Tremor arises from mechanical, reflex, or central oscillatory mechanisms. Transcranial magnetic stimulation (TMS) can transiently perturb ongoing tremor and enables the quantitative assessment of phase resetting, offering circuit-level insight into tremor types. Although numerous studies have applied TMS-induced resetting, the findings have not been systematically reviewed. This study systematically reviews human studies evaluating TMS-induced tremor resetting across tremor types. A systematic search of PubMed and Google Scholar identified human studies using TMS to perturb tremor or rhythmic movement. Search terms included "tremor resetting," "resetting of tremor," "tremor phase shift," "tremor phase reset," "transcranial magnetic stimulation," and "central oscillator." Inclusion criteria were human participants, experimental TMS perturbation, and quantitative tremor phase/resetting outcomes. Exclusion criteria were animal studies, therapeutic repetitive TMS trials without resetting analyses, and isolated case reports. Two researchers independently screened and extracted data. The PRISMA 2020 guidelines were followed. Twenty-one studies were identified, three of which were excluded from the primary synthesis (two case reports and one qualitative-only design). Eighteen studies remained, which addressed essential tremor (ET) (n = 6), Parkinson's disease tremor (PDT) (n = 7), orthostatic tremor (OT) (n = 4), palatal tremor (n = 1), dystonic tremor (DT) (n = 1), and voluntary rhythmic movement (n = 4). M1 stimulation reset ET, postural PDT, OT, palatal tremor, DT, and voluntary rhythmic movements. Rest PDT had inconsistent resetting by M1 stimulation and no resetting by cerebellar stimulation. Cerebellar stimulation reset postural PDT but not ET. The resetting index was associated with the stimulus intensity and duration of the silent period. TMS-induced resetting is a strong physiological tool for differentiating tremor circuits. M1 acts as a major convergence node, while cerebellar involvement is tremor-specific. Methodological heterogeneity and small samples limit the comparability of study results. Advances in targeting technologies and closed-loop and phase-locked protocols could enhance the diagnostic and therapeutic utility of resetting paradigms.
Unravelling a reliable timing of past earthquakes through luminescence dating of fault gouge depends on sufficient frictional heat during a co-seismic event to fully reset the luminescence signal. Laboratory fault-gouge production using a rotary shear apparatus has attracted interest as a method for probing the degree of signal resetting in quartz during friction experiments. However, natural fault gouges are complex, exhibiting a mixture of minerals that are specific to the host rocks. Here, we employed a host rock sample from the Alborz Mountains (Iran) and subjected it to a friction experiment without any chemical treatment, after being reset and irradiated with a known gamma dose. We performed a medium-slip velocity friction experiment with a slip velocity of 0.05 m/s and a normal stress of 12 MPa, while the temperature evolution of the gouge zone was recorded using an infrared camera. The thermographic images show a transient temperature of approximately 296 °C, with the luminescence signal resetting at a small, extremely localised slip patch, confirming the challenges involved in identifying the best spot for signal resetting. However, we identified a high-temperature signal enhancement in the thermoluminescence (TL) curves that might serve as a marker for fault-gouge formation.
The first hitting times of a stochastic process, i.e., the first time a process reaches a particular level, are of significant interest across various scientific disciplines, including biology, chemistry, and economics. We modify the standard setup by allowing the target to spontaneously switch between two states, either active or inactive, and investigate the distribution of first hitting times accrued while the target is active. For this setup, we provide closed formulas for the distribution of the first hitting time. Additionally, we can introduce stochastic resetting to the underlying process and, utilizing our results, derive the formulas for the first time the active target is hit by the process under stochastic resetting. Interestingly, we show that resetting in this setup still leaves some memory; the system is no longer Markovian, which prevents a straightforward application of standard techniques. The analytical results are accompanied by computer simulations of Langevin dynamics.
As ubiquitous features of every natural environment, microbes have profoundly shaped eukaryotic biology throughout evolution. Circadian clocks evolved in all domains of life as central regulators that align physiology with environmental cycles, yet whether they respond directly to microbial signals remains unknown. Here, we demonstrate that evolutionarily diverse microbes potently reset mammalian cellular clocks and can drive phase shifts in plants and algae, indicating cross-kingdom effects of microbes on circadian rhythms. In mammals, exposure to soluble bacterial components distinct from canonical innate immune ligands induces acute PER2 upregulation independently of Bmal1 or nascent transcription. A targeted inhibitor screen and biochemical assays implicate p38 MAPK as a modulator of this response. Taken together, this positions bacterial exposure as a previously unrecognized circadian clock input, revealing a new axis of host-microbe interaction that modulates biological timing at the cellular level.
Sensorimotor transformation, the process of converting sensory input signals into a movement command, is essential for mediating goal-directed movements. Neural correlates of sensorimotor transformation were assessed in the delay period activity of superior colliculus (SC) neurons recorded simultaneously in three male monkeys generating saccades to visual targets. We applied dimensionality reduction on the SC population response and used a proximity index to quantify the relative, probabilistic closeness of the evolving delay period activity to the visual- and motor-dominant subspaces associated with the sensation and action states. Here, we show that sensorimotor transformation is achieved through a drift in population activity from a visual-like to a motor-like representation during the delay period, with transient visual resets following microsaccades. Also, the proximity index was correlated to reaction time throughout the delay period, suggesting a similar movement preparation mechanism is conserved across the skeletomotor and oculomotor systems.
The aim of this exploratory analysis was to investigate effects of time-restricted eating (TRE) on glycemic control and variability in adults with prediabetes. This study utilized data from the Restricted Eating Time (RESET) randomized controlled trial. A subset of 46 participants with prediabetes, allocated to either a 10-hour TRE intervention (n = 20) or the control group (n = 26), was analyzed. Changes in continuous glucose monitoring derived outcomes, fasting glucose and glycosylated hemoglobin (HbA1c), at 6 weeks and 3 months were assessed using a linear mixed-effects model. There were no between-group differences in fasting glucose or HbA1c after 6 weeks and 3 months. The 24-hour and daytime coefficient of variation was reduced within the TRE group after 6 weeks but not after 3 months. Nighttime average sensor glucose was lower in the TRE compared with the control group after 6 weeks [-0.3 mmol/L (-0.6 to -0.1)], but this effect was not maintained after 3 months [-0.1 mmol/L (-0.4 to 0.2)]. TRE may have a small short-term beneficial effect on nighttime glucose levels in adults with prediabetes. Larger long-term TRE studies are warranted.
The NEI Refractive Error Quality of Life Instrument 42 (NEI-RQL-42) was developed to assess how refractive error compensation affects quality of life. The purpose of this study was to reset the NEI-RQL-42 scale model to develop specific scales related to the use of ophthalmic lenses and contact lenses (CLs). A prospective study was designed. Healthy volunteers between 18 and 70 years of age completed the NEI-RQL-42 questionnaire twice, once for spectacles use and once for CLs use. Confirmatory factor analysis was used to evaluate the original factor and refine the subscales to improve the psychometric properties of the NEI-RQL-42 and detect differences between spectacles and CLs. Seventy-five healthy subjects (58 women and 17 men with an average age of 30.53 ± 12.51 years) were included. The original factor structure did not show an acceptable fit for spectacles or CLs. Several items were removed from the spectacles and CLs datasets, and some modifications of the subscales based on modification indices were introduced to obtain acceptable models for both samples. Spectacle users showed significantly higher scores (p < 0.01) on the clarity of vision, diurnal fluctuations, symptoms and satisfaction with correction subscales. On the other hand, CLs users had higher scores on the "activity limitations" subscale (p < 0.01). analysis of the NEI-RQL-42 score with an adequate statistical approach allows us to identify the differences between the effects of spectacles and CLs wear on patients' QoL, providing useful information regarding the impact of refractive error compensation on QoL. Our results suggest that it is unlikely that the same scale can be used for different methods of refractive error compensation, such as spectacles or CLs.
Mismatch repair-deficient (dMMR) tumours are highly sensitive to immune checkpoint blockade in the metastatic setting. Previous trials showed near-universal pathological responses after short-course dual immune checkpoint inhibition in patients with early-stage dMMR colon cancer, and high clinical complete response rates after 6 months of single-agent PD-1 blockade in patients with dMMR rectal cancer. We aimed to evaluate the activity and safety of a short duration of preoperative nivolumab and ipilimumab in patients with early or locally advanced dMMR rectal cancer. In the RESET-R trial, a multicentre, single-arm, phase 2 trial conducted in two hospitals in Denmark, we enrolled patients aged 18 years or older with histologically confirmed stage I-III dMMR rectal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic or local therapy for rectal cancer. Patients received one cycle of nivolumab (3 mg/kg intravenously on days 1 and 15) and ipilimumab (1 mg/kg intravenously on day 1). Patients with definite tumour regression but without clinical complete response at day 43 received a second cycle (nivolumab 3 mg/kg intravenously on days 50 and 65 and ipilimumab 1 mg/kg intravenously on day 50). The primary endpoint was the proportion of patients with a clinical complete response at day 93, defined as no visible or palpable tumour on rectal digital examination, endoscopy, and MRI. In patients with digital and endoscopic complete response, and with non-complete response on MRI, the absence of viable tumour cells in a representative biopsy was also classified as clinical complete response. Patients who had a clinical complete response were recommended to proceed with a watch-and-wait strategy without surgery. Analyses were done in the intention-to-treat population. The study was designed as a Simon two-stage trial, with an analysis for futility after enrolment of 19 participants. The study was to continue to enrol an additional 20 participants if six or more of the initial 19 participants had a clinical complete response, and the regimen would be deemed worthy of further investigation if 16 participants of the total 39 had a clinical complete response. An early interim analysis (and dissemination of the findings) was approved by the trial protocol committee when it became apparent that this measure of success had been met after enrolment of the first 16 participants. The trial is registered with EU Clinical Trials (2022-500646-14-00); the study is ongoing and continues to enrol patients. Between Feb 1, 2023, and Oct 28, 2025, 16 patients (nine [56%] male, seven [44%] female) were enrolled. Four (25%) patients had stage I tumours, two (13%) had stage II tumours, and ten (63%) had stage III tumours. All patients received at least one cycle of nivolumab and ipilimumab. By day 93, all 16 patients (100·0% [95% CI 79·4-100·0]) had a clinical complete response: 11 (68·7% [41·3-89·0]) patients after one cycle and five (31·3% [11·0-58·7]) after two cycles. No patient received chemoradiotherapy or underwent surgery, and no patients had progression or recurrence during follow-up (median 16 months [IQR 9-18]). Grade 3 immune-related adverse events occurred in three (19%) patients (infusion-related reaction, hypophysitis, and serous retinal detachment). No grade 4 or grade 5 toxicities, serious treatment-related adverse events, treatment discontinuations, or treatment-related deaths were reported. All participants in this trial of short-course dual immune checkpoint blockade for dMMR rectal cancer had a clinical complete response with manageable toxicity, allowing them to proceed to a watch-and-wait strategy without surgery. Longer follow-up and completion of enrolment are needed to confirm the durability of these effects and the safety of an organ-preserving strategy. The Danish Comprehensive Cancer Center-ctDNA Research Center, the NEYE Foundation, the Aage and Johanne Louis-Hansen Foundation, and the Eva and Henry Frænkel Memorial Foundation.
Neoadjuvant immune checkpoint inhibition has shown promise in localized deficient mismatch repair (dMMR) colorectal cancer, yet the optimal treatment duration, regimen, and methods for response evaluation remain undefined. This trial aimed to investigate the efficacy and safety of neoadjuvant pembrolizumab for patients with localized dMMR colon cancer. Participants received a single cycle of pembrolizumab (4 mg/kg, max 400 mg, every-6-weeks dosing regimen), followed by a preoperative endoscopy with biopsies and surgery 3-5 weeks later. The primary end point was pathologic complete response (pCR); secondary and exploratory end points included major pathologic response (MPR), safety, survival, and endoscopic response assessment. From February 2023 to March 2024, 85 patients (median age 74 years) were enrolled. All received pembrolizumab; one patient declined surgery. Among 84 patients, pCR was achieved in 44% (37 of 84; 95% CI, 33 to 55), and MPR in 57% (48 of 84; 95% CI, 46 to 68). Two (2%) patients died of complications within 30 days of surgery. At a median follow-up of 18.4 months (IQR, 16.3-21.1), one patient had a recurrence, resulting in overall and disease-free survival rates of 98% and 96%. Grade 3 adverse events occurred in 11% of patients (9 of 85; 95% CI, 3 to 16), with three treatment-related events. In 81 patients, the sensitivity, specificity, and accuracy of the biopsies for predicting pCR were 68%, 75%, and 72%, respectively. In 76 patients, the sensitivity, specificity, and accuracy of the endoscopic images for predicting pCR were 77%, 93%, and 86%, respectively. A single cycle of neoadjuvant pembrolizumab led to pCR in nearly half of patients undergoing surgery for localized dMMR colon cancer. The utility of endoscopic evaluation may inform future strategies for patient selection in nonoperative management pathways.
Fatigue, insomnia, and depression are persistent, burdensome symptoms for patients recovering from hematopoietic cell transplantation (HCT). Restoring Sleep and Energy after Transplant (ReSET) is a novel behavioral intervention designed to alleviate these symptoms by optimizing patients' 24-hr rest-activity patterns. The primary aim was to evaluate feasibility and acceptability of ReSET. An exploratory aim was to determine preliminary effect sizes. This pilot randomized controlled trial compared ReSET to usual care. Participants randomized to ReSET completed three in-person intervention sessions at approximately 3-4, 8 and 12 weeks post-HCT that focused on strategies to improve nighttime sleep and increase non-sedentary daytime activity. All participants wore an actigraphy device (Philips) and completed patient-reported outcome measures (PROMIS sleep disturbance, fatigue, depression) pre-HCT (T0), 9 (T1), and 18 weeks post-HCT (T2). Interviews were conducted at T2. Ability to recruit, retain, and collect complete data from participants and participant engagement with the intervention were the primary measures of feasibility and Y acceptability. Interviews were conducted at T2 to provide supplementary insight regarding participant satisfaction and barriers to completion. Thirty-nine patients were randomized and most (n = 35; 89.7%) completed the study. Most ReSET participants (85%) completed all intervention sessions. PROMs of sleep (η2 = .033) and depression (η2 = .015) improved over time for participants in ReSET compared to usual care. Those randomized to ReSET also showed improved rest-activity rhythms relative to usual care, including mesor (η2 = .044), amplitude (η2 = .087) and R-squared (η2 = .073) actigraphy indices. ReSET demonstrated feasibility, acceptability, and preliminary promise for intervention efficacy.
Posttraumatic stress symptoms (PTSS) affect nearly 50% of children experiencing physical trauma. PTSS often persists after physical recovery and is associated with reduced health-related quality of life. To evaluate efficacy of the online therapist-assisted, trauma-focused Reducing Stress After Trauma (ReSeT) program in reducing PTSS in children after hospitalization for physical injury. A 2-arm randomized clinical trial with 1:1 assignment to the ReSeT program or usual care (UC) was conducted between 2021 and 2024 at 4 sites with level 1 trauma centers. Injured children ages 8 to 17 years were recruited from inpatient and short-stay units. Exclusion criteria included moderate to severe traumatic brain injury, preexisting severe psychiatric problems, current psychotherapy, developmental disorders preventing participation, interpersonal violence, hospitalization for more than 30 days, and injury-related death of friend or family. The ReSeT program has 8 online psychoeducational modules containing 3 to 4 short interactive videos that children completed independently. Modules are followed by an electronic health session with a therapist to practice cognitive behavioral skills and desensitization using trauma narrative techniques. Parents received optional psychoeducational resources. Generalized linear regression, controlling for baseline scores, was used to examine group differences on the Child Posttraumatic Stress Disorder Scale (CPSS) scores obtained 10 weeks (primary outcome) and 6 months (secondary outcome) after randomization. A total of 638 of 722 children screened positive at 1 week, and 271 children and caregivers completed the CPSS at 4 weeks. The highest value from each respondent on each item was summed, and 130 children (48%) had CPSS scores of 11 or greater, indicating potential eligibility for enrollment. A total of 93 children (72%; mean [SD] age, 11.7 [2.4] years; 56 male [60.2%]) were included in the study; 47 were randomized to the ReSeT cohort and 46 were randomized to the UC cohort. Intention-to-treat analyses indicated significant reduction in combined CPSS scores in the ReSeT vs UC cohorts, -4.2 points (95% CI, -7.6 to -0.8 points) at 10 weeks, which was maintained at the 6-month follow-up, -5.5 points (95% CI, -8.9 to -2.1 points). Findings of this randomized clinical trial show that the ReSeT program was an effective, brief, trauma-focused intervention for reducing PTSS after physical injury. It offers a potentially cost-effective, scalable program to address American College of Surgeons standards for psychological screening and treatment for children sustaining PTSS. ClinicalTrials.gov Identifier: NCT04838977.
Ferroptosis has emerged as a viable approach to enhance therapeutic efficacy in triple-negative breast cancer (TNBC), making monitoring essential for prognostic evaluation. However, conventional MR imaging cannot characterize ferroptosis-related biomarkers. Herein, we propose a Relaxation Suppressed Exchange Tuning (ReSET) MRI strategy for ferroptosis modulation and monitoring, which relies on T1 relaxation and chemical exchange saturation transfer (CEST). ReSET was achieved by a tumor-microenvironment-responsive nanoprobe (SiO2@FUDR@MnO2, SiFM), consisting of a mesoporous silica core loaded with chemotherapeutic floxuridine and the MnO2 shell with nanozyme activities. This structure promotes robust ROS generation, which induces lipid peroxidation and ultimately facilitates chemodynamic therapy (CDT)-sensitized ferroptosis. Notably, ReSET takes advantage of the tumor-responsive release of Mn2+ from SiFM, which shortens T1 relaxation and suppresses the saturation transfer efficiency between water and exchangeable endogenous protons reducing magnetization transfer ratio asymmetry (MTRasym). The inverse correlation between the T1 intensity and MTRasym provides a sensitive and specific indicator for visualizing glutathione peroxidase 4 (GPX4) expression, thereby enabling cross-modal monitoring of ferroptosis. Meanwhile, we revealed that the ReSET strategy enables sensitive detection of small lesions in liver micrometastasis models. Overall, we establish a ReSET MRI-guided strategy using a manganese-based nanoplatform, which represents a promising ferroptosis-related theranostic approach for TNBC.
To properly reflect the dynamic environment, the online representations in visual working memory (VWM) must be constantly accessed and modified when the corresponding items change. Such updating depends on a continuous mapping between each VWM representation and a subset of the external environment, instantiated by a "pointer system." If this mapping is disrupted, the representations cannot be updated, and instead VWM removes the unmapped representations and starts anew. During this "resetting" process, people are blind to salient changes in the items whose representations are inaccessible, creating a behavioral cost. The goal of this study was to test whether VWM's pointers are governed by spatiotemporal information or objecthood. In two preregistered studies, participants performed an "online change detection" task, reporting visible changes in items' shapes, which happened during their (task-irrelevant) movement. Experiment 1 showed that when an intact object abruptly changes its spatiotemporal trajectory, the mapping is sustained, with no resetting cost. Experiment 2 showed that when only half the object changes its trajectory, which effectively splits the object in two, the mapping no longer survives, with diminished performance indicating a resetting process. Critically, a behavioral cost was found even for the half that continued in the same spatiotemporal trajectory, pinpointing objecthood as the driving factor. Together, the results demonstrate that resetting does not reflect mere pointer reassignment, but a specific invalidation of the mapping between representations and the environment. In sustaining this mapping, VWM's pointer system relies not on spatiotemporal information per se, but on physical objecthood.
Modeling irregularly sampled multivariate time series is a persistent challenge in domains like healthcare and sensor networks. While recent works have explored a variety of complex learning architectures to solve the prediction problems for irregularly sampled time series, it remains unclear what the true benefits of some of these architectures are, and whether clever modifications of simpler and more efficient RNN-based algorithms are still competitive, i.e. they are on par with or even superior to these methods. In this work, we propose and study GRUwE: Gated Recurrent Unit with Exponential basis functions, that builds upon RNN-based architectures for observations made at irregular times. GRUwE supports both regression-based and event-based predictions in continuous time. GRUwE works by maintaining a Markov state representation of the time series that updates with the arrival of irregular observations. The Markov state update relies on two reset mechanisms: (i) observation-triggered reset to account for the new observation, and (ii) time-triggered reset that relies on learnable exponential decays, to support the predictions in continuous time. Our empirical evaluations across several real-world benchmarks on next-observation and next-event prediction tasks demonstrate that GRUwE can indeed achieve competitive or superior performance compared to the recent state-of-the-art (SOTA) methods. Thanks to its simplicity, GRUwE offers compelling advantages: it is easy to implement, requires minimal hyper-parameter tuning efforts, and significantly reduces the computational overhead in the online deployment.
Differentiating atrioventricular nodal reentrant tachycardia (AVNRT) from non-reentrant junctional tachycardia (JT) can be challenging. In this case, regular narrow QRS complex tachycardia with simultaneous activation of the atrium and ventricle was reproducibly induced following an atrio-His interval jump by a single atrial extrastimulus, initially suggesting typical slow-fast AVNRT. During tachycardia, however, atrial activation and the His-atrial interval spontaneously changed without affecting the tachycardia cycle length. An "atrial-His-His-atrial" response to atrial overdrive pacing, late-coupled atrial premature depolarizations (APDs) that failed to reset tachycardia via slow pathway conduction, and early-coupled APDs that reset tachycardia via fast pathway conduction without terminating tachycardia, favored JT. Finally, slow pathway ablation rendered tachycardia non-inducible. Intranodal AVNRT mimicking JT, which postulates an intranodal reentrant circuit with intervening conduction between the fast and slow pathways, can explain all of these findings and thus be differentiated from JT.
Perceptual processing may rhythmically alternate. There is a line of evidence from dense sampling psychophysics supporting this claim: In such studies, performance in visual target detection or discrimination is repeatedly tested at various fine-grained time intervals relative to a reference event. This reference event is presented at the beginning of each trial, and it is thought to reset some internal oscillation. Performance time courses following the reset often show rhythmic oscillations in the sub-second range. The interpretation has been that several quickly alternating peaks and troughs of perceptual efficiency exist. Here, we propose an alternative. Instead of being rhythmic, the perceptual processing efficiency time course might exhibit only a single peak in each trial. If the temporal location of this peak is constrained to co-occur with one of the peaks of the internal continuing oscillation, rhythmicity in overall performance time courses can be explained when performance is computed across many trials. Applying this perspective to three published datasets (N = 44, N = 34, N = 11) and running simulations, we confirm the possible existence of such phase-aligned peaks in perceptual efficiency. We show that foreperiod priming (behavioural advantage of repeating the same time interval between reference and target from one trial to the next) alternates across time. This is predicted if peaks in perceptual efficiency are consistently allocated to those time intervals that coincide with a peak in the underlying oscillation. Priming therefore works best at these intervals, which coincide with a peak in the underlying oscillation.
The importance of precise timing of neuronal activity, relative to ongoing slower oscillations, is reshaping the engram theory and our understanding of how memories are encoded and stored. The hippocampal theta-wave phase-encoding of neuronal firing predicts behavioral outcomes and cognitive performance in memory tasks. A single external stimulus or a sensory/cognitive cue may induce Phase-Resetting shift of theta waves, without changing their frequency or power. This phenomenon seems to be a core mechanism for temporal coordination, information encoding, and memory formation. We hypothesize that not only Phase-Resetting, but temporally coded neuromodulation packaged around an averaged theta cycle of 140 ms, plays a role in engram formation. Inter-pulse microstimulation patterns (MS) consisting of six stimuli within a 140 ms period were applied to the intermedial CA3 hippocampal area of C57/BL6 mice. Each MS-pattern consisted of a 10-bit word (each bit representing a 14-ms bin), indicating the phase at which MS was applied. The randomized (MSr) or fixed pattern (MSf) stimulus was applied during a 30 s presentation of a pure tone (CS) that terminated with a 2 s/0.4 mA footshock (US). Sham animals underwent surgery and cued fear conditioning, but no MS. Cued fear memory was tested by presenting the CS (without MS) in a different context. The group of mice that received the MSf during conditioning showed higher levels of freezing compared to the Sham group; the MSr group did not. We measured c-Fos/NeuN labeling as a proxy for neuronal activity 90 min after memory retrieval. As expected, since cued-fear memory is predominantly amygdala-dependent, all groups showed an increase in c-Fos expression in the amygdala. However, only the MSf group had higher hippocampal activation after retrieval, suggesting that fixed pattern stimulation framed around an averaged theta cycle led to neuronal integration into the memory trace. Our findings indicate that temporal organization plays a crucial role in how memories are stored and accessed.
In stochastic processes with absorbing states, the quasi-stationary distribution provides valuable insights into the long-term behavior prior to absorption. In this work, we revisit two well-established numerical methods for its computation. The first is an iterative algorithm for solving the nonlinear equation that defines the quasi-stationary distribution. We generalize this technique to accommodate general Markov stochastic processes, either with discrete or continuous state space, and with multiple absorbing states. The second is a Monte Carlo method with resetting, for which we propose a single-trajectory approach that uses the trajectory's own history to perform resets after absorption. In addition to these methodological contributions, we provide a detailed analysis of implementation aspects for both methods. We also compare their accuracy and efficiency across a range of examples. The results indicate that the iterative algorithm is generally the preferred choice for problems with simple boundaries, while the Monte Carlo approach is more suitable for problems with complex boundaries, where the implementation of the iterative algorithm is a challenging task.
This article aimed to articulate the most important unmet scientific needs in rheumatology. At the 25th Advances in Targeted Therapies (ATT) meeting, over 100 investigators joined 6 disease-focused breakout groups (rheumatoid arthritis [RA], psoriatic arthritis [PsA], axial spondyloarthritis [axSpA], systemic lupus erythematous [SLE], systemic sclerosis [SSc], and osteoarthritis [OA]). Each group, led by a facilitator and rapporteur, mapped (i) key unmet needs, (ii) promising mechanistic or therapeutic approaches, and (iii) near-term priorities for research and trials. This report synthesises the consensus highlights. Six disease-focused groups (RA, PsA, axSpA, SLE, SSc, and OA) identified convergent priorities: earlier detection and interception; validated molecular and clinical endotypes to guide therapy; strategies for immune reset and short-course induction combinations with strict safety oversight; metabolic modifiers; precision targets in axSpA and fibroblast-directed approaches in RA; phenotype-driven therapeutic development and intra-articular options in OA; and pragmatic trial designs that include pregnant persons and very early disease. Across immune-mediated diseases, progress will hinge on validated endotypes, practical interception strategies, and trials that reflect real-world populations. The immediate agenda is to de-risk immune reset and induction approaches, standardise tissue and digital biomarkers, and close evidence gaps for refractory disease. Prevention-and ultimately cure-remains the horizon.