Is Gene Therapy the Game-Changer for Autosomal Recessive Deafness 9?Dear editor! One of the most challenging forms of hearing impairment is autosomal recessive profound prelingual deafness (DFNB9), which makes up over 80% of all congenitally occurring hearing loss cases (1). Otoferlin protein, encoded by the OTOF gene, is located at the inner hair cells, which mediates signal transduction for proper sound propagation. The OTOF gene mutations impair the physiological otoferlin function and account for almost 1–8% of all the DFNB9 cases (2). Currently, there are no medical therapies available to combat this disorder, and in this critical context, adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) may offer promising results.AAV1-hOTOF is an experimental gene therapy intended to treat DFNB9. It transports the functional copy of the OTOF gene to the hair cells via an adenovirus vector. This enables the hair cells to produce newly functioning otoferlin protein, thereby regaining proper signal transduction and sound propagation.A groundbreaking clinical trial, recently published in The Lancet, evaluates the efficacy and safety of this AAV1-hOTOF gene therapy for restoring hearing in patients with DFNB9. This first-of-its-kind trial demonstrated that AAV1-hOTOF showed excellent results and helped in reclaiming significant functional hearing in all the patients enrolled in the trial (3). Furthermore, along with enhanced hearing, gene therapy also assisted in improving speech perception in the patients. In addition to its increased efficacy, gene therapy had a favorable safety profile, with no reports of serious adverse events or drug-limiting ototoxicity (3). These findings of a successful response to gene therapy are in line with the case report by Qi et al., which also showed that AAV1-hOTOF helped restore substantial hearing in two children (4).In South Asia, 1.62 out of every 1000 newborns suffer from congenital hearing loss, making it one of the most prevalent chronic pediatric illnesses (5). Due to the unavailability of any medical intervention, DFNB9 goes untreated, substantially affecting the quality of life of patients. However, with the introduction of gene therapies like AAV1-hOTOF, there is newfound hope for these patients. This pioneering therapy may completely eradicate DFNB9 and significantly enhance auditory function, providing a viable substitute for cochlear implants and conventional hearing aids. More clinical trials assessing larger patient populations are warranted to provide greater evidence for the effectiveness and tolerability of this therapy.Keywords: autosomal recessive deafness 9; AAV1-hOTOF; congenital hearing loss; AsiaDisclaimer: None to declareConflict of Interest: None to declareFunding Disclosure: None to declareREFERENCESDuman D, Tekin M. Autosomal recessive nonsyndromic deafness genes: a review. Front Biosci (Landmark Ed). 2012 Jun 1;17(6):2213-36. doi: 10.2741/4046. PMID: 22652773; PMCID: PMC3683827.Azaiez H, Thorpe RK, Smith RJH. OTOF -Related Deafness. 2008 Feb 29 [updated 2021 Jan 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301429.Lv J, Wang H, Cheng X, Chen Y, Wang D, Zhang L, Cao Q, Tang H, Hu S, Gao K, Xun M, Wang J, Wang Z, Zhu B, Cui C, Gao Z, Guo L, Yu S, Jiang L, Yin Y, Zhang J, Chen B, Wang W, Chai R, Chen ZY, Li H, Shu Y. AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial. Lancet. 2024 May 25;403(10441):2317-2325. doi: 10.1016/S0140-6736(23)02874-X. Epub 2024 Jan 24. Erratum in: Lancet. 2024 May 25;403(10441):2292. PMID: 38280389.Qi J, Tan F, Zhang L, Lu L, Zhang S, Zhai Y, Lu Y, Qian X, Dong W, Zhou Y, Zhang Z, Yang X, Jiang L, Yu C, Liu J, Chen T, Wu L, Tan C, Sun S, Song H, Shu Y, Xu L, Gao X, Li H, Chai R. AAV-Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness. Adv Sci (Weinh). 2024 Mar;11(11):e2306788. doi: 10.1002/advs.202306788. Epub 2024 Jan 8. PMID: 38189623; PMCID: PMC10953563.Korver AM, Smith RJ, Van Camp G, Schleiss MR, Bitner-Glindzicz MA, Lustig LR, Usami SI, Boudewyns AN. Congenital hearing loss. Nat Rev Dis Primers. 2017 Jan 12;3:16094. doi: 10.1038/nrdp.2016.94. PMID: 28079113; PMCID: PMC5675031.

As of today, TCP remains the de-facto transport protocol in the Internet. However, TCP may incur high delays, especially when retransmitting lost packets as they have to be retransmitted only by the source and after a timeout that is roughly equal to a round trip time. To reduce such delay, recent work [1–3] proposed to deploy a special network function, called Transport Assistant (TA), that is able to detect and retransmit lost TCP packets from inside the network rather than the source, and thereby, reduces retransmission delays. Unfortunately, there is no study on the impact of the placement of the TA on its performance benefits in terms of packet delivery delay. In this paper, we focus on the TA placement problem. We discuss the trade-offs and parameters to be considered to select the best placement for the TA. We first mathematically model the TCP packet delivery delay, i.e., the time needed to deliver TCP packets, when the TA is deployed. We also formulate, as an Integer Linear Program (ILP), the problem of placing multiple TAs in order to reduce TCP packet delivery delays while minimizing their deployment costs. We consider use-cases, one where a TA could handle a single flow and another where a TA could handle multiple flows. We then propose two heuristics to solve the problem with minimal execution time. Through experiments, we demonstrated that the deployment of TAs could reduce TCP packet delivery delays by up to 30% and could be leveraged to guide routing and load balancing. Moreover, we show that using the proposed heuristics for placing TAs could lead to performance that is close to optimal solutions obtained with the ILP but with lower execution time.

Purpose: Point-of-care cardiovascular left ventricle ejection fraction (LVEF) quantification is established, but automatic tablet-based stroke volume (SV) quantification with handheld ultrasound devices is unexplored. We evaluated a tablet-based monoplane LVEF and LV volume quantification tool (AutoEF) against a computer-based tool (Tomtec) for LVEF and SV quantification. Methods: Patients underwent handheld ultrasound scans, and LVEF and SV were quantified using AutoEF and computer-based software that utilized either apical four-chamber views (AS-mono) or both apical four-chamber and apical two-chamber views (AS-bi). Correlation and Bland-Altman analysis were used to compare AutoEF with AS-mono and AS-bi. Results: Out of 43 participants, 8 were excluded. AutoEF showed a correlation of 0.83 [0.69:0.91] with AS-mono for LVEF and 0.68 [0.44:0.82] for SV. The correlation with AS-bi was 0.79 [0.62:0.89] for LVEF and 0.66 [0.42:0.81] for SV. The bias between AutoEF and AS-mono was 4.88% [3.15:6.61] for LVEF and 17.46 ml [12.99:21.92] for SV. The limits of agreement (LOA) were [-5.50:15.26]% for LVEF and [-8.02:42.94] ml for SV. The bias between AutoEF and AS-bi was 6.63% [5.31:7.94] for LVEF and 20.62 ml [16.18:25.05] for SV, with LOA of [-1.20:14.47]% for LVEF and [-4.71:45.94] ml for SV. Conclusion: LVEF quantification with AutoEF software was accurate and reliable, but SV quantification showed limitations, indicating non-interchangeability with neither AS-mono nor AS-bi. Further refinement of AutoEF is needed for reliable SV quantification at the point of care.

Anti-CD20 antibody as Initial therapy for adult-onset minimal change disease with nephrotic syndrome：a case series reportShuang-xi Li MD1, Jing Xu MD1*1Department of nephrology, Changhai Hospital, the Naval Medical University, Shanghai, China;*Correspondence author :Jing Xu, Department of Nephrology, Changhai Hospital, 168 Changhai Rd，Shanghai, China; 200433. E-mail: [email protected] : MCD：minimal change disease；NS: nephrotic syndrome; CyC: cyclophosphamide; Cys: cyclosporine; TAC: tacrolimus; RTX: rituximab; OTZ: obinutuzumab; IGT: impaired glucose tolerance; ALB: albumin; TG: tolal cholesterol; TC: triglycerides; WBC: white blood cell；Scr: serum creatinine; PR: partial remission; CR:complete remission; AE:adverse eventsKeywords : minimal change disease; CD20; nephrotic syndrome; rituximab; obinutuzumab

Leaping to Diagnosis: The Frog Sign as a Key Clue in AVNRTAuthors: Andreas Müssigbrodt1, Maria Herrera Bethencourt1, Romain Vergier1, Marinela Blidar1, Alberto Alfie2

As a young scientist in Brazil, my journey began in a public school, where I faced the typical challenges of the Brazilian public education system, such as a lack of resources and support. With immense dedication and resilience, I successfully gained admission to the University of São Paulo (USP), a prestigious institution and one of the top universities in Latin America. Currently, my research focuses on the relationship between the nervous and immune systems in psychosis, a topic I am deeply passionate about. In this piece, I will delve deeper into the challenges and achievements of being a young scientist in Brazil. I also discuss the systemic issues within the Brazilian education and research system, and the changes needed to foster a more supportive and resourceful environment for emerging scientists.

The increasing amounts of end-of-life lithium-ion batteries (EOL LIBs) require novel and safe solutions allowing for the minimisation of the health and environmental hazards. Arguably, the best approach to the problem of EOL LIBs is recycling and recovery of the metals contained within the cells. This allows the diversion of the EOL battery cells from the environment but also the recovery of precious metals that can be reused in the manufacturing of new products, allowing to reduce the requirements of virgin materials from the mining industry. The most significant hindrance to the recycling process of EOL LIBs is their unstable chemical nature and significant safety hazards related to opening the air-tight casings. To minimise these issues, the end-of-life cells must be stabilised in one of the few available ways. This review aims at a comprehensive presentation of the studied chemical methods of EOL LIB cells discharge and stabilisation. The advantages and disadvantages of the method and its variations are discussed based on the literature published to date. The literature review found that a significant number of authors make use of chemical stabilisation techniques without proper comprehension of the associated risks. Many authors focus solely on the cheapest and fastest way to stop a cell from producing an electrical charge without extra thought given to the downstream recycling processes of safety hazards related to the proposed stabilisation method. Only a few studies highlighted the risks and problems associated with chemical stabilisation techniques.

The anti-IgE autoantibodies are biomarkers of early omalizumab response in patients with chronic spontaneous urticariaYusuke Niwa1,2), Koremasa Hayama1,2)*, Shota Toyoshima3), Keisuke Shimizu1,2), Maho Tagui1,2), Mana Ito1,2), Tomomi Sakamoto2), Tadashi Terui1,2), Hideki Fujita1,2), Yoshimichi Okayama2,4,5,6,7)*1) Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan2) Center for Allergy, Nihon University School of Medicine, Tokyo, Japan3) Department of Biochemistry & Molecular Biology, Nippon Medical School, Tokyo, Japan4) Department of Allergy, Internal Medicine, Misato Kenwa Hospital, Saitama, Japan5) Department of Medicine, Division of Respiratory Medicine, Nihon University School of Medicine, Tokyo, Japan6) Department of Internal Medicine, Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Tokyo, Japan7) Advanced Medical Science Research Center, Gunma Paz University, Graduate School of Health Sciences, Gunma, Japan*Corresponding authors:Koremasa Hayama, M.D, Ph.D.Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, JapanTel.: +81-3-3972-8111 (Ext. 8144): Fax: +81-3-5995-9841E-mail: [email protected] Okayama, M.D, Ph.D.Department of Allergy, Internal Medicine, Misato Kenwa Hospital, 4-491-1 Takano, Misato-shi, Saitama 341-8555, JapanTel.: +81-48-955-7171: Fax: +81-48-955-5120E-mail: [email protected]

Early in our scientific careers, we learn about the many advantages of working abroad to upskill and expand our research horizons. Born and raised in Montevideo, Uruguay, I always had a clear passion for science and foreign cultures, nurtured by my family. I had been preparing for a career in science and living abroad all my life, so when the time came, I felt ready. Looking back a decade, I realize how little I knew about the challenges ahead and how much I learned ‘on the go’. The significant personal and professional transition of continuing your career abroad is exciting but also challenging, especially for those coming from countries with limited budgets and more flexible research environments. The exposure to state-of-the-art technologies, new ways of thinking, and working within unfamiliar regulatory frameworks without your usual support network, at times can feel overwhelming. Like navigating uncharted waters, succeeding abroad requires not only planning but resilience and adaptability. Embracing uncertainty and learning to slow down when needed can be invaluable. By sharing my experiences, I hope to offer useful insights for those preparing to emigrate or establish themselves elsewhere.

Regulation of the thermal performance of electrical components is a key aspect. Phase-change materials can be incorporated into a fin heat sink (FHS) to enhance thermal management by maintaining a stable temperature. Three types (square, triangular, and circular) of aluminum FHSs of different configurations are investigated numerically in this paper. Studies are conducted with and without PCMs. Paraffin wax, stearic acid, and polyethylene glycol are used as PCMs to find the best combinations for thermal cooling and to determine the impact of using PCMs in the heat sinks. The results obtained show that, by adding PCMs, temperature rise can be delayed, and polyethylene glycol performs better than other PCMs. Moreover, the square fin heat sink increases the thermal regulation period. As the height of the fins increases from 10 mm to 16 mm, thermal efficiency increases. Hence, the findings of this paper would be beneficial for effective thermal management in the electronic industry.

Ramaria has been a remarkable taxon throughout the history of macrofungi. However, there is a lack of information on these macrofungi. This study determined the order of nucleotides in the mitochondrial genomes (mitogenomes) of three Ramaria species, followed by a detailed investigation of the obtained genetic information. Circular mitogenomes of Ramaria brunnecliacina, R. ichnusensis, and R. flavescens had sizes of 78,960, 61,851, and 81,282 bp, respectively. The genomes exhibited variations in genetic content, gene length, tRNA, and codon usage. Ramaria mitogenomes demonstrated variable evolutionary rates across several protein-coding genes. Results revealed significant gene rearrangements in Ramaria mitogenomes, including gene displacement and tRNA duplication. Bayesian inference and maximum likelihood methods, yielded well-supported phylogenetic trees for Basidiomycota. Phylogenetic analysis, using a comprehensive collection of conserved mitochondrial proteins, yielded a strong and reliable phylogenetic tree for Basidiomycetes, which clarified the evolutionary connections between Ramaria and other Basidiomycetes members. R. brunnecliacina and R. flavescens were identified as closely related species. Species of Ramaria, a paraphyletic group, exhibited a close genetic relationship with other species belonging to the subclass Phallomycetidae. This study presents a basic structure for understanding the evolutionary dynamics, genetic makeup, and taxonomy categorization of this significant fungal community.

Iris longnanensis Z.F. Bai, Y.E. Xiao, F.Y. Yu (Iridaceae: subgenus Iris section Pseudoregelia), a novel herbaceous species native to the arid and thermal valleys of Longnan city, Gansu province, China, is herein described and illustrated. Morphologically akin to I. leptophylla Lingelsheim, I. longnanensis is distinguished by its dense, persistent foliage and strikingly short new leaves (6.6–15.1 cm) during the blooming season, along with its distinctive purplish-brown flowering stem. Phylogenetic analyses based on chloroplast DNA sequences corroborate the classification of I. longnanensis within section Pseudoregelia, highlighting the significance of this new species discovery for understanding the evolution and diversity within the genus.

The increase in the use of trails for outdoor recreation observed in recent decades has led to greater pressure on existing trails and the creation of informal new trails, resulting in damage and degradation of these infrastructures. This degradation is concerning because many of these trails are located in protected natural areas, which aim to conserve natural resources and associated biodiversity. Concurrently, ecosystems worldwide have also been experiencing increased degradation, prompting the United Nations to declare the current decade as the Decade for Ecosystem Restoration. In this context, through a systematic review of the scientific literature, we aimed to better understand what science has discovered to enhance the management of degraded trails in protected natural areas worldwide. We observed that the number of research studies has been growing, particularly in the last decade, and is concentrated in countries with developed economies and by researchers from these countries. The terms used to describe a trail are quite diverse in the literature. Furthermore, some terms used in trail management, such as building or construction, maintenance, and repair, are uniformly utilized by authors. However, terms to address the reversal of trail degradation, such as restoration, recovery, and rehabilitation, are used quite variably among authors. Thus, future research could help clarify the use of these terms. We also noted that many studies have been dedicated to investigating the state of degradation of the trails in protected areas. However, only a minority of articles have addressed strategies to reverse the scenario of trail degradation, especially through experiments to identify the most effective strategies for different situations. This observation is concerning since the degradation of ecosystems and trails can become extremely costly or even irreversible. Therefore, further scientific studies are crucial to improve trail management, especially to reverse the scenario of trail degradation in protected natural areas.

Quercus chungii is an endemic tree species in China, rare and endangered in subtropical areas of China. Understanding its population structure and temporal dynamics is crucial for conserving and restoring Q. chungii population and its associated ecosystems. However, large knowledge gaps remain about its population structure and temporal change, and its key demographic rates across size classes. In this study, we investigated the population structures of Q. chungii in 2013 and 2023 in a nature reserve specifically established to better conserve Q. chungii and its associated ecosystems. We found that Q. chungii increased in its overall abundance, frequency and tree size in the past decade, suggesting active regeneration and fast growth rate of this species and the effectiveness of past conservation efforts. The age structure in 2023 shows a pyramid shape, with a sharp decline in the numbers of individuals from germinated seeds to seedlings and from seedlings to saplings. These lead to the low numbers of seedlings and saplings and high age-specific death probabilities at the early developmental stages. These results indicate potential risks of future population decline. These risks may have already manifested over the past decade, as a high mortality rate during the seedling-to-sapling transition could be one of the primary reasons contributing to the decreased proportion of saplings in 2023 compared to 2013. We propose that future studies may benefit from in-depth studies on the regeneration processes of Q. chungii by considering seed predation and germination under changing climate. This study improves the prediction of population development of Q. chungii and provide theoretical guidance for the conservation of Q. chungii.

Early approval mechanisms, such as conditional approval in the EU, have been used extensively to provide timely access to therapeutic innovations to cancer patients with unmet medical needs. While based on promising early evidence, such approvals are challenging from many perspectives due to the lack of comprehensive data. The limitation typically relates to data that demonstrates clinical benefit via particular endpoints and is only acceptable when the early evidence is particularly convincing to assume that the benefits of early access are greater than the potential harms. This paper describes the requirements for conditional approval and reviews common pitfalls in oncology, such as misunderstandings about the strength of evidence from exploratory trials and secondary analyses, lack of planning, and opportunities to improve communication. Thereafter, we present a framework (“EDGE”) on how to improve the submission and evaluation of drug applications for conditional approval in the EU.

In this work, we study and solve the normalized Ricci flow equation for circle bundles over surfaces. Moreover, we study the asymptotic behavior of the solutions and their connections to some model geometries.

Teleost fishes are a highly diverse and ecologically essential group of aquatic vertebrates and include coho salmon, Onchorhynchus kisutch. Coho are semelparous and all ovarian follicles develop synchronously. Owing to their ubiquitous distribution, teleost provide critical sources of food worldwide through subsistence, commercial fisheries, and aquaculture. Enhancement of commercial hatchery practices requires a detailed knowledge of teleost reproductive physiology. Despite decades of research on teleost reproductive processes, an in-depth proteome of teleost ovarian development has yet to be generated. We describe a coho salmon ovarian proteome of over 5700 proteins, generated with data independent acquisition, revealing the suite of detectable proteins that change through the transition from primary to secondary ovarian follicle development. This transition is critical for puberty onset, egg quality, and further embryonic development. Primary ovarian follicle development was marked by differential abundances of proteins involved in carbohydrate metabolism, protein turnover, and the complement pathway, suggesting elevated metabolism as the oocytes enter maturation. The greatest proteomic shift occurred during the transition from primary to secondary follicle growth, with increased abundance of proteins underlying cortical alveoli formation, extracellular matrix reorganization, iron binding, and cell-cell signaling. This work provides a foundation for identifying biomarkers of salmon oocyte stage and quality.

Urbanisation has reduced the abundance and diversity of many taxonomic groups, and the effects may be more pronounced on islands, which have a smaller regional species pool to compensate. Green spaces within urban environments may help to safeguard wildlife assemblages, and the associated habitat heterogeneity can even increase species diversity. Here, total abundance and species diversity of butterflies, birds, and vegetation at nine rural and nine urban locations were quantified on Lipsi Island, Greece. Sites were assessed using Pollard walks for butterflies, point-count surveys for birds, and quadrats for vegetation. There was no significant difference in the abundance or species diversity of butterflies or vegetation among rural and urban locations, which could pertain to the low building density within urbanised areas and the minimal extent of urbanisation on the island. However, urban areas hosted a significantly greater abundance and richness of birds compared to rural sites. The community composition of butterflies, birds, and vegetation also differed significantly between urban and rural locations, highlighting the impact of urbanisation on species across a broad range of trophic groups. This study contributes to ecological knowledge on the impacts of urbanisation across multiple trophic levels in island ecosystems, with comparisons across a gradient of island size and urbanisation intensity needed in future research.