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We noninvasively visualized the upper dermal microvasculature of 31 patients after hematopoietic cell transplantation (HCT) by reflectance confocal videomicroscopy. The microvessel diameter and number and diameter of adherent and rolling leukocytes for patients after HCT were similar to historically published values in healthy subjects. We also observed "paused" leukocytes i.e. leukocytes that temporarily stop, coinciding with the simultaneous stopping of the rest of the blood flow. The number and diameter of paused leukocytes, and the duration of leukocyte being paused for patients after HCT were also similar to historically published values in healthy subjects. However, we observed more blood vessels per imaging field of view (500 × 500 μm2) in the skin of patients after HCT than healthy subjects (a median of 3 versus 2). The number of blood vessels in a field of view was not correlated with the number of adherent and rolling leukocytes. Vessel size (flow width) had a meaningful correlation with the diameter, but not number, of paused leukocytes. Paused leukocyte diameter had no correlation with the duration of pausing. Reflectance confocal videomicroscopy enables characterization of intact upper dermal microvasculature of patients with extremely altered immune system.

Female reproduction is an energetically expensive process, so species evolve to balance survival with reproductive output. Many female organisms can temporarily pause their reproduction, including egg development, in response to physiological stress. The cellular mechanisms initiating and maintaining a stress-induced pause in oogenesis have been most extensively studied in Drosophila melanogaster. While the molecular control of paused oogenesis in response to starvation have been well characterized in flies, it remains unknown if these mechanisms are shared by other species with regulated pauses in oogenesis. Eusocial insects are characterized by a reproductive division of labor, with colonies of reproductive queens and sterile female workers. The social paper wasp, Polistes , has a dynamic dominance-based hierarchy for queen status. Worker Polistes are kept sterile by a combination of social and nutritional stressors. Here, we establish Polistes as a model to explore adult female reproductive plasticity. Through immunohistochemistry we have directly compared the Drosophila and Polistes ovarian structure and identified critical regions of the ovary in wasps that undergo regulated cell elimination during reproductive pause in flies. By comparing tissue structure, cell organization and rates of cell death between Polistes queens and workers we identified apoptosis as a key regulator maintaining worker sterility. Critically, this mechanism appears to be partially conserved with that in Drosophila . Finally, we find that changes in the timing and location of cell death in Polistes workers implicate oocyte identity and oocyte growth as additional potential regulators of temporary disruption of oogenesis. Establishing the social paper wasp, Polistes , as a new model for female adult reproductive plasticity via temporary pausing of oogenesis in the sterile female workers.

Cardioneural ablation (CNA) is an emerging strategy for vagally mediated arrhythmias, but its role in patients with underlying conduction system disease remains undefined. Here, a young patient with PRKAG2-mediated cardiomyopathy presented with refractory paroxysmal atrial fibrillation (AF) despite prior accessory atrioventricular pathway (AP) ablation and antiarrhythmic therapy. Episodes of AF were triggered consistently by cold milk ingestion, and dual-chamber pacemaker interrogation revealed a high atrial pacing burden due to sinus pauses, suggesting a vagally mediated mechanism superimposed on underlying conduction disease. Extracardiac vagal stimulation during electrophysiology study unmasked residual AP conduction and resulted in sinus pause and AV block. These findings confirmed vagal tone as the dominant arrhythmia modulator and prompted repeat AP ablation and CNA. At follow-up, CNA eliminated vagally mediated sinus pauses, reducing atrial and ventricular pacing burden to 0%, with only low-burden asymptomatic AF persisting.

Disfluency in spontaneous speech has been reported to be a potential marker for cognitive impairment. However, consistent working definitions are lacking, and it remains unknown whether disfluency measures operate similarly across languages. This study investigates how cognitive status shapes disfluency in Chinese and English, aiming to delineate both language-general patterns and cross-linguistic differences. A total of 100 speech samples elicited via the Cookie Theft task (50 Chinese, 50 English) were selected from the MCGD corpus (Chinese) and DementiaBank (English), equally stratified into cognitively normal and impaired groups based on MMSE scores. Following manual annotation, speech samples were analysed using ten disfluency measures across three dimensions: temporal, pausal, and repetition-repair. Results showed that six measures were sensitive to cognitive status across both language groups, and language did not significantly moderate the effect of cognitive impairment on disfluency. Temporal measures declined consistently with cognitive impairment across both languages, with cognitively impaired individuals showing significantly reduced speech rate, phonation-time ratio, and mean length of runs. Pausal measures generally increased with cognitive impairment, with cognitively impaired individuals showing significantly longer silent pauses and more frequent filled pauses. For repetition-repair measures, repetitions increased with cognitive impairment in both languages but showed a higher baseline frequency in Chinese than in English, whereas repairs displayed less consistent patterns across the two language groups. Collectively, these findings support the value of disfluency measures as cross-linguistically relevant markers of cognitive impairment, while underscoring the importance of language-sensitive interpretation for specific disfluency types.

Plasmodium spp. have different modes of cell division from most eukaryotes. Little is known about how these are controlled, and cell cycle checkpoints are particularly poorly characterized. However, parasites can arrest their cell cycle when treated with the frontline antimalarial drug artemisinin, and artemisinin-resistant parasites can modulate their cell cycle progression, so it is important to understand these aspects of Plasmodium biology. Here, we show that P. falciparum displays hallmarks of an intra-S-phase checkpoint when exposed to DNA damage, including acute reduction of DNA replication and phosphorylation of a putative damage-marker histone. Compounds that inhibit human checkpoint kinases can inhibit this arrest of DNA replication and synergize with DNA damage in parasite killing. This suggests the existence of checkpoint kinase activity in P. falciparum, yet these kinases have no clear homologues in Plasmodium genomes. Their closest homologs are the phosphatidylinositol lipid kinases. We hypothesize that phosphatidylinositol 3-kinase-which is reportedly upregulated in artemisinin-resistant parasites-may moonlight in this role, and we characterize this essential kinase for the first time via expansion microscopy. Finally, we show that the cryptic checkpoint-kinase activity may also regulate the ring-stage survival phenotype after artemisinin damage, which resembles a G1/S checkpoint. Hence, we suggest that checkpoint kinase inhibitors are candidates for synergy with artemisinin.IMPORTANCEMalaria parasites infect red blood cells, wherein they replicate to produce many new parasites. This is unusual because most cells replicate simply by copying their genome and splitting in half (called binary fission), but malaria parasites make ~20 genome copies and then partition them simultaneously into 20 new cells (called schizogony). Here, we studied how schizogony is controlled: in particular, are there "checkpoints," i.e., pathways that can pause the cell cycle? We found that DNA damage did cause checkpoint hallmarks, yet the key proteins that enforce this in other cells are absent in malaria parasites. Furthermore, this checkpoint activity may be involved in the response to an antimalarial drug, in which parasites pause their cycle before active replication begins. This implies that inhibiting the checkpoint could exacerbate parasite killing by such drugs. Cancer therapies often work like this-by damaging DNA and also preventing the cancer cells from repairing it.

Develop a conceptual framework for trust in AI in high-stakes, resource-constrained contexts, using Palestinian nurses as a strategically selected critical case study. Qualitative descriptive study. Twenty-five nurses without gatekeeper involvement; first author directly approached participants through professional networks. No administrators facilitated recruitment; four declined and were replaced. Face-to-face interviews (45-75 min, Arabic) analysed via reflexive thematic analysis with NVivo 12 solely a data-management tool, not an analytic method. Translation: two bilingual researchers independently translated excerpts, reconciled discrepancies, and a third expert back-checked a random sample. Quotations are literal translations with minimal edits. Transcripts checked against recordings; dialect, pauses, idioms, culturally specific expressions preserved in Arabic analysis and discussed before translation. Credibility with explicit demonstration of how each strategy shaped findings. Four themes: Explainable Trust, Double-Edged Sword Contextual Intelligence versus Algorithmic Ignorance Co-Design. The four themes correspond to the four domains of the conceptual framework introduced in the theoretical section; however, participant narratives inductively enriched each domain with context-specific subthemes (e.g., 'override mandate'), and the framework was iteratively refined during analysis rather than deductively imposed. Trust is an active socio-technical precondition. The framework offers analytically transferable principles applicable beyond Palestine to any context marked by inequality, professional expertise, and high stakes, while acknowledging local variation. However, given the hypothetical nature of participants' responses (no direct GenAI experience), findings should be treated as formative. Nurses must be involved in AI design, training, governance, with autonomy and override authority. Trust as sequenced 'Algorithm of Trust': explainability, risk-benefit, contextual intelligence, co-design. Informs global stakeholders. Adhered to COREQ guidelines. No patient or public involvement. Participants were registered nurse experts.

High-frequency oscillations (HFOs; 250-500 Hz) in electrocorticography (ECoG) are promising biomarkers for delineating the epileptogenic zone during epilepsy surgery. Accurate, intraoperative real-time detection of HFOs may guide surgical resection to improve seizure outcome. We used intraoperative ECoG from 22 patients from Zurich (Nicolet recording device, recording under Sevoflurane) with annotated HFOs to train an innovative automated HFO detector implemented in a spiking neural network (SNN) on neuromorphic hardware. We validated whether the detector could identify clinically relevant HFOs in an independent cohort of 54 patients from Utrecht (Micromed recording device, recording during a pause in propofol administration) by examining whether HFOs remained after resection and whether this predicted seizure outcome. We then tested the detector in real time during surgery, giving direct feedback to the neurosurgeon. The optimal detection parameters yielded Spearman R = .71 between channelwise HFO rates detected by the proposed SNN detection and those previously detected by the Spectrum Detector in the training dataset. We found postresection HFOs in nine patients who had poor surgery outcome and in one patient with good surgery outcome in the validation data, resulting in a diagnostic odds ratio = 17 (95% confidence interval = 2.0-150). During a live surgery, the detector analyzed incoming intraoperative ECoG during acquisition, HFOs were successfully captured, and HFO feedback was available within 1 min after completion of the recording period. Our automatic detector was easily transferred between centers and anesthesia protocols. We showed the direct use of intraoperative HFO detection as possible real-time feedback to the surgeon to tailor resection, yielding high predictive power of seizure outcome.

Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is standard following PCI. Ticagrelor is increasingly preferred due to its potent, reversible platelet inhibition. While generally safe, ticagrelor has been associated with conduction abnormalities, including sinus pauses and atrioventricular (AV) block, though clinically significant bradyarrhythmias remain rare. We report a rare case of symptomatic 2:1 Mobitz type II AV block following ticagrelor initiation post-PCI and emphasize the importance of timely recognition to avoid unnecessary pacemaker implantation. We describe a 68-year-old woman presenting with unstable angina. Coronary angiography revealed significant mid-RCA disease, and PCI with a sirolimus-eluting stent was performed successfully. She was discharged on aspirin and ticagrelor, without rate-limiting drugs, as her baseline heart rate was 60 bpm. Two weeks later, she developed dizziness and dyspnea (NYHA III). ECG showed 2:1 Mobitz type II AV block with a ventricular rate of 40 bpm. Repeat angiography confirmed a patent stent, and thyroid profile was normal. Holter monitoring corroborated persistent AV block. Ticagrelor was discontinued and replaced with clopidogrel, resulting in the restoration of sinus rhythm. On follow-up, the patient remained asymptomatic with normal ECG findings. Ticagrelor can rarely induce clinically significant AV block even in the absence of other rate-limiting drugs. Clinicians should maintain a high index of suspicion when post-PCI patients on ticagrelor present with bradyarrhythmias. Withdrawal of ticagrelor should be considered before resorting to pacemaker implantation, thereby preventing unnecessary interventions.

In precise imaging techniques such as dynamic imaging with radiopharmaceuticals, achieving a high-concentration bolus in target sites is crucial. However, dilution within infusion tubing severely compromises bolus integrity. Although pulsed flushing is clinically used to clear intravenous tubing, its efficacy in mitigating radiopharmaceutical dilution and the optimal protocol parameters remain insufficiently elucidated. This study employed a theoretical analysis of dilution mechanisms and utilized computational fluid dynamics simulations to compare the efficacy of pulsed flushing with different volumes and frequencies, verifying its feasibility. Subsequently, in vivo rat pharmacokinetic experiments were performed to systematically assess the pulsed flushing strategy. Theoretical and computational fluid dynamics analyses indicate that while higher continuous flow rates shorten injection time, it exacerbates the "tailing" phenomenon caused by parabolic flow patterns. In contrast, a high frequency, small-volume pulsed flushing strategy generates a greater number of vortices at abrupt cross-section changes in the tubing during injection pauses, effectively clearing residual drug and thereby significantly suppressing axial dispersion of the bolus. Compared to continuous flushing, pulsed flushing demonstrates superior performance in reducing the final residual rate and controlling tailing. In vivo experiments in rats further confirmed that, compared to manual operation, the automated pulsed flushing strategy produces boluses with better morphology during the initial injection phase, exhibits greater consistency both between and within individuals, and leaves no radioactive residue at the puncture site. High frequency, small-volume pulsed flushing is an effective strategy for clearing dead space and suppressing the tubing dilution effect through vortex induction, outperforming traditional manual and continuous automatic injection. Appropriate selection of pulse bolus volume parameters is the core solution for overcoming the dilution challenge in automatic bolus injection and for improving injection consistency.

The SARS-CoV-2 pandemic has underscored the urgent need for broad-spectrum antivirals in pandemic preparedness efforts. Nucleoside analogs targeting viral polymerases are often considered in this context. Here, we employ ensemble biochemical assays and single-molecule magnetic tweezers to characterize the detailed mechanism of action of the adenosine analog CMX521 (developed through Phase 1 clinical studies), a broad-spectrum antiviral against caliciviruses and coronaviruses, against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The triphosphate form of CMX521 is efficiently incorporated by RdRp, even against saturating ATP concentrations. Analog incorporation induces only a brief pause in nascent RNA synthesis. When embedded in the template strand, CMX521 causes the polymerase to stall ~9 s on average due to impaired uridine opposite incorporation. Multiple CMX521 residues in the template strand completely inhibit polymerase elongation. When the coronavirus polymerase is associated with the viral helicase, CMX521 strongly promotes copy-back RNA synthesis suggesting a second inhibitory mechanism for CMX521. Collectively, our findings establish a two-pronged mode of coronavirus polymerase inhibition by CMX521.

Gliclazide, a second-generation sulfonylurea, is frequently utilized for glycemic management in type 2 diabetes mellitus (T2DM), attributed to its cardiovascular safety profile and minimal hypoglycemia risk. Sulfonylurea-induced bradycardia is a rare and underreported phenomenon. A 68-year-old male with a long history of T2DM and hypertension presented with presyncope, lethargy, and dizziness 10 days following the initiation of modified-release gliclazide at a dosage of 60 mg once daily. Upon evaluation, the heart rate was recorded at 42 beats per minute with a regular rhythm. Electrocardiogram indicated sinus bradycardia accompanied by intermittent junctional escape beats. Echocardiography, cardiac biomarkers, thyroid function tests, and electrolyte levels were within normal limits. Twenty-four-hour Holter monitoring revealed sinus bradycardia with pauses lasting up to 3.2 seconds. No evidence was found of underlying conduction abnormalities or concurrent use of other bradycardia-inducing medications. A diagnosis of bradycardia induced by gliclazide was established based on the temporal correlation and the resolution of symptoms following the discontinuation of the medication. After a modification in his antidiabetic treatment, the patient continued to exhibit no symptoms. This case underscores the necessity of identifying rare yet significant cardiac adverse effects associated with gliclazide, particularly in elderly patients, to facilitate prompt intervention and prevent unwarranted investigations.

Swallow syncope is a rare situational syncope caused by an exaggerated vagal reflex and may result in bradyarrhythmia or atrioventricular block. A 63-year-old man with recurrent syncope triggered by beer ingestion underwent cardiovascular, gastrointestinal, ambulatory electrocardiographic, and electrophysiological evaluation, including provocation testing. Only ice-cold beer reproducibly induced transient AH block. Other foods and beverages, including cold soda, cold sake, and room-temperature beer, were negative. Ambulatory monitoring documented a symptomatic 7.9-second pause. Disopyramide was ineffective. Permanent pacemaker implantation prevented recurrent symptoms despite repeat provocation. This case highlights a highly specific trigger for swallow syncope and the diagnostic value of targeted provocation testing.

The perception of prosodic phrase boundaries remains a core difficulty for second language (L2) learners. Drawing on the categorical perception framework, which examines how listeners apply continuous or categorical auditory memory strategies (i.e., gradient or categorical perception) to map acoustic waves onto linguistic representations, this study investigates the effects of acoustic properties, first language (L1) transfer, and L2 proficiency on the perception of L2 prosodic boundaries cues. Three experiments were conducted to assess the perception of three specific boundary cues (pauses, final lengthening, and pitch). Participants included English-speaking monolinguals along with Mandarin L1 speakers with high- and low-proficiency in L2 English. The results revealed that the degree of categorization was descending: pauses > final lengthening > pitch, demonstrating that physical properties significantly influence the perception of boundary acoustic cues. Furthermore, for lengthening and pitch cues, the high-proficiency L2 group exhibited sharper identification slopes and higher discrimination peaks than monolinguals. This overshooting effect reflects a non-linear developmental trajectory in L2 prosody acquisition. These findings challenge the traditional view of L2 speech perception, which assumes that learners gradually and linearly acquire native-like speech.

Olorofim, a novel dihydroorotate dehydrogenase inhibitor, may be efficacious in patients with disseminated coccidioidomycosis (DCM) who lack alternative treatment options. To evaluate olorofim effectiveness and adverse events in patients with DCM. Single-group, open-label, phase 2b study. (ClinicalTrials.gov: NCT03583164). Ten U.S. sites. Forty-one patients with DCM and limited or no treatment options. Patients received olorofim alone or in combination with ongoing standard of care during an 84-day main treatment phase. Extended treatment was offered to patients. Mycoses Study Group-European Organization for Research and Treatment of Cancer (MSG-EORTC) criteria for global response based on subcategories of clinical, radiologic, and mycologic response were adjudicated by an independent data review committee (DRC) at days 42 and 84 (main treatment phase). Because the slow pace of serologic improvement in DCM limits global response to stable at best, this article focuses on patient clinical responses. Treatment-emergent adverse events (TEAEs) were compiled for both treatment phases. Forty-one patients with DCM were enrolled from May 2019 to August 2022. Thirty-nine (95.1%) did not have immunosuppression. Central nervous system disease was present in 30 (73.2%) patients, and 13 (43.3%) had a ventriculoperitoneal shunt with or without an Ommaya reservoir. Clinical success as adjudicated by the DRC occurred in 31 of 41 patients (75.6% [95% CI, 59.7% to 87.6%]) at day 42 and 30 of 41 patients (73.2% [CI, 57.1% to 85.8%]) at day 84. The main TEAE was hepatic biochemistry elevation in 9 of 41 patients (21.9%), which was managed by liver enzyme monitoring and dose reduction or pause in 8 patients (19.5%) and drug discontinuation in 1 patient (2.4%). This was a single-group, open-label trial, but a randomized controlled trial would be preferable. Olorofim showed effectiveness in patients with DCM with limited or no therapeutic options. F2G, Ltd.

5-azacitidine (5-AZA) is the first hypomethylating agent synthetized and the cornerstone treatment for high-risk myelodysplastic neoplasms (MDS) and chronic myelomonocytic leukaemia (CMML). Although the validated schedule is 75 mg/m2 for 7 days (7-0-0), alternative schedules have been studied in terms of efficacy, complications and survival. The 7-0-0 shows an overall survival (OS) between 21 and 25 months in prospective and 16.5-27 months in retrospective studies and complete response (CR) rates between 7% and 18%. Alternative schedules, mostly 5-day (5-0-0) or 7-day with weekend pause (5-2-2) at 75 mg/m2, perform equally in terms of OS and CR with the 7-0-0, with a slight superiority for the 5-2-2, although direct comparisons are rare and almost always non-significant. Similarly, transfusion independence, time to leukaemia transformation and toxicities did not differ significantly across studies. For more intensive schedules, using 100 mg/m2 for 5 days, literature is limited, but response rates, survival and safety seem to be comparable to the 75 mg/m2 dose. In CMML, 5-AZA monotherapy yields satisfying overall response rates of 40% or more, with myelodysplastic subtype responding better than myeloproliferative. In all, alternative 5-AZA schedules seem non-inferior in terms of efficacy and toxicities and can be used as an alternative according to local protocols and patient choice.

Tardive seizures are a rare but serious complication of electroconvulsive therapy, which can lead to early termination of an ECT course. A recent review by Warren et al discussed the reported prevalence of and risk factors for these events. While uncommon, our experience at Yale Psychiatric Hospital has revealed that tardive seizures occur more frequently than historically described, requiring urgent treatment for seizure termination and adjustments to subsequent ECT treatments. In our experience, most patients can safely continue ECT without further tardive seizures if appropriate adjustments are made. To our knowledge, there is no standardized algorithm for the management of tardive seizures, nor an explicit set of guidelines for risk mitigation if ECT will be continued. We provide both based on the data for management of status epilepticus, guided by our clinical experience and focused on short-acting agents appropriate for an ECT PACU setting. We also provide recommendations about when ECT should be paused and further workup pursued.