Nara Medical University

This post-marketing surveillance study investigated safety and effectiveness of lisdexamfetamine dimesylate (LDX) in paediatric attention-deficit/hyperactivity disorder (ADHD) in routine clinical practice in Japan. Patients (aged 6 to<18years) were enrolled in this prospective, observational study from January 2020 to December 2023 and received an LDX dose determined by the investigator. Safety (including dependence and abuse) and effectiveness were evaluated for 2years after treatment initiation. Dependence and abuse were also assessed for 3 additional years in those still receiving LDX. The data cut-off date for this interim analysis was 21 January 2024. Overall, 1819 patients were enrolled across 188 sites and case report forms were collected for 1012 patients. Of these, 1006 and 916 patients were included in the safety and effectiveness analyses, respectively. The adverse drug reactions (ADRs) of decreased appetite (19.3%), insomnia (3.7%), nausea (3.4%), weight decrease (2.8%), headache (2.6%), aggression (2.4%), initial insomnia (1.8%), irritability (1.8%), tic (1.6%), and agitation (1.3%), were reported in≥1% of patients. Eight serious ADRs occurred in five patients: decreased appetite (n=3), and anger, hyperthyroidism, palpitations, poor weight gain, and suicide attempt (n=1 each). For ADRs defined as important identified risks or important potential risks of LDX, one non-serious syncope event was observed. No dependence- or abuse-related events of LDX were reported. An increasing proportion of patients had improvements in the Clinical Global Impression-Improvement scale during the first year of observation, and improvements were maintained through the second year. Improvements from baseline in ADHD-Rating Scale-IV total and subscale scores increased over the 2-year observation period; significant improvements in the total score were observed at all time points (p<0.0001). No ADRs requiring new safety measures were observed. The effectiveness of LDX was confirmed in real-world practice. This study is ongoing, and the final results will be reported upon completion. University Hospital Medical Information Network (UMIN) Clinical Trials Registry (identifier: UMIN000039018).

Carbapenem-resistant Acinetobacter baumannii (CRAb) is designated by the World Health Organization as a critical priority pathogen, and most clinical CRAb isolates are multidrug-resistant (MDRA). However, an in vivo mouse imaging model of infection using clinical MDRA isolates has not been curated. Using antibiotic resistance genes as plasmid selection markers is incompatible with antimicrobial drug evaluation and prevents their application to MDRA isolates. To overcome this limitation, we constructed a firefly luciferase plasmid using tellurite resistance genes as non-antibiotic selection markers, enabling luminescence in multiple clinical MDRA isolates without altering susceptibility. Using a mouse pneumonia model and near-infrared luciferin derivative (TokeOni), we achieved noninvasive visualization of lung colonization by clinical MDRA isolates. Luminescence dynamics during treatment mirrored the in vitro minimum inhibitory concentration and survival outcomes, providing a therapeutic response readout. This platform overcomes a major bottleneck in MDR pathogen imaging and supports the evaluation of infection dynamics and drug efficacy.

Streptococcus pneumoniae commonly colonizes the nasopharynx asymptomatically, but certain conditions trigger its transition to invasive disease. The mechanisms driving this expansion are not fully understood. We used a murine model of pneumococcal nasopharyngeal colonization followed by respiratory syncytial virus (RSV) infection to investigate bacterial expansion. We measured bacterial loads in nasal and bronchoalveolar lavage fluids and analyzed growth arrest-specific protein 6 (Gas6) expression. The effect of the Axl receptor inhibitor BGB324 (bemcentinib) on RSV-mediated growth was assessed, and macrophage phenotypes were analyzed in vivo and in vitro. RSV infection increased bacterial loads and upregulated Gas6 expression in the nasal cavity. Inhibition of the Axl receptor with BGB324 effectively attenuated RSV-mediated pneumococcal growth. Furthermore, RSV infection decreased M1-like macrophage markers in the nasal cavity. In vitro assays confirmed that Gas6 suppresses M1 polarization, fostering an environment conducive to bacterial proliferation. Our findings reveal that the RSV-induced Gas6/Axl axis facilitates pneumococcal overgrowth by modulating macrophage function. Targeting this axis or modulating macrophage polarization may offer novel therapeutic strategies for preventing severe pneumococcal infections exacerbated by RSV.

The recurrences of acute coronary syndrome (ACS) and target vessel failure after percutaneous coronary intervention (PCI) remain clinical concerns. Intravascular imaging, such as optical coherence tomography (OCT) or intravascular ultrasound (IVUS), has demonstrated clinical benefits in patients with stable coronary disease; however, the benefits of its use remains unclear in patients with ACS. This study aimed to investigate the benefit of imaging-guided PCI in patients with ACS on the recurrence of ACS using a nationwide database in Japan. This retrospective observational study used records from the National Database between April 2014 and March 2021. We included patients hospitalised with ACS aged ≥20 years who had undergone first-time PCI and divided them into imaging-guided PCI (OCT or IVUS) and angiography-guided PCI groups. The primary outcome was ACS recurrence during a 3-year follow-up period. We analysed the association between intravascular imaging and the outcome using inverse probability of treatment weighting. Among the patients with ACS, angiography-guided PCI, OCT-guided PCI, and IVUS-guided PCI were performed in 32,044, 22,748, and 297,944 patients, respectively. During the study period, both OCT- and IVUS-guided PCI rates increased, from 4.7% to 6.9% and from 77.0% to 87.9%, respectively. OCT-guided PCI was associated with a lower risk of ACS recurrence (hazard ratio [HR] 0.81, 95% confidence interval [CI]: 0.71-0.91; p<0.001); IVUS-guided PCI was also associated with a lower risk of ACS recurrence (HR 0.76, 95% CI: 0.71-0.82; p<0.001). In real-world clinical practice, the rates of both OCT- and IVUS-guided PCI have increased and have been associated with a lower risk of ACS recurrence compared with angiography-guided PCI in patients with ACS.

Intraventricular hemorrhage (IVH) is a serious complication in extremely preterm infants, in whom the first 72 hours of life are critical. We evaluated the impact of an ultrasound-guided circulatory management protocol on IVH incidence. This retrospective study included infants who were born before 28 weeks of gestation and admitted to a tertiary neonatal intensive care unit between January 2018 and September 2024. In June 2022, a new protocol was introduced that incorporated three daily ultrasound assessments, adequate and tailored sedation, and targeted nitroglycerin use guided by ultrasound hemodynamic findings. Clinical outcomes and blood pressure trends were compared between the pre- and post-implementation groups. Ninety-two infants (49 pre-implementation and 43 post-implementation) were analyzed. The incidence of overall IVH decreased from 37% to 9% (p = 0.002), and severe IVH declined from 16% to 2% (p = 0.03). After implementation, increases in blood pressure were slower, and variability was reduced. No increase in hypotension duration or adverse outcomes was observed. After the implementation of the ultrasound-guided circulatory management protocol, the IVH incidence significantly decreased. These findings also support the potential of ultrasound by neonatologists in the circulatory management of extremely preterm infants. An ultrasound-guided circulatory management protocol reduced the incidence of intraventricular hemorrhage in extremely preterm infants. The protocol included frequent cardiac and cranial ultrasound assessments, adequate and tailored sedation, and selective nitroglycerin use guided by real-time ultrasound hemodynamic findings. After implementation, blood pressure rose more gradually and fluctuated less, indicating improved hemodynamic stability. These findings support a feasible, individualized approach to protect the immature brain during the most vulnerable period. The study also highlights the potential role of ultrasound by neonatologists in optimizing the care for extremely preterm infants.

Although the spleen has been implicated in myeloid malignancy progression, the underlying mechanisms and microenvironmental remodeling remain poorly understood. Here, we investigated how splenic mesenchymal stromal/progenitor cells (MSPCs) expressing the transcription factor T-cell leukemia homeobox 1 (Tlx1) influence hematopoiesis and myeloid disease progression. We assessed their impact on hematopoietic stem/progenitor cells (HSPCs), leukemic cell recruitment, and disease progression. In vitro, Tlx1-overexpressing splenic stromal cells promoted the proliferation and survival of HSPCs. In vivo, using a murine acute myeloid leukemia (AML) model, AML progression induced extramedullary hematopoiesis (EMH) in the spleen through Tlx1 upregulation in MSPCs. This Tlx1-dependent remodeling facilitated leukemic cell recruitment and retention, whereas Tlx1 ablation in MSPCs significantly reduced leukemic cell accumulation in the spleen. Prolonged EMH in vivo was associated with the development of a myeloid malignancy. Collectively, these findings demonstrate that Tlx1-driven remodeling of the splenic microenvironment supports HSPC expansion and fosters conditions that promote myeloid malignancy development. Thus, targeting Tlx1-mediated alterations in the splenic niche may represent a therapeutic strategy for AML and related myeloid malignancies.

Progressive collapsing foot deformity (PCFD) is a complex condition characterized by multiple combined deformities, with a higher reported prevalence in women. Most studies of PCFD morphology have focused on single joints and evaluated both sexes together, leaving the interrelationship of multiple joints in females specifically unassessed. In this study, we developed a multi-domain statistical shape model (SSM) from reconstructions of simulated weight-bearing computed tomography (SW-CT) image data to investigate variations in 3D foot alignment in women by comparing the morphology of patients with PCFD to that of their asymptomatic control counterparts. We developed an SSM to analyze the 3D alignment in the foot, including the distal tibia, distal fibula, talus, calcaneus, navicular, cuboid, and each of the cuneiforms and metatarsal bones. Model results were compared between 23 female patients with PCFD and 23 female asymptomatic individuals. Although the Chopart, subtalar, and Lisfranc joints were dorsiflexed and abducted, the Chopart and subtalar joints were inverted whereas the Lisfranc joint was everted, indicating that deformity of the Lisfranc joint occurred in the opposite direction to that of the subtalar and Chopart joints. The application of a multi-domain SSM from SW-CT to evaluate alignment deformities in patients with PCFD represents a new and novel approach to understanding the pathophysiology of this condition. In PCFD, the subtalar and Chopart joints showed coordinated changes, whereas the Lisfranc joint demonstrated variation in the opposite direction. Also, the talonavicular joint spreads out medially in a fan-like direction in PCFD.