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Perinatal women were particularly impacted during the pandemic, with documented consequences for both mothers’ and infants’ well-being. This study investigated the longitudinal relationships between COVID-19-related experiences during the peripartum and women’s depression and anxiety symptoms at long-term follow-up. We explored the moderating role of long COVID for the first time, along with perceived partner support and maternal self-efficacy. A sample of 190 US perinatal women completed a survey from May 21, 2020, to September 15, 2021 (T1), and again between December 14, 2022, and February 14, 2024 (T2). The survey assessed COVID-19-related experiences, mental health, long COVID, maternal self-efficacy, partner support, and life events. Anxiety was associated with both long COVID and decreased partner support, and both depression and anxiety were linked to lower self-efficacy. A larger number of COVID-19-related experiences during the peripartum period was associated with higher levels of later depression and anxiety symptoms. Long COVID exacerbated these links, while partner support buffered them. Maternal self-efficacy dampened the association between COVID-19-related experiences and subsequent depression, but not anxiety. Findings suggest that COVID-19 has lasting effects on perinatal women’s mental health, with partner support and maternal self-efficacy acting as resilience factors, highlighting the potential benefit of targeted interventions to enhance these modifiable factors.
Background: Neck vessel imaging is often performed in hyperacute stroke to allow neurointerventionalists to estimate access complexity. This study aimed to assess clinician agreement on catheterization strategies based on imaging in these scenarios. Methods: An electronic portfolio of 60 patients with acute ischemic stroke was sent to 53 clinicians. Respondents were asked: (1) the difficulty of catheterization through femoral access with a regular Vertebral catheter, (2) whether to use a Simmons or reverse-curve catheter initially, and (3) whether to consider an alternative access site. Agreement was assessed using Fleiss’ Kappa statistics. Results: Twenty-two respondents (7 neurologists, 15 neuroradiologists) completed the survey. Overall there was slight interrater agreement (κ=0.17, 95% CI: 0.10–0.25). Clinicians with >50 cases annually had better agreement (κ=0.22) for all questions than those with fewer cases (κ=0.07). Agreement did not significantly differ by imaging modality: CTA (κ=0.18) and MRA (κ=0.14). In 40/59 cases (67.80%), at least 25% of clinicians disagreed on whether to use a Simmons or reverse-curve catheter initially. Conclusions: Agreement on catheterization strategies remains fair at best. Our results suggest that visual assessment of pre-procedural vessels imaging is not reliable for the estimation of endovascular access complexity.
Background: Treatment of aneurysmal subarachnoid hemorrhage (aSAH) in a high-volume center by experienced cerebrovascular and neuroendovascular surgeons improves outcomes. We studied whether rural aSAH patients experience treatment delays in British Columbia. Methods: Vancouver Ruptured Aneurysm Database (VRAD) started in 2023 to prospectively capture consecutive aSAH patients at Vancouver General Hospital (VGH), an academic neurosurgical hospital with comprehensive stroke center capabilities. We included patients ≥18 years-old, presenting ≤72h post-ictus and excluded untreated aneurysms and patients not residing in British Columbia. Patients were classified as rural or urban using the provincial government categorization of rurality. Results: We included 84 patients, 65.5% urban and 34.5% rural, with mean age 57.7 years (SD: 15.6) and 64.3% female. Aneurysm treatment consisted of 75% microsurgical clipping and 25% endovascular techniques. Median time from ictus to VGH was 5.9h [IQR: 2.6-16.6] urban and 13.2h [IQR: 8.3-27.8] rural, p=0.001. Median transfer time was 4.7h [IQR: 2.5-8.8] urban and 11.9h [IQR: 6.7-13.5] rural, p=0.006. Ictus to treatment time was 5.9h longer for rural patients, p=0.077. Conclusions: Rural aSAH patients in British Columbia take 7.3 hours longer to reach a neurosurgical center capable of comprehensive aneurysm treatment compared to urban patients. Improved inter-hospital transfer systems may reduce geographic disparities for aSAH in British Columbia.
The Australian SKA Pathfinder (ASKAP) offers powerful new capabilities for studying the polarised and magnetised Universe at radio wavelengths. In this paper, we introduce the Polarisation Sky Survey of the Universe’s Magnetism (POSSUM), a groundbreaking survey with three primary objectives: (1) to create a comprehensive Faraday rotation measure (RM) grid of up to one million compact extragalactic sources across the southern $\sim50$% of the sky (20,630 deg$^2$); (2) to map the intrinsic polarisation and RM properties of a wide range of discrete extragalactic and Galactic objects over the same area; and (3) to contribute interferometric data with excellent surface brightness sensitivity, which can be combined with single-dish data to study the diffuse Galactic interstellar medium. Observations for the full POSSUM survey commenced in May 2023 and are expected to conclude by mid-2028. POSSUM will achieve an RM grid density of around 30–50 RMs per square degree with a median measurement uncertainty of $\sim$1 rad m$^{-2}$. The survey operates primarily over a frequency range of 800–1088 MHz, with an angular resolution of 20” and a typical RMS sensitivity in Stokes Q or U of 18 $\mu$Jy beam$^{-1}$. Additionally, the survey will be supplemented by similar observations covering 1296–1440 MHz over 38% of the sky. POSSUM will enable the discovery and detailed investigation of magnetised phenomena in a wide range of cosmic environments, including the intergalactic medium and cosmic web, galaxy clusters and groups, active galactic nuclei and radio galaxies, the Magellanic System and other nearby galaxies, galaxy halos and the circumgalactic medium, and the magnetic structure of the Milky Way across a very wide range of scales, as well as the interplay between these components. This paper reviews the current science case developed by the POSSUM Collaboration and provides an overview of POSSUM’s observations, data processing, outputs, and its complementarity with other radio and multi-wavelength surveys, including future work with the SKA.
Non-technical summary. New approaches to ensure the resilience of urban water supply are urgently needed. This requires moving beyond managing water scarcity through infrastructural measures to understanding resilience as an outcome of complex interactions between people, water resources, and technological infrastructure. We conducted expert interviews and a household survey in a water scarcity ‘hotspot’ and found that water experts emphasize water system deficits and inefficiencies, while citizens complement public water service deficits through (unaccounted-for) coping mechanisms. This leads to uncertainties regarding the outcomes of management interventions. We suggest that integrating different stakeholder perspectives into water management strategies could enhance urban water resilience.
Technical summary. There is limited understanding of how to address the complex dynamics shaping the resilience of increasingly water-scarce cities, globally. By conceptualizing urban water systems as social–ecological–technological systems (SETS) and analysing their interactions from different stakeholder perspectives, we create a pluralistic, yet systematic, understanding of SETS interactions. We conducted expert interviews (N = 19) and a household survey (N = 300) in Amman, one of the world’s water scarcity hotspots, and analysed the data in three steps: (1) We analysed the SETS through the lens of its different actor groups, and, inspired by frame analysis, interpreted each group's system perspective – local experts focus on deficits of SETS elements and aim to increase available resources, while international experts emphasize the efficiency of SETS interactions. Households cope with deficient water supplies by mobilizing adaptive strategies. (2) Combining these three perspectives, we derived uncertainties resulting from different (and unrecognized) stakeholder views, missing knowledge, and unpredictable system dynamics. (3) We identified and characterized new SETS interactions for an urban, resource-constrained environment, which contributes to a typology aiming for better comparability across SETS. Our results have implications for resilience-oriented urban water management and governance in terms of what to manage (fast/slow variables, connectivity), how (learning/experimenting), and by whom (broad participation).
Social media summary. Addressing uncertainty by reframing resilience-oriented urban water management with complementary system perceptions.
We discuss the modal, linear stability analysis of generalized Couette–Poiseuille (GCP) flow between two parallel plates moving with relative speed in the presence of an applied pressure gradient vector inclined at an angle $0\leqslant \phi \leqslant 90^\circ$ to the plate relative velocity vector. All possible GCP flows can be described by a global Reynolds number $Re$, $\phi$ and an angle $0\leqslant \theta \leqslant 90^\circ$, where $\cos \theta$ is a measure of the relative weighting of Couette flow to the composite GCP flow. This provides a novel and uncommon group of generally three-dimensional base velocity fields with wall-normal twist, for which Squire's theorem does not generally apply, requiring study of oblique perturbations with wavenumbers $(\alpha,\beta )$. With $(\theta,\phi )$ fixed, the neutral surface $f(\theta,\phi ;Re,\alpha,\beta )=0$ in $(Re, \alpha,\beta )$ space is discussed. A mapping from GCP to plane Couette–Poiseuille flow stability is found that suggests a scaling relation $Re^*\alpha /k = H(\theta ^*)$ that collapses all critical parameters, where ${Re}^*= Re\,({\alpha _1}/{\alpha })\,({\sin \theta }/{\sin {\theta }^*})$ and $\tan \theta ^*=({\alpha _{1}}/\alpha )\tan \theta$, with $\alpha _1=\alpha \cos \phi +\beta \sin \phi$. This analysis does not, however, directly reveal global critical properties for GCP flow. The global $Re_{cr}(\theta,\phi )$ shows continuous variation, while $\alpha _{cr}(\theta,\phi )$ and $\beta _{cr}(\theta,\phi )$ show complex behaviour, including discontinuities owing to jumping of critical states across neighbouring local valleys (in $Re$) or lobes of the neutral surface. The discontinuity behaviour exists for all low $\phi$. For $\phi \gtrsim 21^\circ$, variations of $\alpha _{cr}(\theta )$ and $\beta _{cr}(\theta )$ are generally smooth and monotonic.
Adolescents with depression have distinct affective reactions to daily events, but current research is controversial. The emotional context insensitivity theory suggests blunted reactivity in depression, whereas the hypotheses of negative potentiation and mood brightening effect suggest otherwise. While nonlinear associations between depression severity and affective reactivity have been observed, studies with a separate subclinical group remain rare. Subthreshold depression (SD), defined by two to four symptoms lasting for two weeks or more, provides a dimensional view to the underpinnings of affective reactivity. In this study, we compared positive affect (PA) and negative affect (NA) reactivity to positive and negative daily events (uplifts and stress) among adolescents with Major Depressive Disorder (MDD), SD and healthy controls (HC) using experience sampling methods (ESM).
Objectives
We hypothesized a stepped difference in affective reactivity along the depression spectrum: the MDD group will have the strongest reactivity of PA and NA to uplifts and stress, followed by SD and HC.
Methods
Three groups (MDD, SD, and HC) of adolescents were recruited from an epidemiologic sample entitled ‘Hong Kong Child and Adolescent Psychiatric Epidemiologic Survey: Age 6 to 17’. Group status was determined by the Diagnostic Interview Schedule for Children Version 5. They completed an experience sampling diary on smartphone for 14 consecutive days, with 5-10 entries per day. Momentary levels of PA (happy, relaxed, contented), NA (irritated, low, nervous), uplifts and stress experienced before the entry were measured on a 1-7 Likert scale.
Results
The sample consisted of 19 adolescents with MDD, 30 with SD, and 59 HC. The M:F ratio was 17:19. The age range was 12-18 with a mean of 14.8. The overall ESM completion rate was 46%. The MDD group had the highest levels of stress and NA, and the lowest levels of uplifts and PA, followed by the SD and HC groups respectively (p<0.01). Across groups, levels of PA were positively associated with uplifts and negatively associated with stress, whereas levels of NA were positively associated with stress and negatively associated with uplifts. The Group x Uplift interaction effect on PA was significant, with greater PA reactivity in SD (p<0.01) and MDD (p=0.07) when compared with HC. The Group x Uplift interaction effect on NA was significant, with greater NA reactivity in SD than HC (p<0.01). The Group x Stress interaction effect on PA was significant, with greater PA reactivity in SD than HC (p<0.01) and MDD (p<0.01). The Group x Stress interaction effect with NA is non-significant.
Conclusions
Contrary to our hypothesis, adolescents with SD experienced strongest PA and NA reactivity in uplifts and PA reactivity in stress. It provides evidence towards a nonlinear relationship between severity of depression and affective reactivity.
Bipolar disorder is highly prevalent and consists of biphasic recurrent mood episodes of mania and depression, which translate into altered mood, sleep and activity alongside their physiological expressions.
Aims
The IdenTifying dIgital bioMarkers of illnEss activity and treatment response in BipolAr diSordEr with a novel wearable device (TIMEBASE) project aims to identify digital biomarkers of illness activity and treatment response in bipolar disorder.
Method
We designed a longitudinal observational study including 84 individuals. Group A comprises people with acute episode of mania (n = 12), depression (n = 12 with bipolar disorder and n = 12 with major depressive disorder (MDD)) and bipolar disorder with mixed features (n = 12). Physiological data will be recorded during 48 h with a research-grade wearable (Empatica E4) across four consecutive time points (acute, response, remission and episode recovery). Group B comprises 12 people with euthymic bipolar disorder and 12 with MDD, and group C comprises 12 healthy controls who will be recorded cross-sectionally. Psychopathological symptoms, disease severity, functioning and physical activity will be assessed with standardised psychometric scales. Physiological data will include acceleration, temperature, blood volume pulse, heart rate and electrodermal activity. Machine learning models will be developed to link physiological data to illness activity and treatment response. Generalisation performance will be tested in data from unseen patients.
Results
Recruitment is ongoing.
Conclusions
This project should contribute to understanding the pathophysiology of affective disorders. The potential digital biomarkers of illness activity and treatment response in bipolar disorder could be implemented in a real-world clinical setting for clinical monitoring and identification of prodromal symptoms. This would allow early intervention and prevention of affective relapses, as well as personalisation of treatment.
In response to the Omicron surge in early 2022, the HTA Philippines evaluated the acceptability of Filipinos in using self-administered antigen tests (SAAgTs) as part of COVID-19 HTAs in the Philippines.
Methods
Scoping review from literature databases was initially conducted to identify preset codes in the use of SAAgT. Preset codes were used to establish the questions for focus group discussions (FGDs). Semi-structured questionnaires were created through Delphi technique. FGDs with four stakeholder groups (i.e., nine healthcare workers [HCWs], seven representatives of at-risk groups, six economic frontliners, and seven representatives of micro–small–medium-sized enterprises) were conducted.
Results
Discomfort in being a target of stigma and being prescribed an “illness identity” when suspected or confirmed COVID-19-positive, along with lack of confidence to perform self-test, caused hesitancy in self-testing among participants. The need for subsidies for test kits from the government or employers was emphasized to increase its accessibility. Having a designated access point and reporting system for SAAgT was highlighted to avoid nepotism (padrino system attributed to debt of gratitude), inequitable distribution, and lapses in reporting. A participatory approach to education was perceived as crucial to reduce any misconceptions associated with the use of SAAgT.
Conclusions
All FGD groups expressed favorable reviews on the implementation of SAAgT because it can potentially reduce the burden of health facility-administered tests. These findings were considered by the HTA Council in the recommendation of SAAgT as part of the overarching national strategies for the diagnosis and screening of COVID-19.
The laboratory generation and diagnosis of uniform near-critical-density (NCD) plasmas play critical roles in various studies and applications, such as fusion science, high energy density physics, astrophysics as well as relativistic electron beam generation. Here we successfully generated the quasistatic NCD plasma sample by heating a low-density tri-cellulose acetate (TCA) foam with the high-power-laser-driven hohlraum radiation. The temperature of the hohlraum is determined to be 20 eV by analyzing the spectra obtained with the transmission grating spectrometer. The single-order diffraction grating was employed to eliminate the high-order disturbance. The temperature of the heated foam is determined to be T = 16.8 ± 1.1 eV by analyzing the high-resolution spectra obtained with a flat-field grating spectrometer. The electron density of the heated foam is about under the reasonable assumption of constant mass density.
In preparation for an experiment with a laser-generated intense proton beam at the Laser Fusion Research Center at Mianyang to investigate the 11B(p,α)2α reaction, we performed a measurement at very low proton energy between 140 keV and 172 keV using the high-voltage platform at the Institute of Modern Physics, Lanzhou. The aim of the experiment was to test the ability to use CR-39 track detectors for cross-section measurements and to remeasure the cross-section of this reaction close to the first resonance using the thick target approach. We obtained the cross-section σ = 45.6 ± 12.5 mb near 156 keV. Our result confirms the feasibility of CR-39 type track detector for nuclear reaction measurement also in low-energy regions.
The Australian SKA Pathfinder (ASKAP) radio telescope has carried out a survey of the entire Southern Sky at 887.5 MHz. The wide area, high angular resolution, and broad bandwidth provided by the low-band Rapid ASKAP Continuum Survey (RACS-low) allow the production of a next-generation rotation measure (RM) grid across the entire Southern Sky. Here we introduce this project as Spectral and Polarisation in Cutouts of Extragalactic sources from RACS (SPICE-RACS). In our first data release, we image 30 RACS-low fields in Stokes I, Q, U at 25$^{\prime\prime}$ angular resolution, across 744–1032 MHz with 1 MHz spectral resolution. Using a bespoke, highly parallelised, software pipeline we are able to rapidly process wide-area spectro-polarimetric ASKAP observations. Notably, we use ‘postage stamp’ cutouts to assess the polarisation properties of 105912 radio components detected in total intensity. We find that our Stokes Q and U images have an rms noise of $\sim$80 $\unicode{x03BC}$Jy PSF$^{-1}$, and our correction for instrumental polarisation leakage allows us to characterise components with $\gtrsim$1% polarisation fraction over most of the field of view. We produce a broadband polarised radio component catalogue that contains 5818 RM measurements over an area of $\sim$1300 deg$^{2}$ with an average error in RM of $1.6^{+1.1}_{-1.0}$ rad m$^{-2}$, and an average linear polarisation fraction $3.4^{+3.0}_{-1.6}$ %. We determine this subset of components using the conditions that the polarised signal-to-noise ratio is $>$8, the polarisation fraction is above our estimated polarised leakage, and the Stokes I spectrum has a reliable model. Our catalogue provides an areal density of $4\pm2$ RMs deg$^{-2}$; an increase of $\sim$4 times over the previous state-of-the-art (Taylor, Stil, Sunstrum 2009, ApJ, 702, 1230). Meaning that, having used just 3% of the RACS-low sky area, we have produced the 3rd largest RM catalogue to date. This catalogue has broad applications for studying astrophysical magnetic fields; notably revealing remarkable structure in the Galactic RM sky. We will explore this Galactic structure in a follow-up paper. We will also apply the techniques described here to produce an all-Southern-sky RM catalogue from RACS observations. Finally, we make our catalogue, spectra, images, and processing pipeline publicly available.
Virtual reality exposure therapy (VRET) is a treatment in a virtual environment based on the representation of a patient’s disease in virtual reality. VRET means getting used to a specific situation by intentionally facing the patient’s fearful situation based on the ‘exposure technique.’ By repeatedly exposing the patient to a fearful situation, in the end, inducing the intensity of fear to decrease without avoiding the situation. Virtual reality exposure therapy (VRET) was initially used to treat phobias, anxiety disorders, and stress. It has been proven to be an effective psychotherapy method mainly focusing on acrophobia, flight phobia, arachnophobia, social phobia, and post-traumatic stress disorder (PTSD).
Objectives
Virtual reality exposure therapy (VRET) is used to treat phobias, anxiety disorders, and stress. The virtual reality treatment system can reproduce virtual scenes with the environment modified or removed, and can familiarize patients with such environments. This study aims to verify the degree of improvement of the symptoms of panic disorder by conducting VRET that we have made considering the degree of gradual exposure to the panic disorder group and the control group.
Methods
A total of 60 subjects were included in this study, including 43 patients with panic disorder and 17 control group. Subjects were systematically exposed to specific situations over five steps. We checked the heart rate, body temperature, EEG and symptoms before and after exposure using the following assessment instruments; Subjective Units of Discomfort (SUD), Anxiety Sensitivity Index (ASI), Panic Disorder Severity Scale. Repeated measures ANOVA was performed separately for presence, SUDS (distress) scores, and PDSS across time points.
Results
In the patient group, the program proved to be effective as the sensitivity to anxiety decreased significantly after the VR program (F=3.570, p<0.05). Among the subcategories of ASI, the fear of anxiety symptoms showed statistical significance between sessions (F=3.883, p<0.05) and in the interaction between group and time (F=4.585, p<0.01). The study confirmed the effectiveness of the VR program in situations that mainly induce panic attacks in patients diagnosed with panic disorder (elevator riding, driving a car, driving a car in a tunnel, driving a car in rain). The program effect was significant through repeated measurement ANOVA for each variable of EEG (Alpha, Beta, Delta, Gamma, Theta) (F=3.249, p<0.01).
Conclusions
VRET is the process of gradually being exposed to fear stimuli, deliberately confronting and experiencing a fear situation, and learning that nothing dangerous will happen. Even if the patient experiences bodily sensations that are the subject of fear, they can reduce their fear of bodily sensations by repeatedly confirming that they are safe and getting used to them.
Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.
As a typical plasma-based optical element that can sustain ultra-high light intensity, plasma density gratings driven by intense laser pulses have been extensively studied for wide applications. Here, we show that the plasma density grating driven by two intersecting driver laser pulses is not only nonuniform in space but also varies over time. Consequently, the probe laser pulse that passes through such a dynamic plasma density grating will be depolarized, that is, its polarization becomes spatially and temporally variable. More importantly, the laser depolarization may spontaneously take place for crossed laser beams if their polarization angles are arranged properly. The laser depolarization by a dynamic plasma density grating may find application in mitigating parametric instabilities in laser-driven inertial confinement fusion.
The objective of this project was to collect scientific data to assist in the development of guidelines for the humane relocation of threatened and endangered arboreal non-human primate species. A troop of 31 Lowland Sykes monkeys (Cercopithecus mitis albotorquatus) was habituated to fruit bait for capture in a village and relocation to a previously selected suitable site in a protected forest reserve approximately 30 km away. Sixty-five percent (n = 20) of the animals were captured and relocated. This subgroup comprised one adult male, eight adult females, two subadult females, three juvenile males, four juvenile females and two infant males. Although the relocated group originated from one single group, post-translocation telemetry signals demonstrated that it split into two groups, which established themselves approximately 2–4 km apart in their new territory; the adult male eventually became solitary. The factors of importance for the successful capture and relocation of forest primates were found to include: proper understanding of troop home-range utilisation and of social bond organisation within the troop, method and period of habituation, method of release, suitability of the new habitat with respect to the ecological niche requirements of the species in question, and the period of post-relocation monitoring.
Limited studies provide direct evidence of Clonorchis sinensis adults in the early stage of gallbladder stone formation. Our current research systematically studied 33 gallbladder stones resembling adult worms and shed light on the definite connection of C. sinensis infection with concomitant cholelithiasis. A total of 33 gallbladder stones resembling adult C. sinensis worms were systematically analysed. Fourier transform infrared spectroscopy, scanning electron microscopy and X-ray energy spectrometry were used to analyse the composition and microstructure. Meanwhile, a histopathological examination of the stone was carried out. The 33 gallbladder stones resembling adult C. sinensis worms included nine calcium carbonate (CaCO3) stones, 12 bilirubinate stones and 12 mixed stones. Clonorchis sinensis eggs were found in 30 cases, including all CaCO3 and mixed stones. Parasite tissues were detected in 12 cases, which were mainly CaCO3 stones or bilirubinate–CaCO3 mixed stones. The outer layer of stones was wrapped with 12.88% calcium salt, as revealed by X-ray energy spectrometry, while surprisingly, many C. sinensis eggs were found in the inner part of these stones. Based on our current findings, we concluded that calcification and packaging occurred after C. sinensis adult entrance into the gallbladder, subsequently leading to the early formation of CaCO3 or bilirubinate–CaCO3 mixed gallbladder stones. This discovery highlights definite evidence for C. sinensis infection causing gallbladder stones.