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ObjectivesTo predict the burden of HIV in the United States (US) nationally and by region, transmission type, and race/ethnicity through 2030.MethodsUsing publicly available data from the CDC NCHHSTP AtlasPlus dashboard, we generated 11-year prospective forecasts of incident HIV diagnoses nationally and by region (South, non-South), race/ethnicity (White, Hispanic/Latino, Black/African American), and transmission type (Injection-Drug Use, Male-to-Male Sexual Contact (MMSC), and Heterosexual Contact (HSC)). We employed weighted (W) and unweighted (UW) n-sub-epidemic ensemble models, calibrated using 12 years of historical data (2008-2019), and forecasted trends for 2020-2030. We compared results to identify persistent, concerning trends across models.ResultsWe projected substantial decreases in incident HIV diagnoses nationally (W: 27.9%, UW: 21.9%), and in the South (W:18.0%, UW: 9.2%) and non-South (W: 21.2%, UW: 19.5%) from 2019 to 2030. However, concerning nondecreasing trends were observed nationally in key sub-populations during this period: Hispanic/Latino persons (W: 1.4%, UW: 2.6%), Hispanic/Latino MMSC (W: 9.0%, UW: 9.9%), people who inject drugs (PWID) (W: 25.6%, UW: 9.2%), and White PWID (W: 3.5%, UW: 44.9%). The rising trends among Hispanic/Latino MMSC and overall PWID were consistent across the South and non-South regions.ConclusionsAlthough the forecasted national-level decrease in the number of incident HIV diagnoses is encouraging, the US is unlikely to achieve the Ending the HIV Epidemic in the US goal of a 90% reduction in HIV incidence by 2030. Additionally, the observed increases among specific subpopulations highlight the importance of a targeted and equitable approach to effectively combat HIV in the US.

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Abstract Background The incidence of periodontitis is high in older individuals. However, its impact on multi-organ frailty remains unclear. We developed mouse models with varying severity and duration of periodontitis to examine its effects. Methods We generated mouse models with mild and severe periodontitis, categorizing the disease duration into 3-month and 5-month periods for analysis. The organs assessed for frailty included the gastrocnemius muscle, soleus muscle, brain, and femur. Results Our study found that periodontitis induced systemic inflammation resembling inflammaging and other symptoms characteristic of age-induced frailty. Notably, muscle impairment developed specifically in slow-twitch muscles, and the femur emerged as the most vulnerable bone, exhibiting reduced bone mineral density even with mild and short-duration periodontitis. This condition resulted in the co-occurrence of bone fragility and slow-twitch muscle dysfunction. Cognitive function assessment revealed increased activated microglia and decreased adult neurogenesis in the hippocampus, impairing spatial learning. Thus, periodontitis induced both physical and cognitive frailties. Therapeutic intervention for the periodontitis, which halted the exacerbation of bone resorption markers, did not restore femur bone mineral density. Conclusion This study underscores the role of periodontitis in inducing multifaceted organ frailty with vulnerability, varying by organ, and the necessity of early intervention, particularly regarding bone density loss.

Introduction Desmoid tumors are rare, locally invasive, non‐metastasizing intermediate grade neoplasms. According to the organ procurement and transplantation network report, approximately one million solid organ transplants have been performed globally, from which only three desmoid tumors have been reported. Case presentation We present the case of a 61‐year‐old male who developed an asymptomatic abdominal mass 3 years after kidney transplantation. Computed tomography revealed a 50‐mm mass attached to the Hem‐o‐lok clip beneath the right rectus abdominis muscle. A needle biopsy revealed β‐catenin positivity, which raised suspicion for a desmoid tumor. Due to progressive tumor enlargement, surgical excision was performed. The patient was discharged on postoperative day 5 without any surgical complications. Conclusion This is the first documented case of an extra‐abdominal desmoid tumor after kidney transplantation. Although no recurrence has been observed over a 5‐year follow‐up period, careful long‐term monitoring is required because of the high recurrence rate of desmoid tumors.

Introduction: Tau protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and in regulating neuronal excitability. Among tau-coding microtubule associated protein tau (MAPT) gene mutations, the A152T mutation is reported to increase the risk of AD and neuronal excitability in mouse models. Methods: To investigate the effects of MAPT gene expression and its mutations on neuronal activity in human neurons, we employed genome editing technology to introduce the A152T or P301S mutations into induced pluripotent stem cells (iPSCs). We then differentiated them into excitatory and inhibitory neurons. As a control, iPSCs in which the MAPT gene was replaced with a fluorescent protein were also created. Results: In excitatory neuronal cultures, the A152T mutation was found to enhance spontaneous neuronal activity and the association of tau and Fyn. However, in inhibitory neuron-enriched cultures, the A152T mutation did not affect neuronal activity. Inhibition of NMDA receptors (NMDAR) and the reduction of tau protein levels decreased neuronal excitability in both A152T/A152T and healthy control (WT/WT) excitatory neurons. In addition, the A152T mutation increased the interaction between tau and Fyn. These findings suggest that the tau-Fyn interaction plays a critical role in regulating neuronal activity under physiological conditions, while the A152T mutation enhances neuronal activity by strengthening this endogenous interaction between tau and Fyn. In addition, transcriptomic analysis revealed structural changes specific to excitatory neurons with the A152T mutation. Common changes observed in both A152T and P301S lines recapitulated a dedifferentiation phenotype, consistent with previous reports. Conclusions: These data demonstrate that the A152T mutation in the MAPT gene increases neuronal excitability through the tau-Fyn-NMDAR pathway in excitatory neurons, shedding light on its role in AD pathogenesis.

Abstract Background Hemophilia B is an inherited disorder caused by a mutation in the FIX gene, which results in insufficient blood clotting factor IX (FIX) production from hepatocytes. Currently, there are no treatments for hemophilia B patients. The patients should be continuously administrated with clotting factor concentrates 2–3 times a month to prevent bleeding. Therefore, this study aimed to develop an engineered FIX-secreting hepatocyte sheet that can release FIX for an extended period. Within this study, the engineered FIX-secreting hepatocyte sheet was developed by integrating two core technologies, including a gene editing platform to generate FIX-secreting cells and cell sheet technology to improve cell delivery efficacy. Methods The human FIX gene was inserted into the APOC3 site of iPSCs by CRISPR/Cas9, which secretes the target protein after differentiation into hepatocytes. FIX-secreting hepatocyte sheets were obtained by temperature-responsive polymer grafted cell culture dishes (TRCD). Immunohistochemical and functional tests were performed for hepatocyte-like cells differentiated from FIX KI-iPSCs and wild-type iPSCs (WT-iPSCs). After validating the functional activity and secretion of FIX protein, the engineered hepatocyte-like cell sheets were transplanted to NOD/SCID mice for the in vivo experiments. Results The insertion of the human FIX gene into the APOC3 site demonstrated a significant increase in FIX secretion in hepatocyte-like cells differentiated from FIX KI-iPSCs compared with those obtained from WT-iPSCs. Among the iPSCs to hepatocyte differentiation stages, the hepatic endoderm stage was most suitable for seeding the cells on TRCD and generating cell sheets by temperature changes from 37oC to room temperature when the hepatocyte-like cells have reached maturity. The engineered FIX-secreting cell sheets showed intensive expression of the FIX proteins without losing hepatocyte morphology for 20 days. Furthermore, an in vivo study showed that engineered FIX-secreting cell sheets retained their FIX secretion functions for two weeks, whereas single-cell injected traditionally were barely detected in the experimental animals. Conclusions The engineered FIX-secreting cell sheets fabricated from functionally improved iPSCs with practical cell delivery tools could be a promising tool for clinically treating Hemophilia B.

Probabilistic approaches using fragility functions effectively assess building damage caused by major earthquakes and consequent repair costs. Existing fragility functions, however, are limited to reinforced concrete (RC) frames designed according to U.S. standards, making them unsuitable for frames designed according to other design standards. This study addresses this limitation by developing fragility functions for RC frames with interior beam – column joints classified based on joint strength margins. These margins were calculated using the joint ultimate strength relative to the ultimate strengths of beams and columns, enabling evaluations independent of design standards. Damage states (DSs) from DS1 to DS3 were defined to represent residual cracking, concrete damage, and ultimate state, respectively, with DS3 further subdivided into DS3–1 and DS3–2. Relationships between story drift ratios at damage states and joint strength margins were analyzed using Japanese experimental data. RC frames were ranked by joint strength margins, and a Bayesian approach was applied to evaluate fragility function parameters for each DS across these ranks.

Abstract Ex vivo studies of the brain are often employed as experimental systems in neuroscience. In general, brains for ex vivo MRI studies are usually fixed with paraformaldehyde to preserve molecular structure and prevent tissue destruction during long-term storage. As a result, fixing brain tissue causes microstructural changes and a decrease in brain volume. Therefore, the purpose of this study was to investigate the regional effect of brain volume and microstructural changes on the restricted diffusion of water molecules in the common marmoset brain using in vivo and ex vivo brains from the same individual. We used 9.4T magnetic resonance imaging and also compared the T2-weighted images and diffusion-weighted imaging (DWI) data between in vivo and ex vivo brains to investigate changes in brain volume and diffusion of water molecules in 12 common marmosets. We compared fractional anisotropy, mean diffusivity, AD (axial diffusivity), and radial diffusivity values in white matter and gray matter between in vivo and ex vivo brains. We observed that AD showed the strongest correlation with regional volume changes in gray matter. The results showed a strong correlation between AD and changes in brain volume. By comparing the in vivo and ex vivo brains of the same individual, we identified significant correlations between the local effects of perfusion fixation on microstructural and volumetric changes of the brain and alterations in the restricted diffusion of water molecules within the brain. These findings provide valuable insights into the complex relationships between tissue fixation, brain structure, and water diffusion properties in the marmoset brain.

BACKGROUND: Geographical variations in mood and psychotic disorders have been found in upper-income countries. We looked for geographic variation in these disorders in Colombia, a middle-income country. We analyzed electronic health records from the Clínica San Juan de Dios Manizales (CSJDM), which provides comprehensive mental healthcare for the one million inhabitants of Caldas. METHODS: We constructed a friction surface map of Caldas and used it to calculate the travel-time to the CSJDM for 16,295 patients who had received an initial diagnosis of mood or psychotic disorder. Using a zero-inflated negative binomial regression model, we determined the relationship between travel-time and incidence, stratified by disease severity. We employed spatial scan statistics to look for patient clusters. RESULTS: We show that travel-times (for driving) to the CSJDM are less than 1 h for ~50% of the population and more than 4 h for ~10%. We find a distance-decay relationship for outpatients, but not for inpatients: for every hour increase in travel-time, the number of expected outpatient cases decreases by 20% (RR = 0.80, 95% confidence interval [0.71, 0.89], p = 5.67E-05). We find nine clusters/hotspots of inpatients. CONCLUSIONS: Our results reveal inequities in access to healthcare: many individuals requiring only outpatient treatment may live too far from the CSJDM to access healthcare. Targeting of resources to comprehensively identify severely ill individuals living in the observed hotspots could further address treatment inequities and enable investigations to determine factors generating these hotspots.

Abstract Chronic complete spinal cord injury (SCI) is difficult to treat because of scar formation and cavitary lesions. While human iPS cell-derived neural stem/progenitor cell (hNS/PC) therapy shows promise, its efficacy is limited without the structural support needed to address cavitary lesions. Our study investigated a combined approach involving surgical scar resection, decellularized extracellular matrix (dECM) hydrogel as a scaffold, and hNS/PC transplantation. To mitigate risks such as prion disease associated with spinal cord-derived dECM, we used kidney-derived dECM hydrogel. This material was chosen for its biocompatibility and angiogenic potential. In vitro studies with dorsal root ganglia (DRG) confirmed its ability to support axonal growth. In a chronic SCI rat model, scar resection enhanced the local microenvironment by increasing neuroprotective microglia and macrophages, while reducing inhibitory factors that prevent axonal regeneration. The combination of scar resection and dECM hydrogel further promoted vascular endothelial cell migration. These changes improved the survival of transplanted hNS/PCs and facilitated host axon regeneration. Overall, the integrated approach of scar resection, dECM hydrogel scaffolding, and hNS/PC transplantation has been proven to be a more effective treatment strategy for chronic SCI. However, despite histological improvements, no functional recovery occurred and further research is needed to enhance functional outcomes.