bluuebunny/crossref_metadata_2025 huggingface dataset:
Synaptic and cognitive impairment associated with L444P heterozygous glucocerebrosidase mutation
Authors: Lado Wudu , Ham Ahrom , Li Hongyu , Zhang Hong , Chang Audrey Yuen , Sardi Sergio Pablo , Alcalay Roy N , Arancio Ottavio , Przedborsky Serge , Tang Guomei
Published: November 2024

Cognitive impairment is a common but poorly understood non-motor aspect of Parkinson’s disease, negatively affecting patient’s functional capacity and quality of life. The mechanisms underlying cognitive impairment in Parkinson’s disease are still elusive, limiting treatment and prevention strategies.

This study investigates the molecular and cellular basis of cognitive impairment associated with heterozygous mutations in GBA1, the strongest risk gene for Parkinson’s disease that encodes glucocerebrosidase (GCase), a lysosome enzyme that degrades the glycosphingolipid glucosylceramide into glucose and ceramide. Using a Gba1L444P/+ mouse model, we provide evidence that L444P heterozygous Gba1 mutation (L444P/+) causes hippocampus-dependent spatial and reference memory deficits independently of α-synuclein (αSyn) accumulation, GCase lipid substrate accumulation, dopaminergic dysfunction and motor deficits. The mutation disrupts hippocampal synaptic plasticity and basal synaptic transmission by reducing the density of hippocampal CA3-CA1 synapses, a mechanism that is dissociated from αSyn-mediated presynaptic neurotransmitter release. Using a well-characterized Thy1-αSyn pre-manifest Parkinson’s disease mouse model overexpressing wild type human αSyn, we find that the L444P/+ mutation exacerbates hippocampal synaptic αSyn accumulation, synaptic and cognitive impairment in young Gba1L444P/+:Thy1-αSyn double mutant animals. With age, Thy1-αSyn mice manifest motor symptoms, and the double mutant mice exhibit more exacerbated synaptic and motor impairment than the Thy1-αSyn mice.

Taken together, our results suggest that heterozygous L444P GBA1 mutation alone perturbs hippocampal synaptic structure and function, imposing a subclinical pathological burden for cognitive impairment. When co-existing αSyn overexpression is present, heterozygous L444P GBA1 mutation interacts with αSyn pathology to accelerate Parkinson’s disease-related cognitive impairment and motor symptoms.
Germline alteration analysis reveals EPHB4R91H mutation as a key player in multiple primary lung tumors
Authors: Li Jing , Li Yanan , Wang Xinjuan , Zhou Zhigang , Li Xiangnan , Yue Songwei , Wang Huaqi , Yang Ming , Zhang Guojun
Published: November 2024

Multiple primary lung tumors are garnering attention from clinicians, with adenocarcinoma emerging as the predominant histological type. Because of the heterogeneity and diffuse distribution of lesions in the same patient, the treatment of multiple primary lung adenocarcinoma (MPLA) is a significant challenge. As a kind of variation unaffected by tumor heterogeneity, germline alterations may play a key role in the development of MPLA. Here, whole-exome sequencing of peripheral blood was employed to obtain germline alteration data. Intergroup comparative analyses on rare and deleterious alterations of MPLA, solitary lung adenocarcinoma, and healthy individuals in an MPLA family were performed to clarify the candidate alterations. Whole-exome sequencing and targeted Sanger sequencing were performed in 27 disseminated MPLA patients to detect the mutation site that had been screened. A rare and deleterious germline alteration, EPHB4R91H, was found in all of the patients of an MPLA family and a patient with disseminated MPLA. It was revealed that EPHB4R91H was able to enhance the proliferation, migration, and invasion ability of A549 cells through increased binding affinity to ephrinB2, which in turn activated the EPHB4/ERK/JNK/MAPK pathway. Our findings corroborate that germline alterations are involved in the development of MPLA. And it was found for the first time that the EPHB4R91H mutation promotes the development of MPLA by enhancing its affinity for ephrinB2 and thereby active EPHB4/ERK/JNK/MAPK pathway.
Monitoring of nonspatial information within working memory in the common marmoset (Callithrix jacchus)
Authors: Zlatkina Veronika , Frey Stephen , Petrides Michael
Published: November 2024

The mid-dorsolateral prefrontal cortical region (areas 46 and 9/46) is critical for the monitoring of information in working memory both in the macaque monkey brain and the human brain. The presence of this cytoarchitectonic region in the New World marmoset brain was in debate, but recent anatomical evidence demonstrated a limited area 46. This finding raised the question of the extent to which the marmoset brain can support the cognitive control process of monitoring information within working memory. This cognitive control process was assessed in adult marmosets and was shown to be limited to the monitoring of only two items in contrast to macaque monkeys, who can monitor as many as five items in working memory. The results are consistent with the limited development of the relevant prefrontal region in the marmoset and contribute to understanding the evolution of higher cognitive control processes in the primate brain.
Catalytic construction of stereogenic boron center on BODIPY via enantioselective Suzuki–Miyaura coupling
Authors: Kondo Aiko , Takano Hideaki , Shinokubo Hiroshi
Published: November 2024

Catalytic and enantioselective construction of the boron-stereogenic center is challenging due to the instability of the tetracoordinate boron center. We herein report the enantioselective intermolecular Suzuki–Miyaura coupling of dichloro BODIPY through desymmetrization. The mechanistic study reveals that kinetic resolution plays an important role in the improvement of enantioselectivity.
Association Between Use of a Voluntary Isolation Center and Reduced Household SARS-CoV-2 Transmission: A Matched Cohort Study From Toronto, Canada
Authors: Brown Kevin A , Ulloa Ana Cecilia , Buchan Sarah A , Daneman Nick , Gournis Effie , Laxer Rachel , Schwartz Kevin L , Edwards Jocelyn
Published: November 2024

Background

Throughout the coronavirus disease 2019 (COVID-19) pandemic, many jurisdictions established isolation centers to help reduce household transmission; however, few real-world studies support their effectiveness. We compared transmission among households where first cases used the Toronto Voluntary Isolation Centre (TVIC) with households that received routine self-isolation guidance, prior to widespread vaccine availability.

Methods

Households with a first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case that had symptom onset between September 2020 and March 2021 and that used TVIC were propensity score matched with up to 10 self-isolation households. Follow-up began for TVIC households on the day after check-in or, for matched self-isolation households, the equivalent delay since first-case symptom onset. The outcome, 28-day secondary attack rate, was analyzed using proportional hazards models.

Results

A total of 303 TVIC households were matched with 2943 self-isolation households. Median duration from first-case symptom onset to TVIC check-in was 3 days (interdecile range [IDR] = 1–6); median check-out date was 11 days after onset (IDR = 10–13). The attack rate among TVIC households was 5.2% (53/1015) compared with 8.4% (787/9408) among self-isolation households (hazard ratio [HR] = 0.50; 95% confidence interval [CI], .28–.90). Greater reductions were observed when first cases isolated sooner after symptom onset (HR = 0.37; 95% CI, .13–1.04) and in larger (HR = 0.30; 95% CI, .14–.67) and more crowded (HR = 0.34; 95% CI, .15–.77) households.

Conclusions

Use of a voluntary isolation center was associated with a 50% reduction in household SARS-CoV-2 prior to the availability of vaccines. Beyond SARS-CoV-2, voluntary isolation centers may help control resurgences of other communicable infections or future pandemic pathogens, particularly for individuals who experience difficulties isolating.
Temporomandibular joint assessment in MRI images using artificial intelligence tools: where are we now? A systematic review
Authors: Manek Mitul , Maita Ibraheem , Bezerra Silva Diego Filipe , Pita de Melo Daniela , Major Paul W , Jaremko Jacob L , Almeida Fabiana T
Published: November 2024

Objectives

To summarize the current evidence on the performance of artificial intelligence (AI) algorithms for the temporomandibular joint (TMJ) disc assessment and TMJ internal derangement diagnosis in magnetic resonance imaging (MRI) images.

Methods

Studies were gathered by searching 5 electronic databases and partial grey literature up to May 27, 2024. Studies in humans using AI algorithms to detect or diagnose internal derangements in MRI images were included. The methodological quality of the studies was evaluated using the Quality Assessment Tool for Diagnostic of Accuracy Studies-2 (QUADAS-2) and a proposed checklist for dental AI studies.

Results

Thirteen studies were included in this systematic review. Most of the studies assessed disc position. One study assessed disc perforation. A high heterogeneity related to the patient selection domain was found between the studies. The studies used a variety of AI approaches and performance metrics with CNN-based models being the most used. A high performance of AI models compared to humans was reported with accuracy ranging from 70% to 99%.

Conclusions

The integration of AI, particularly deep learning, in TMJ MRI, shows promising results as a diagnostic-assistance tool to segment TMJ structures and classify disc position. Further studies exploring more diverse and multicentre data will improve the validity and generalizability of the models before being implemented in clinical practice.
Preparing for downstream tasks in artificial intelligence for dental radiology: a baseline performance comparison of deep learning models
Authors: Fernandes Fara A , Ge Mouzhi , Chaltikyan Georgi , Gerdes Martin W , Omlin Christian W
Published: November 2024

Objectives

To compare the performance of the convolutional neural network (CNN) with the vision transformer (ViT), and the gated multilayer perceptron (gMLP) in the classification of radiographic images of dental structures.

Methods

Retrospectively collected two-dimensional images derived from cone beam computed tomographic volumes were used to train CNN, ViT, and gMLP architectures as classifiers for four different cases. Cases selected for training the architectures were the classification of the radiographic appearance of maxillary sinuses, maxillary and mandibular incisors, the presence or absence of the mental foramen, and the positional relationship of the mandibular third molar to the inferior alveolar nerve canal. The performance metrics (sensitivity, specificity, precision, accuracy, and f1-score) and area under the curve (AUC)—receiver operating characteristic and precision-recall curves were calculated.

Results

The ViT with an accuracy of 0.74-0.98, performed on par with the CNN model (accuracy 0.71-0.99) in all tasks. The gMLP displayed marginally lower performance (accuracy 0.65-0.98) as compared to the CNN and ViT. For certain tasks, the ViT outperformed the CNN. The AUCs ranged from 0.77 to 1.00 (CNN), 0.80 to 1.00 (ViT), and 0.73 to 1.00 (gMLP) for all of the four cases.

Conclusions

The ViT and gMLP exhibited comparable performance with the CNN (the current state-of-the-art). However, for certain tasks, there was a significant difference in the performance of the ViT and gMLP when compared to the CNN. This difference in model performance for various tasks proves that the capabilities of different architectures may be leveraged.
Incidence, Disease Burden, and Clinical Presentation of Patients Newly Diagnosed With Inflammatory Bowel Disease in a Population-Based Inception Cohort
Authors: Attauabi Mohamed , Madsen Gorm Roager , Bendtsen Flemming , Seidelin Jakob Benedict , Burisch Johan
Published: November 2024

Background and Aims

Emerging data indicate a stabilizing incidence of inflammatory bowel diseases (IBD), including ulcerative colitis (UC), Crohn’s disease (CD), and IBD unclassified (IBDU) in Western countries. We aimed to investigate the incidence of IBD, its initial clinical presentation, and patient-reported burden.

Methods

Copenhagen IBD Inception Cohort is a prospective, population-based cohort of patients with newly diagnosed IBD according to the ECCO guidelines in the period between May 2021 and May 2023, within a catchment area covering 20% of the Danish population.

Results

Based on 554 patients (UC: 308, CD: 201, and IBDU: 18), the incidence rates per 100 000 person-years were as follows: IBD: 23.4 (95% confidence interval, 21.5–25.4), UC: 14.0 (12.6–15.6), CD: 8.6 (7.4–9.8), and IBDU: 0.8 (0.5–1.3). The median diagnostic delay was significantly shorter for UC (2.5 months [interquartile range {IQR} 1–6]) than for CD (5 months [IQR 1.5–11], p < 0.01). Moderate-to-severe disability was reported by 34% of CD patients and 22% of UC patients (p = 0.01), severe fatigue by 30% and 26% (p = 0.43), and severely impaired health-related quality of life (HRQoL) by 43% and 30% of patients, respectively (p = 0.01). Hospitalization rates (UC: 20%, CD: 34%, p < 0.01), and need for immunomodulators, biologics, or surgery within 3 months of diagnosis, were high in both UC (3%, 7%, and 37%, respectively) and CD (31%, 18%, and 10%, respectively).

Conclusions

We found a high incidence of IBD in Copenhagen with a substantial disease burden characterized by early and high requirements for advanced therapies and high rates of fatigue, disability, and impaired HRQoL at diagnosis.
National health expenditure per capita is associated with CRT implantation practice: findings from the ESC CRT Survey II with 11 088 patients
Authors: Normand Camilla , Bogale Nigussie , Linde Cecilia , Tsintzos Stelios , Ihara Zenichi , Dickstein Kenneth
Published: November 2024

Aims

Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in selected patients with heart failure (HF) and electrical dyssynchrony. This treatment receives class IA recommendations in European Society of Cardiology (ESC) guidelines. However, despite these strong recommendations, CRT implantation practice varies greatly in Europe. The purpose of the sub-analysis of CRT Survey II data was to describe how countries’ health per capita expenditure affects CRT implantation practice.

Methods and results

Between 2015 and 2016, two ESC associations, European Heart Rhythm Association and Heart Failure Association, conducted the CRT Survey II, a survey of CRT implantations in 11 088 patients in 42 ESC member states. We analysed CRT patient selection and guideline adherence in those countries according to high or low health expenditure per capita. There were 21 high health expenditure countries (n = 6844 patients) and 21 (n = 3852) with low health expenditure. The countries with the lowest health expenditure were more likely to implant CRT in patients who had strong guideline recommendations for implantation, younger patients and those recently hospitalized for HF or with symptomatic HF (67% vs. 58%, P < 0.001). The ratio of CRT-Pacemaker (CRT-P) to CRT-Defibrillator (CRT-D) was similar in both spending groups, as was the percentage of CRT implantation in women.

Conclusion

CRT Survey II has demonstrated a non-uniform delivery of healthcare. Countries with low health expenditure per capita appear to be reserving CRT therapy for younger patients, those with class IA indication and patients with more severe symptoms of heart failure.
Clinical stage IA non-small cell lung cancer with occult pathologic N1 and N2 disease after segmentectomy: does a completion lobectomy justify?
Authors: Luo Xun , Hayanga Jeremiah William Awori , Mehaffey James Hunter , Lamb Jason , Campbell Stuart , Reddy Shalini , Badhwar Vinay , Toker Alper
Published: November 2024

OBJECTIVES

When final pathology shows pathologic N1 or N2 disease after a pulmonary segmentectomy for early stage non-small cell lung cancer (NSCLC), completion of lobectomy could be considered and recommended as an option for treatment. We explored outcomes after segmentectomy for clinical stage IA NSCLC with occult pN1 or pN2 disease.

METHODS

We identified clinical stage IA NSCLC undergoing segmentectomy or lobectomy from the National Cancer Database (NCDB) between 2010 and 2020. We categorized patients by pathologic N diseases (pN0/pN1/pN2). We compared segmentectomy to lobectomy adjusting for patient and clinical characteristics. We explored survival using time-varied Cox regression, 30-day, 90-day mortality and unplanned 30-day readmission using logistic regression, and length of stay using Poisson regression.

RESULTS

Of 123 085 clinical IA NSCLC, 7.9% underwent segmentectomy. Pathology showed 2.8% pN1 and 1.9% pN2 after segmentectomy, and 6.5% pN1 and 3.7% pN2 after lobectomy. For pN1, segmentectomy conferred 33% better survival within 2 years (aHR = 0.67, P = 0.03), but similar survival after 2 years (aHR = 1.06, P = 0.7). For pN2, segmentectomy had similar survival with lobectomy (aHR = 0.96, P = 0.7). For all clinical IA NSCLC, segmentectomy was associated with lower 30-day mortality (aOR = 0.55, P < 0.001), 90-day mortality (aOR = 0.57, P < 0.001), readmission (aOR = 0.86, P = 0.01) and shorter length of stay (aRR = 0.76, P < 0.001) than lobectomy.

CONCLUSIONS

Outcomes after segmentectomy for clinical stage IA NSCLC may be associated with better short-term mortality, readmission rate and length of stay. Survival with occult pN1 and pN2 after segmentectomy is at least equivalent to lobectomy in completely resected clinical stage IA patients. A completion lobectomy may not be needed after pN1 and N2 findings after the permanent pathology was released.
Prone position in obese patients with acute respiratory distress syndrome after cardio-thoracic surgery
Authors: Bouteau Astrid , Sarfati Celine , Cachanado Marine , Perrier Johann , Imbert Audrey , Genty Thibaut , Stéphan François
Published: November 2024

OBJECTIVES

Prone positioning (PP) has benefits in patients with acute respiratory distress syndrome. The objective of this study was to compare the effects and complications of PP in obese versus non-obese patients with moderate-to-severe acute respiratory distress syndrome after cardiothoracic surgery.

METHODS

We retrospectively analysed a database established in 2014–2021 in an intensive care unit. The primary end point was the change in PaO2/FiO2 induced by PP. Secondary end points included pressure ulcers, mediastinitis and intensive care unit mortality. The groups with versus without obesity (body mass index >30 kg/m2) were compared, and a mixed linear model was built to identify factors associated with the PaO2/FiO2 change.

RESULTS

81 patients with acute respiratory distress syndrome (36 with vs 45 without obesity) and 189 PP sessions were included. PP duration was 17.2 ± 4.5 h in obese and 18.0 ± 3.8 h in non-obese patients (P = 0.23). Mean number of sessions was 2.6 ± 1.4 in obese and 2.1 ± 1.3 in non-obese patients (P = 0.10). Median PaO2/FiO2 increase after the 1st PP session was 75.0% [14.5–123.0] and 72% [15.5–130.5] in the groups with versus without obesity (P = 0.67). Stage 3/4 pressure ulcers were more common in the obese group (44.4% vs 22.2%; P = 0.03) and occurred chiefly on the face. No significant differences between the obese and non-obese groups were found for mediastinitis (16.7% vs 8.9%, P = 0.33) or intensive care unit mortality (22% vs 20%, P = 0.81).

CONCLUSIONS

Improvement of oxygenation was not statistically different between patients with versus without obesity. Pressure ulcers were more common in the obese group, whereas mediastinitis was not. No patient experienced wound dehiscence.
Cardiovascular magnetic resonance imaging in mitral valve disease
Authors: Garg Pankaj , Pavon Anna Giulia , Penicka Martin , Uretsky Seth
Published: November 2024

This paper describes the role of cardiovascular magnetic resonance (CMR) imaging in assessing patients with mitral valve disease. Mitral regurgitation (MR) is one of the most prevalent valvular heart diseases. It often progresses without significant symptoms, leading to left ventricular overload, dysfunction, frequent decompensated heart failure episodes, and excess mortality. Cardiovascular magnetic resonance assessment is recommended for MR when routine ultrasound imaging information is insufficient or discordant. A well-planned CMR can provide an in-depth assessment of the mitral valve apparatus, leaflet morphology, and papillary muscles. In addition, it can precisely inform the impact of MR on left atrial and ventricular remodelling. The review aims to highlight established and emerging techniques for morphological assessment, flow assessment (including regurgitation and stenosis), myocardial assessment, and haemodynamic assessment of mitral valve disease by CMR. It also proposes a simplified clinical flow chart for CMR assessment of the mitral valve.
Hill-Robertson interference may bias the inference of fitness effects of new mutations in highly selfing species
Authors: Daigle Austin , Johri Parul
Published: November 2024

The accurate estimation of the distribution of fitness effects (DFE) of new mutations is critical for population genetic inference but remains a challenging task. While various methods have been developed for DFE inference using the site frequency spectrum of putatively neutral and selected sites, their applicability in species with diverse life history traits and complex demographic scenarios is not well understood. Selfing is common among eukaryotic species and can lead to decreased effective recombination rates, increasing the effects of selection at linked sites, including interference between selected alleles. We employ forward simulations to investigate the limitations of current DFE estimation approaches in the presence of selfing and other model violations, such as linkage, departures from semidominance, population structure, and uneven sampling. We find that distortions of the site frequency spectrum due to Hill-Robertson interference in highly selfing populations lead to mis-inference of the deleterious DFE of new mutations. Specifically, when inferring the distribution of selection coefficients, there is an overestimation of nearly neutral and strongly deleterious mutations and an underestimation of mildly deleterious mutations when interference between selected alleles is pervasive. In addition, the presence of cryptic population structure with low rates of migration and uneven sampling across subpopulations leads to the false inference of a deleterious DFE skewed towards effectively neutral/mildly deleterious mutations. Finally, the proportion of adaptive substitutions estimated at high rates of selfing is substantially overestimated. Our observations apply broadly to species and genomic regions with little/no recombination and where interference might be pervasive.
The presentation and treatment of Dupuytren’s disease in Dutch general practitioner care
Authors: van Straalen Roel J M , Broekstra Dieuwke C , Werker Paul M N , de Boer Michiel R
Published: November 2024

Background

When research and management of Dupuytren’s disease (DD) shift from symptom relief to preventing contractures, general practitioner (GP) care may become more central to treatment. However, the presentation and course of DD in GP care are underexplored and this has been recognized as a knowledge gap that hinders effective treatment decisions. This study is the first to map the trajectory of DD patients in GP care.

Methods

Using electronic health records from Dutch general practices in a regional research network, we conducted a registration-based cohort study in a dynamic population. Descriptive statistics detailed patient demographics, number of contacts, and symptoms per contact. The time and number of contacts before diagnosis were also analysed. Sankey diagrams illustrated the relationship between management options and symptoms.

Results

Over a 16-year period, 84% of patients with a DD diagnosis had visited their GP for this reason, with 73% only having one GP contact. The diagnosis was made at first contact for 93% of patients. Initial contacts often reported a lump (57.3%), but this symptom was less frequent in subsequent visits. ‘Daily life impairment’ increased after the first contact. The most common management options were referral to secondary care (37.7%) and watchful waiting (35.1%).

Conclusion

The diagnosis and management of DD in GP care are in line with the current guidelines. Less than half of the DD patients were referred to secondary care during follow-up. This may give room for preventive treatment that limits progression. Future studies should focus on the accuracy of diagnosis and the feasibility of effective treatments in GP care.
Proper counseling for diagnosis and management of cannabinoid hyperemesis syndrome: a case report
Authors: Cholette-Tétrault Samuel , Grad Roland
Published: November 2024

Background

Cannabinoid hyperemesis syndrome (CHS) is an increasingly recognized condition linked to chronic cannabis use, yet it remains frequently overlooked in clinical practice. The syndrome is characterized by cyclic episodes of severe nausea, vomiting, and abdominal pain, often relieved temporarily by hot showers or baths. With the rising prevalence of cannabis use following its legalization, the incidence of CHS has surged, presenting a significant challenge in both diagnosis and management within primary healthcare settings. Understanding the epidemiology, risk factors, and potential long-term sequelae of CHS is crucial for timely identification and intervention. This case report highlights the challenge of diagnosis and management of CHS in primary healthcare.

Objective(s)

To emphasize the importance of proper counseling and the use of Rome IV criteria in diagnosing CHS. To illustrate how this may reduce patient suffering and unnecessary investigation.

Case

A 22-year-old female with chronic, daily cannabis use presented with recurrent episodes of intense nausea, vomiting, and abdominal pain over a 2-year period. Extensive diagnostic evaluations were inconclusive. A tentative diagnosis of CHS was made by a medical student and family doctor based on published criteria. The Rome IV criteria were then applied for confirmation of diagnosis and management. In so doing, the patient was advised to cease cannabis use for a minimum of 3 months. Initially, symptom improvement was reported with cannabis cessation. However, symptoms recurred following a relapse in cannabis use.

Conclusion

To confirm the diagnosis of CHS, counseling should specify the need for a minimum of 3 months of cannabis cessation to achieve symptom relief. Increased physician and patient awareness of this minimal time period for drug cessation can help to avoid unnecessary investigations, and prolonged patient suffering. This case emphasizes the need for vigilance in recognizing CHS and consideration of cannabis as a potential cause of cyclic vomiting.
Modelling of two-dimensional seismic waves in double-porosity media using the frequency-domain finite-element method
Authors: Jiang Yaochang , Gao Yongxin , Wang Dongdong , Song Yongjia , Zhou Guanqun , Yao Cheng
Published: November 2024

We present a frequency-domain finite-element (FDFE) method for simulating PSV-mode seismic waves (including two slow compressional waves) in 2-D double-porosity media. A functional, whose extremum corresponds to the governing equations with boundary conditions for 2-D PSV waves, is constructed. Solving the boundary value problem of the governing equations is thus equivalent to finding the extremum of the associated functional. We use structured rectangular elements to discretize the computational domain and employ perfectly matched layers (PMLs) to absorb the seismic waves. The FDFE method is validated by comparing the results with those from a semi-analytic method. Numerical simulations are conducted to investigate the propagation of seismic waves in double-porosity media. Assuming a non-viscous pore fluid, we simulate the propagation of slow P waves (P2 and P3 waves) in a two-layer model consisting of double-porosity media. We observe the reflection and transmission of the P2 and P3 waves at the interface. Additionally, we simulate the propagation of seismic waves in a model with irregular interfaces. Seismic signals collected from horizontal and vertical receiver arrays have demonstrated that the P1 wave experiences higher attenuation in a double-porosity medium.
Weather at the core: defining and categorizing geomagnetic excursions and reversals
Authors: Constable Catherine , Morzfeld Matthias
Published: November 2024

Paleomagnetic records provide us with information about the extreme geomagnetic events known as excursions and reversals, but the sparsity of available data limits detailed knowledge of the process and timing. To date there are no agreed on criteria for categorizing such events in terms of severity or longevity. In an analogy to categorizing storms in weather systems, we invoke the magnitude of the global (modified) paleosecular variation index $P_{i_D}$ to define the severity of the magnetic field state, ranging in level from 0 to 3, and defined by instantaneous values of $P_{i_D}$ with level 0 being normal ($P_{i_D}\lt 0.5$) to extreme ($P_{i_D}\ge 15$). We denote the time of entry to an excursional (or reversal) event by when $P_{i_D}$ first exceeds 0.5, and evaluate its duration by the time at which $P_{i_D}$ first returns below its median value, termed the end of event threshold. We categorize each excursional event according to the peak level of $P_{i_D}$ during the entire event, with a range from Category-1 (Cat-1) to Cat-3. We explore an extended numerical dynamo simulation containing more than 1200 events and find that Cat-1 events are the most frequent (72 per cent), but only rarely lead to actual field reversals where the axial dipole, $g_1^0$, has reversed sign at the end of the event. Cat-2 account for about 20 per cent of events, with 34 per cent of those leading to actual reversals, while Cat-3 events arise about 8 per cent of the time but are more likely to produce reversals (43 per cent). Higher category events take as much as 10 times longer than Cat-1 events. Two paleomagnetic field models separately cover the Laschamp excursion and Matuyama–Brunhes (M-B) reversal which are Cat-2 events with respective durations of 3.6 and 27.4 kyr. It seems likely that Cat-2 may be an underestimate for M-B due to limitations in the paleomagnetic records. Our overall results suggest no distinction between excursions and reversals other than a reversal having the ending polarity state opposite to that at the start.
Indonesian medical interns’ intention to practice in rural areas
Authors: Findyartini Ardi , Qorina Fona , Putera Azis Muhammad , Anugrapaksi Eghar , Khumaini Aulia Nafi Syifa Putri , Putera Ikhwanuliman , Syahmar Ikrar , Samarasekera Dujeepa D
Published: November 2024

The maldistribution of physicians, especially in rural areas, remains a global public health challenge. The internship programme for medical doctors is one of the efforts undertaken to address this issue. However, evidence aiming to disentangle this persistent challenge in the Indonesian context has been scant. This study aims to identify factors influencing medical doctors’ intentions to practise in rural areas and how these factors affect their decisions. We adopted a sequential explanatory mixed-method design using a validated questionnaire. Then, focus group discussions were conducted with medical doctors from three different regions (West, Central, and East) to gain in-depth understanding of motivations, intentions, and barriers to practicing in rural areas. Participants were intern doctors who had been practising for at least 6 months in their internship locations. Quantitative analysis was based on a questionnaire addressing each factor, rated using five-point Likert scales, with bivariate and multivariate logistic regression analyses. The qualitative results were analysed using thematic analysis. In total, 498 respondents completed the questionnaire where 9.6%, 49%, and 40.9% intend to practise in rural, suburban, and urban areas, respectively. Three factors were positively associated with a preference for rural practice: prior living experience in rural areas, accessibility to cultural centres and events, and personal savings as funding resources during medical school. However, the importance of ‘internet accessibility’ was negatively associated with a preference for rural practice. Furthermore, the qualitative study involving 18 participants resulted in four main themes: the role of the internship programme in enhancing motivation as medical doctors, factors generally influencing the intention to practise, factors influencing the intention to practise in rural areas, and policy recommendations to increase the intention to practise in rural areas. Addressing the challenge of attracting and retaining medical doctors in rural areas requires multisectoral approaches involving both personal and professional factors.
Managing medicines in decentralization: discrepancies between national policies and local practices in primary healthcare settings in Indonesia
Authors: Fanda Relmbuss Biljers , Probandari Ari , Kok Maarten Olivier , Bal Roland A
Published: November 2024

In Indonesia, primary health centres (PHCs) are mandated to provide essential medicines to ensure equal access to medication for all Indonesians, as stated in the national medicine policy. However, limited information is available regarding the actual practices of health workers within the context of decentralized governance. This paper investigates the discrepancies between national policies and local practices in two Indonesian districts, shedding light on coping mechanisms employed in each phase of medicine management within PHCs. The mixed-method study began by identifying pertinent policies addressing medicine management in PHCs. Subsequently, panel data on patient visits to tuberculosis, maternal and neonatal health (MNH), and noncommunicable disease (NCD) services were collected from 2019 to 2022. After analysing the panel data, interviews were conducted with 56 health workers including physicians, nurses, pharmacists, midwives, and public health programme managers regarding their views on fluctuations in medicine stocks and the patient visit data. These participants included pharmacists and programme managers specializing in tuberculosis, MNH, and NCD care and were affiliated with PHCs and district health offices. Our findings highlight the occasional unavailability of essential medicines in PHCs, with stockouts being attributed to supplier shortages at provincial and national levels and to variations in the capacity of the local health system. Low-skilled pharmaceutical staff are a contributing factor in each phase of medicine management. Additionally, health workers employ coping mechanisms, such as deviating from policy on the use of capitation funds to purchase medicines, to manage temporary stockouts. To tackle systemic stockouts, central government should prioritize capacity-building among health workers, by establishing a continuous and easily accessible local learning system.
The regulation of miRNAs using curcumin and other polyphenols during the prevention and treatment of Alzheimer’s disease
Authors: Wang XiYun , Zhang Sale , Li Ying , Zhang Yu
Published: November 2024

Alzheimer’s disease (AD), a prevalent neurodegenerative disorder, predominantly affects individuals over the age of 65 and poses significant challenges in terms of effective management and treatment. The disease’s pathogenesis involves complex molecular pathways including misfolded proteins accumulation, neuroinflammation, and synaptic dysfunction. Recent insights have highlighted the role of microRNAs (miRNAs) as critical regulators within these pathways, where they influence gene expression and contribute to the pathophysiological landscape of AD. Notably, emerging research has demonstrated that polyphenols, including curcumin, might modulate miRNA activity, thus offering a novel approach to mitigate AD symptoms and progression. This review explores the potential mechanisms through which polyphenols regulate miRNA expression and activity, specifically focusing on autophagy enhancement and inflammation reduction in the context of AD. We provide a detailed examination of key studies linking miRNA dysregulation to AD pathogenesis and discuss how polyphenols might correct these aberrations. The findings presented here underscore the therapeutic potential of polyphenols in AD treatment via miRNA modulation, pointing to new directions in disease management strategies and highlighting the need for targeted research into miRNA-based interventions.
De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias
Authors: Sandal Priyanka , Jong Chian Ju , Merrill Ronald A , Kollman Grace J , Paden Austin H , Bend Eric G , Sullivan Jennifer , Spillmann Rebecca C , Shashi Vandana , Vulto-van Silfhout Anneke T , Pfundt Rolph , de Vries Bert B A , Li Pan P , Bicknell Louise S , Strack Stefan
Published: November 2024

The heterotrimeric protein phosphatase 2A (PP2A) complex catalyzes about half of Ser/Thr dephosphorylations in eukaryotic cells. A CAG repeat expansion in the neuron-specific protein PP2A regulatory subunit PPP2R2B gene causes spinocerebellar ataxia type 12 (SCA12). We established five monoallelic missense variants in PPP2R2B (four confirmed as de novo) as a cause of intellectual disability with developmental delay (R149P, T246K, N310K, E37K, I427T). In addition to moderate to severe intellectual disability and developmental delay, affected individuals presented with seizures, microcephaly, aggression, hypotonia, as well as broad-based or stiff gait. We used biochemical and cellular assays, including a novel luciferase complementation assay to interrogate PP2A holoenzyme assembly and activity, as well as deregulated mitochondrial dynamics as possible pathogenic mechanisms. Cell-based assays documented impaired ability of PPP2R2B missense variants to incorporate into the PP2A holoenzyme, localize to mitochondria, induce fission of neuronal mitochondria, and dephosphorylate the mitochondrial fission enzyme dynamin-related protein 1. AlphaMissense-based pathogenicity prediction suggested that an additional seven unreported missense variants may be pathogenic. In conclusion, our studies identify loss-of-function at the PPP2R2B locus as the basis for syndromic intellectual disability with developmental delay. They also extend PPP2R2B-related pathologies from neurodegenerative (SCA12) to neurodevelopmental disorders and suggests that altered mitochondrial dynamics may contribute to mechanisms.
Brain multi-omic Mendelian randomisation to identify novel drug targets for gliomagenesis
Authors: Thornton Zak A , Andrews Lily J , Zhao Huiling , Zheng Jie , Paternoster Lavinia , Robinson Jamie W , Kurian Kathreena M
Published: November 2024

Background

Genetic variants associated with molecular traits that are also associated with liability to glioma can provide causal evidence for the identification and prioritisation of drug targets.

Methods

We performed comprehensive two-sample Mendelian randomisation (Wald ratio and/or IVW) and colocalisation analyses of molecular traits on glioma. Instrumentable traits (QTLs P < 5 × 10−8) were identified amongst 11 985 gene expression measures, 13 285 splicing isoforms and 10 198 protein abundance measures, derived from 15 brain regions. Glioma summary-level data was extracted from a genome-wide association meta-analysis of 12 496 cases and 18 190 controls.

Results

We found evidence for causal effect of 22 molecular traits (across 18 genes/proteins) on glioma risk. Thirteen molecular traits have been previously linked with glioma risk and five were novel; HBEGF (5q31.3) expression and all glioma [OR 1.36 (95%CI 1.19–1.55); P = 4.41 × 10−6]; a CEP192 (18p11.21) splice isoform and glioblastoma [OR 4.40 (95%CI 2.28–8.48); P = 9.78 × 10−4]; a FAIM (3q22.3) splice isoform and all glioma [OR 2.72–3.43; P = 1.03 × 10−5 to 1.09 × 10−5]; a SLC8A1 (2p22.1) splice isoform and all glioma [OR 0.37 (95%CI 0.24–0.56; P = 5.72 × 10−6]; D2HGDH (2q37.3) protein and all glioma [OR 0.86 (95%CI 0.80–0.92); P = 5.94 × 10−6)].

Conclusions

We provide robust causal evidence for prioritising genes and their protein products in glioma research. Our results highlight the importance of alternative splicing as a mechanism in gliomagenesis and as an avenue for exploration of drug targets.
Integrative multi-environmental genomic prediction in apple
Authors: Jung Michaela , Quesada-Traver Carles , Roth Morgane , Aranzana Maria José , Muranty Hélène , Rymenants Marijn , Guerra Walter , Holzknecht Elias , Pradas Nicole , Lozano Lidia , Didelot Frédérique , Laurens François , Yates Steven , Studer Bruno , Broggini Giovanni A L , Patocchi Andrea
Published: November 2024

Genomic prediction for multiple environments can aid the selection of genotypes suited to specific soil and climate conditions. Methodological advances allow effective integration of phenotypic, genomic (additive, nonadditive), and large-scale environmental (enviromic) data into multi-environmental genomic prediction models. These models can also account for genotype-by-environment interaction, utilize alternative relationship matrices (kernels), or substitute statistical approaches with deep learning. However, the application of multi-environmental genomic prediction in apple remained limited, likely due to the challenge of building multi-environmental datasets and structurally complex models. Here, we applied efficient statistical and deep learning models for multi-environmental genomic prediction of eleven apple traits with contrasting genetic architectures by integrating genomic- and enviromic-based model components. Incorporating genotype-by-environment interaction effects into statistical models improved predictive ability by up to 0.08 for nine traits compared to the benchmark model. This outcome, based on Gaussian and Deep kernels, shows these alternatives can effectively substitute the standard genomic best linear unbiased predictor (G-BLUP). Including nonadditive and enviromic-based effects resulted in a predictive ability very similar to the benchmark model. The deep learning approach achieved the highest predictive ability for three traits with oligogenic genetic architectures, outperforming the benchmark by up to 0.10. Our results demonstrate that the tested statistical models capture genotype-by-environment interactions particularly well, and the deep learning models efficiently integrate data from diverse sources. This study will foster the adoption of multi-environmental genomic prediction to select apple cultivars adapted to diverse environmental conditions, providing an opportunity to address climate change impacts.
Defining the causes for Fontan circulatory failure in total cavopulmonary connection patients
Authors: Van Puyvelde Joeri , Rega Filip , Budts Werner , Van De Bruaene Alexander , Cools Bjorn , Gewillig Marc , Eyskens Benedicte , Heying Ruth , Salaets Thomas , Meyns Bart
Published: November 2024

OBJECTIVES

This study aims to identify the causes of failure in Fontan patients with a total cavopulmonary connection.

METHODS

We conducted a comprehensive review of all patients who underwent a total cavopulmonary connection procedure at our centre between 1988 and 2023, aiming to identify and analyse the factors contributing to Fontan failure (defined as mortality, heart transplantation, Fontan takedown, protein-losing enteropathy, plastic bronchitis or New York Heart Association Functional Classification class III or IV).

RESULTS

The study included 217 patients (median age at time of Fontan completion 3.7 years) with a median follow-up of 12.7 years (interquartile range 7.2–17.7). Systolic ventricular function decreased significantly over time in patients with right ventricular dominant morphology (P = 0.002), while systolic ventricular function remained stable in patients with left ventricular dominant morphology. Fontan failure occurred in 24 patients, with estimated freedom from Fontan failure rates of 97.7% [95% confidence interval (CI), 95–99] at 1 year, 93.9% (95% CI, 89–97) at 15 years and 77.2% (95% CI, 65–86) at 20 years of follow-up. Systolic ventricular dysfunction was the most common cause of failure (29%), followed by atrioventricular valve regurgitation (16.7%), a high pulmonary vascular resistance (16.7%), restrictive pathophysiology (16.7%) and obstruction (12.5%). Patients with right ventricular dominance developed most often systolic ventricular dysfunction, while patients with left ventricular dominant morphology developed most often restrictive pathophysiology or a high pulmonary vascular resistance.

CONCLUSIONS

Approximately 10% of patients experienced Fontan failure within 15 years postoperatively. Patients with right ventricular dominance experienced progressive decline due to systolic dysfunction, while those with left ventricular dominance exhibited failure due to restrictive pathophysiology or high pulmonary vascular resistance.
Risk of psychiatric hospitalization in low-income youth: longitudinal findings from the 100 Million Brazilian Cohort
Authors: Toledo Lidiane , Rodrigues Rodrigo , Alves Flávia , Guedes Fillipe , de Araújo Jacyra Azevedo Paiva , Naslund John A , Barreto Maurício L , Patel Vikram , Machado Daiane Borges
Published: November 2024

Background

Youth psychiatric hospitalizations have been associated with negative outcomes, including premature death and post-discharge self-harm. Identifying risk factors for youth psychiatric hospitalization is crucial for informing prevention strategies. We aimed to evaluate the risk factors for psychiatric hospitalizations among low-income youth in Brazil.

Methods

This cohort study used interpersonal violence and psychiatric hospitalization data linked to the 100 Million Brazilian Cohort baseline. We considered 9 985 917 youths aged 5–24 years who enrolled at the baseline, between 2011 and 2018. We estimated the incidence rate (IR) with 95% confidence interval (CI) for psychiatric hospitalization by calculating the number of hospitalizations per person-year in 100 000 individuals at risk. The multilevel, multivariate Cox proportional hazards regression estimated the hazard risks (HR) with 95% CI for psychiatric hospitalization.

Results

The IR of psychiatric hospitalization was 12.28 per 100 000 person-years (95% CI, 11.96–12.6). Interpersonal violence victimization was the main risk factor for youth psychiatric hospitalization (HR, 5.24; 95% CI, 4.61–5.96). Other risk factors for psychiatric hospitalization included living with the oldest family member who had low education (HR, 2.51; 95% CI, 2.16–2.91) or was unemployed (HR, 1.49; 95% CI, 1.36–1.62), living with seven or more family members (HR, 1.84; 95% CI, 1.49–2.26) and being male (HR, 1.28; 95% CI, 1.21–1.36).

Conclusions

Urgent action is needed to prevent youth from suffering violence. Addressing this may alleviate the mental health burden in developmental ages, benefiting youth, families and the government through reduced costs in preventable psychiatric hospitalizations.