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Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI. Traumatic brain injury (TBI) is a serious and poorly understood medical condition. Here, the authors show that TBI induces long-lasting deficits in brain lymphatic drainage. They report that defects in this drainage pathway provoke severe TBI pathogenesis that can be rescued with VEGF-C treatment.

Major changes in atmospheric and ocean chemistry occurred in the Paleoproterozoic era (2.5 to 1.6 billion years ago). Increasing oxidation dramatically changed Earth’s surface, but few quantitative constraints exist on this important transition. This study describes the sedimentology, mineralogy, and geochemistry of a 2-billion-year-old, ~800-meter-thick evaporite succession from the Onega Basin in Russian Karelia. The deposit consists of a basal unit dominated by halite (~100 meters) followed by units dominated by anhydrite-magnesite (~500 meters) and dolomite-magnesite (~200 meters). The evaporite minerals robustly constrain marine sulfate concentrations to at least 10 millimoles per kilogram of water, representing an oxidant reservoir equivalent to more than 20% of the modern ocean-atmosphere oxidizing capacity. These results show that substantial amounts of surface oxidant accumulated during this critical transition in Earth’s oxygenation.

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

BackgroundJuvenile systemic sclerosis (jSSc) is an extremely rare orphan disease. To date, there is very limited published data regarding incidence and prevalence of jSSc. Specifically, there are no published data on jSSc incidence rates by age group and only one Columbian report of jSSc prevalence rates by age group. These data are important given the significant developmental differences between age subsets.ObjectivesTo evaluate jSSc age-subset incidence and prevalence using U.S. administrative claims data.MethodsChildren <18 years old with medical claims for SSc and who received methotrexate, mycophenolate mofetil, or cyclophosphamide at a pediatric age (<18 years old) were identified from the OPTUM Clinformatics claims database 2007-2021. jSSc patients were identified using ≥2 medical claims (710.1, 517.2 for ICD-9-CM codes and M34, M34.x for ICD-10-CM codes) for SSc on different dates within a 1-year period. Incidence and prevalence were estimated overall, by age group, and were age and sex adjusted using 2020 US census data.ResultsAdjusted incidence and prevalence estimates are presented in the table below. Overall, jSSc incidence and prevalence rates among children in the US were 1.4 per million person-years (PY) and 7.3 per million, respectively. Both incidence and prevalence rates increased with age.Table 1.AgeAdjusted incidence per 1,000,000PYAdjusted prevalence per 1,000,000Overall (0-≤18)1.4 (0.9, 1.9)7.3 (5.5, 9.1)0-<60.6 (<0.01, 1.4)0.6 (<0.01, 1.4)6-<100.5 (<0.01, 1.1)3.1 (0.6, 5.6)10-<121.7 (0.03, 3.3)5.2 (0.6, 9.7)12-<182.7 (1.5, 3.8)16.6 (12, 21.3)ConclusionjSSc is an extremely rare disease with incidence and prevalence rates increasing with age. Specifically, incidence and prevalence rates vary dramatically for different age subsets, with increasing rates at 10 years and older. To our knowledge, this is the first study to estimate jSSc incidence and prevalence rates by age group.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsJohn Mattson Employee of: Boehringer Ingelheim Pharmaceuticals Inc, Haikun Bao Employee of: Boehringer Ingelheim Pharmaceuticals Inc, Mary Flack Employee of: Boehringer Ingelheim Pharmaceuticals Inc, Karen Coeytaux Employee of: Boehringer Ingelheim Pharmaceuticals Inc.

In recent years, with technological advances in arthroscopy and magnetic resonance imaging and improved biomechanical studies of the meniscus, there has been some progress in the diagnosis and treatment of injuries to the roots of the meniscus. However, the biomechanical effect of posterior lateral meniscus root tears on the knee has not yet become clear. The purpose of this study was to determine the effect of a complete radial posterior lateral meniscus root tear on the knee contact mechanics and the function of the posterior meniscofemoral ligament on the knee with tear in the posterior root of lateral meniscus. A finite element model of the knee was developed to simulate different cases for intact knee, a complete radial posterior lateral meniscus root tear, a complete radial posterior lateral meniscus root tear with posterior meniscofemoral ligament deficiency, and total meniscectomy of the lateral meniscus. A compressive load of 1000N was applied in all cases to calculate contact areas, contact pressure, and meniscal displacements. The complete radial posterior lateral meniscus root tear decreased the contact area and increased the contact pressure on the lateral compartment under compressive load. We also found a decreased contact area and increased contact pressure in the medial compartment, but it was not obvious compared to the lateral compartment. The lateral meniscus was radially displaced by compressive load after a complete radial posterior lateral meniscus root tear, and the displacement took place mainly in the body and posterior horn of lateral meniscus. There were further decrease in contact area and increases in contact pressure and raidial displacement of the lateral meniscus in the case of the complete posterior lateral meniscus root tear in combination with posterior meniscofemoral ligament deficiency. Complete radial posterior lateral meniscus root tear is not functionally equivalent to total meniscectomy. The posterior root torn lateral meniscus continues to provide some load transmission and distribution functions across the joint. The posterior meniscofemoral ligament prevents excessive radial displacement of the posterior root torn lateral meniscus and assists the torn lateral meniscus in transmitting a certain amount of stress in the lateral compartment.

Mass-independent isotopic signatures for δ33S, δ34S, and δ36S from sulfide and sulfate in Precambrian rocks indicate that a change occurred in the sulfur cycle between 2090 and 2450 million years ago (Ma). Before 2450 Ma, the cycle was influenced by gas-phase atmospheric reactions. These atmospheric reactions also played a role in determining the oxidation state of sulfur, implying that atmospheric oxygen partial pressures were low and that the roles of oxidative weathering and of microbial oxidation and reduction of sulfur were minimal. Atmospheric fractionation processes should be considered in the use of sulfur isotopes to study the onset and consequences of microbial fractionation processes in Earth's early history.

Generalized Pustular Psoriasis (GPP) is a rare, severe, life-threatening form of psoriasis and often resistant to conventional systemic therapy. It can be induced by deficiency of interleukin (IL)-36 receptor antagonist. Treatment of patients with GPP is often difficult, and there is no consensus on the best options available to date. However, multiple biologics approved for use in plaque-type psoriasis have also been used in GPP. Here, we report a 6-year-old boy with GPP who was misdiagnosed with AGEP and was treated with corticosteroids but did not respond well. He showed significant improvement following secukinumab treatment. Our case report indicates that IL-17A inhibition as a promising therapeutic option for pediatric GPP without combination with other systemic agents.

Bone Morphogenetic Proteins might be the most prospective in glioma treatment because of the facts that they can differentiate glioma cells, inhibit tumor growth and manage glioma stem cells. Its clinical application is hindered by several challenges, including limited permeability across the blood-brain barrier, which impedes effective delivery to the central nervous system; high susceptibility to enzymatic degradation, which compromises stability and therapeutic efficacy; and nonselective binding, which reduces specificity and may result in unintended off-target effects. This review systematically covers the advanced BMP delivery systems such as nanoparticles, smart carriers, gene therapy, and exosome-based system. Hydrogels, scaffolds, and microspheres' local delivery methods are also discussed as prospective options. The in vitro studies reveal that BMPs are effective and using in vivo glioma models there is also evidence of the effectiveness of BMPs. In addition, new clinical trials reveal concern with safety, tolerability, and therapeutic effects of BMPs, especially their combination with chemotherapy and immunotherapy. BMP specificity and therapeutic performance are further optimized by Personalized medicine and CRISPR/Cas engineering. However, regulatory barriers and product commercialization are challenging issues. This review highlights the need for novel approaches and advanced technologies to address the challenges associated with BMP delivery, aiming to establish BMP-based therapies as an effective treatment strategy for glioma.

Properties near public transportation systems are usually sold at a premium owing to the willingness of firms and people to pay for access to workplace and leisure. However, the economic impact of major infrastructure investments remains an empirical question plagued by identification issues. We investigate the economic impacts of a major transportation development project currently under construction in Hong Kong: the Tuen Mun–Chek Lap Kok tunnel, namely the effects on property prices of the expansion of the regional road network in the Greater Bay Area. We identify a significant accessibility premium well before the tunnel is completed. There is also a change in market structure of increased preference for residential property in areas closer to the tunnel, reflected by higher price appreciation. The findings help guide urban planning and public investment decisions, as well as the design and implementation of land value capture policy. 由于公司和个人愿意为临近工作场所和休闲场所付费，公共交通系统附近的物业通常有一个溢价。然而，重大基础设施投资的经济影响仍然是一个经验问题，受到各种识别的困扰。我们研究香港目前正在兴建的一项大型交通发展项目—屯门至赤腊角隧道的经济影响，即大湾区区域道路网络扩展对物业价格的影响。早在隧道竣工之前，我们就发现了显著的便利溢价。市场结构也发生了变化，人们更加青睐靠近隧道的地段的住宅，导致这些住宅升值更快。研究结果有助于指导城市规划和公共投资决策，以及土地价值获取政策的设计和实施。

The purpose of this study was to assess the pharmacokinetic (PK) characteristics, clinical efficiency, and pharmacoeconomic parameters of piperacillin/tazobactam administered by extended infusion (EI) or intermittent infusion (II) in the treatment of hospital-acquired pneumonia (HAP) in critically ill patients with low illness severity in China. Fifty patients completed the study, with 25 patients receiving 4/0.5 g piperacillin/tazobactam over 30 min as the II group and 25 patients receiving 4/0.5 g piperacillin/tazobactam over 3 h every 6 h as the EI group. Drug assay was performed using high-performance liquid chromatography (HPLC). The percentage of the dosing interval for which the free piperacillin concentration (% f T) exceeds the minimum inhibitory concentration (MIC) was calculated. The patients’ therapy cost, clinical efficiency, and adverse effects were also recorded. % f T>MIC was about 100, 98.73, and 93.04 % in the EI arm versus 81.48, 53.29, and 42.15 % in the II arm, respectively, when the microorganism responsible for HAP had an MIC of 4, 8, and 16 mg/L. The therapy cost in the EI group was lower than that of the II group ($1351.72 ± 120.39 vs. $1782.04 ± 164.51, p  = 0.001). However, the clinical success rate, clinical failure rate, and drug-related adverse events did not significantly differ between groups. EI treatment with piperacillin/tazobactam was a cost-effective approach to the management of HAP, being equally clinically effective to conventional II.