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The management of paroxysmal atrial fibrillation with conversion pauses remains challenging, with catheter ablation and permanent pacemaker implantation representing the main therapeutic strategies. Catheter ablation may eliminate atrial fibrillation paroxysms and prevent conversion pauses, whereas pacemaker implantation combined with antiarrhythmic therapy for rhythm control is another accepted option. We report a case of successful management of paroxysmal atrial fibrillation with conversion pauses using antiarrhythmic agents for rhythm control prior to catheter ablation. A 61-year-old woman had episodes of palpitations, dizziness, and presyncope. Ambulatory 12-lead 24-hour ECG monitoring showed 51 episodes of atrial fibrillation and atrial flutter with conversion pauses after each of them; the longest pause was 7460 ms. Atrial fibrillation lasted for 46.9% of the total monitoring time. When ambulatory 24-hour monitoring was performed, the patient was highly symptomatic (complaints of palpitations and fear of death were predominant, but dizziness episodes were also noted). Catheter ablation was unavailable in the short-term period and permanent pacemaker implantation was not accepted by the patient. Thus, flecainide at a dose of 100 mg BID under close supervision for rhythm control was administered. Also, anticoagulation with edoxaban was provided. The patient remained asymptomatic until ablation was performed. Pulmonary vein isolation with pulsed field ablation and cavotricuspid isthmus ablation was performed 10 days after ambulatory ECG monitoring. There were no paroxysms of atrial fibrillation after ablation. Antiarrhythmic agents in patients with conversion pauses may worsen sinus node function but may also eliminate atrial fibrillation paroxysms preventing conversion pauses. Thus, catheter ablation may be an option for a patient presenting with atrial fibrillation and conversion pauses to avoid unnecessary permanent pacemaker implantation. Short-term pharmacological bridging with flecainide under close supervision may be used in patients with atrial fibrillation and conversion pauses without other signs of sinus node dysfunction, providing effective rhythm control.
Intercellular junctions are critical to normal functioning and remodeling of various tissues in the reproductive system; however, their importance in the avian ovary is poorly understood. The aim of this study was to examine the expression and localization of essential tight (claudin 1, occludin, zonula occludens 1 [ZO1 gene]), adherens (E-cadherin [CDH1], β-catenin [CTNNB1]), and gap (connexin 43 [GJA1]) junction proteins in the hen ovarian follicles during a pause in laying induced by fasting. 32-week-old Hy-Line Brown hens were randomly divided into two groups: the control group (fed ad libitum; n = 8) and the experimental group (fasted; n = 8), which was subjected to an induced pause in egg laying by complete feed withdrawal for five consecutive days. Tissue samples from prehierarchical (white and yellowish) and hierarchical (small yellow and the largest yellow preovulatory F3-F1) follicles were collected on day six of the experiment from the control hens (laying) and hens that had been fasted (non-laying). Quantitative RT-PCR and Western blot analyses showed differences in the expression of examined proteins on mRNA and/or protein levels between the white and yellowish follicles, as well as between the largest yellow preovulatory F3-F1 follicles and the theca and granulosa layers of these follicles. Immunofluorescence revealed differences in staining intensity between the layers of follicle wall, with localization of all proteins mainly in the granulosa layer. In fasted hens, the atresia of the largest yellow follicles was accompanied by: (1) no changes in mRNA transcript abundance of tight and adherens junction proteins in prehierarchical follicles, and a decrease in GJA1 mRNA level in the white follicles; (2) mostly a decrease in mRNA transcript levels of each type of molecules in the yellow atretic follicles; (3) a decrease, no changes, or an increase in examined protein abundances in the white and yellowish follicles; (4) a decrease in cell junction protein abundances in F3-F1 follicles; and (5) a marked reduction in immunoreactivity for occludin, E-cadherin, β-catenin, and connexin 43 in the wall of atretic follicles. Our results provide novel insights into the molecular composition of tight, adherens, and gap junctions and their contribution to the remodeling of the follicular wall during follicle development and fasting-induced atresia of yellow preovulatory follicles in hens.
Air embolism is a rare but potentially fatal complication of laparoscopic surgery, especially among pediatric patients. A common theory as to why air embolism occurs during laparoscopy is that ambient air in the insufflation tubing can enter the vascular system when a trocar or Veress needle is inserted into a vessel or highly vascularized tissue. While some laparoscopic surgeons initiate CO2 insufflation before attaching the tubing, there are no guidelines that recommend a delay after starting the flow of CO2 and before connecting the insufflation tubing. We therefore assessed this "pause" at different flow rates and pressures. We connected standard ten-foot laparoscopic insufflation tubing to a STORZ ENDOFLATOR® 50. We then attached the end of the tubing to a three-way stopcock connected to an end-tidal CO2 monitor on an anesthesia machine. We turned on the insufflator at various flow rates and pressures and measured the time from initiation of insufflation to a visible increase on the end-tidal CO2 monitor. We repeated each test at each insufflation setting 10 times. The average time for CO2 to reach the distal end of the insufflation tubing at clinically relevant settings for pediatric (or adult) laparoscopy ranged from 3.32 ± 0.27s (at 20 L/min, 20 mmHg) to 3.46 ± 0.10s (at 4 L/min, 6 mmHg). We found little variation in timing across clinically relevant flow rates and pressures, likely due to the slow increase in the insufflator flow rate. We recommend waiting at least ten seconds, regardless of flow rate or pressure, between starting the flow of CO2 and connecting the insufflation tubing to laparoscopic trocars or Veress needles. This pause will help ensure that there is no ambient air in the tubing during laparoscopy. Whereas CO2 embolism may occur, air embolism should be a never event when using this guideline.
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.
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.
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.
Early online safety habits shape later behaviors, and core capabilities remain protective across ages, warranting population‑wide approaches. Families function as cross‑age safety systems with bidirectional learning and shared social learning mechanisms across cohorts, suggesting transferable, lifespan‑spanning intervention principles. This umbrella review synthesizes 66 systematic reviews and meta-analyses on digital interventions for cyberbullying and online harm across the lifespan. A comprehensive search following the PRISMA structure was conducted using databases including PubMed, PsycINFO, MEDLINE, ERIC, Sociological Abstracts, Social Service Abstracts, Scopus, EMBASE, for reviews published through December 31, 2025. Stronger effects were observed for multi‑component, theory‑driven programs that combine easy‑to‑hard practice, timely feedback, and reminders. At the micro level, university bystander programs and media literacy showed the largest gains, particularly in multi‑session formats. At the meso level, organizational trainings produced immediate improvements with boosters and policy supports; community and clinical delivery improved reach for older adults when paired with assisted reporting. At the macro level, platform warning messages and pause‑and‑verify prompts offer scalable benefits, and gendered risk patterns and increasing campus fraud prevalence underscore the need for tailored scenarios and just‑in‑time prompts. Policy and practice should adopt a family‑based lens, integrate boosters and cross‑sector coordination. Future research should standardize behavioral outcomes, use pragmatic and hybrid designs with longer follow‑up, and expand to underserved settings and emerging threats.
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.
Prosodic synchrony differences between autistic and non-autistic individuals have been increasingly documented, but findings remain heterogeneous. This study delineates a multi-timescale profile of static and dynamic pitch synchrony in autistic children during naturalistic Mandarin caregiver-child interactions to deepen understanding of interactional characteristics in autism. Sixty Mandarin-speaking children with autism spectrum disorder (ASD), developmental delay, or typical development (TD) participated in 10-min caregiver-child free-play interactions (20 per group). Prosodic synchrony was indexed from fundamental frequency (F0) using a multi-timescale analytical framework informed by Wynn and Borrie (2022), with dynamic time warping (DTW) for utterance alignment and pseudo-pair normalization for synchrony estimation. Analyses were performed at three timescales: turn level (adjacent caregiver-to-child utterance pairs), block level (short sequences of alternating turns separated by brief pauses), and conversation level (the full interaction). Static synchrony captured overall similarity averaged within a timescale, while dynamic synchrony captured systematic time-varying changes in synchrony over the interaction. Group effects and temporal structure were evaluated using linear mixed-effects models and generalized additive mixed models (GAMMs). The results indicated that children with ASD demonstrated significantly reduced static prosodic synchrony compared to their TD peers, consistently observed across turn-level (p = .005), block-level (p = .001), and conversation-level analyses (p = .005). Although dynamic synchrony was rarely observed, group-wise comparisons of smooth trajectories revealed that children with developmental disorders showed pronounced deviations in prosodic synchrony relative to their TD peers within specific temporal segments. Moreover, group differences emerged in trajectory variability, with the ASD group showing greater range and standard deviation of dynamic synchrony trajectories (p < .001). The results offer a multi-scale behavioral profile of prosodic synchrony in neurodevelopmental conditions. Turn-level synchrony may be informative for early screening, and dynamic-trajectory variability may support differential characterization and intervention tracking. https://doi.org/10.23641/asha.32867315.
Early detection of cognitive impairment remains a critical public health challenge. While biomarkers such as neuroimaging and cerebrospinal fluid analyses offer high sensitivity, their limited accessibility hampers widespread screening, especially in underserved settings. Speech-based markers have emerged as promising, noninvasive indicators of cognitive decline. To develop and validate SpeechDETECT, an end-to-end speech-processing pipeline that captures fine-grained acoustic and temporal markers of cognitive impairment and provides interpretable outputs suitable for large-scale screening. SpeechDETECT comprises six modules: (1) noise reduction / amplitude normalization; (2) an eight-domain voice-analysis framework (e.g., frequency parameters, speech fluency); (3) 50 ms segment-level feature extraction; (4) feature visualization; (5) dimensionality reduction / selection (Joint Mutual Information Maximization, LassoNet, PCA); and (6) classifier training with SHapley Additive exPlanations (SHAP). Performance was benchmarked against six acoustic toolkits (e.g., GeMAPS) on two English datasets: the DementiaBank Pitt corpus (train = 166, test = 71) with single cookie-theft picture description task and NIA PREPARE Phase 2 corpus (train = 1 064, test = 267) with multiple speech tasks. A Multi-Layer Perceptron trained on PCA-derived SpeechDETECT features achieved an F1-score = 0.81% and AUC-ROC = 0.80 on the Pitt test set, outperforming the best competing toolkit (AUC = 0.76). On the PREPARE test set-comprising ≤ 30 s recordings from four speech tasks-the same model attained F1 ≈ 0.67% and AUC-ROC = 0.70, demonstrating good generalizability. Cumulative-gains analysis showed that screening the top 40% of ranked participants captured ~ 70% of cognitively-impaired (CI) cases in Pitt and ~ 63% in PREPARE. SHAP revealed speech-fluency metrics (hesitation rate, pause ratio) and high-frequency formant dynamics as the most discriminative features. SpeechDETECT delivers accurate (AUC up to 0.80) and interpretable detection of early cognitive impairment across both structured and multi-task speech settings. Its fully automated, domain-informed approach enables scalable, speech-based screening and provides a foundation for multimodal systems that combine acoustic markers with clinical or biomarker data to further improve diagnostic precision. The SpeechDETECT toolkit is openly available on GitHub at https://github.com/SpeechCARE/SpeechDETECT-Toolkit for researchers and clinicians. A demo tutorial video showing pipeline usage is available at https://github.com/SpeechCARE/SpeechDETECT-Toolkit/blob/main/SpeechDETECT.mp4.
Transient loss of consciousness has overlapping cardiac and neurologic causes, and distinguishing syncope from seizure can be difficult. The co-occurrence of a primary cardiac rhythm disorder with a possible coexisting epileptic process is infrequently reported, as most cases instead describe one condition mimicking or triggering the other. We present a case of a 77-year-old woman with hypertension, hyperlipidemia, and paroxysmal atrial fibrillation who awoke with an abnormal chest sensation, a dream-like experience, and urinary incontinence and was admitted for evaluation of a possible seizure. Continuous telemetry captured a 50-second sinus arrest (initially reported as an eight-second pause), followed by an episode of atrial fibrillation with rapid ventricular response, establishing tachy-brady syndrome secondary to severe sinus node dysfunction. The patient underwent dual-chamber pacemaker implantation. Routine electroencephalography performed the following day showed occasional left temporal focal slowing and sharp waves without captured seizures, raising concern for possible focal epilepsy; incidentally identified right-sided meningiomas were discordant with the left temporal focus. The prolonged sinus arrest occurred during sleep without accompanying clinical seizures and showed a tachy-brady pattern typical of intrinsic sinus node disease, arguing against ictal asystole. Although the telemetry findings strongly supported intrinsic sinus node dysfunction, the interictal EEG abnormalities raised the possibility of an additional epileptogenic tendency. The patient was started on levetiracetam for a provisional diagnosis of epilepsy, pending reassessment. This case illustrates that a cardiac rhythm disorder and a possible coexisting epileptic process can occur together and that identifying one etiology should not preclude investigation of the other. Clinicians should maintain a low threshold for both continuous cardiac monitoring and EEG in patients with atypical transient loss of consciousness, as findings favoring one diagnosis do not preclude the other.
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.
Although acute health crises can disrupt routines and open a window for behaviour change, these teachable moments are rarely harnessed by intervention designs. The RETURN intervention (comprising a dental nurse-led conversation, short peer videos and booklets supporting knowledge, skills and action-planning) aimed to change planned dental visiting behaviour among adults previously reliant on urgent care. The RETURN trial recruited 1179 predominantly socio-economically disadvantaged urgent dental care users. This qualitative study explored how RETURN impacted meaning, motivations, and practices related to routine dental visiting. In-depth interviews were conducted with 55 participants (39 intervention) at 6, 12 and 18-months post-intervention and analysed using reflexive thematic analysis. Urgent dental problems provide a liminal (transitional) space where routines and dental visiting identities are destabilised. RETURN enabled a reflective pause where participants could distance themselves from previous patterns of behaviour, re-evaluate their oral health trajectory and priorities, reduce shame and self-blame, and rework aspects of their self-identity. Intervention components operated synergistically while enabling individually patterned engagement. Four themes generated were: 1. pausing and labelling the problem; 2. reducing ambivalence and energising motivation; 3. normalising struggle, cultivating hope and grit; 4. developing knowledge and skills to enact change. Booklets functioned as a material artefact extending engagement for over 12 months beyond the brief intervention delivery. For some, capabilities developed transferred to other domains of life. Findings position urgent care as an under-utilised site for identity work and sustained behaviour change, with the potential to support disadvantaged groups in service use, thus narrowing health inequalities. The RETURN trial was registered at isrctn.com (ISRCTN84666712).
Cardioneuroablation (CNA) is an emerging therapy for cardioinhibitory vasovagal syncope, but its autonomic effects in athletes remain poorly defined. A 44-year-old endurance athlete presented with recurrent syncope and a documented 20-second sinus pause. Structural heart disease was excluded, and tilt testing was nondiagnostic. To avoid pacemaker implantation and preserve athletic capacity, targeted CNA of the paraseptal ganglionated plexi was performed. This resulted in increased resting heart rate and a blunted atropine response. Shortly after, she developed symptomatic orthostatic tachycardia with hypotension. Symptoms resolved with short-term, low-dose beta-blocker therapy, which was subsequently discontinued. At a 12-month follow-up, she remained asymptomatic and returned to unrestricted endurance training. Although CNA is increasingly used to treat vasovagal syncope, postprocedural autonomic imbalance, including reflex tachycardia, is under-recognized, particularly in athletes. CNA may induce transient orthostatic tachycardia in athletes. Anticipatory counseling and structured follow-up are essential.
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.
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.