Xenografted human iPSC-derived neurons with the familial Alzheimer's disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator.

Alzheimer's disease (AD) is the most common cause of dementia, and disease mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying the familial AD APPV717I mutation after cell injection into the mouse forebrain. APPV717I mutant iPSCs and isogenic controls were differentiated into neurons revealing enhanced Aß42 production, elevated phospho-tau, and impaired neurite outgrowth in APPV717I neurons. Two months after transplantation, APPV717I and control neural cells showed robust engraftment but at 12 months post-injection, APPV717I grafts were smaller and demonstrated impaired neurite outgrowth compared to controls, while plaque and tangle pathology were not seen. Single-nucleus RNA-sequencing of micro-dissected grafts, performed 2 months after cell injection, identified significantly altered transcriptome signatures in APPV717I iPSC-derived neurons pointing towards dysregulated synaptic function and axon guidance. Interestingly, APPV717I neurons showed an increased expression of genes, many of which are also upregulated in postmortem neurons of AD patients including the transmembrane protein LINGO2. Downregulation of LINGO2 in cultured APPV717I neurons rescued neurite outgrowth deficits and reversed key AD-associated transcriptional changes related but not limited to synaptic function, apoptosis and cellular senescence. These results provide important insights into transcriptional dysregulation in xenografted APPV717I neurons linked to synaptic function, and they indicate that LINGO2 may represent a potential therapeutic target in AD.

A finite element model for predicting impact-induced damage to a skin simulant.

A finite element model was developed for assessing the efficacy of rugby body padding in reducing the risk of sustaining cuts and abrasions. The model was developed to predict the onset of damage to a soft tissue simulant from concentrated impact loading (i.e., stud impact) and compared against a corresponding experiment. The damage modelling techniques involved defining an element deletion criterion, whereby those on the surface of the surrogate were deleted if their maximum principal stress reached a predefined value. Candidate maximum principal stress values for element deletion criteria were identified independently from puncture test simulations on the soft tissue simulant. Experimental impacts with a stud were carried out at three energies (2, 4 and 6 J), at three angular orientations (0°, 15° and 30°) and compared to corresponding simulations. Suitable maximum principal stress values for element deletion criteria settings were first identified for the 4 J impact, selecting the candidates that best matched the experimental results. The same element deletion settings were then applied in simulations at 2 and 6 J and the validity of the model was further assessed (difference < 15% for the force at tear and < 30% for time to tear). The damage modelling techniques presented here could be applied to other skin simulants to assess the onset of skin injuries and the ability of padding to prevent them.

Clinical Characteristics as Predictors of Early and Delayed Cerebral Infarction in Aneurysmal Subarachnoid Hemorrhage Patients: A Meta-Analysis of 4527 Cases.

BACKGROUND: Predictors of delayed cerebral infarction (DCI) and early cerebral infraction (ECI) among aneurysmal subarachnoid hemorrhage (aSAH) patients remain unclear. We aimed to systematically review and synthesize the literature on predictors of ECI and DCI among aSAH patients. METHODS: We systematically searched PubMed, EMBASE, Cochrane Library, and Scopus databases comprehensively from inception through January 2024 for observational cohort studies examining predictors of DCI or ECI following aneurysmal SAH. Studies were screened, reviewed, and meta-analyzed, adhering to PRISMA and Cochrane guidelines. The data were pooled as Odds ratios (OR) with 95% confidence intervals (CI) using RevMan 5.4 software. Methodologic quality was assessed with the Newcastle-Ottawa Scale. RESULTS: Our meta-analysis included 12 moderate to high-quality cohort studies comprising 4527 patients. Regarding DCI predictors, Higher severity scores (O.R.=1.49, 95%CI [1.12,1.97], P=0.005) and high Fisher scores (O.R.=2.23, 95%CI [1.28,3.89], P=0.005) on presentation were significantly associated with an increased risk of DCI. Also, the female sex and the presence of vasospasm were significantly associated with an increased risk of DCI (O.R.=3.04, 95%CI [1.35,6.88], P=0.007). In contrast, preexisting hypertension (p=0.94), aneurysm treatment (p=0.14), and location (p=0.16) did not reliably predict DCI risk. Regarding ECI, the pooled analysis demonstrated no significant associations between sex (P=0.51), pre-existing hypertension (P=0.63), severity (P=0.51), or anterior aneurysm location versus posterior (P=0.86) and the occurrence of ECI. CONCLUSION: Female sex, admission disease severity, presence of vasospasm and Fisher grading can predict DCI risk post-aSAH. Significant knowledge gaps exist for ECI predictors. Further large standardized cohorts are warranted to guide prognosis and interventions.

Mapping the Evolutionary Space of SARS-CoV-2 Variants to Anticipate Emergence of Subvariants Resistant to COVID-19 Therapeutics.

New sublineages of SARS-CoV-2 variants-of-concern (VOCs) continuously emerge with mutations in the spike glycoprotein. In most cases, the sublineage-defining mutations vary between the VOCs. It is unclear whether these differences reflect lineage-specific likelihoods for mutations at each spike position or the stochastic nature of their appearance. Here we show that SARS-CoV-2 lineages have distinct evolutionary spaces (a probabilistic definition of the sequence states that can be occupied by expanding virus subpopulations). This space can be accurately inferred from the patterns of amino acid variability at the whole-protein level. Robust networks of co-variable sites identify the highest-likelihood mutations in new VOC sublineages and predict remarkably well the emergence of subvariants with resistance mutations to COVID-19 therapeutics. Our studies reveal the contribution of low frequency variant patterns at heterologous sites across the protein to accurate prediction of the changes at each position of interest.

Oxidative and Extractive Desulfurization of Fuel Oils Catalyzed by N-Carboxymethyl Pyridinium Acetate and N-Carboxyethyl Pyridinium Acetate Acidic Ionic Liquids: Experimental and Computational DFT Study.

This study reports on the synthesis, characterization, and application of two acidic ionic liquids, namely, N-carboxymethylpyridinium acetate ([HO2CCH2Py][CH3CO2] or AIL1) and N-carboxyethylpyridinium acetate ([HO2C(CH2)2Py][CH3CO2] or AIL2), as both extractants and catalysts for the oxidative and extractive desulfurization (OEDS) of model fuel oils containing heteroaromatic sulfur compounds. The structural properties of the synthesized acidic ionic liquids (ILs) were confirmed by 1H NMR, 13C NMR, and FT-IR spectroscopic analysis. To optimize the performance of the acidic AILs in the desulfurization process, the effects of different parameters, such as H2O2 dosage, reaction time, and temperatures, were investigated. The experimental results showed that AIL1 has exceptionally high desulfurization-extraction rates, with values of 99.8%, 97.8%, and 95.4%, for DBT, BT, and 4,6-DMDBT, respectively, under the optimum conditions established. Under the same conditions, the desulfurization-extraction rates using AIL2 reached 91.6%, 87.3%, and 82.4%, respectively, for DBT, 4, 6-DMDBT, and BT. Both ionic liquids can be recycled up to 9 times without a significant decrease in their sulfur removal efficiencies. Furthermore, density functional theory (DFT) calculations were conducted to evaluate the electronic interaction energies (ΔIE) between the AILs with each of the sulfur-containing compounds and their putative oxidized products. The computational findings strongly supported the experimental outcomes.

Ferrer Adjustable Speaking Valve for Early Phonation in a Deconditioned Patient.

A patient with multiple comorbidities and an eight-year history of tracheostomy was being treated for tracheitis. At this point, she became incapable of using regular speaking valves, and multiple attempts to reintroduce the speaking valve failed. A Ferrer adjustable speaking valve (FASV) was designed with gradations of outflow closure, allowing air to go through the vocal cords for phonation. The FASV was offered to her through the compassionate use program at the FDA. At 20% initial closure, the patient was able to tolerate the valve and was advanced to 50% closure, at which point she could phonate partially. The use of the valve was terminated at the time of her transfer, 23 days after the initiation of use. This suggests the safety and possible efficacy of using an adjustable speaking valve earlier than regular valves, allowing patients to communicate earlier and further exercise their diaphragms.

Sphingosine is involved in PAPTP-induced death of pancreas cancer cells by interfering with mitochondrial functions.

Pancreas ductal adenocarcinoma belongs to the most common cancers, but also to the tumors with the poorest prognosis. Here, we pharmacologically targeted a mitochondrial potassium channel, namely mitochondrial Kv1.3, and investigated the role of sphingolipids and mutated Kirsten Rat Sarcoma Virus (KRAS) in Kv1.3-mediated cell death. We demonstrate that inhibition of Kv1.3 using the Kv1.3-inhibitor PAPTP results in an increase of sphingosine and superoxide in membranes and/or membranes associated with mitochondria, which is enhanced by KRAS mutation. The effect of PAPTP on sphingosine and mitochondrial superoxide formation as well as cell death is prevented by sh-RNA-mediated downregulation of Kv1.3. Induction of sphingosine in human pancreas cancer cells by PAPTP is mediated by activation of sphingosine-1-phosphate phosphatase and prevented by an inhibitor of sphingosine-1-phosphate phosphatase. A rapid depolarization of isolated mitochondria is triggered by binding of sphingosine to cardiolipin, which is neutralized by addition of exogenous cardiolipin. The significance of these findings is indicated by treatment of mutated KRAS-harboring metastasized pancreas cancer with PAPTP in combination with ABC294640, a blocker of sphingosine kinases. This treatment results in increased formation of sphingosine and death of pancreas cancer cells in vitro and, most importantly, prolongs in vivo survival of mice challenged with metastatic pancreas cancer. KEY MESSAGES: Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. The mitochondrial Kv1.3 ion channel blocker induced mitochondrial sphingosine. Sphingosine binds to cardiolipin thereby mediating mitochondrial depolarization. Sphingosine is formed by a PAPTP-mediated activation of S1P-Phosphatase. Inhibition of sphingosine-consumption amplifies PAPTP effects on PDAC in vivo.

Can Artificial Intelligence Mitigate Missed Diagnoses by Generating Differential Diagnoses for Neurosurgeons?

BACKGROUND/OBJECTIVE: Neurosurgery emphasizes the criticality of accurate differential diagnoses, with diagnostic delays posing significant health and economic challenges. As large language models (LLMs) emerge as transformative tools in healthcare, this study seeks to elucidate their role in assisting neurosurgeons with the differential diagnosis process, especially during preliminary consultations. METHODS: This study employed 3 chat-based LLMs, ChatGPT (versions 3.5 and 4.0), Perplexity AI, and Bard AI, to evaluate their diagnostic accuracy. Each LLM was prompted using clinical vignettes, and their responses were recorded to generate differential diagnoses for 20 common and uncommon neurosurgical disorders. Disease-specific prompts were crafted using Dynamed, a clinical reference tool. The accuracy of the LLMs was determined based on their ability to identify the target disease within their top differential diagnoses correctly. RESULTS: For the initial differential, ChatGPT 3.5 achieved an accuracy of 52.63%, while ChatGPT 4.0 performed slightly better at 53.68%. Perplexity AI and Bard AI demonstrated 40.00% and 29.47% accuracy, respectively. As the number of considered differentials increased from 2 to 5, ChatGPT 3.5 reached its peak accuracy of 77.89% for the top 5 differentials. Bard AI and Perplexity AI had varied performances, with Bard AI improving in the top 5 differentials at 62.11%. On a disease-specific note, the LLMs excelled in diagnosing conditions like epilepsy and cervical spine stenosis but faced challenges with more complex diseases such as Moyamoya disease and amyotrophic lateral sclerosis. CONCLUSIONS: LLMs showcase the potential to enhance diagnostic accuracy and decrease the incidence of missed diagnoses in neurosurgery.

Impact of environmental pollutants on pediatric brain tumor incidence in New Jersey.

OBJECTIVE: The relationship between environmental contaminants and brain tumor incidence in adults has been thoroughly explored but research into how these contaminants affect pediatric brain tumor (PBT) incidence has not been explored. Children, typically having more limited geographical movement and thus more consistent environmental contaminant exposure, might offer more reliable insights into which environmental contaminants affect the incidence of brain tumors. The present study is the first to focus on exploring whether a possible association exists between the incidence of PBTs and exposure to environmental pollutants in New Jersey (NJ). METHODS: Linear regressions were run between PBT incidence and the concentration of air quality pollutants such as Ozone (O3), Particulate Matter 2.5 (PM2.5), Particulate Matter 10 (PM10), and Carbon Monoxide (CO). Similarly, linear regressions were run between PBT incidence and Elevated Blood Lead Levels (BLL). RESULTS: The study observed a significant positive relationship between O3 and PBT incidence (ß = 0.34, p = 0.028). However, the relationship between PBT incidence, and environmental pollutants such as CO (ß = 0.0047, p = 0.098), PM2.5 (ß = -0.2624, p = 0.74), and PM10 (ß = -0.7353, p = 0.073) were found to be nonsignificant. For elevated BLL, nonsignificant relationships with PBT incidence were observed at 10-14 µg/dL (ß = -39.38, p = 0.30), 15-19 µg/dL (ß = -67.00, p = 0.21), and 20-44 µg/dL (ß = -201.98, p = 0.12). CONCLUSIONS: The results indicate a possible impact of O3 on the incidence of PBTs in NJ. In contrast to the significant links found in prior studies of adult brain tumors, the associations between PBT occurrence and particulate matter were not significant. These findings highlight the importance of further investigating how environmental factors, especially O3, relate to PBTs.

Modification of Living Diatom, Thalassiosira weissflogii, with a Calcium Precursor through a Calcium Uptake Mechanism: A Next Generation Biomaterial for Advanced Delivery Systems.

The diatom's frustule, characterized by its rugged and porous exterior, exhibits a remarkable biomimetic morphology attributable to its highly ordered pores, extensive surface area, and unique architecture. Despite these advantages, the toxicity and nonbiodegradable nature of silica-based organisms pose a significant challenge when attempting to utilize these organisms as nanotopographically functionalized microparticles in the realm of biomedicine. In this study, we addressed this limitation by modulating the chemical composition of diatom microparticles by modulating the active silica metabolic uptake mechanism while maintaining their intricate three-dimensional architecture through calcium incorporation into living diatoms. Here, the diatom Thalassiosira weissflogii was chemically modified to replace its silica composition with a biodegradable calcium template, while simultaneously preserving the unique three-dimensional (3D) frustule structure with hierarchical patterns of pores and nanoscale architectural features, which was evident by the deposition of calcium as calcium carbonate. Calcium hydroxide is incorporated into the exoskeleton through the active mechanism of calcium uptake via a carbon-concentrating mechanism, without altering the microstructure. Our findings suggest that calcium-modified diatoms hold potential as a nature-inspired delivery system for immunotherapy through antibody-specific binding.

Analysis of Concussions Reported in American Professional Football Injury Reports in the 2019 Through 2023 Regular Seasons.

OBJECTIVE: The National Football League (NFL) has seen increasing scrutiny regarding its management of concussions, especially following an on-field incident involving the Miami Dolphins' quarterback Tua Tagovailoa in the 2022 season. We hope to elucidate the recent trends in the diagnosis and management of concussions during the course of 5 NFL seasons from 2019 to 2023. METHODS: We queried the NFL injury reports from the 2019 through 2023 database recording players listed with concussions. The weeks missed were calculated using the NFL game logs. Players' concussions that did not occur in the games, those complicated by other injuries, and those affected by roster status were excluded. RESULTS: Searches of the NFL injury reports resulted in the identification of 664 of 692 concussions (96%) that occurred in regular season games across the 2019-2023 seasons. During the course of these 5 seasons, 31% of the players returned without missing a game, 39% of the players missed 1 game, and 30% of the players missed ≥2 games. No significant difference in the number of concussions per game or weeks missed was observed across the seasons observed. Players with concussions on teams that made the playoffs saw fewer weeks missed than those on non-playoff teams (0.86 vs. 1.37; P = 0.002). CONCLUSIONS: Since the start of the 2021 NFL season, an increasing incidence of concussions has been noted; however, there was no change observed in the number of weeks missed after the concussions. Trends in the rates of concussions across the seasons remain largely stable, despite increased scrutiny over concussions in the sport.

2023 Management Recommendations of Bangladesh Rheumatology Society on Pharmacological Treatment of Rheumatoid Arthritis With Synthetic and Biologic Disease-Modifying Drugs.

Rheumatoid arthritis (RA) is the most common inflammatory polyarthritis in Bangladesh. Bangladesh Rheumatology Society (BRS) proposes these management recommendations to treat the considerable burden of RA in the resource-constrained situation based on the best current evidence combined with societal challenges and opportunities. BRS formed a task force (TF) comprising four rheumatologists. The TF searched for all available literature, including updated American College of Rheumatology (ACR), European Alliance of Associations for Rheumatology (EULAR), and Asia-Pacific League of Associations for Rheumatology (APLAR) and several other guidelines, and systematic literature reviews until October 2023, and then a steering committee was formed, which included rheumatologists and internists. We followed the EULAR standard operating procedures to categorize levels of evidence and grading of recommendations. This recommendation has two parts -- general (diagnosis of RA, nomenclature of disease-modifying anti-rheumatic drugs [DMARDs], disease activity indices) and management portion. The TF agreed on four overarching principles and 12 recommendations. Overarching principles deal with early diagnosis and disease activity monitoring. Recommendations 1-5 discuss using glucocorticoids, NSAIDs, and conventional synthetic DMARDs (csDMARD). Recommendations 6-9 stretch the use of targeted synthetic DMARDs (tsDMARDs) and biological DMARDs (bDMARDs). The suggested DMARD therapy includes initiation with methotrexate (MTX) or another csDMARD (in case of contraindication to MTX) in the first phase and the addition of a tsDMARD in the second phase, switching to an alternative tsDMARDs or bDMARDs in the subsequent phases. The TF included the Padua prediction score for the thromboembolism risk estimation. Recommendations 10-12 cover infection screening, vaccination, and DMARD tapering. Bangladesh has a higher prevalence of RA. This recommendation will serve as a tool to treat this high burden of patients with RA scientifically and more effectively.

Lived experiences of COVID-19 patients admitted in isolation wards of healthcare centers in Peshawar, Pakistan: A phenomenological perspective.

The emergence of COVID-19 caused a significant global threat, affecting populations worldwide. Its impact extended beyond just physical health, as it inflicted severe damage and challenges to individuals' well-being, leading to a deterioration in mental health. The lived experiences of patients hold a paramount position to explore and understand their perception of care which can ultimately strengthen the health system's delivery domain. This study explores the lived experiences of patients in the isolation ward, their recovery, and the quality of care being provided in the hospital and its effects on their mental health. Study design: A phenomenological qualitative study using in-depth interviews. Methods: We conducted 11 in-depth interviews of COVID-19 patients admitted to the isolation ward of the public hospitals of Peshawar, Pakistan. Participants who stayed for a minimum of 10 days in an isolation ward were included in this study. Interviews were transcribed and analyzed using NVivo 12 software and generated five themes through inductive analysis. Results: Five themes emerged from the participants' lived experiences: Heading towards the hospital, Health Care Quality, Impact on Mental Health, Recovering from COVID-19 and Back on one's feet. These included all the positive and negative lived experiences. Socio-environmental factors along with their experiences of the disease itself and with the healthcare providers guided their reaction which was important conciliators in their experiences during the pandemic. Conclusion: Based on the findings, the environment of isolation had a major influence on the mental well-being of the individuals involved. Considering the important role of the ward environment in shaping patient experiences and outcomes prompts a reevaluation of healthcare practices and policies. By addressing these factors healthcare systems can strive for greater effectiveness, resilience, and compassion in managing the pandemic's impact on patient care.

Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment.

Despite significant advancements in the treatment of other cancers, pancreatic ductal adenocarcinoma (PDAC) remains one of the world's deadliest cancers. More than 90% of PDAC patients harbor a Kirsten rat sarcoma (KRAS) gene mutation. Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. We then provide a comparison of clinically relevant KRAS inhibitors to second-line PDAC treatment options. Finally, we discuss putative resistance mechanisms that may limit the clinical effectiveness of KRAS-targeted therapies and provide a brief overview of promising therapeutic approaches in development that are focused on mitigating these resistance mechanisms.

Impact of ABCB1 and ABCG2 Transporter in Outcome of Gallbladder Cancer.

Background: Gallbladder cancer (GBC) is a biologically aggressive malignancy requiring appropriate biomarkers to improve its outcome. Role of ABC transporters (ABCB1 and ABCG2) has been linked to cancer aggressiveness, tumorigenesis and multidrug resistance. Herein, we studied the prognostic implication of ABCB1 and ABCG2 in GBC. Methods: Fresh tissue (tumour & normal) samples collected from 54 patients who underwent R0 resection, were analysed for mRNA and protein expression of ABCB1 and ABCG2 by quantitative Real-Time PCR and western blotting, respectively, in this prospective study. The molecular findings were correlated with clinical-pathological parameters using χ2 and fisher exact test. The molecular changes in ABCB1 and ABCG2 were analysed for predicting overall survival (OS), disease-free survival (DFS) and response to chemotherapy using Kaplan-Meier log-rank test and Cox regression multivariate analysis. Results: The mean age of the cohort was 50 ± 13.2 with 26 (48.1%) in patients having early stage gallbladder cancer (GBC). Over-expression of ABCB1 and ABCG2 was noted in 32/54 (59%) and 40/54 (74%) cases, respectively. The protein expression of ABCB1(P-glycoprotein) and ABCG2 (BCRP) was higher in 27/54 (50%) and 37/54 (59%) cases, respectively. The mean OS and DFS was 20.7 ± 11.5 and 19.3 ± 12.2 months at median follow-up of 24 months. The TNM stage, lymph node metastasis, and presence of gallstone were significant factors for predicting OS and DFS on multivariate analysis. Both ABCB1 and ABCG2 did not show any significant correlation with OS and DFS with similar incidences of late death and recurrence among over-expression and down-expression. Sub-group comparison suggests that change in expression pattern of ABCB1 and ABCG2 may not affect response to chemotherapy in GBC. Conclusion: Altered expression of ABCB1 and ABCG2 may not be a useful prognostic marker for survival or response to chemotherapy in GBC. Presently, histo-pathological characteristics and associated gallstones are the important predictors for survival and recurrence in GBC.

Influence of donor-recipient sex on engraftment of normal and leukemia stem cells in xenotransplantation.

Immunodeficient mouse models are widely used for the assessment of human normal and leukemic stem cells. Despite the advancements over the years, reproducibility, as well as the differences in the engraftment of human cells in recipient mice remains to be fully resolved. Here, we used various immunodeficient mouse models to characterize the effect of donor-recipient sex on the engraftment of the human leukemic and healthy cells. Donor human cells and recipient immunodeficient mice demonstrate sex-specific engraftment levels with significant differences observed in the lineage output of normal CD34+ hematopoietic stem and progenitor cells upon xenotransplantation. Intriguingly, human female donor cells display heightened sensitivity to the recipient mice's gender, influencing their proliferation and resulting in significantly increased engraftment in female recipient mice. Our study underscores the intricate interplay taking place between donor and recipient characteristics, shedding light on important considerations for future studies, particularly in the context of pre-clinical research.

Rituximab in Childhood and Juvenile Pemphigus Vulgaris: A Systematic Review.

Pemphigus vulgaris (PV) is a chronic autoimmune blistering disorder characterized by the loss of intraepithelial adhesion, affecting the skin and mucous membranes. Both males and females are affected, although it predominantly affects females in their fifth and sixth decades of life. Approximately 1.4 to 3.7% of PV cases occur in the pediatric population (≤18 years of age), and may be classified into childhood/pediatric PV, which affects individuals under 12 years old, and juvenile/adolescent PV, affecting those between 12 and 18 years old. Due to its rare occurrence in children and adolescents, there is often a delay in diagnosis and treatment in this age group. A systematic literature search was conducted on MEDLINE/PubMed, Web of Science, EMBASE, SCOPUS, and Cochrane Library databases to evaluate the efficacy of rituximab (RTX) in childhood and juvenile PV patients. The Joanna Briggs Institute (JBI) Critical Appraisal Checklist was employed to assess the risk of bias in case reports and series, while the Cochrane ROBINS-I tool was utilized for evaluating observational studies or non-randomized intervention studies. A total of 18 studies encompassing 46 juvenile or childhood PV patients in the pediatric and adolescent age groups were included for qualitative synthesis. The studies included nine case reports, two case series, five retrospective studies, one prospective study, and one open-label pilot study. Almost all cases of childhood and juvenile PV achieved either complete or partial remission after undergoing RTX treatment during the final follow-up periods. Furthermore, most cases reported no relapse, and only minor adverse events were noted in the RTX treatment group. Despite its potential benefits, the utilization of RTX in pediatric patients raises concerns due to the scarcity of evidence and the absence of controlled studies specific to this age group. Further exploration is necessary to establish a standardized treatment regimen for RTX in pediatric PV, which involves identifying the optimal dosage, frequency, treatment cycle duration, and maintenance therapy duration.

Impact of Nanoencapsulated Rosemary Essential Oil as a Novel Feed Additive on Growth Performance, Nutrient Utilization, Carcass Traits, Meat Quality and Gene Expression of Broiler Chicken.

This study evaluated the effect of free and nanoencapsulated rosemary essential oil (REO) as an antibiotic alternative in broiler diets on growth performance, nutrient digestibility, carcass traits, meat quality and gene expression. Four hundred twenty day-old commercial broiler chicks (VENCOBB) were randomly allocated to seven dietary treatments, each having four replicates of fifteen chicks. The dietary treatments comprised control (CON) fed a basal diet only, AB (basal diet + 10 mg enramycin/kg), CS (basal diet + 150 mg chitosan nanoparticles/kg), REOF100 and REOF200 (basal diet + 100 mg and 200 mg free REO/kg, respectively), and REON100 and REON200 (basal diet + 100 mg and 200 mg nanoencapsulated REO/kg, respectively). Overall (7-42 d), REON200 showed the highest (p < 0.001) body weight gain (1899 g/bird) and CON had the lowest gain (1742 g/bird), while the CS, REOF100 and REOF200 groups had a similar gain, but lower than that of the AB and REON100 groups. Feed intake was not affected by dietary treatments. Overall, the feed efficiency increased (p = 0.001) by 8.47% in the REON200 group and 6.21% in the AB and REON100 groups compared with the CON. Supplementation of REO improved (p < 0.05) dry matter and crude protein digestibility, with the highest values in REON100 and REON200. Ether extract, crude fiber, calcium and phosphorus digestibility values showed no difference among the groups. The dressing, breast, thigh % increased (p < 0.05) and abdominal fat % decreased (p < 0.001) more in the REON200 group than with other treatments and CON. In breast meat quality, water holding capacity and extract reserve volume increased (p < 0.05) while drip loss and cholesterol content decreased (p < 0.05) in REON100 and REON200. No change was observed in the breast meat color among dietary treatments and CON. The REON100 and REON200 groups had reduced (p < 0.05) meat lipid peroxidation as depicted by the decreased levels of TBARS, free fatty acids and peroxide value compared to other treatments and CON. The expression of the Mucin 2, PepT1 and IL-10 genes was upregulated (p < 0.001) and TNF-α downregulated (p < 0.001) by dietary addition of REO particularly in the nanoencapsulated form compared with the CON. In conclusion, nanoencapsulated REO, especially at 200 mg/kg diet, showed promising results as an antibiotic alternative in improving the performance, nutrient digestibility, carcass traits, meat quality and upregulation of growth and anti-inflammatory genes.

Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .