Generating ESC-Derived RGCs for Cell Replacement Therapy.

In several ocular diseases, degeneration of retinal neurons can lead to permanent blindness. Transplantation of stem cell (SC)-derived RGCs has been proposed as a potential therapy for RGC loss. Although there are reports of successful cases of SC-derived RGC transplantation, achieving long-distance regeneration and functional connectivity remains a challenge. To address these hurdles, retinal organoids are being used to study the regulatory mechanism of stem cell transplantation. Here we present a modified protocol for differentiating human embryonic stem cells (ESCs) into retinal organoids and transplanting organoid-derived RGCs into the murine eyes.

HLA Awareness in tissue decellularization: A paradigm shift for enhanced biocompatibility, studied on the model of the human fascia lata graft.

Last twenties, tissue engineering has rapidly advanced to address the shortage of organ donors. Decellularization techniques have been developed to mitigate immune rejection and alloresponse in transplantation. However, a clear definition of effective decellularization remains elusive. This study compares various decellularization protocols using the human fascia lata model. Morphological, structural and cytotoxicity/viability analyses indicated that all the five tested protocols were equivalent and met Crapo's criteria for successful decellularization. Interestingly, only the in vivo immunization test on rats revealed differences. Only one protocol exhibited Human Leucocyte Antigen (HLA) content below 1% residual threshold, the only criterion preventing rat immunization with an absence of rat anti-human IgG switch after one month (N=4 donors for each of the 7 groups, added by negative and positive controls, n=28). By respecting a refined set of criteria, i.e. lack of visible nuclear material, <50ng DNA/mg dry weight of extracellular matrix, and <1% residual HLA content, the potential for adverse host reactions can be drastically reduced. In conclusion, this study emphasizes the importance of considering not only nuclear components but also major histocompatibility complex in decellularization protocols and proposes new guidelines to promote safer clinical development and use of bioengineered scaffolds.

Profiles, exposure assessment and expanded screening of PAHs and their derivatives in one petroleum refinery facility of China.

This study investigated environmental distribution and human exposure of polycyclic aromatic hydrocarbons (PAHs) and their derivatives in one Chinese petroleum refinery facility. It was found that, following with high concentrations of 16 EPA PAHs (∑Parent-PAHs) in smelting subarea of studied petroleum refinery facility, total derivatives of PAHs [named as XPAHs, including nitro PAHs (NPAHs), chlorinated PAHs (Cl-PAHs), and brominated PAHs (Br-PAHs)] in gas (mean= 1.57 × 104 ng/m3), total suspended particulate (TSP) (mean= 4.33 × 103 ng/m3) and soil (mean= 4.37 × 103 ng/g) in this subarea had 1.76-6.19 times higher levels than those from other subareas of this facility, surrounding residential areas and reference areas, indicating that petroleum refining processes would lead apparent derivation of PAHs. Especially, compared with those in residential and reference areas, gas samples in the petrochemical areas had higher ∑NPAH/∑PAHs (mean=2.18), but lower ∑Cl-PAH/∑PAHs (mean=1.43 × 10-1) and ∑Br-PAH/∑PAHs ratios (mean=7.49 × 10-2), indicating the richer nitrification of PAHs than chlorination during petrochemical process. The occupational exposure to PAHs and XPAHs in this petroleum refinery facility were 24-343 times higher than non-occupational exposure, and the ILCR (1.04 × 10-4) for petrochemical workers was considered to be potential high risk. Furthermore, one expanded high-resolution screening through GC Orbitrap/MS was performed for soils from petrochemical area, and another 35 PAHs were found, including alkyl-PAHs, phenyl-PAHs and other species, indicating that profiles and risks of PAHs analogs in petrochemical areas deserve further expanded investigation.

Assessment of internal exposure risk from metals pollution of occupational and non-occupational populations around a non-ferrous metal smelting plant.

Non-ferrous metal smelting poses significant risks to public health. Specifically, the copper smelting process releases arsenic, a semi-volatile metalloid, which poses an emerging exposure risk to both workers and nearby residents. To comprehensively understand the internal exposure risks of metal(loid)s from copper smelting, we explored eighteen metal(loid)s and arsenic metabolites in the urine of both occupational and non-occupational populations using inductively coupled plasma mass spectrometry with high-performance liquid chromatography and compared their health risks. Results showed that zinc and copper (485.38 and 14.00 µg/L), and arsenic, lead, cadmium, vanadium, tin and antimony (46.80, 6.82, 2.17, 0.40, 0.44 and 0.23 µg/L, respectively) in workers (n=179) were significantly higher compared to controls (n=168), while Zinc, tin and antimony (412.10, 0.51 and 0.15 µg/L, respectively) of residents were significantly higher than controls. Additionally, workers had a higher monomethyl arsenic percentage (MMA%), showing lower arsenic methylation capacity. Source appointment analysis identified arsenic, lead, cadmium, antimony, tin and thallium as co-exposure metal(loid)s from copper smelting, positively relating to the age of workers. The hazard index (HI) of workers exceeded 1.0, while residents and control were approximately at 1.0. Besides, all three populations had accumulated cancer risks exceeding 1.0 × 10-4, and arsenite (AsIII) was the main contributor to the variation of workers and residents. Furthermore, residents living closer to the smelting plant had higher health risks. This study reveals arsenic exposure metabolites and multiple metals as emerging contaminants for copper smelting exposure populations, providing valuable insights for pollution control in non-ferrous metal smelting.

Metabolic landscape of human alveolar type II epithelial cells undergoing epithelial-mesenchymal transition induced directly by silica exposure.

Epithelial-mesenchymal transition (EMT) plays an irreplaceable role in the development of silicosis. However, molecular mechanisms of EMT induced by silica exposure still remain to be addressed. Herein, metabolic profiles of human alveolar type II epithelial cells (A549 cells) exposed directly to silica were characterized using non-targeted metabolomic approaches. A total of 84 differential metabolites (DMs) were identified in silica-treated A549 cells undergoing EMT, which were mainly enriched in metabolisms of amino acids (e.g., glutamate, alanine, aspartate), purine metabolism, glycolysis, etc. The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica. Remarkably, glutamine catabolism was significantly promoted in the silica-treated A549 cells, and the levels of related metabolites (e.g., succinate) and enzymes (e.g., α-ketoglutarate (α-KG) dehydrogenase) were substantially up-regulated, with a preference to α-KG pathway. Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail (zinc finger transcription factor). Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.

Estudo longitudinal de famílias / Longitudinal study of families / Estudio longitudinal de familias

Introdução: O desenvolvimento da família é influenciado por diversos fatores de sua organização interna e de ordem ambiental, social, cultural, econômica e política. Em contexto de pobreza os riscos são maiores. Fatores de proteção, como boa organização familiar e rede social de apoio podem diminuir as consequências negativas da pobreza. São escassas as pesquisas longitudinais sobre vulnerabilidade e resiliência nas famílias. Objetivo: Este artigo descreve o desenvolvimento de três famílias ao longo de 15 anos, estudadas por meio de entrevistas em casa, parte de uma coorte populacional de um bairro de Porto Alegre (RS). Buscaram-se associações entre a qualidade das relações nessas famílias e sua saúde física e mental, especialmente a do filho, foco da pesquisa. Métodos: Selecionaram-se no arquivo da pesquisa as três primeiras famílias (do total de 148) das quais se tinham os resultados completos das cinco visitas realizadas aos quatro meses e aos dois, quatro, nove e 15 anos de um filho. Realizou-se análise qualitativa dos registros em busca de categorias para compreender a vida e as relações interpessoais nas famílias. O estudo foi realizado em conjunto por duas pesquisadoras, médicas especialistas em desenvolvimento humano. As categorias identificadas na análise e estudadas nas cinco etapas foram: configuração familiar, situação socioeconômica, situações traumáticas, saúde física, saúde relacional e mental, evolução cognitiva e escolar do filho. Resultados: As três famílias, todas de classe C, com filhos sem problemas de saúde física, tiveram evolução suficientemente boa, apesar de todas enfrentarem múltiplos problemas, inclusive separações e mortes precoces. A relação com o sistema de saúde e escola era boa e similar para as três. A jovem com menos problemas de saúde mental foi aquela que sofreu perdas mais importantes: morte dos pais. Tinha uma estrutura familiar multigeracional sólida desde a primeira infância, com relações interpessoais predominantemente colaborativas e amorosas. Conclusões: O artigo busca avançar na compreensão da resiliência nas famílias em situações de vulnerabilidade. Concluímos que essas três famílias, uma delas mais que as outras, foram suficientemente saudáveis na tarefa de educar seus filhos sem desenvolverem problemas mentais graves. Propomos que o bom desenvolvimento se associa com a adequação e amorosidade dos cuidados com a etapa do ciclo vital, mesmo enfrentando situações problemáticas. Essas qualidades precisam estar associadas à estabilidade socioeconômica básica e a bons serviços de saúde e escola.

Introduction: Family development is influenced by it's internal organization and environmental factors, socioeconomic, cultural and political. In poor contexts there are more risks to development. Protection factors like good family organization and social network may decrease the risks. Longitudinal research about vulnerability and resilience in families is scarse. Objective: This article describes the development of three families over 15 years through interviews at home. The families were part of a populational cohort of a neighborhood in Porto Alegre (RS). We looked for links between the quality of relationships and the physical and mental health of these families, especially of the child focus of the research. Methods: We selected in the research archives the first three families (of a total of 148) for which we had full results of the five interviews at four months and two, four, nine and fifteen years of a child. We did a qualitative analysis of the records looking for parameters to understand the life and interpersonal relationships of these families. This study was done by two researchers, both experts in Human Development. The categories identified in the analysis of the five phases were: family structure, socioeconomic situation, traumatic experiences, physical, mental and relational health and cognitive evolution of the child. Results: All three families belonged to economical class C. The children were in good physical health and had sufficiently good general development, having faced multiple problems, including parental separation and early parental death. The relationship with the health and school systems was good in all of them. The youth with less mental health problems was the one who suffered the heaviest loss: early death of both parents. Her family had strong multigenerational ties since her early days, with predominant collaborative and loving relationships. Conclusions: This article aims to contribute to the comprehension of resilience in families in the context of vulnerability. We can say that these three families were healthy enough in the task of bringing up children without any serious mental health problem. We suggest that healthy development is associated with loving interfamily relationships adequate to each phase of development, notwithstanding dramatic events. This needs to be supported by basic economic stability and adequate school and health systems.

Introducción: El desarrollo de la familia es influenciado por su organización interna y factores ambientales, sociales, culturales, económicos y políticos. En contextos pobres los riesgos son mayores. Factores de protección como buena organización familiar y red social de apoyo pueden disminuir las consecuencias negativas de la pobreza. Son pocas las investigaciones longitudinales de vulnerabilidad y resiliencia de las familias. Objetivo: Este artículo describe el estudio del desarrollo de tres familias a lo largo de 15 años, a través de entrevistas en domicilio, parte de una cohorte poblacional de un barrio de Porto Alegre (RS). Se buscaron correlaciones entre la calidad de las relaciones de esas familias y su salud física y mental, especialmente la del hijo foco de la investigación. Métodos: Fueron seleccionadas en el archivo de la investigación las tres primeras familias (de un total de 148) de las cuales se tenían los resultados completos de las cinco visitas realizadas, a los 4 meses, y a los 2, 4, 9, y 15 años de un hijo. Fue realizado un análisis cualitativo de los registros en busca de categorías para comprender la vida y las relaciones interpersonales en las familias. El estudio fue hecho en conjunto por dos investigadoras, médicas especialistas en desarrollo humano. Las categorías identificadas en el análisis y estudiadas en las cinco etapas fueron: configuración familiar, situación socioeconómica, situaciones traumáticas, salud física, salud relacional y mental, evolución cognitiva y escolar del hijo. Resultados: Las tres familias, todas de clase C, con hijos sin problemas de salud física, tuvieron evolución suficientemente buena, a pesar de que todas enfrentaron múltiples problemas, incluso separaciones y muertes precoces. La relación con el sistema de salud y escuela era buena y similar para las tres. La joven con menos problemas de salud mental fue aquella que sufrió las mayores pérdidas: muerte de los padres. Tenía una estructura familiar multigeneracional sólida desde la primera infancia, con relaciones interpersonales predominantemente colaborativas y amorosas. Conclusiones: El artículo pretende avanzar en la comprensión de la resiliencia en las familias en situaciones de vulnerabilidad. Concluimos que esas tres familias, una de ellas más que las otras, fueron suficientemente saludables en la tarea de educar a sus hijos sin que desarrollaran problemas mentales graves. Proponemos que el buen desarrollo se asocia con el amor y adecuación de los cuidados a la etapa del ciclo vital, aun enfrentando situaciones problemáticas. Esas calidades necesitan estar asociadas a la estabilidad socioeconómica básica y buenos servicios de salud y escuela.

Age-related physiological dysregulation progresses slowly in semi-free-ranging chimpanzees.

Background and objectives: Lifestyle has widespread effects on human health and aging. Prior results from chimpanzees (Pan troglodytes), one of humans' closest evolutionary relatives, indicate that these lifestyle effects may also be shared with other species, as semi-free-ranging chimpanzees fed a naturalistic diet show healthier values in several specific health biomarkers, compared with their sedentary, captive counterparts. Here, we examined how lifestyle factors associated with different environments affect rates of physiological aging in closely related chimpanzees. Methodology: We compared physiological dysregulation, an index of biological aging, in semi-free-ranging chimpanzees in an African sanctuary versus captive chimpanzees in US laboratories. If the rate of aging is accelerated by high-calorie diet and sedentism, we predicted greater age-related dysregulation in the laboratory populations. Conversely, if costs of a wild lifestyle accelerate aging, then semi-free-ranging chimpanzees at the sanctuary, whose environment better approximates the wild, should show greater age-related dysregulation. We further tested whether dysregulation differed based on sex or body system, as in humans. Results: We found that semi-free-ranging chimpanzees showed lower overall dysregulation, as well as lower age-related change in dysregulation, than laboratory chimpanzees. Males experienced lower dysregulation than females in both contexts, and the two populations exhibited distinct aging patterns based on body system. Conclusions and implications: Our results support the conclusion that naturalistic living conditions result in healthier aging in chimpanzees. These data provide support for the proposal that lifestyle effects on human health and aging are conserved from deeper into our evolutionary history.

The role of m6A-associated membraneless organelles in the RNA metabolism processes and human diseases.

N6-methyladenosine (m6A) is the most abundant post-transcriptional dynamic RNA modification process in eukaryotes, extensively implicated in cellular growth, embryonic development and immune homeostasis. One of the most profound biological functions of m6A is to regulate RNA metabolism, thereby determining the fate of RNA. Notably, the regulation of m6A-mediated organized RNA metabolism critically relies on the assembly of membraneless organelles (MLOs) in both the nucleus and cytoplasm, such as nuclear speckles, stress granules and processing bodies. In addition, m6A-associated MLOs exert a pivotal role in governing diverse RNA metabolic processes encompassing transcription, splicing, transport, decay and translation. However, emerging evidence suggests that dysregulated m6A levels contribute to the formation of pathological condensates in a range of human diseases, including tumorigenesis, reproductive diseases, neurological diseases and respiratory diseases. To date, the molecular mechanism by which m6A regulates the aggregation of biomolecular condensates associated with RNA metabolism is unclear. In this review, we comprehensively summarize the updated biochemical processes of m6A-associated MLOs, particularly focusing on their impact on RNA metabolism and their pivotal role in disease development and related biological mechanisms. Furthermore, we propose that m6A-associated MLOs could serve as predictive markers for disease progression and potential drug targets in the future.

Transcriptome analysis reveals EBF1 ablation-induced injuries in cardiac system.

Rationale: Regulatory processes of transcription factors (TFs) shape heart development and influence the adult heart's response to stress, contributing to cardiac disorders. Despite their significance, the precise mechanisms underpinning TF-mediated regulation remain elusive. Here, we identify that EBF1, as a TF, is highly expressed in human heart tissues. EBF1 is reported to be associated with human cardiovascular disease, but its roles are unclear in heart. In this study, we investigated EBF1 function in cardiac system. Methods: RNA-seq was utilized to profile EBF1 expression patterns. CRISPR/Cas9 was utilized to knock out EBF1 to investigate its effects. Human pluripotent stem cells (hPSCs) differentiated into cardiac lineages were used to mimic cardiac development. Cardiac function was evaluated on mouse model with Ebf1 knockout by using techniques such as echocardiography. RNA-seq was conducted to analyze transcriptional perturbations. ChIP-seq was employed to elucidate EBF1-bound genes and the underlying regulatory mechanisms. Results: EBF1 was expressed in some human and mouse cardiomyocyte. Knockout of EBF1 inhibited cardiac development. ChIP-seq indicated EBF1's binding on promoters of cardiogenic TFs pivotal to cardiac development, facilitating their transcriptional expression and promoting cardiac development. In mouse, Ebf1 depletion triggered transcriptional perturbations of genes, resulting in cardiac remodeling. Mechanistically, we found that EBF1 directly bound to upstream chromatin regions of cardiac hypertrophy-inducing genes, contributing to cardiac hypertrophy. Conclusions: We uncover the mechanisms underlying EBF1-mediated regulatory processes, shedding light on cardiac development, and the pathogenesis of cardiac remodeling. These findings emphasize EBF1's critical role in orchestrating diverse aspects of cardiac processes and provide a promising therapeutic intervention for cardiomyopathy.

Early moderate prenatal alcohol exposure and maternal diet impact offspring DNA methylation across species.

Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in newborn pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.

Drinking excessive amounts of alcohol during pregnancy can cause foetal alcohol spectrum disorder and other conditions in children that affect their physical and mental development. Many countries advise women who are pregnant or trying to conceive to avoid drinking alcohol entirely. However, surveys of large groups of women in Western countries indicate that most women continue drinking low to moderate amounts of alcohol until they discover they are pregnant and then stop consuming alcohol for the rest of their pregnancy. It remains unclear how this common drinking pattern affects the foetus. The instructions needed to build and maintain a human body are stored within molecules of DNA. Some regions of DNA called genes contain the instructions to make proteins, which perform many tasks in the body. Other so-called 'non-coding' regions do not code for any proteins but instead have roles in regulating gene activity. One way cells control which genes are switched on or off is adding or removing tags known as methyl groups to certain locations on DNA. Previous studies indicate that alcohol may affect how children develop by changing the patterns of methyl tags on DNA. To investigate the effect of moderate drinking during the early stages of pregnancy, Bestry et al. exposed pregnant mice to alcohol and examined how this affected the patterns of methyl tags on DNA in their offspring. The experiments found moderate levels of alcohol were sufficient to alter the patterns of methyl tags in the brains and livers of the newborn mice. Most of the changes were observed in non-coding regions of DNA, suggesting alcohol may affect how large groups of genes are regulated. Fewer changes in the patterns of methyl tags were found in mice whose mothers had diets rich in two essential nutrients known as folate and choline. Further experiments found that some of the affected mouse genes were similar to genes linked to foetal alcohol spectrum disorder and other related conditions in humans. These findings highlight the potential risks of consuming even moderate levels of alcohol during pregnancy and suggest that a maternal diet rich in folate and choline may help mitigate some of the harmful effects on the developing foetus.

A multicentre clinical trial evaluating the outcomes of two application regimens of a unique keratin-based graft in the treatment of Wagner grade one non-healing diabetic foot ulcers.

Diabetic foot complications that lead to lower extremity amputations pose a significant challenge to the entire global health system. In this multicentre clinical trial, 26 patients with chronic Wagner one diabetic foot ulcers (DFUs) were treated with a unique human keratin matrix graft applied either weekly or bi-weekly, in addition to standard of care. The hypothesis was that bi-weekly application would be similar to weekly application. The primary endpoint was complete wound closure by 12 weeks, and secondary endpoints included healing time, percent area reduction and weekly changes in peripheral neuropathy, pain and quality of life. In the intent-to-treat population, 77% (10/13) of DFUs treated with bi-weekly application healed compared with 69% (9/13) treated with weekly application. The mean time to heal within 12 weeks in the bi-weekly group was 61 days and in the weekly group was 54 days. The mean percent area reduction at 12 weeks was 94.7% in the bi-weekly group compared with 84.8% in the weekly group. The number of grafts used in the bi-weekly group was 3.9 compared with 6.2 in the weekly group. The results of this trial confirm our hypothesis that whether bi-weekly or weekly application of the unique keratin matrix graft is used to treat nonhealing indolent DFUs, there is a high rate of complete healing. Based on these results, future studies should be conducted that further investigate the use of this novel human keratin matrix graft for the treatment of chronic DFUs.

Increased Human Chorionic Gonadotropin Level in a Nonsexually Active Young Female.

BACKGROUND: Quantitative and qualitative human chorionic gonadotropin (hCG) tests are obtained in the emergency department (ED) to determine if a female of child-bearing age is pregnant. A positive hCG result is commonly assumed to indicate an intrauterine or other form of pregnancy. However, elevated hCG levels can also result from various other conditions, such as ovarian tumors, pituitary tumors, and thyroid disorders. Intracranial germ cell tumors, rare central nervous system tumors capable of secreting hCG, primarily affect adolescent and young adult females. CASE REPORT: A 16-year-old female student without significant past medical history presented to our ED with a complaint of intermittent bilateral frontal headache for two days. Last menstrual period started two days prior to presentation. The headache was associated with phonophobia, photophobia, nausea, and vomiting. Serum quantitative hCG was elevated. She denied history of sexual activity or sexual assault. Transabdominal ultrasound was negative for intrauterine pregnancy. Obstetrics and gynecology as well as pediatric oncology were consulted. Subsequent investigations, including brain imaging, revealed a 3.5 cm mass in the right caudate nucleus and corpus callosum. The patient was diagnosed with an intracranial nongerminomatous germ cell tumor, necessitating hospitalization and prompt initiation of chemotherapy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: An elevated quantitative hCG is not always indicative of pregnancy, especially in a young patient without sexual history. In the case of a nonrevealing transabdominal ultrasound, obstetrics and gynecology should be consulted for discussion of further testing and imaging. Emergency physicians should include malignancy high on their differential since prompt initiation of chemotherapy, evaluation by surgical services, and family planning will be required.

Safety and Tolerability of Anti-microRNA-328 Ophthalmic Solution, SHJ002, in Pediatric Subjects: First-in-Human Clinical Study.

PURPOSE: microRNA-328 has been reported as a risk factor for myopia development. SHJ002 is an antisense for microRNA-328, and SHJ002 was formulated as ophthalmic solution for a novel microRNA therapy. We aimed to investigate the safety and tolerability of SHJ002 ophthalmic solution in children. METHODS: This was a single-center, open-label, first-in-human trial in healthy children (NCT04928144). All subjects received the study medication. The trial had 2 stages. Stage 1 was an intrasubject dose-escalation study, and stage 2 was the highest tolerable dose study. The SHJ002 ophthalmic solution was instilled in a randomly selected study eye in each participant, whereas the other untreated eye served as a negative control. Three participants were assigned to stage 1, and they received eye drops of 3 concentrations (0.025%, 0.08%, and 0.25%), each of which was used for 3 consecutive days. The highest tolerable dose from stage 1 was used in stage 2 where another 9 participants were recruited for 28-day treatment. Ocular assessments, physical examination, and vital signs were measured to evaluate safety and tolerability. FINDINGS: There were 4 boys and 8 girls with a mean age of 12.3 years and a SD of 1.56. All participants were Asians. All 3 concentrations used in stage 1 were well tolerated, and the dose of 0.25% was used in stage 2. There were no reports of discomfort. There was only 1 mild adverse event (punctate keratitis) in the untreated eye in 1 participant, which was deemed as "unrelated to study drug." IMPLICATIONS: SHJ002 is a novel microRNA therapy that uses eye drop instillation. SHJ002 ophthalmic solution is generally safe and tolerable, which warrants further investigations in Phase II and III trials. CLINICALTRIALS: gov identifier: NCT04928144.

Considerations on expanding criminal offender DNA databases with Y-STR profiles.

Although national criminal offender DNA databases (NCODDs) including autosomal short tandem repeats (STRs) have been a successful tool to identify criminals for decades in many countries, yet there are many criminal cases they cannot solve. In cases with mixed male-female samples, particularly sexual assault, expanding NCODDs with Y-chromosomal STR (Y-STR) profiles allows database matching in the absence of autosomal STR profiles. Although Y-STR matches are not individual-specific, this can be largely overcome with rapidly mutating Y-STRs (RM Y-STR) allowing separation of paternally related men. Expanding NCODDs with Y-STR profiles is also beneficial for law enforcement in cases without known suspects via familial searching. Expanding NCODDs with Y-STR profiles may raise concerns about genetic privacy and fundamental human rights. A legal analysis of the European Convention on Human Rights revealed that when primarily for reidentifying convicted sex offenders, it would be in line with the case law of the European Court of Human Rights, while a generalized approach primarily for familial searching and involving all types of offenders may not. This paper aims to stimulate a debate among various stakeholders regarding the benefits and risks of expanding NCODDs with Y-STR profiles that in some countries has already been practically implemented.

A Review of Human Papillomavirus Vaccination and Associated Ethical Concerns.

Since its Fast-Track approval by the Federal Drug Administration, the human papillomavirus (HPV) vaccine has been marked by controversies. Unconfirmed reports of adverse events in both Japan and Denmark led to suspensions of national vaccination programs, which setback the fight against cervical cancer and associated mortality and morbidity. Despite follow-up studies of vaccine adverse reports, additional randomized control trials, and review reports from both the World Health Organization and the European Commission, there is still a great deal of hesitancy around the vaccine. While all three version of the HPV vaccine have been shown to be efficacious and safe, additional ethical dilemmas deserve to be considered as well.

Overtrust in AI Recommendations About Whether or Not to Kill: Evidence from Two Human-Robot Interaction Studies.

This research explores prospective determinants of trust in the recommendations of artificial agents regarding decisions to kill, using a novel visual challenge paradigm simulating threat-identification (enemy combatants vs. civilians) under uncertainty. In Experiment 1, we compared trust in the advice of a physically embodied versus screen-mediated anthropomorphic robot, observing no effects of embodiment; in Experiment 2, we manipulated the relative anthropomorphism of virtual robots, observing modestly greater trust in the most anthropomorphic agent relative to the least. Across studies, when any version of the agent randomly disagreed, participants reversed their threat-identifications and decisions to kill in the majority of cases, substantially degrading their initial performance. Participants' subjective confidence in their decisions tracked whether the agent (dis)agreed, while both decision-reversals and confidence were moderated by appraisals of the agent's intelligence. The overall findings indicate a strong propensity to overtrust unreliable AI in life-or-death decisions made under uncertainty.

Modelling the age distribution of longevity leaders.

Human longevity leaders with remarkably long lifespan play a crucial role in the advancement of longevity research. In this paper, we propose a stochastic model to describe the evolution of the age of the oldest person in the world by a Markov process, in which we assume that the births of the individuals follow a Poisson process with increasing intensity, lifespans of individuals are independent and can be characterized by a gamma-Gompertz distribution with time-dependent parameters. We utilize a dataset of the world's oldest person title holders since 1955, and we compute the maximum likelihood estimate for the parameters iteratively by numerical integration. Based on our preliminary estimates, the model provides a good fit to the data and shows that the age of the oldest person alive increases over time in the future. The estimated parameters enable us to describe the distribution of the age of the record holder process at a future time point.

A unified web cloud computing platform MiMedSurv for microbiome causal mediation analysis with survival responses.

In human microbiome studies, mediation analysis has recently been spotlighted as a practical and powerful analytic tool to survey the causal roles of the microbiome as a mediator to explain the observed relationships between a medical treatment/environmental exposure and a human disease. We also note that, in a clinical research, investigators often trace disease progression sequentially in time; as such, time-to-event (e.g., time-to-disease, time-to-cure) responses, known as survival responses, are prevalent as a surrogate variable for human health or disease. In this paper, we introduce a web cloud computing platform, named as microbiome mediation analysis with survival responses (MiMedSurv), for comprehensive microbiome mediation analysis with survival responses on user-friendly web environments. MiMedSurv is an extension of our prior web cloud computing platform, named as microbiome mediation analysis (MiMed), for survival responses. The two main features that are well-distinguished are as follows. First, MiMedSurv conducts some baseline exploratory non-mediational survival analysis, not involving microbiome, to survey the disparity in survival response between medical treatments/environmental exposures. Then, MiMedSurv identifies the mediating roles of the microbiome in various aspects: (i) as a microbial ecosystem using ecological indices (e.g., alpha and beta diversity indices) and (ii) as individual microbial taxa in various hierarchies (e.g., phyla, classes, orders, families, genera, species). To illustrate its use, we survey the mediating roles of the gut microbiome between antibiotic treatment and time-to-type 1 diabetes. MiMedSurv is freely available on our web server ( http://mimedsurv.micloud.kr ).

Transfusion-related acute lung injury (TRALI) following intravenous immunoglobulin infusion in a rituximab immunosuppressed patient with long-shedding SARS-CoV-2.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare life-threatening complication of blood product transfusion. Intravenous immunoglobulin (IVIG)-related TRALI is scarcely reported. CASE PRESENTATION: A 63-year-old male patient suffering from multiple sclerosis treated with half-yearly rituximab infusions, was hospitalized due to dry cough, daily fever and shivering for seven days despite antibiotic therapy. Because of the history of COVID-19 one month prior without the symptoms having improved since, persistent bilateral multifocal areas of ground glass opacities in chest computed tomography and positive SARS-CoV-2 PCR from bronchoalveolar lavage with a cycling time of 30.1 COVID-19 due to long-shedding SARS-CoV-2 under immunosuppression with rituximab was diagnosed. He received treatment with nirmatrelvir und ritonavir and because of diagnosed IgG deficiency additionally a single dose of 20 g IVIG. During the IVIG infusion, the patient acutely developed tachycardia, hypotension, fever, chills, and hypoxemic respiratory failure due to pulmonary edema. TRALI was promptly diagnosed, and the patient was transferred to the intensive care unit for non-invasive ventilation for less than 24 h. The patient was discharged home from regular ward 72 h later in a good general condition and no remaining symptoms of TRALI. CONCLUSION: IVIG-related TRALI is a rare but life-threating condition and prompt recognition is lifesaving. Due to an increased use of IVIG not only in long-shedding SARS-CoV-2, an increase of TRALI incidence is expected.