OBJECTIVE: Thromboembolic (TE) events are among the most feared complications after flow diversion (FD) and have been reported to occur even with adequate dual antiplatelet therapy. Herein, the authors characterize thrombotic and embolic events that developed after FD, focusing on the morbidity of each of these events and the predisposing factors associated with their development.
METHODS: A retrospective analysis of aneurysms treated with FD at a single institution in the US between 2013 and 2023 was performed. The authors documented the emergence of intraprocedural and postoperative TE events. A survival analysis and a Cox regression model was conducted to identify predictors associated with these events.
RESULTS: The authors included 651 procedures performed in 591 patients to treat 746 aneurysms. TE events occurred in 38 of the procedures performed (5.8%), causing permanent deficit in 20 patients and death in 4 patients. Eleven cases presented with acute stent thrombosis, 11 with large-vessel occlusion, and 9 with perforator strokes. At a median follow-up of 9.5 months, 73.0% of patients with an ischemic event had a modified Rankin Scale score ≤ 2. Three of the deaths were secondary to occlusion at the basilar trunk and vertebral artery. In patients with TE events in the anterior circulation, 7 of 11 patients with middle cerebral artery occlusion and 9 of 12 patients with internal carotid artery occlusion achieved independence. Time-to-event Cox regression analysis demonstrated that TE events were more frequent in patients exhibiting aspirin resistance (hazard ratio 2.66; 95% CI 1.10-6.70).
CONCLUSIONS: TE events after FD result from multiple factors, including age, aneurysm characteristics, aneurysm location, antiplatelet resistance, and procedural factors. In our cohort, we found the highest morbidity for patients with TE events presenting with large-vessel occlusion at the middle cerebral artery, and vertebrobasilar system.

OBJECTIVE: Child maltreatment (CM) is a major risk factor across the lifespan. While research on CM and its consequences has risen strongly during the last decades, research is mainly focused on the prevalence of types of CM incidents. As valid prevalence rates on timing and chronicity of CM are lacking to date, we aimed to assess the timing of experienced CM by describing the age of onset, duration, and prevalence at each year of age for each CM subtype in a population-based sample.
METHODS: Cross-sectional, observational study in a representative sample.
METHODS: Using different sampling steps including a random route procedure, a probability sample of the German population above the age of 16, encompassing 2514 persons (50.6% female, mean age: 50.08 years) was generated. Participants were asked about sociodemographic information in a face-to-face interview, CM was assessed using the ICAST-R questionnaire.
RESULTS: The earliest mean age of onset was seen in neglect with 8.07 (±3.07) years for boys and 7.90 (±2.96) years for girls, while the mean age of onset for sexual abuse was in adolescence with 13.65 (±3.86) years for boys and 13.91(±3.17) years for girls. The overall duration of CM was lowest for sexual abuse with 2.12 (±2.01) years for boys and 2.35 (±1.73) years for girls, the highest duration was seen for emotional abuse with 4.00 (±3.54) years for boys and 4.21 (±3.77) years for girls.
CONCLUSIONS: Our novel results provide important epidemiological information for prevention efforts.

Invasions are commonly found to benefit from disturbance events. However, the importance of the relative timing of the invasion and disturbance for invader success and impact on community composition remains uncertain. Here, we experimentally test this by invading a five-species bacterial community on eight separate occasions-four before a disturbance and four after. Invader success and impact on community composition was greatest when the invasion immediately followed the disturbance. However, the subsequent invasions had negligible success or impact. Pre-disturbance, invader success and impact was greatest when the invader was added just before the disturbance. Importantly, however, the first three pre-disturbance invasion events had significantly greater success than the last three post-disturbance invasions. Moreover, these findings were consistent across a range of propagule pressures. Overall, we demonstrate that timing is highly important for both the success and impact on community composition of an invader, with both being lower as time since disturbance progresses.

Managing patients with severe symptomatic tricuspid regurgitation (TR) remains extremely challenging, with a lack of consensus on when and how to treat it. Tricuspid valve pathology has been disregarded for a very long time because of the established belief that treating left-sided heart diseases would lead to the resolution or significant improvement of TR. Initially considered benign, severe TR has been found to be a strong predictor of prognosis. Despite the increasing prevalence and the disabling nature of this disease, the great majority of patients with clinically significant TR have seldom been considered for structural interventions. Numerous surgical and transcatheter treatment options are now available; however, optimal timing and procedural selection remain crucial aspects influencing outcomes. According to recent evidence in the literature, early referral is associated with good short and long-term outcomes, and various predictors of favorable outcomes following either surgical or transcatheter treatment have been identified. Evaluation by a multidisciplinary heart team with expertise in tricuspid valve disease is of paramount importance to identify adequate treatment for every patient.

BACKGROUND: Infections caused by multi-drug resistant Gram-negative pathogens are associated with worse clinical outcomes in critically ill patients. We evaluated hospital outcomes based on adequacy of overall and newer antibacterial therapy for Enterobacterales (ENT) and Pseudomonas aeruginosa (PsA) in US patients.
METHODS: Hospitalized adults ≥ 18 years old with facility-reported antibiotic susceptibility from 2018-2022 across 161 facilities in the BD Insights Research Database were identified as ENT- or PsA-positive. Generalized linear mixed models were used to evaluate the impact of inadequate empiric therapy (IET) and time to initiate newer antibacterials (ceftazidime-avibactam; ceftolozane-tazobactam; cefiderocol; meropenem-vaborbactam; eravacycline; and imipenem-cilcastatin-relebactam) on hospital mortality and post-culture length of stay (LOS).
RESULTS: Among 229,320 ENT and 36,027 PsA susceptibility results, 1.7% and 16.8% were carbapenem non-susceptible (carb-NS), respectively. Median time to first susceptibility result was longer for carb-NS vs. carb susceptible in ENT (64 h vs. 48 h) and PsA (67 h vs. 60 h). For ENT, IET was associated with significantly higher mortality (odds ratio [OR],1.29 [95% CI, 1.16-1.43, P < 0.0001]) and longer hospital LOS (14.8 vs. 13.3, P < 0.0001). Delayed start to newer antibacterial therapy was associated with significantly greater hospital mortality for ENT (P = 0.0182) and PsA (P = 0.0249) and significantly longer post-culture LOS for ENT (P < 0.0001) and PsA (P < 0.0001).
CONCLUSIONS: Overall, IET and delayed use of newer antibacterials are associated with significantly worse hospital outcomes. More rapid identification of high-risk patients can facilitate adequate therapy and timely use of newer antibacterials developed for resistant Gram-negative pathogens.

Background: Nitroglycerin is suggested to improve flap survival based on promising results; however, there are no data on the effectiveness of treatment initiation time. This study aimed to compare the effect of various nitroglycerin treatment initiation times on partial flap survival. Materials and Methods: The study included 50 Sprague-Dawley rats. Modified McFarlane flaps were elevated on the dorsum of each rat. Group A received placebo treatment. Groups B, C, D, and E received topical nitroglycerin 2% starting 1 day before surgery, on the day of surgery, postoperative d 2, and postoperative d 4, respectively. After 7 days, the flap survival rates were calculated. Afterward, the severity and extent of inflammation and ischemia, and the severity of edema were evaluated histologically. Results: The flap survival rate was highest in group B, followed by groups C, D, E, and A. The difference between groups B and C was not significant, whereas the difference between group B and groups A, D, and E was. In addition, the difference between groups A, D, and E was not significant. Histological analysis showed that inflammation was less severe in groups B and C than in groups A, D, and E. Ischemia was the most severe in groups A and D and was the least severe in group C. Conclusion: Topical nitroglycerin treatment increases flap survival when initiated before or on the day of surgery, but has no benefit when initiated on postsurgery d 2 or 4. Preoperative initiation of nitroglycerin treatment positively affects flap survival.
Contexte: L’utilisation de la nitroglycérine a été proposée pour améliorer la survie d’un lambeau à partir de résultats prometteurs. Il n’y a cependant aucune donnée sur l’efficacité du délai d’instauration du traitement. Cette étude a visé à comparer l’effet de différents moments d’instauration du traitement avec la nitroglycérine sur la survie d’un lambeau partiel. Matériels et méthodes: L’étude a inclus 50 rats Sprague-Dawley. Des lambeaux modifiés de McFarlane ont été surélevés sur le dos de chaque rat. Le groupe A a reçu un placebo, tandis que les groupes B, C, D et E ont reçu de la nitroglycérine topique à 2% en commençant, respectivement, la veille de la chirurgie, le jour de la chirurgie, 2 jours et 4 jours postopératoires. Les taux de survie du volet ont été calculés après 7 jours. Ensuite, la sévérité et l’étendue de l’inflammation et de l’ischémie ainsi que la sévérité de l’œdème ont été évaluées histologiquement. Résultats: Le taux de survie des volets a été le plus élevé dans le groupe B, suivi des groupes C, D, E et A. La différence entre les groupes B et C n’était pas significative, tandis que la différence entre le groupe B et les groupes A, D et E l’était. En outre, la différence entre les groupes A, et E n’était pas significative. L’analyse histologique a montré que l’inflammation était moins sévère dans les groupes B et C que dans les groupes A, D et E. L’ischémie a été la plus importante dans les groupes A et D et la moins importante dans le groupe C. Conclusion: Le traitement topique avec la nitroglycérine augmente la survie d’un lambeau quand il est commencé le jour de la chirurgie ou avant, mais il n’apporte pas d’avantage s’il est instauré au 2e ou au 4e jour postopératoire. L’instauration d’un traitement par la nitroglycérine en préopératoire a un effet positif sur la survie des lambeaux.

BACKGROUND: There are increased indications that physical activity timing, irrespective of intensity, impacts insomnia and circadian clock function. Here, we describe the rationale and design of a randomized cross-over study, called ON TIME, to examine the effects of (changing) physical activity timing on insomnia severity and on multiple exploratory outcomes that are linked to circadian clock function.
METHODS: We will conduct a randomized cross-over trial in 40 healthy older adults (aged 65 to 75 years) with subclinical or clinical insomnia (Insomnia Severity Index (ISI) scores of ≥ 10) from the Dutch municipality of Leiden and surroundings. Participants will undergo 3 intervention periods (14 days each) consecutively: one sedentary period and two periods of increased physical activity (one period with morning activity and one period with evening activity). The intervention periods are separated by a wash-out period of 1 week. In both active intervention arms, participants will follow coached or uncoached outdoor physical exercise sessions comprising endurance, strength, and flexibility exercises for 14 days. The primary outcome is change in insomnia severity as measured by the ISI. Additional exploratory outcomes include multiple components of objective sleep quality measured with tri-axial accelerometry and subjective sleep quality assessed by questionnaires as well as dim light melatonin onset and 24-h rhythms in heart rate, heart rate variability, breathing rate, oxygen saturation, mood, and objective emotional arousal and stress. Additionally, we will collect diary data on eating patterns (timing and composition). Finally, fasting blood samples will be collected at baseline and after each intervention period for measurements of biomarkers of metabolic and physiological functioning and expression of genes involved in regulation of the biological clock.
CONCLUSIONS: We anticipate that this study will make a significant contribution to the limited knowledge on the effect of physical activity timing. Optimizing physical activity timing has the potential to augment the health benefits of increased physical exercise in the aging population.
BACKGROUND: Trial was approved by the Medical Ethics Committee Leiden, The Hague, Delft, The Netherlands (June, 2023). The trial was registered in the CCMO-register https://www.toetsingonline.nl/to/ccmo_search.nsf/Searchform?OpenForm under study ID NL82335.058.22 and named (\"Ouderen op tijd in beweging\" or in English \"Older adults exercising on time\"). At time of manuscript submission, the trial was additionally registered at ClinicalTrials.gov under study ID: NL82335.058.22 and is awaiting approval.

BACKGROUND: Pertussis vaccination in pregnancy has been introduced in an increasing number of countries to better protect infants against the disease in their first weeks of life. The optimal timing of pertussis vaccination in pregnancy is however still under debate.
METHODS: We systematically reviewed published literature on safety, immunogenicity and effectiveness of pertussis vaccination in pregnancy related to timing of vaccination. The search was conducted using PubMed, MEDLINE and Web of Science and yielded 1623 articles, thereof 777 duplicates. Screening resulted in the inclusion of 45 publications reporting on safety (n = 11), immunogenicity (n = 26) and/or effectiveness (n = 9). We also mapped pertussis recommendations in pregnancy by government institutions globally according to the recommended timing of vaccination.
RESULTS: Overall, the selected publications did not indicate increased safety concerns associated with timing of pertussis vaccination in pregnancy. Immunogenicity studies often suggested optimal protection at birth after early third trimester vaccination. Few studies investigated qualitative antibody characteristics, and none investigated antibody titers in breastmilk or cellular-mediated immunity related to timing of vaccination. Effectiveness studies showed decreased vaccine effectiveness of late third trimester pertussis vaccination compared to vaccination earlier in pregnancy. Worldwide, a general recommendation for pertussis vaccination in pregnancy was found for 58 countries, with as many as 22 different recommended timings registered.
CONCLUSIONS: The timing of pertussis vaccination in pregnancy seems to impact immunogenicity and vaccine effectiveness, with optimal immune responses at birth suggested following early third trimester vaccination and reduced vaccine effectiveness of late third trimester pertussis vaccination suggested compared to vaccination earlier in pregnancy. However, inconsistent and lacking data are reflected in the divergent national recommendations for pertussis vaccination in pregnancy worldwide.
CONCLUSIONS: Pertussis vaccination in pregnancy aims to protect infants in their first weeks of life. Our review suggests that immunogenicity and vaccine effectiveness are impacted by the timing of vaccination in pregnancy. National recommendations for pertussis vaccination in pregnancy vary widely worldwide.

UNASSIGNED: Patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) consists of a heterogenic population and improvement in identification of a specific risk profile is needed. In this study we aimed to obtain better insight in the role of different biomarkers for patients undergoing a routine invasive diagnostic strategy within 24 hours after admission.
UNASSIGNED: An Immediate or Early Invasive Strategy in Non-ST-Elevation Acute Coronary Syndrome (OPTIMA-2) study was a randomized controlled prospective open-label multicentre trial, randomizing NSTE-ACS patients. An invasive strategy was either immediate ( < 3 hours) or early (12-24 hours). Peak high-sensitive TroponinT (hsTropT) value was determined within the first 48 hours of admission. N-terminal proB-type natriuretic peptide (NTpro-BNP) and high-sensitivity C-reactive protein (hsCRP) values were determined at admission and at discharge. These biomarkers were then divided into tertiles and related to clinical outcomes up to one year. The relation between these biomarkers and myocardial function recovery established by echocardiography was analyzed as a secondary endpoint.
UNASSIGNED: The OPTIMA-2 study included 249 patients. Overall, there was no significant increase in the risk of developing an adverse cardiovascular event in the first year if biomarker tertiles at admission were compared. However, mean NT-proBNP levels at admission were higher for patients that experienced all-cause death withing the first year (1.93 ± 0.49 vs 1.42 ± 0.58, p = 0.05). Also, peak hs-cTnT (232.0 ± 2846.0 vs 71.5 ± 1152.0, p = 0.06) values at baseline were higher in patients experiencing a myocardial infarction within 1-year. NT-proBNP levels at admission and at discharge correlated with recovery of the left ventricular (LV) function at 30 days (coefficient 0.021 (95% CI = 0.009-0.033) and coefficient 0.016 (95% CI = 0.005-0.027)).
UNASSIGNED: In NSTE-ACS patients treated by an early invasive strategy and administration of modern anticoagulant and antiplatelet therapy, multiple biomarker measurements during admission could not predict the occurrence of recurrent cardiovascular events within the first year of follow-up.

OBJECTIVE: Cerebral arteriovenous malformations (AVMs) are a challenging pathology in pediatric patients, carrying a high risk of morbidity and mortality. Treatment modalities include resection, endovascular embolization and stereotactic radiosurgery (SRS). There is currently no consensus favoring one modality over another. Timing of multimodal therapy with embolization/SRS and resection is not well explored in the literature. Here we present a series of pediatric AVM patients, with special attention paid to the timing of treatment.
METHODS: Electronic medical records of all pediatric patients (<18 years at treatment) with AVMs treated at our institution were retrospectively reviewed after IRB approval. Demographic information, AVM characteristics, treatment variables and outcomes were recorded.
RESULTS: 27 total patients were included. 21 (77.8%) presented with a ruptured AVM. 6 patients (28.6%) had an GCS of 3 to 10, and underwent treatment within 24 hours of presentation. 10 patients (47.6 %) with a GCS of 12 to 15 were treated between 24 to 120 hours. 5 patients (23.8%) were treated 3 weeks to 14 months after AVM rupture. 96% of our cohort, regardless of rupture status, had mRS of 1-2 at most recent follow-up.
CONCLUSIONS: We present our institution\'s experience with pediatric AVM\'s, focusing on the timing of treatment. Based on our experience, early treatment of AVMs seems to be safe and effective regardless of rupture status.