A 78 year old lady sought medical attention for palpitations with documented regular wide complex tachycardia with a left bundle branch block (figure [1](#fig-cap-0001)) as well as atrial fibrillation. She presented for a catheter ablation for atrial fibrillation and presumed CTI-dependent atrial flutter. As a part of the procedure, we performed an electrophysiology study. We performed pacing manoeuvres to evaluate for the presence of a concealed accessory pathway. She had an underlying left bundle branch block observed in sinus rhythm. Results of para-Hisian pacing maneuver are displayed in figure [2](#fig-cap-0002) with intracardiac electrograms and corresponding 12-lead ECG. Para-Hisian pacing is performed at a constant pacing interval through the distal electrode of the His bundle catheter. There is a decapolar catheter in the coronary sinus with the proximal electrode positioned at the Os. Here are some questions to consider: There are 4 different paced morphologies observed. What does each one of these represent? How can we interpret the findings of this maneuver? What role does pre-existing left bundle branch block play in our interpretation?

Background: We sought to evaluate the anatomic and functional lesion development over time at different atrial sites immediately following delivery of pulsed field ablation (PFA). Methods: Using a porcine model, PFA ablations were performed in the superior vena cava (SVC), right atrial lateral wall (RA), left atrial appendage (LAA) and right superior pulmonary vein using four different PFA profiles. Mapping was done sequentially in 5–20-minute increments up to 280-minutes post lesion delivery for low voltage area (LVA) assessment and conduction velocity. Lesion characteristics were noted with voltage mapping immediately post ablation and at the serial time points. Results: In 9 animals, 33 sites were ablated. None of the four different profiles across all sites any statistical difference on acute lesion formation or persistence. Higher tissue contact was observed in the SVC and RSPV and lower tissue contact was observed in the LAA and RA locations. Higher contact areas were noted to have higher density electroanatomic low voltage area (LVA) (12/14 vs 5/18, p=0.01) and larger lesions on gross pathology (2 /14 vs 6/16, p =0.01) compared to lower contact areas. Lesion regression occurred in 16/33 sites. Sustained lesions were significantly more prevalent in higher versus lower contact sites (65% vs 38%, p=0.037). Conclusion: The development of significant and durable lesions for PFA appears to be dependent on tissue proximity and contact.

Traditional natural products have been the focus of research to explore their medicinal properties. One such medicinally important plant is Morus alba, which is growing very quickly, especially in Asia, and has tremendous pharmacological activities due to the presence of phytochemicals in various parts of this plant. In this review, we provide a comprehensive summary of the phytochemistry, biosynthetic pathways, and pharmacological activities of glycoside flavonoids in the leaves of Morus alba has been studied. In the past centuries, mulberry has been considered a food source for silkworms, and its leaves are used to feed animals for livestock. However, in recent years, mulberry has attained a special place in research because of its phytochemical composition and benefits to human health, including antioxidant, anticancer, antidiabetic, and immunomodulatory effects. Phytochemicals are bioactive compounds present in plants that work with nutrients and dietary fiber to protect against diseases. Morus alba also contains many phytochemicals, such as flavonoids, phenols, and anthocyanins. The biosynthetic pathway is greener and more efficient for producing structurally diverse natural products. This pathway acts as an alternative to chemical synthesis and microbial transformation, which suffer from complex routes, difficult isomer separation, and high cost. The mechanism of the flavonoid biosynthesis pathway in mulberry leaves is not yet clear, and currently, this is a much-needed topic for scientists to explore.

Persons with dependent personality disorder (DPD) have difficulties describing their inner world, and in realizing their negative ideas about the self, such as being weak, unworthy or powerless are just ideas. As a consequence, they tend to over-rely on others and may lose control over their emotions. Treating these persons can gain benefits from including body-focused techniques as they can promote a) awareness of internal states, b) better emotion regulation, c) the capacity to consider their negative ideas about themselves as not necessarily true, and d) gain power of and agency. We will describe the therapist used body-focused techniques in the context of Metacognitive Interpersonal Therapy when treating Lia, a 40-year-old woman suffering from DPD who also suffered from generalized anxiety disorder and had difficulties in making autonomous choices. She had a romantic relationship with a man she described as distant and judgmental so she felt lonely and not entitled to express her discomfort or capable to break up. The therapist used body-focused techniques, together with behavioural exposure, mindfulness and guided imagery, in order to let Lia be more aware of her thoughts and feelings, and then to regulate affects and realize she had previously capacities. At therapy termination anxiety diminished and she could break up with the partner and start a new one where she felt free to express herself. We suggest how bodily-focused techniques can be used to enhance therapy effectiveness in DPD.

The COVID-19 pandemic has necessitated a rapid transformation in healthcare delivery, prompting a shift from traditional in-person services to digital platforms. This comprehensive review explores the transition of the clinic, a community-based pain clinic, to online services, examining the challenges, benefits, and implications for patient care and accessibility. This paper delves into the experiences of patients and providers, highlighting the role of digital health in improving accessibility and overcoming geographical barriers. The paper also addresses the behavioural changes required for effective online interactions and the importance of setting clear expectations to support virtual modalities for pain care. Through a qualitative analysis, key themes and insights are identified, providing a nuanced understanding of the impact of digital transformation on pain management services to create an evidence-based discussion.

Pathological ambivalence, which refers to the simultaneous experience of opposing and contradictory thoughts or emotions, is a relatively understudied construct despite its integral role in early formulations of schizophrenia and schizotypy. The Schizotypal Ambivalence Scale (SAS) was developed to measure this synchronic ambivalence characteristic of schizophrenia-spectrum psychopathology. Interview, questionnaire, and ambulatory assessment studies have demonstrated the SAS is associated with multidimensional schizotypy. The present study examined the expression of ambivalence, as measured by the SAS, in daily life using experience sampling methodology (ESM) in 227 young adults. We also examined ambivalence as a predictor of reactivity, variability, and instability affective dynamics. Participants were prompted by a smartphone application eight times per day for one week to complete ESM questionnaires that assessed affect, social functioning, situation appraisals, and schizotypic experiences in daily life. Overall, SAS scores were associated with daily life experiences of positive, negative, and disorganized schizotypic experiences, emotional dysregulation, and social impairment. SAS scores also predicted time-dependent affective dynamics. Specifically, ambivalence predicted reactivity and variability of negative affect, as well as variability of appraising the current situation as positive. The present study supports results from interview and questionnaire studies that pathological ambivalence is a cross-cutting component of multidimensional schizotypy and provides further support for the construct validity of the SAS.

Background: Various biomarkers are used to define peanut allergy (PA). We aimed to observe changes in PA resolution and persistence over time comparing biomarkers in PA and peanut sensitised but tolerant (PS) children in a population-based cohort. Methods: Participants were recruited from the EAT and EAT-On studies, conducted across England and Wales and were generally well exclusively breastfed babies recruited at 3 months old and followed up until 11 years old. Clinical characteristics, skin prick test (SPT), sIgE to peanut and peanut components and mast cell activation tests (MAT) were assessed at 12m, 36m and 7-11y. Results: The prevalence of PA was 2.1% with only 1 child having PA resolution at 7-11y. PA children had larger SPT size, higher peanut-sIgE, Ara h 2-sIgE and MAT (all p<0.001) compared to PS children at 36m and 7-11y. SPT, peanut-sIgE, Ara h 2-sIgE and MAT between children with persistent PA, new PA, outgrown PA and PS were statistically significant at both 36m and 7-11y (p<0.001). Those with persistent PA had SPT, peanut-sIgE and Ara h 2-sIgE that increased over time and MAT which was highest at 36m. New PA children had increased SPT and peanut-sIgE from 36m to 7-11y, but MAT remained low. PS children had low biomarkers across time. Conclusions: In this cohort, few children outgrow or develop new PA between 36m and 7-11y. Children with PA have significantly higher SPT, peanut-sIgE, Ara h 2-sIgE and MAT compared to PS children, evident from 12-36m of age.

Fluorescence imaging, a key technique in life science research, frequently utilizes fluorogenic probes for precise imaging in living systems. Tetrazine is an effective emission quencher in the design of fluorogenic probes, which can be selectively damaged upon bioorthogonal click reactions, leading to considerable emission enhancement. Despite significant efforts to increase the emission enhancement ratio upon click reaction (IAC/IBC) of tetrazine-functionalized fluorogenic probes, the influence of molecular aggregation on the emission properties has been largely overlooked in the design of these probes. In this study, we reveal that an ultrahigh IAC/IBC can be realized in the aggregate system when tetrazine is paired with aggregation-induced emission (AIE) luminogens. Tetrazine can increase its quenching efficiency upon aggregation and drastically reduce background emissions. Subsequent click reactions damage tetrazine and trigger significant AIE, leading to considerably enhanced IAC/IBC. We further showcase the capability of these ultra-fluorogenic systems in selective imaging of multiple organelles in living cells. We propose the term “Matthew Effect” in Aggregate Emission to describe the unique fluorogenicity of these probes, potentially providing a universal approach to attain ultrahigh emission enhancements in diverse fluorogenic aggregate systems.

The less oxygen-dependent, cellular organelle-specific photosensitizers (PSs) with long-term in-vivo imaging and efficient reactive oxygen species (ROS) generation capabilities are highly desirable for imaging-guided photodynamic therapy (PDT) under hypoxia, but still challenging. In this contribution, three mitochondria-targeting, aggregation-induced emission (AIE)-based photosensitizers termed as TPEPyTMB-1 (monomeric), TPEPyTMB-2 (dimeric) and TPEPyTMB-3 (trimeric) were synthesized to enhance the AIE-effect, ROS generation, and mitochondria-targeting ability. The rationally synthesized AIE-PSs efficiently produce a mixture of type-1 and type-2 ROS with excellent photophysical properties in terms of near-infrared (NIR) emission, large Stock-shift (> 225 nm) and high photostability. The biocompatible AIE-PSs nanoparticles (AIE-PSs NPs) were fabricated using an amphiphilic block copolymer (DSPE-PEG). Among them, TPEPyTMB-3 NPs with superior intracellular ROS production efficiency as well as greater mitochondria-targeting capabilities, demonstrated efficient PDT efficacy in both normoxia and hypoxia environments. In-vivo results revealed that TPEPyTMB-3 NPs can effectively inhibit the growth of subcutaneous tumors, under white light irradiation with minimized systemic toxicity. Moreover, TPEPyTMB-3 NPs accumulated at tumor sites and displayed outstanding long-term in-vivo imaging capability (up to 7 days). This study provides a new perspective for developing the emerging AIE-PSs to maximize PDT performance through the trimerization of small AIE-photosensitizer.

Brain functional modular organization changes with age. Considering the brain as a dynamic system, recent studies have suggested that time-varying connectivity provides more information on brain functions. However, the spontaneous reconfiguration of modular brain structures over time during ageing remains poorly understood. In this study, we investigated the age-related dynamic modular reconfiguration using resting-state functional MRI data (615 participants, aged 18-88 years) from Cam-CAN. We employed a graph-based modularity analysis to investigate modular variability and the transition of nodes from one module to another in modular brain networks across the adult lifespan. Results showed that modular structure exhibits both linear and nonlinear age-related trends. The modular variability is higher in early and late adulthood, with higher modular variability in the association networks and lower modular variability in the primary networks. In addition, the whole brain transition matrix showed that the times of transition from other networks to the dorsal attention network were the largest. Furthermore, the modular structure was closely related to the number of cognitive components and memory-related cognitive performance, suggesting a potential contribution to flexibility cognitive function. Our findings highlighted the notable dynamic characteristics in large-scale brain networks across the adult lifespan, which enhanced our understanding of the neural substrate in various cognition during ageing. These findings also provided further evidence that dedifferentiation and compensation are the outcomes of functional brain interactions.

Introduction: Post-ablation chest pain is a common occurrence in patients after radiofrequency (RF) pulmonary vein isolation (PVI) ablation for the treatment of atrial fibrillation (AF), with a reported incidence of up to 50%. Pain can be caused by pericarditis, vagal plexus thermal injury, gastroparesis, or local inflammation. Active esophageal cooling is FDA cleared for reducing the likelihood of ablation-related esophageal injury resulting from RF cardiac ablation procedures, but cooling has also been reported to have pleiotropic effects which may mitigate inflammation and reduce the likelihood of post-ablation chest pain. The aim of this study is to quantify the change in incidence of post-ablation chest pain after the adoption of active esophageal cooling during RF ablations. Methods: Data from a community hospital registry were obtained for the 12 months prior to (pre-adoption), and the 12 months after adoption (post-adoption) of active esophageal cooling in December 2021 during RF ablations. Type of ablation was recorded, along with patient’s age, post-ablation symptoms, and type of prophylactic treatment utilized. Incidence rates of chest pain before and after adoption of esophageal cooling were then compared. Results: Data were reviewed from 183 patients. In the pre-adoption cohort, patients were given 2 weeks of daily sucralfate and pantoprazole, with an additional 4 weeks in cases with persisting symptoms. In this group, 90 patients (66.7% persistent AF) with a mean age of 69.6 years (SD ± 10.34) received PVI, with 62 (68.9%) receiving roof lines, 60 (66.7%) receiving floor lines, and 41 (45.6%) reporting post-ablation chest pain requiring extension of treatment to 6 weeks. In the post-adoption cohort, 2 days of sucralfate and pantoprazole was given, and a total of 93 patients (75.2% persistent AF) with a mean age of 68.3 years (SD ± 10.28) received PVI, with 79 (84.5%) receiving roof lines, 75 (80.6%) receiving floor lines, and none reporting post-ablation chest pain (p<0.0001). Conclusion: Adoption of active esophageal cooling was associated with a significant reduction in post-ablation chest pain despite increased use of posterior wall isolation and decreased use of prophylactic treatment.

The present work was carried out to evaluate the possible effects of chronic alcohol intake on the histology and ultrastructure of the endometrial lining epithelium of the uterine horn of Calomys callosus. 20 adult female rodents, Calomys callosus, three months old, were used. These animals were divided equally into 2 experimental groups called control and alcoholic. The control group received a solid diet (mouse food) and tap water “ad libitum”. The alcoholic group received the same solid diet and ethanol was diluted to 20% in water. At the end of 120 days of treatment with 20% alcohol, all animals were anesthetized with ethyl ether and sacrificed. Daily observations of the animals’ behavior, carried out throughout the treatment period, made it possible to verify a certain lethargy of the animals in the alcoholic group, concerning the animals in the control group, regarding responses to physical and sound stimuli. Macroscopically, no difference was observed in the uterus between the groups analyzed. In light microscopy, the animals in the alcoholic group showed the same histological characteristics as the control group, however, a marked atrophy of the epithelial tissue covering the endometrium could be observed. This atrophy is confirmed by the results of transmission electron microscopy, where important changes were also observed in alcoholic animals: a large increase in lipid droplets, dispersed throughout the cytoplasm, digestive vacuoles, and an increase in the cisterns of the granular endoplasmic reticulum. The presence of invasive immune cells in the epithelial tissue was also observed. Scanning electron microscopy analyses showed the presence of lipid droplets in the endometrial lumen. Ethanol ingestion caused epithelial lesions in the uterine horn, causing apoptosis, and interfering with the secretory mechanism.

Biologists have long debated why some plant species produce many seeds synchronously during some years and few during others. One hypothesis is that selection on phenological synchrony of flowering improves pollination efficiency and leads to increased fecundity. In an 11-year study of valley oak (Quercus lobata), we found that, indeed, trees that produced flowers during mid-season tended to produce more acorns. But, is synchrony the key factor? Here, we test the phenological synchrony hypothesis versus the alternative hypothesis that the environment principally shapes flowering phenology and acorn production. At our site, we find that a tree’s microenvironment is associated with both timing of phenology and acorn production. Timing of flowering depends on air temperature and crop size is not related to synchrony but is best predicted by relative elevation – likely a proxy for substrate quality and access to water. We conclude that microenvironment - not phenological synchrony - shapes acorn production.

Understanding how species adjust to seasonality is fundamental in ecology, especially with rapidly increasing global air temperatures. Bioacoustic monitoring offers promise for tracking shifts in seasonal timing of vocal species, as recent automated sound recorders enable large-scale and long-term data collection. Yet, analyzing vast datasets necessitates automation and innovative detection methods. Here, we introduce BioSoundNet, a deep learning model designed for bird vocalization detection. Trained on field data and open-access databases, BioSoundNet achieved AUC scores of 0.88-0.93 and average precisions of 0.87-0.97 across five datasets spanning various ecosystems, and effectively captured the temporal patterns of avian acoustic activity at different time scales. Our findings underline the importance of evaluating models in ecological contexts and to address the potential consequences of missing detections. Operating efficiently on standard computers, BioSoundNet is a robust tool for automated bird vocalization detection, providing a valuable resource for ecological phenology studies and acoustic dataset analysis.

Decisions about a current stimulus are influenced by previously encountered stimuli, leading to sequential bias. However, the specific processing levels at which serial dependence emerges remain unclear. Despite considerable evidence pointing to contributions from perceptual and post-perceptual processes, as well as response carryover effects impacting subsequent judgments, research into how different task measurements affect sequential dependencies is limited. To address this gap, the present study investigated the role of task type in shaping sequential effects in time perception, employing a random-dot kinematogram (RDK) in a post-cue paradigm. Participants had to remember both the duration and the direction of the RDK movement and perform the task based on a post-cue, which was equally likely to be direction or duration. To delineate the task type, we employed the temporal bisection task in Experiment 1 and the duration reproduction task in Experiment 2. Both experiments revealed a significant sequential bias: durations were perceived as longer following longer previous durations, and vice versa. Intriguingly, the sequential effect was enhanced in the reproduction task following the same reproduction task (Experiment 2), but did not show significant variation by the task type in the bisection task (Experiment 1). Moreover, comparable response carryover effects were observed across two experiments. We argue that the differential impacts of task types on sequential dependence lies in the involvement of memory reactivation process in the decision stage, while the post-decision response carryover effect may reflect the assimilation by subjective, rather than objective, durations, potentially linking to the sticky pacemaker rate and/or decisional inertia.

To explore the effects of a novel magnesium alloy (Mg-3Nd-1Gd-0.3Sr-0.2Zn-0.4Zr (wt%)) on osteoblast proliferation and adhesion, and to clarify the underlying molecular mechanisms. In vitro DAPI and ALP analyses revealed that the new magnesium alloy was able to promote osteoblast adhesion in a dose-dependent manner. CCK-8 assays also revealed alloy-dependent changes in MC3T3-E1 cell proliferation after 1, 3, 5, and 7 days, with significantly higher proliferation levels in the group treated with the magnesium alloy leaching solution (P<0.05). This new magnesium alloy was also able to enhance fibronectin, collagen type I, integrin α2, FAK, and GLUT3 expression at the mRNA and protein levels, driving MC3T3-E1 cell proliferation and adhesion via the ERK and FAK/Akt/mTOR pathways. Consistent with the observation, the addition of inhibitors specific for these pathways was sufficient to disrupt the adhesion and proliferation of these MC3T3-E1 cells. Relative to titanium alloys, the new magnesium alloy developed in this study was better able to promote MC3T3-E1 cell proliferation and adhesion through the ERK and FAK/Akt/mTOR signaling pathways, respectively.

Transdermal drug delivery has made great progress in transdermal delivery of macromolecules in recent years, offering a non-invasive and convenient approach for drug administration. By bypassing first-pass metabolism and reducing the risk of drug toxicity, transdermal drug delivery holds great promise in the field of medicine. However, the permeability of the skin barrier limits the range of drugs that can be effectively delivered. To overcome this challenge, researchers have been exploring the integration of multiple technologies to enhance transdermal drug delivery. This review provides an overview of different transdermal drug delivery methods, including microneedles and microneedle combination technologies needle-free injectors, and other methods such as chemical enhancers, temporary pressure, and transferosomes. The advantages, limitations, and considerations for each method are discussed, taking into account factors such as drug delivery efficiency, patient compliance, skin damage, and post treatment skin recovery. Furthermore, the review highlights the potential of combining these technologies to improve drug permeation across the skin barrier. Integration of physical enhancement techniques such as microneedles and sonophoresis, chemical enhancers, and novel drug delivery systems like nanoparticles and hydrogels have shown promising results in enhancing drug delivery efficiency, increasing drug stability, and achieving controlled release. Additionally, the combination of technologies allows for the optimization of drug delivery parameters, enabling personalized and targeted therapy.

Carbon-Nitride (CNx) coatings deposited by means of plasma vapour deposition led to the formation of g-C3N4 phase in a mainly amorphous matrix, Nanoindentation was performed on these coatings deposited on 304 SS (stainless steel) substrates. The positioning of the indentation i.e inside the grain formed and at the boundary showed prolific features pertaining to the understanding of extension of plastic volume and variations in interfacial fracture energies and the role played by ductile substrates in preventing damage to a component. The amorphous nature of the gain boundary is detrimental to the overall performance of the system as confirmed by the strain rate variations and has been suggested to get rid of by post deposition treatment

INTRODUCTIONPyoderma gangrenosum (PG) is a rare, primary sterile, inflammatory, non-infective, and non-malignancy skin disease that is classified into four variants (ulcerative, pustular, bullous, and vegetative) (Table 1). Up to 50% of PG cases might have systemic diseases such as hematological malignancy, rheumatoid arthritis, paraproteinemia, myeloproliferative disorder, and inflamatory bowel diseases such as Crohn’s disease and ulcerative colitis. It’s found that up to 5% of cases of PG have ulcerative colitis and 1.5% have Crohn’s disease (1), (2), (3), (4), (5). In the 1930s, Brunsting et al. were the first to define PG as a disease entity. They described it in five patients who presented with large, painful necrotic ulcers with undermined borders of bluish coloration enclosed by regions of erythema. In those five patients, four had ulcerative colitis. The cause is still unknown, though it was hypothetically thought to be a bacterial disease and sometimes a cutaneous manifestation of inflammatory bowel disease, which has been refuted by current studies (2).The incidence of PG annually in the United States is estimated to be 1 case in 100,000, while the worldwide incidence is between 3 and 10 million. General PG is a diagnosis of exclusion, with penile conditions having considerable differentials, including infections such as syphilis, amoebiasis, herpes simplex, mycobacterial ulceration, and non-infectious origins of venereal ulceration like cutaneous Crohn’s disease, squamous cell carcinoma, and ulcerating sarcoidosis. It should be considered in lesions where antimicrobial or antiviral therapy has not responded or for the non-confirmatory diagnosis of skin conditions (6). Frequently, PG occurs between the ages of 25 and 54, though it might occur at any age. It is extremely rare in pediatrics; 4% of cases have been reported in pediatrics and infants; in infants alone, 8.8% of all pediatric cases are reported. The youngest reported case is 3 weeks old. Females are more affected than males, and their peak age is in their third and fourth decades, while their counterpart males are in their fifth decade. The initial lesion is a tender pustule, whereas in infants, the areas involved are perianal and genital, and in children, the lesions involve the head, face, and gluteal areas (4).Typically, PG lesions start as small vesiculopustular, which progresses to an ulcer with violaceous overhanging borders, and these occur mostly in the lower extremities, though not limited to other organs. In this typical form, it is believed that if the condition is associated with arthritis, they become more refractory to treatment than those without arthritis. Atypical forms are clinically presented as superficial lesions with blue-gray bullous borders involving the extremities, head, and neck. Regardless of the presence of other systemic conditions, it can be acute or chronic. A PG patient presents with a condition called pathergy, which is the development of a lesion at a site of trauma, whether it be iatrogenic, animal bites, or any injury, and it is due to hyper-reactivity of the skin (8). Apart from PG, other conditions that may present with pathology are sweet syndrome, blindloop syndrome, erythema elevatum diutinum, and Behcet’s disease. Pathergy should not be confused with the Koebner/isomormorphic response, which is the formation of new skin lesions in areas that were not involved in trauma. 10–30% of PG reported cases are idiopathic; 20% of patients will present with a Koebner response, while 20–30% will present with pathology (9, 10).

In this paper, the prescribed-time consensus problem of multi-agent systems with finite control gain is investigated. A novel control Lyapunov function (CLF) framework for prescribed-time stability is developed by using the time space deformation approach. For both leaderless and leader-following prescribed-time consensus, new switching time-varying gain-based protocols are proposed, in which, the infinite time-varying control gain is turned off before the prescribed time and the global finiteness of control gain is thus guaranteed. It is mathematically proved that the agents equipped with the proposed protocols can achieve less conservative prescribed-time consensus in both leaderless cases and leader-following cases, on the basis of the developed CLF framework. The superiority of the proposed prescribed-time protocols in terms of consensus accuracy, control energy consumption, and control peak value is demonstrated through comparison simulations using illustrative examples.

Berenike Lisa Blaser1*, Mathias Weymar1,2, & Julia Wendt11 University of Potsdam, Department of Biological Psychology and Affective Science, Faculty of Human Sciences, Karl-Liebknecht Strasse 24/25, 14476 Potsdam, Germany2Faculty of Health Sciences Brandenburg, University of Potsdam, Potsdam, Germany * Correspondence:Berenike Lisa BlaserUniversity of PotsdamKarl-Liebknecht Strasse 24/2514476 Potsdam, Germany Email: berenike.blaser@uni-potsdam.de Running head: Smartphone-based Heart Rate Variability Biofeedback for PMS Keywords: smartphone photoplethysmography, mHealth, heart rate variability, biofeedback, vagal tone, premenstrual syndrome, premenstrual symptoms, menstrual cycle, stress, depression, attentional control AbstractIntroductionHeart rate variability biofeedback (HRVB) is a well-studied intervention known for its positive effects on emotional, cognitive, and physiological well-being, including relief from depressive symptoms. However, its practical use is hampered by high costs and a lack of trained professionals. Smartphone-based HRVB, which eliminates the need for external devices, offers a promising alternative, albeit with limited research. Additionally, premenstrual symptoms are highly prevalent among menstruating individuals, and there is a need for low-cost, accessible interventions with minimal side effects. With this pilot study, we aim test, for the first time, the influence of smartphone-based HRVB on depressive and premenstrual symptoms, as well as anxiety/stress symptoms and attentional control.MethodsTwenty-seven participants with above-average premenstrual or depressive symptoms underwent a 4-week photoplethysmography smartphone-based HRVB intervention using a waitlist-control design. Laboratory sessions were conducted before and after the intervention, spaced exactly 4 weeks apart. Assessments included resting vagally mediated heart rate variability (vmHRV), attentional control via the revised attention network test (ANT-R), depressive symptoms assessed with the BDI-II questionnaire, and stress/anxiety symptoms measured using the DASS questionnaire. Premenstrual symptomatology was recorded through the PAF questionnaire if applicable. Data analysis employed linear mixed models.ResultsWe observed improvements in premenstrual, depressive, and anxiety/stress symptoms, as well as the Executive Functioning Score of the ANT-R during the intervention period but not during the waitlist phase. However, we did not find significant changes in vmHRV or the Orienting Score of the ANT-R.DiscussionThese findings are promising, both in terms of the effectiveness of smartphone-based HRVB and its potential to alleviate premenstrual symptoms. Nevertheless, to provide a solid recommendation regarding the use of HRVB for improving premenstrual symptoms, further research with a larger sample size is needed to replicate these effects. 1               IntroductionHeart rate variability biofeedback (HRVB) is a well-researched intervention that has demonstrated effectiveness in a wide range of areas (Lehrer et al., 2020), including relieving anxiety and stress (Goessl et al., 2017), ameliorating depression (Pizzoli et al., 2021), improving sleep (Stein & Pu, 2012), alleviating asthma symptoms (Lehrer et al., 2004), and even enhancing sports performance (Jiménez Morgan & Molina Mora, 2017). However, despite its potential, this user-friendly method has seen limited practical implementation. This can be attributed, in part, to the high costs associated with necessary stationary and mobile electrocardiography (ECG) devices, as well as the required training and expertise of staff members entrusted with its administration, which further strains healthcare systems. Encouragingly, smartphone apps capable of assessing heart rate through the device's camera, without additional equipment, are promising to yield similar results (Yuda et al., 2020). Nevertheless, empirical validation of smartphone-based HRVB applications remains limited. This study aims to validate the effectiveness of an HRVB intervention applied through smartphones, specifically targeting the alleviation of depressive symptoms, a well-documented outcome of conventional HRVB. Additionally, we explore a novel application of HRVB for premenstrual symptoms.HRVB is a method in which vagally mediated heart rate variability (vmHRV), an indicator of parasympathetic activity (Laborde et al., 2023; Penttilä et al., 2001), is systematically increased through slow, controlled breathing and visual feedback of heart rate oscillations. The primary driving mechanism involves slow-paced breathing at 0.1 Hz or an individual resonance frequency (Laborde, Allen, Borges, Iskra, et al., 2022). It is believed to exert its various beneficial effects through bottom-up modulation of a neural network described by Thayer and Lane (2000) in their neurovisceral integration model. This model delineates a network of interconnected structures known as the central autonomic network (CAN), responsible for integrating information and regulating appropriate responses. At the core of this regulatory network, Thayer and Lane (2009) propose an inhibitory connectivity between the medial prefrontal cortex (mPFC) and the amygdala. The stronger this connectivity, the greater an individual's capacity to downregulate a presumed default stress response and deliver a precise and personalized reaction to internal and environmental demands. VmHRV is considered both a peripheral index for this capacity and a reciprocal element within this network (Thayer et al., 2009). This theory is grounded in a substantial body of evidence linking low vmHRV to psychopathology (Heiss et al., 2021) and reduced performance in cognitive self-control tasks (Holzman & Bridgett, 2017; Zahn et al., 2016). When practiced over several weeks, HRVB enhances the capacity of the CAN through coherence phenomena involving the synchronization of breathing rate, blood pressure, and heart rate oscillations (Sevoz-Couche & Laborde, 2022). These phenomena contribute to several bottom-up routes. The most crucial of these routes involve input into the CAN through baroreceptors via the nucleus of the solitary tract, stretch receptors in the lungs, and a vagal afferent pathway (Lehrer & Gevirtz, 2014; Noble & Hochman, 2019; Sevoz-Couche & Laborde, 2022).HRVB interventions have demonstrated the potential to improve various affective and cognitive outcomes associated with CAN capacity, including depression (Pizzoli et al., 2021) and anxiety (Goessl et al., 2017). Our study aims to expand these effects in the context of a smartphone-based intervention. While vmHRV is reliably associated with cognitive outcomes, particularly executive functions, the impact of HRVB on these variables is less clear (Tinello et al., 2022). In a systematic review, Tinello et al. (2022) found that existing effects are primarily observed in the domain of attentional control and are often found in patient populations or individuals experiencing high levels of stress. Given that attention is strongly linked to vmHRV, we also investigate the effect of HRVB on attentional control using the revised Attention Network Test (ANT-R, Blaser et al., 2023a; Fan et al., 2009).Expanding on these replications, we further investigate HRVBs impact on premenstrual syndrome (PMS), a highly prevalent condition characterized by a diverse collection of psychological and physiological symptoms. These symptoms typically manifest in individuals with active menstrual cycles during the week leading up to menstruation and tend to subside shortly after. As many as 90% of menstruating individuals regularly encounter at least one symptom of PMS (Tschudin et al., 2010). Commonly reported symptoms encompass heightened stress reactivity, anxiety, depressive mood, breast tenderness, and abdominal pain (Allen et al., 1991).As a component of the gender data gap, premenstrual syndrome (PMS) remains significantly under-researched (Zehravi et al., 2023). Even today, treatment options remain limited, primarily centered on addressing specific psychological or physiological symptoms through hormonal cycle suppression or antidepressant medication in both clinical practice and research (Ryu & Kim, 2015). Both of these approaches are associated with substantial adverse side effects (Price et al., 2009; Robinson et al., 2004; Skovlund et al., 2016).Premenstrual symptoms have been linked to cyclic fluctuations in vagally mediated heart rate variability (vmHRV) (Schmalenberger et al., 2019). Individuals who experience more severe symptoms tend to exhibit a pronounced reduction in vmHRV during the luteal phase of their menstrual cycle, coinciding with the experience of these symptoms (Matsumoto et al., 2007). Matsumoto et al. (2007) have suggested a potential causal relationship in this regard. One possible explanation for this phenomenon lies in a metabolite of progesterone, one of the main fluctuating gonadal steroids during the menstrual cycle. Sundström-Poromaa et al. (2003) have identified this metabolite, namely Allopregnanolone (ALLO), an allosteric Gamma-Aminobutyric Acid (GABA) receptor modulator as a likely cause of the experience of premenstrual symptoms (Hantsoo & Epperson, 2020). As ALLO operates on the GABAergic system, the proposed CAN in the neurovisceral integration theory (Thayer & Lane, 2000, 2009) might also be affected. In this theory, successful adaptation relies on inhibitory connectivity between the mPFC and the amygdala. The strength of these connections, which are part of the central nervous system's inhibitory GABAergic network, are influenced by GABA levels in the mPFC (Delli Pizzi et al., 2017). Compromised inhibition in this circuit due to ALLO withdrawal and/or maladaptive ALLO responses may lead to a compromised self-regulatory capacity of the organism on both affective and physiological levels, as observed in PMS.Following this line of reasoning, HRVB is a promising candidate to counteract some of these effects through two mechanisms. Firstly, the most pronounced effects of HRVB are observed in stress management (Goessl et al., 2017). If stress throughout the cycle causes irregularities in the ALLO system during the premenstrual phase, reducing stress throughout the cycle may prevent some of the symptom development. Existing evidence already suggests that various relaxation techniques can positively impact PMS (Jose et al., 2022). Secondly, HRVB is assumed to increase the inhibitory capacity of the mPFC over the amygdala and, as a result, enhance the inhibition of the default stress response (Schumann et al., 2021). Although GABAergic transmission may be compromised during the premenstrual phase, boosting the baseline inhibitory strength between these two brain structures could raise inhibition levels. This might make it less likely for a sudden drop to cross the threshold to trigger symptoms that cause significant distress.Initial studies have already provided evidence of the effectiveness of HRVB for mental health outcomes when administered through smartphones. Previous studies that utilized smartphone-based HRVB interventions to improve outcomes like depressive or anxiety symptoms, however, have typically relied on external devices connected to the smartphone via Bluetooth. These devices include wearable ECG-measuring breast straps (Chung et al., 2021; Herhaus et al., 2022; Lin, 2018; Schumann et al., 2022; Schumann et al., 2021) or earlobe-clip pulse measuring devices (Economides et al., 2020; Minen et al., 2021; Schuman et al., 2023). Acquiring a wearable device presents a significant obstacle for potential HRVB users. Smartphone cameras can now measure heart rate when the user places a finger on the camera. An application activates the camera flash and analyzes the red-to-green ratio in the image at high frequency, generating pulse curves. This process is known as photoplethysmography (PPG) and closely resembles the process behind the optical sensors that emit infrared or green light in commonly used pulse measurement devices. Yuda et al. (2020) suggest that the heart rate variability indicator used in smartphone apps, which they term 'pulse rate variability' as measured through PPG, may contain distinct information compared to its ECG-measured counterpart. Nevertheless, recent research has demonstrated very high correlations between HRV parameters measured through ECG and PPG of over .9 (van Dijk et al., 2023), even though the reliability is somewhat dependent on sampling rate of the device (Guede-Fernández et al., 2020). Moreover, the associations with mental health outcomes are also evident when assessing vmHRV via PPG using the smartphone camera (Liu et al., 2020). This supports the use of PPG as a foundation for HRVB.In this study, we investigated the novel application of a 4-week smartphone-based HRVB intervention using PPG via smartphone camera instead of an external device for alleviating depressive and premenstrual symptoms. Our sample comprised young adults who either exhibited above-average PMS or depressive symptoms. Additionally, we examined the impact of the intervention on various other outcomes, including anxiety and stress symptoms, attentional control, and vmHRV.2               Methods2.1         ParticipantsA G*Power analysis revealed that a sample size of 40 was necessary to detect an effect size of .4, based on a meta-analytic effect of HRVBFB on depressive symptoms reported by Pizzoli et al. (2021), with a power of .8 and a one-tailed alpha error probability of .05. However, due to recruitment difficulties and resourcing issues by the company providing the app during the extended recruitment period, we were unable to reach our target of 40 participants.Twenty-nine participants were recruited from the student population of the University of Potsdam for this study. Recruitment was carried out via the online recruiting platform for study participants of the cognitive sciences (Sona Systems, https://www.sona-systems.com) of University Potsdam as well as via flyers on campus and advertisement in university mailing lists. Inclusion criteria required participants to have either above-average premenstrual symptomatology (short version Premenstrual Assessment Form, PAF20 ≥ 50), depressive symptoms that indicate at least minimal depression (Beck’s Depression Inventory, BDI-II ≥ 9), or both. Participants who exceeded a BDI-II score of 14 received a consultation with a clinical psychologist to discuss possible necessary treatment prior to study participation.Exclusion criteria included factors proposed by Laborde et al. (2017) such as pregnancy, heart rate-altering chronic diseases or medication. We additionally excluded competitive athletes to avoid ceiling effects, since this population has systematically increased vmHRV (Da Silva et al., 2015). Participants currently in any treatment or planning significant lifestyle changes during the period of study participation were also excluded. In addition, participants were required to be at least 18 years of age.All participants provided informed consent prior to their inclusion for a study protocol approved by the ethics committee of the University of Potsdam (No. 30/2022). Participants who met the inclusion criteria were eligible for study participation and received either course credits or monetary compensation.2.2         ProcedureThe study protocol was preregistered on Open Science Framework (osf.io/68fzq). The study procedure began with an online screening questionnaire to determine eligibility based on inclusion and exclusion criteria, as well as to assess sociodemographic factors such as age, gender, study program, and BMI. Participants were also required to provide information about their menstrual cycle to ensure that the appropriate questionnaires were administered. Additionally, participants were asked to provide their email address for communication throughout the study.All eligible participants took part in a 4-week biofeedback intervention during which they practiced smartphone-based HRVB for at least 5 minutes every day. After the first and second week, participants additionally received an online coaching session to improve their technique and address any technical or other difficulty they encountered.Before and after the 4-week intervention, participants completed laboratory sessions that were scheduled at the same time, exactly 4 weeks apart (T1 and T5). During these sessions, various measures were collected, including vagally mediated heart rate variability by ECG, attentional control using the reaction time paradigm ANT-R (Fan et al., 2009), and self-reported symptoms of depression, premenstrual syndrome (PMS), and anxiety/stress via questionnaires.To ensure balanced allocation of participants to the waitlist group, half of the participants within each group of inclusion criteria (depression, PMS, or both) were pseudo-randomly assigned to the waitlist group. The waitlist group additionally completed a laboratory session four weeks prior to study inclusion, during which the same parameters were assessed (W1).Throughout the study, participants completed short versions of the depressive and premenstrual symptom questionnaires and underwent a photoplethysmography based HRV measurement at home using the biofeedback app, each week on the same day and at the same time that they chose (W2-W4 and T2-T4). Participants received automated email reminders and a link to the respective questionnaire to ensure compliance. The results of these measurements are not analysed and reported in this report. Figure 1 provides an overview of the study procedure.All participants received an introduction to smartphone-based HRVB during T1. The waitlist group received a tutorial on conducting vmHRV measurements at home with the app during W1, while the intervention-only group received this tutorial during T1.Since PMS occurs only once during each menstrual cycle, and cycle lengths can vary significantly both between and within individuals, we included a follow-up measurement of the online questionnaire 4 weeks after T5. If a participant reported no new menstruation onset during the last two weeks of the intervention, indicating no new premenstrual phase, we used the PMS values reported in the follow-up measurement as the post-intervention values, describing the next premenstrual phase after completing the intervention. Figure 1. Study procedure

Kidney stones require surgical removal when they grow too large to be broken up externally or to pass on their own. Upper tract urothelial carcinoma are also sometimes treated endoscopically in a similar procedure. These surgeries are difficult, particularly for trainees who often miss tumors, stones or stone fragments, requiring re-operation. One cause of difficulty is the high cognitive strain surgeons experience in creating accurate mental models during the endoscopic operation. Furthermore, there are no patient-specific simulators to facilitate training or standardized visualization tools for ureteroscopy despite its high prevalence. We propose ASSIST-U, a system to automatically create realistic ureteroscopy images and videos solely using preoperative CT images to address these unmet needs. We train a 3D UNet model to automatically segment CT images and construct 3D surfaces. These surfaces are then skeletonized for rendering and camera position tracking. Finally, we train a style transfer model using Contrastive Unpaired Translation (CUT) to synthesize realistic ureteroscopy images. Cross validation on the UNet model achieved a Dice score of 0.853 $\pm$ 0.084 for the CT segmentation step. CUT style transfer produced visually plausible images; the Kernel Inception Distance to real ureteroscopy images was reduced from 0.198 (rendered) to 0.089 (synthesized). We also qualitatively demonstrate the entire pipeline from CT to synthesized ureteroscopy. The proposed ASSIST-U system shows promise for aiding surgeons in visualization of kidney ureteroscopy.

Purpose: To evaluate the efficacy and safety of vitrectomy combined with inverted internal limiting membrane (ILM) flap technique and perfluoropropane tamponade (C3F8) for the treatment of high myopia macular holes (HMMH) with or without macular foveoschisis (MF). Methods: This is a retrospective, observational case series study. Sixty-seven eyes of 67 patients who underwent vitrectomy with inverted ILM flap and C3F8 tamponade were enrolled. The main outcome measures were best-corrected visual acuity (BCVA), the closure rate of HMMH and the integrity of ellipsoid zone (EZ) and external limiting membrane (ELM) at the final follow-up visit. Results：There was no significant difference in the BCVA and the closure rate of HMMH at the final follow-up between the two groups. However, the recovery of ELM and EZ was significantly higher in the no MF group than in the MF group at the final follow-up. Specifically, ELM and EZ were restored in 17 eyes (50.0%) and 10 eyes (29.4%) of the no MF group, respectively, while only 4 eyes (12.1%) and 2 eyes (6.1%) of the MF group achieved ELM and EZ restoration, respectively. Conclusion: Vitrectomy with inverted ILM flap technique and C3F8 tamponade is an effective and safe method to achieve a high anatomical success rate of HMMH closure and improve visual function. However, the presence of foveoschisis may impair the structural recovery of the outer retinal layer.

Linear Programs (LPs) are one of the major building blocks of AI and have championed recent strides in differentiable optimizers for learning systems. While there exist efficient solvers for even high-dimensional LPs, explaining their solutions has not received much attention yet, as explainable artificial intelligence (XAI) has mostly focused on deep learning models. LPs are mostly considered whitebox and thus assumed simple to explain but we argue that they are not easy to understand in terms of relationships between inputs and outputs. To mitigate this rather non-explainability of LPs we show how to adapt attribution methods by encoding LPs in a neural fashion. The encoding functions consider aspects such as feasibility of the decision space, the cost attached to each input and the distance to special points of interest. Using a variety of LPs, including a very large-scale LP with 10k dimensions, we demonstrate the usefulness of explanation methods using our neural LP encodings, though, the attribution methods Saliency and LIME are indistinguishable for low perturbation levels. In essence, we demonstrate that LPs can and should be explained which can be achieved by representing an LP as a neural network.