with diamino-dicarboxylic (DADC) termini, largely expanding the chemical landscape of archaeal SMs. This sheds light on the chemical novelty of archaeal metabolites and emphasizes their potential as an untapped resource for natural product discovery. Additionally, archaeal lanthipeptides demonstrate specific antagonistic activity against haloarchaea, mediating the unique biotic interaction in the halophilic niche. Furthermore, they showcase a new ecological role of RiPPs in enhancing the host’s motility by inducing the rod-shaped cell morphology and upregulating the archaellin gene expression, facilitating the archaeal interaction with abiotic environments. These discoveries broaden our understanding of archaeal chemical language and provide promising prospects for future exploration of SM-mediated interaction.

Abstract Figure
Structure of the F-tractin–F-actin complex
Authors: Shatskiy Dmitry , Sivan Athul , Wedlich-Söldner Roland , Belyy Alexander
Published: October 2024

F-tractin is a short peptide widely used to visualize the actin cytoskeleton in live eukaryotic cells. Similar to other actin-binding probes, F-tractin alters actin organization and impairs cell migration when expressed at high levels. In addition, the probe has been reported to directly induce actin bundling. To elucidate the mechanism behind these effects, we determined the structure of the F-tractin–F-actin complex using electron cryo-microscopy. Our analysis revealed that the F-tractin peptide consists of a flexible N-terminal region and an amphipathic C-terminal helix. The N-terminal part is completely dispensable for F-actin binding but is responsible for the actin bundling effect. The C-terminal helical region interacts with a hydrophobic pocket formed by two neighboring actin subunits, a region identified as an interface for many other actin-binding polypeptides, including Lifeact, the most widely used actin-binding probe. Thus, rather than contrasting F-tractin and Lifeact, our data indicate that these peptides have analogous modes of interaction with F-actin. Our study dissects the structural elements of F-tractin and provides a mechanistic basis for the selection and future development of actin probes.
Pseudohypoxia-stabilized HIF2⍺ transcriptionally inhibits MNRR1, a druggable target in MELAS
Authors: Purandare Neeraja , Pasupathi Vignesh , Xi Yue , Rajan Vikram , Vegh Caleb , Firestine Steven , Kozicz Tamas , Fribley Andrew M. , Grossman Lawrence I. , Aras Siddhesh
Published: October 2024

Abstract

The observation that amounts of the mitochondrial regulator MNRR1 (CHCHD2, AAG10, PARK22) are reduced in several pathologies, and that restoration of its level normalizes the pathological phenotype, prompted a search for compounds that could increase MNRR1 levels. High throughput screening of a 2400-compound drug and natural products library uncovered the antifungal drug nitazoxanide and its metabolite tizoxanide as effective enhancers of MNRR1 transcription. Using the mitochondrial disease MELAS (in which various mixtures, called heteroplasmy, of wild-type and mutant mitochondrial DNA (mtDNA) coexist) as a test, we showed that treating a cybrid MELAS model with tizoxanide could restore cellular respiration, enhance mitophagy, and, importantly, shift heteroplasmy toward more wild-type mtDNA. Furthermore, in MELAS patient fibroblasts, the compound could improve mitochondrial biogenesis, enhance autophagy, and protect the fibroblasts from LPS-induced inflammation. Chemical activation of MNRR1 is thus a potential strategy to improve mitochondrial deficits seen in MELAS. Investigation of the mechanism by which MNRR1 is reduced identified that two factors compete to regulate transcription at the MNRR1 promoter – RBPJκ, which stimulates it, and HIF2α, which inhibits it. In MELAS cells there is a pseudohypoxic state that stabilizes HIF2α, leading to transcriptional inhibition of MNRR1. Nitazoxanide reduces the levels of HIF2α by increasing the levels of PHD3, the prolyl hydroxylase that degrades HIF2α.
A filamentous scaffold for gene regulation
Authors: Rasmussen Tim , Küspert Jannik , Schönemann Lars , Geiger Dietmar , Böttcher Bettina
Published: October 2024

Proteins of the Drosophila behaviour/human splicing (DBHS) family are involved in many aspects of gene regulation and maintenance like transcription, splicing and DNA repair. The three known members of this family in humans, Non-POU domain-containing octamer-binding protein (NONO), splicing factor proline/glutamine rich (SFPQ), and paraspeckle protein component 1 (PSPC1), form homo- and heterodimers to fulfil these functions by mediating contacts between RNA, DNA, and other protein factors. The dimers can further dynamically oligomerise through α-helical coiled-coils to larger aggregates, which is crucial for many functions of DBHS proteins. While the atomic structures of the dimers are established, the native arrangement in higher oligomers was unknown. Here we present the structure of a filamentous NONO/SFPQ heterooligomer fromCricetulus griseusresolved by cryo-EM. Globular heterodimer domains are alternating on both sides of a strand that is stabilized by an interdigitating network of coiled-coil interactions. Two of these strands assemble into a double strand with only few interactions between them. The globular domains of SFPQ face the counter strand and form a groove while those of NONO face outwards. The different environments of NONO and SFPQ in the filament provide the basis for a differential functionality.

GRAPHICAL ABSTRACT
In-cell residue-resolved NMR of micromolar α-synuclein and tau at 310K
Authors: Chérot Hélène , Pred’homme Théophile , Theillet Francois-Xavier
Published: October 2024

Aggregates of non-globular proteins are associated to several degenerative disorders, e.g. α-synuclein and tau involved in Parkinson’s and Alzheimer’s diseases. Do these proteins suffer progressive changes in conformations and interactions in pathologic situations? In-cell NMR provides atomic-scale information in live cells but, until now, only at ~283 K in the case of unfolded proteins. Here, we report new labeling and acquisition methods enabling in-cell NMR at 310 K to study these proteins at micromolar concentrations, i.e. native cellular abundances. We used stable human cell lines expressing α-synuclein or tau upon induction in a culture medium supplemented with13C-labeled amino acids, or precursors thereof. Acquiring13Cα-13CO spectra permitted an early residue-resolved analysis of α-synuclein and tau at 310 K and <10 μM in HEK cells at 700 MHz. We detected disordered conformations and identical patterns of cellular interactions for α-synuclein wild-type and two mutants (F4A, A30P). Only the disordered N-terminus of tau was observable, even upon microtubule dismantling by colchicin. Our approach offers an excellent scalability -in signal and resolution-up to 1.2 GHz.13C-labeling and13C-detected NMR in live human cells are thus viable techniques for in-cell structural biology.
Using machine learning and centrifugal microfluidics at the point-of-need to predict clinical deterioration of patients with suspected sepsis within the first 24 h.
Authors: dos Santos Claudia , Malic Lidija , Zhang Peter , Plant Pamela , Clime Liviu , Nassif Christina , DaFonte Dillon , Haney Evan , Moon Byeong-Ui , Sit Victor , Brassard Daniel , Mournier Maxence , Chircher Eryn , Tsoporis James , Falsafi Reza , Bains Manjeet , Baker Andrew , Trahtemberg Uriel , Lukic Ljuboje , Marshall John , Geissler Matthias , Hancock Robert EW , Veres Teodor
Published: October 2024

Sepsis is the bodys dysfunctional response to infection associated with organ failure. Delays in diagnosis have a substantial impact on survival. Herein, samples from 586 in-house patients were used in conjunction with machine learning and cross-validation to narrow a gene expression signature of immune cell reprogramming to predict clinical deterioration in patients with suspected sepsis within the first 24 hours (h) of clinical presentation using just six genes (Sepset). The accuracy of the test (~90% in early intensive care unit (ICU) and 70% in emergency room patients) was validated in 3,178 patients from existing independent cohorts. A real-time reverse transcriptase polymerase chain reaction (RT-PCR)-based test was shown to have a 98% sensitivity in >230 patients to predict worsening of the sequential organ failure scores or admission to the ICU within the first 24 h following Sepset detection. A stand-alone centrifugal microfluidic instrument that integrates the entire automated workflow for detection of the Sepset classifier in whole blood using digital droplet PCR was developed and tested. This PREcision meDIcine for CriTical care (PREDICT) system had a high sensitivity of 92%, specificity of 89%, and an overall accuracy of 88% in identifying the risk of imminent clinical deterioration in patients with suspected sepsis.
Automated Transformation of Unstructured Cardiovascular Diagnostic Reports into Structured Datasets Using Sequentially Deployed Large Language Models
Authors: Shankar Sumukh Vasisht , Dhingra Lovedeep S , Aminorroaya Arya , Adejumo Philip , Nadkarni Girish N , Xu Hua , Brandt Cynthia , Oikonomou Evangelos K , Pedroso Aline F , Khera Rohan
Published: October 2024

Background

Rich data in cardiovascular diagnostic testing are often sequestered in unstructured reports, with the necessity of manual abstraction limiting their use in real-time applications in patient care and research.

Methods

We developed a two-step process that sequentially deploys generative and interpretative large language models (LLMs; Llama2 70b and Llama2 13b). Using a Llama2 70b model, we generated varying formats of transthoracic echocardiogram (TTE) reports from 3,000 real-world echo reports with paired structured elements, leveraging temporal changes in reporting formats to define the variations. Subsequently, we fine-tuned Llama2 13b using sequentially larger batches of generated echo reports as inputs, to extract data from free-text narratives across 18 clinically relevant echocardiographic fields. This was set up as a prompt-based supervised training task. We evaluated the fine-tuned Llama2 13b model, HeartDx-LM, on several distinct echocardiographic datasets: (i) reports across the different time periods and formats at Yale New Haven Health System (YNHHS), (ii) the Medical Information Mart for Intensive Care (MIMIC) III dataset, and (iii) the MIMIC IV dataset. We used the accuracy of extracted fields and Cohen’s Kappa as the metrics and have publicly released the HeartDX-LM model.

Results

The HeartDX-LM model was trained on randomly selected 2,000 synthetic echo reports with varying formats and paired structured labels, with a wide range of clinical findings. We identified a lower threshold of 500 annotated reports required for fine-tuning Llama2 13b to achieve stable and consistent performance. At YNHHS, the HeartDx-LM model accurately extracted 69,144 out of 70,032 values (98.7%) across 18 clinical fields from unstructured reports in the test set from contemporary records where paired structured data were also available. In older echo reports where only unstructured reports were available, the model achieved 87.1% accuracy against expert annotations for the same 18 fields for a random sample of 100 reports. Similarly, in expert-annotated external validation sets from MIMIC-IV and MIMIC-III, HeartDx-LM correctly extracted 201 out of 220 available values (91.3%) and 615 out of 707 available values (87.9%), respectively, from 100 randomly chosen and expert annotated echo reports from each set.

Conclusion

We developed a novel method using paired large and moderate-sized LLMs to automate the extraction of unstructured echocardiographic reports into tabular datasets. Our approach represents a scalable strategy that transforms unstructured reports into computable elements that can be leveraged to improve cardiovascular care quality and enable research.
Estimation of Direct and Indirect Polygenic Effects and Gene-Environment Interactions using Polygenic Scores in Case-Parent Trio Studies
Authors: Wang Ziqiao , Grosvenor Luke , Ray Debashree , Ruczinski Ingo , Beaty Terri H. , Volk Heather , Ladd-Acosta Christine , Chatterjee Nilanjan
Published: October 2024

Family-based studies provide a unique opportunity to characterize genetic risks of diseases in the presence of population structure, assortative mating, and indirect genetic effects. We propose a novel framework, PGS-TRI, for the analysis of polygenic scores (PGS) in case-parent trio studies for estimation of the risk of an index condition associated with direct effects of inherited PGS, indirect effects of parental PGS, and gene-environment interactions. Extensive simulation studies demonstrate the robustness of PGS-TRI in the presence of complex population structure and assortative mating compared to alternative methods. We apply PGS-TRI to multi-ancestry trio studies of autism spectrum disorders (Ntrio= 1,517) and orofacial clefts (Ntrio= 1,904) to establish the first transmission-based estimates of risk associated with pre-defined PGS for these conditions and other related traits. For both conditions, we further explored offspring risk associated with polygenic gene-environment interactions, and direct and indirect effects of genetically predicted levels of gene expression and metabolite traits.
A Decade of Progress in HIV, Malaria, and Tuberculosis Initiatives in Malawi
Authors: Mangal Tara Danielle , Molaro Margherita , Nkhoma Dominic , Colbourn Timothy , Collins Joseph H. , Janoušková Eva , Graham Matthew M. , Lin Ines Li , Mnjowe Emmanuel , Mwenyenkulu Tisungane E. , Mohan Sakshi , She Bingling , Tamuri Asif U. , Twea Pakwanja D. , Winskill Peter , Phillips Andrew , Mfutso-Bengo Joseph , Hallett Timothy B.
Published: October 2024

Objective

Huge investments in HIV, TB, and malaria (HTM) control in Malawi have greatly reduced disease burden. However, the joint impact of these services across multiple health domains and the health system resources required to deliver them are not fully understood.

Methods

An integrated epidemiological and health system model was used to assess the impact of HTM programmes in Malawi from 2010 to 2019, incorporating interacting disease dynamics, intervention effects, and health system usage. Four scenarios were examined, comparing actual programme delivery with hypothetical scenarios excluding programmes individually and collectively.

Findings

From 2010-2019, HTM programmes were estimated to have prevented 1.08 million deaths and 74.89 million DALYs. An additional 15,600 deaths from other causes were also prevented. Life expectancy increased by 13.0 years for males and 16.9 years for females.

The HTM programmes accounted for 24.2% of all health system interactions, including 157.0 million screening/diagnostic tests and 23.2 million treatment appointments. Accounting for the anticipated health deterioration without HTM services, only 41.55 million additional healthcare worker hours were required (17.1% of total healthcare worker time) to achieve these gains. The HTM programme eliminated the need for 123 million primary care appointments, offset by a net increase in inpatient care demand (9.4 million bed-days) that would have been necessary in its absence.

Conclusions

HTM programmes have greatly increased life expectancy, providing direct and spillover effects on health. These investments have alleviated the burden on inpatient and emergency care, which requires more intensive healthcare provider involvement.
Exploring the Relationship Between Education and Academic Ability in Childhood with Healthcare Utilisation in Adulthood: Findings from the Aberdeen Children of the 1950’s (ACONF)
Authors: Stannard S , Fraser SDS , Owen R , Berrington A , Paranjothy S , Alwan NA
Published: October 2024

Background

Interactions with secondary care, including multiple outpatient appointments and hospital admissions, represents a common and often burdensome aspect of healthcare utilisation for people living with multiple long-term conditions. Lifecourse factors such as education and academic ability may play a role in shaping the risk of healthcare utilisation later in adulthood. We explored the association between education and academic ability in childhood and both outpatient appointments and hospital admissions in adulthood, accounting for the mediating role of adult factors, including long-term conditions.

Method

The analytical sample consisted of 7183 participants in the Aberdeen Children of the 1950’s. Three outcomes were measured using routine healthcare records (SMR00/SMR001/SMR004) over a five-year period (2004-2008) using the ‘burden’ cut-offs of: (1) ≥5 outpatient appointments, (2) ≥2 hospital admissions, or (3) ≥3 outpatient appointments plus ≥1 hospital admission. We constructed a childhood (age 6-11) education and academic ability domain and calculated predicted risk scores of the three outcomes for each cohort member. Nested logistic regression models investigate the association between domain predicted risk scores and odds of each of the three outcomes accounting for childhood confounders (maternal age, Rutter behaviour, physical grade at birth, birthweight, sex mother’s pre-marital occupation, and father’s social class) and self-reported adult mediators, including body mass index, smoking, employment status, housing tenure, having long-term conditions, and age left school.

Result

Adjusting for childhood confounders, lower childhood education and academic ability was associated with ≥ 5 outpatient appointments (OR1.03 95%CI 1.01-1.05), ≥ 2 hospital admissions (OR1.04 95%CI 1.03-1.6) and combined ≥3 outpatient appointments plus ≥ 1 hospital admissions (OR1.04 95%CI 1.02-1.06). Accounting for adult mediators (including long-term conditions), associations remained statistically significant, but their effect sizes were slightly reduced. When age left school was included in the final model, the association between the exposure and the combined outpatient appointments and hospital admissions (OR1.02 95%CI 1.00-1.04), ≥ 2 hospital admissions (OR1.02 95%CI 0.99-1.05) and ≥ 5 outpatient appointments (OR1.01 95%CI 0.99-1.03) were attenuated.

Conclusions

Education and academic ability in early life may be related to the burden of multiple hospital admissions and outpatient appointments later in life. This relationship was not fully explained by accounting for multiple long-term conditions and other potential mediating factors in adulthood. However, the age at which the participant left school seems to substantially mediate this relationship underscoring the positive impact of time spent in formal education on health during the lifecourse.
The Double Burden of TB/HIV co-infection: Evidence from Central Region of Ghana
Authors: Lugutuah Martin Badagda , Boateng Daniel , Konadu Phenehance Effah , Okoh-Owusu Marion , Nakua Emmanuel Kwaku
Published: October 2024

The synergistic burden of Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) is a significant health risk in low and middle-income economies. This study estimated the prevalence and predictors of TB/HIV co-infection in the Central region of Ghana. Using a cross-sectional study, we randomly selected five districts and employed a retrospective records review of TB cases registered between 2019 and 2022. A stepwise multivariate logistic regression was used to identify important predictors of TB/HIV co-infection. The overall prevalence of TB/HIV co-infection in the study period was 10.92%. This was highest at 55 (15.54%) among the age group 25 – 40 years. The burden of TB/HIV co-infection was highest at 36 (19.25%) in the Gomoa East district and lowest at 30 (8.38%) in Mfantseman municipal. In the adjusted model, TB patients 60 years and above had 78% lower odds of being HIV infected (AOR: 0.22; 95% CI: 0.08 – 0.66). Males were 37% less likely to be co-infected (AOR: 0.63; 95% CI: 0.42 – 0.96). Also, pulmonary-positive TB patients were 5 times more likely to be co-infected (AOR: 5.04; 95% CI: 1.71 – 14.85). Furthermore, TB patients who died in the course of treatment were 2 times more likely to be infected with HIV (AOR:2.15; 95% CI: 1.05 – 4.40). TB patients treated in the Gomoa East district were 2.7 times more likely to be HIV-infected (AOR: 2.67; 95% CI: 1.34 – 5.35). The burden of TB/HIV co-infection was moderate in the study sites and significantly associated with age, sex, bacteriological confirmation, type of TB, treatment outcome, treatment district, and year of treatment. There is a need for targeted interventions such as community awareness creation that is specific to sexually active female groups. Efforts to improve TB case detection such as health facility-based screening of patients with Respiratory Tract Infections (RTI) and contact tracing should be intensified.
Genetic architecture of cardiac structure and function
Authors: Lu Chang , McGurk Kathryn A , Zheng Sean L , de Marvao Antonio , Inglese Paolo , Bai Wenjia , Ware James S , O’Regan Declan P
Published: October 2024

The heart is the first organ to develop in the mammalian embryo and its architecture is dependent on the spatial organisation of diverse cell types and morphogenetic transformations shaped by biophysical forces. Cardiac remodelling occurs in the mature heart and is a cascade of adaptations in response to stress that are primed in early life. A key question remains as to the processes that regulate the geometry and motion of the heart, and how it adapts to stress. Here we performed a spatially-resolved genome-wide association study of three-dimensional cardiac traits in 47,549 participants of UK Biobank. We found 42 loci associated with cardiac structure and contractility many of which reveal patterns of spatial organisation in the heart. Newly discovered loci relate to pathways implicated in cardiomyocyte differentiation and chamber development as well as those linked to cardiomyopathies. These findings provide a comprehensive description of the pathways that orchestrate heart development and mechanisms that regulate adaptation in health and disease.
A Large-Scale, International Cross-Sectional Survey of Published Pediatrics Authors: Perceptions of Complementary, Alternative, and Integrative Medicine
Authors: Ng Jeremy Y. , Deol Gursimran , Anheyer Dennis , Cramer Holger
Published: October 2024

Background

The use of complementary, alternative, and integrative medicine (CAIM) is commonly used among pediatric patients for various conditions. Pediatrics clinicians and researchers’ perceptions towards the incorporation of CAIM therapies have varied. This study aims to investigate the perceptions of both pediatrics researchers and clinicians regarding CAIM.

Methods

We conducted a large-scale, international cross-sectional online survey with published pediatrics authors who have published their work in pediatrics medical journals that are indexed in MEDLINE. In total, 34 494 researchers and clinicians were invited to complete the survey. The survey recorded respondents’ perceptions on various CAIM therapies. Descriptive statistics were generated from the quantitative survey results. A thematic analysis was conducted for responses to open ended questions.

Results

In total, 731 pediatrics clinicians and/or researchers responded to the survey, with about half of the respondents being faculty members/principal investigators (56.10%) and/or clinicians (43.45%) and from the Americas (46.56%) or Europe (30.53%). Over half of the respondents viewed mind-body therapies favourably (62.01%) and the fewest respondents held favourable perceptions of biofield therapies (6.98%). Respondents agreed or strongly agreed that there is value in conducting further research on CAIM therapies (85.52%) and disagreed or strongly disagreed that they felt comfortable recommending most CAIM therapies to patients (64.83%). A thematic analysis of our findings demonstrates that many pediatrics clinicians and/or researchers support further research on CAIM.

Conclusion

The findings from this study demonstrate that pediatrics clinicians and researchers have varying perceptions towards CAIM therapies. Respondents had the most positive perceptions of mind-body therapies and felt they did not have adequate training on CAIM. Further research is needed to establish more evidence-based educational resources on CAIM.
Epigenetic and Genetic Profiling of Comorbidity Patterns among Substance Dependence Diagnoses
Authors: Pathak Gita A. , Pietrzak Robert H. , Lacobelle AnnMarie , Overstreet Cassie , Wendt Frank R. , Deak Joseph D. , Friligkou Eleni , Nunez Yaira , Montalvo-Ortiz Janitza L. , Levey Daniel F. , Kranzler Henry R. , Gelernter Joel , Polimanti Renato
Published: October 2024

Objective

This study investigated the genetic and epigenetic mechanisms underlying the comorbidity patterns of five substance dependence diagnoses (SDs; alcohol, AD; cannabis, CaD; cocaine, CoD; opioid, OD; tobacco, TD).

Methods

A latent class analysis (LCA) was performed on 31,197 individuals (average age 42±11 years; 49% females) from six cohorts to identify comorbid DSM-IV SD patterns. In subsets of this sample, we tested SD-latent classes with respect to polygenic burden of psychiatric and behavioral traits and epigenome-wide changes in three population groups.

Results

An LCA identified four latent classes related to SD comorbidities: AD+TD, CoD+TD, AD+CoD+OD+TD (i.e., polysubstance use, PSU), and TD. In the epigenome-wide association analysis,SPATA4cg02833127 was associated with CoD+TD, AD+TD, and PSU latent classes. AD+TD latent class was also associated with CpG sites located onARID1B,NOTCH1,SERTAD4,andSIN3B, while additional epigenome-wide significant associations with CoD+TD latent class were observed inANO6andMOV10genes. PSU-latent class was also associated with a differentially methylated region inLDB1. We also observed shared polygenic score (PGS) associations for PSU, AD+TD, and CoD+TD latent classes (i.e., attention-deficit hyperactivity disorder, anxiety, educational attainment, and schizophrenia PGS). In contrast, TD-latent class was exclusively associated with posttraumatic stress disorder-PGS. Other specific associations were observed for PSU-latent class (subjective wellbeing-PGS and neuroticism-PGS) and AD+TD-latent class (bipolar disorder-PGS).

Conclusions

We identified shared and unique genetic and epigenetic mechanisms underlying SD comorbidity patterns. These findings highlight the importance of modeling the co-occurrence of SD diagnoses when investigating the molecular basis of addiction-related traits.
Incidence of Pulmonary Hypertension in the Echocardiography Referral Population
Authors: Garry Jonah David , Kundu Suman , Annis Jeffrey , Alcorn Charles , Eden Svetlana , Smith Emily , Greevy Robert , Maron Bradley A. , Freiberg Matthew S. , Brittain Evan L.
Published: October 2024

Rationale: Incidence rates for pulmonary hypertension using diagnostic data in patients with cardiopulmonary disease are not known. Objectives: To determine incidence rates of, risk factors for, and mortality hazard associated with pulmonary hypertension among patients referred for transthoracic echocardiography Methods: Retrospective cohort study using data from the Veterans Health Administration (1999-2020) and Vanderbilt University Medical Center (1994-2020). Pulmonary hypertension was defined as pulmonary artery systolic pressure >35mmHg with prevalent cases excluded. Heart failure and chronic obstructive pulmonary disease were the primary exposures of interest. The primary outcome was incident pulmonary hypertension. Secondarily, we examined mortality rate following incident diagnosis. Measurements and Main Results: We identified 245,067 VA patients (94% male, 20% Black) and 117,526 Vanderbilt patients (46% male, 11% Black) without pulmonary hypertension, of whom 38,882 VA patients and 8,061 Vanderbilt patients developed pulmonary hypertension. Only 18-19% of patients with echo-based pulmonary hypertension also had a diagnostic code. Hazard of pulmonary hypertension was 4-fold higher in patients with heart failure and chronic obstructive pulmonary disease compared to patients without either. Mortality rates increased from pulmonary artery systolic pressure of 35mmHg to 45mmHg then plateaued. Independent risk factors for incident pulmonary hypertension included older age, male sex, black race, and cardiometabolic comorbidities. Conclusions: Pulmonary hypertension incidence rates estimated by diagnostic data are higher than code-based rates. Heart failure and chronic obstructive pulmonary disease strongly associate with incident pulmonary hypertension. Pulmonary artery systolic pressure >45mmHg at diagnosis is associated with high mortality. New pulmonary hypertension on echocardiography is an important prognostic sign.
Incidence of Right Ventricular Dysfunction in an Echocardiographic Referral Cohort
Authors: Garry Jonah D. , Huang Shi , Annis Jeffrey , Kundu Suman , Hemnes Anna , Freiberg Matthew , Brittain Evan L.
Published: October 2024

Introduction

Incidence rates (IRs) of RV dysfunction (RVD) are unknown. We examined the rates, risk factors, and heart failure (HF) hospitalization hazard associated with incident RVD in patients referred for Transthoracic Echocardiogram (TTE).

Methods

In this retrospective cohort study, we extracted tricuspid regurgitant velocity (TRV) and tricuspid annular systolic plane excursion (TAPSE) from TTEs at Vanderbilt (2010-2023). We followed patients from their earliest TTE with normal RV function (TAPSE≥17mm) and a reported TRV. The primary outcome was new RVD (TAPSE<17mm), and the secondary outcome was HF hospitalization after second TTE. Poisson regression and multivariable cox models estimated IRs and hazard ratios, adjusted for demographics, comorbidities, and TTE measures.

Results

Among 45,753 patients (63 years [IQR 50-72], 45% Male, 13% Black) meeting inclusion criteria, 13,735 (30.1%) underwent a follow up TTE and 4,198 (9.2%) developed RVD. The IR of RVD in the full cohort was 3.2/100 person/years (95%CI 3.1-3.3) and 8.2 (95%CI 8.0-8.5) in the repeat TTE cohort. IRs increased with rising RVSP. Risk factors for incident RVD were most prominently HF (HR 1.88; 95%CI 1.75–2.03), left-sided valvular disease (HR 1.68; 95%CI 1.53–1.85), and other cardiovascular comorbidities. Baseline RVSP >35 mmHg associated with TAPSE decline over time. Incident RVD increased hazard of HF hospitalization (HR 2.02; 95%CI 1.85-2.21). Hazard of HF hospitalization increased when TAPSE declined by ≥5mm.

Conclusions

RVD incidence is substantial among patients referred for TTE. Clinical monitoring is warranted if RVSP >35mmHg. Cardiovascular comorbidities drive RVD in this population. Incident RVD associates with increased hazard of HF hospitalization.