Mean cycloplegic refractive error in emmetropic adults – The Tehran Eye Study / Error refractivo ciclopléjico medio en adultos emétropes: estudio ocular de Teherán

Purpose: In children under 20 years, refractive development targets a cycloplegic refractive error of +0.5 to +1.5D, while presbyopes over 40 years generally have non-cycloplegic errors of ≥ +1D. Some papers suggest these periods are separated by a period of myopic refractive error (i.e., ≤ –0.50D), but this remains unclear. Hence, this work investigates the mean cycloplegic refractive error in adults aged between 20 – 40 years. Methods: In 2002 a cross-sectional study with stratified cluster sampling was performed on the population of Tehran, providing cycloplegic and non-cycloplegic refractive error data for the right eyes of 3,576 participants, aged 30.6 ± 18.6 years (range: 1–86 years). After grouping these data into age groups of 5 years, the refractive error histogram of each group was fitted to a Bigaussian function. The mean of the central, emmetropized peak was used to estimate the mean refractive error without the influence of myopia. Results: The mean cycloplegic refractive error at the emmetropized peak decreased from +1.10 ± 0.11D (95 % confidence interval) to +0.50 ± 0.04D before 20 years and remains stable at that value until the age of 50 years. The non-cycloplegic refractive error also sees a stable phase at 0.00 ± 0.04D between 15 – 45 years. After 45 – 50 years both cycloplegic and non-cycloplegic refractive error become more hypermetropic over time, +1.14 ± 0.12D at 75 years. Conclusions: The cycloplegic refractive error in adults is about +0.50D between 20 – 50 years, disproving the existence of the myopic period at those ages.(AU)

Puberty Blocker and Aging Impact on Testicular Cell States and Function.

Spermatogonial stem cell (SSC) acquisition of meiotogenetic state during puberty to produce genetically diverse gametes is blocked by drugs collectively referred as 'puberty blocker' (PB). Investigating the impact of PB on juvenile SSC state and function is challenging due to limited tissue access and clinical data. Herein, we report largest clinically annotated juvenile testicular biorepository with all children with gender dysphoria on chronic PB treatment highlighting shift in pediatric patient demography in US. At the tissue level, we report mild-to-severe sex gland atrophy in PB treated children. We developed most extensive integrated single-cell RNA dataset to date (>100K single cells; 25 patients), merging both public and novel (52 month PB-treated) datasets, alongside innovative computational approach tailed for germ cells and evaluated the impact of PB and aging on SSC. We report novel constitutional ranges for each testicular cell type across the entire age spectrum, distinct effects of treatments on prepubertal vs adult SSC, presence of spermatogenic epithelial cells exhibiting post-meiotic-state, irrespective of age, puberty status, or PB treatment. Further, we defined distinct effects of PB and aging on testicular cell lineage composition, and SSC meiotogenetic state and function. Using single cell data from prepubertal and young adult, we were able to accurately predict sexual maturity based both on overall cell type proportions, as well as on gene expression patterns within each major cell type. Applying these models to a PB-treated patient that they appeared pre-pubertal across the entire tissue. This combined with the noted gland atrophy and abnormalities from the histology data raise a potential concern regarding the complete 'reversibility' and reproductive fitness of SSC. The biorepository, data, and research approach presented in this study provide unique opportunity to explore the impact of PB on testicular reproductive health.

EVOLUTIONARY CO-OPTION OF AN ANCESTRAL CLOACAL REGULATORY LANDSCAPE DURING THE EMERGENCE OF DIGITS AND GENITALS.

The transition from fins to limbs has been a rich source of discussion for more than a century. One open and important issue is understanding how the mechanisms that pattern digits arose during vertebrate evolution. In this context, the analysis of Hox gene expression and functions to infer evolutionary scenarios has been a productive approach to explain the changes in organ formation, particularly in limbs. In tetrapods, the transcription of Hoxd genes in developing digits depends on a well-characterized set of enhancers forming a large regulatory landscape1,2. This control system has a syntenic counterpart in zebrafish, even though they lack bona fide digits, suggestive of deep homology3 between distal fin and limb developmental mechanisms. We tested the global function of this landscape to assess ancestry and source of limb and fin variation. In contrast to results in mice, we show here that the deletion of the homologous control region in zebrafish has a limited effect on the transcription of hoxd genes during fin development. However, it fully abrogates hoxd expression within the developing cloaca, an ancestral structure related to the mammalian urogenital sinus. We show that similar to the limb, Hoxd gene function in the urogenital sinus of the mouse also depends on enhancers located in this same genomic domain. Thus, we conclude that the current regulation underlying Hoxd gene expression in distal limbs was co-opted in tetrapods from a preexisting cloacal program. The orthologous chromatin domain in fishes may illustrate a rudimentary or partial step in this evolutionary co-option.

Research on the coordinated development of provincial urbanization and carbon emission efficiency of construction industry in China.

BACKGROUND: Energy conservation and emission reduction policies restrict the economic and social development of all countries in the world, and the impact on China, which has low urbanization, is more serious. In the process of promoting urbanization, the pressure of carbon emission reduction in the construction industry has increased, and the high emissions of the construction industry have made the low-carbon development of cities face severe challenges. China is at a critical stage of urbanization development, and there is become a general consensus on how to improve the carbon emission efficiency of the construction industry. The interaction between urbanization and the carbon emission efficiency of the construction industry is a long-term and complex process. As one of the industries contributing to China's urbanization process and carbon emissions, it is of great practical significance to explore the coordination relationship between urbanization and the carbon emission efficiency of the construction industry (CEECI) to realize the goal of "double carbon", promoting urbanization construction and solving the problem of "green development". Taking 30 provinces in China as the research target area, the double weighted summation method and the undesirable output superefficiency window-EBM-DEA model are used to measure the provincial urbanization level and CEECI, respectively. Then, the coupling coordination degree model of the relative development index is introduced, and the spatial autocorrelation model and the spatial and temporal differentiation characteristics of the coordination level of urbanization and the CEECI are analysed. RESULTS: From 2010 to 2021, China's urbanization level increased steadily, but the growth rate gradually decreased. There were significant differences in urbanization levels among provinces. The eastern provinces have a higher level of urbanization but lack an impetus in the later period, while the western provinces have a lower level of urbanization but a faster growth rate. The low-carbon development trend of China's construction industry is good, and the overall development of the CEECI shows an "N" type, and the inflection points appear in 2013 and 2018. The interprovincial urbanization level is significantly different from that of the CEECI, and the development form of the central and western provinces is better than that of the eastern provinces. The coordination level of urbanization and the CEECI in China is transitioning from the running-in stage to the coordination stage, and the coupling coordination degree between systems is on the rise, while the relative development degree is on the decline. The spatial distribution pattern is in a dynamic state of change, and the overall distribution pattern is "high in the east and low in the central and western regions". The differences among provinces were significantly decreased, with 63.33% of provinces at the high running-in level. The provinces that entered the coordination stage were mainly located in the eastern region, and only Beijing was in the coordination stage by the end of the study. In addition, 90% of the provinces exhibited lagging efficiency, and only Jiangxi, Guangxi and Chongqing, which had low coordination levels maintained synchronous development of the two systems. The coordination level between provincial urbanization and the CEECI showed a positive spatial distribution, the global Moran index showed a "V" shape trend, and the spatial dependence of the coordination level between the two systems gradually weakened. In the local spatial distribution, there are two types of convergence: high and low. CONCLUSIONS: The coordination degree of urbanization and the CEECI analysed in this study is an extension of the research on the relationship between the two. By integrating the two into a unified framework, the method of combining quantitative and qualitative analysis is used to further explore the coordination relationship between the two, which not only enhances the scientificity and accuracy of the research but also extends the breadth and depth of relevant theoretical research. At the same time, according to the coordination type between urbanization and the CEECI, China should propose corresponding targeted coordination and optimization paths from the perspective of urbanization and low-carbon development of the construction industry to achieve high-quality development of China's economy and society.

Functional myelin in cognition and neurodevelopmental disorders.

In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible for the formation of the myelin sheath that surrounds the axons of neurons. The myelin sheath plays a crucial role in the transmission of neuronal information by promoting the rapid saltatory conduction of action potentials and providing neurons with structural and metabolic support. Saltatory conduction, first described in the peripheral nervous system (PNS), is now generally recognized as a universal evolutionary innovation to respond quickly to the environment: myelin helps us think and act fast. Nevertheless, the role of myelin in the central nervous system, especially in the brain, may not be primarily focused on accelerating conduction speed but rather on ensuring precision. Its principal function could be to coordinate various neuronal networks, promoting their synchronization through oscillations (or rhythms) relevant for specific information processing tasks. Interestingly, myelin has been directly involved in different types of cognitive processes relying on brain oscillations, and myelin plasticity is currently considered to be part of the fundamental mechanisms for memory formation and maintenance. However, despite ample evidence showing the involvement of myelin in cognition and neurodevelopmental disorders characterized by cognitive impairments, the link between myelin, brain oscillations, cognition and disease is not yet fully understood. In this review, we aim to highlight what is known and what remains to be explored to understand the role of myelin in high order brain processes.

In vivo activities of heparan sulfate differentially modified by NDSTs during development.

Heparan sulfate proteoglycans (HSPGs) serve as co-receptors for growth factor signaling during development. It is well known that the level and patterns of sulfate groups of heparan sulfate (HS) chains, or HS fine structures, have a major impact on HSPG function. On the other hand, the physiological significance of other structural features of HS, including NS/NA domain organization, remains to be elucidated. A blueprint of the HS domain structures is mainly controlled by HS N-deacetylase/N-sulfotransferases (NDSTs). To analyze in vivo activities of differentially modified HS, we established two knock-in (KI) Drosophila strains with the insertion of mouse Ndst1 (mNdst1) or Ndst2 (mNdst2) in the locus of sulfateless (sfl), the only Drosophila NDST. In these KI lines, mNDSTs are expressed from the sfl locus, in the level and patterns identical to the endogenous sfl gene. Thus, phenotypes of Ndst1 KI and Ndst2KI animals reflect the ability of HS structures made by these enzymes to rescue sfl mutation. Remarkably, we found that mNdst1 completely rescued the loss of sfl. mNdst2 showed a limited rescue ability, despite a higher level of HS sulfation compared to HS in mNdst1 KI. Our study suggests that independent of sulfation levels, additional HS structural features controlled by NDSTs play key roles during tissue patterning.

Hearing loss in juvenile rats leads to excessive play fighting and hyperactivity, mild cognitive deficits and altered neuronal activity in the prefrontal cortex.

Background: In children, hearing loss has been associated with hyperactivity, disturbed social interaction, and risk of cognitive disturbances. Mechanistic explanations of these relations sometimes involve language. To investigate the effect of hearing loss on behavioral deficits in the absence of language, we tested the impact of hearing loss in juvenile rats on motor, social, and cognitive behavior and on physiology of prefrontal cortex. Methods: Hearing loss was induced in juvenile (postnatal day 14) male Sprague-Dawley rats by intracochlear injection of neomycin under general anesthesia. Sham-operated and non-operated hearing rats served as controls. One week after surgery auditory brainstem response (ABR) measurements verified hearing loss or intact hearing in sham-operated and non-operated controls. All rats were then tested for locomotor activity (open field), coordination (Rotarod), and for social interaction during development in weeks 1, 2, 4, 8, 16, and 24 after surgery. From week 8 on, rats were trained and tested for spatial learning and memory (4-arm baited 8-arm radial maze test). In a final setting, neuronal activity was recorded in the medial prefrontal cortex (mPFC). Results: In the open field deafened rats moved faster and covered more distance than sham-operated and non-operated controls from week 8 on (both p < 0.05). Deafened rats showed significantly more play fighting during development (p < 0.05), whereas other aspects of social interaction, such as following, were not affected. Learning of the radial maze test was not impaired in deafened rats (p > 0.05), but rats used less next-arm entries than other groups indicating impaired concept learning (p < 0.05). In the mPFC neuronal firing rate was reduced and enhanced irregular firing was observed. Moreover, oscillatory activity was altered, both within the mPFC and in coherence of mPFC with the somatosensory cortex (p < 0.05). Conclusions: Hearing loss in juvenile rats leads to hyperactive behavior and pronounced play-fighting during development, suggesting a causal relationship between hearing loss and cognitive development. Altered neuronal activities in the mPFC after hearing loss support such effects on neuronal networks outside the central auditory system. This animal model provides evidence of developmental consequences of juvenile hearing loss on prefrontal cortex in absence of language as potential confounding factor.

A Novel Curriculum for Internal Medicine Residents to Care for High-Need, High-Cost Patients.

OBJECTIVES: High-need, high-cost (HNHC) patients represent a small proportion of patients in the US, but result in disproportionately higher healthcare utilization. Teaching Internal Medicine (IM) resident trainees to provide high value care for HNHC patients is critical. We sought to improve resident attitudes and increase clinical skills associated with treating HNHC patients by creating a curriculum that leveraged the UCLA Extensivist Program, a patient-centered medical home for HNHC patients. METHODS: We developed a curriculum for PGY-2 and PGY-3 IM residents centered on caring for HNHC patients over the course of 6, 4h sessions during 1 academic year. Participants completed pre- and post-intervention surveys assessing self-rated attitudes and skills associated with caring for an HNHC patient population. RESULTS: Twenty-one IM residents completed the curriculum and 41 were in the control group. There were no statistically significant differences in assessed attitudes and skills, but there were trends of improvement, including a decrease in participants who agreed or strongly agreed they felt overwhelmed when seeing patients for posthospital discharge follow up (45.0% pre- to 41.7% post-intervention) and an increase in participants who agreed or strongly agreed they have the skills to successfully transition HNHC patients between inpatient and ambulatory settings (20.0% pre- to 33.3% post-intervention). Participants reported better understanding of resources available to HNHC patients, effective coordination of transitions of care, and comprehensive assessment of social determinants of health. CONCLUSION: A curriculum to improve resident attitudes and skills associated with caring for HNHC patients was successfully implemented in an IM program at a large academic medical center. The curriculum may be adapted for other training programs; long-term training woven throughout training may be important to significantly improve resident education on how to care for HNHC patients.

Elderly's Homesickness: Development of Elderly Homesickness Questionnaire.

Introduction: Homesickness is a result of migration, and is related to adjustment difficulties and health problems, as well as clinical disorders. The aim of this study was to measure and explore the homesickness of Chinese elderly. Methods: A total of 355 non-local Chinese elderly in Shenzhen were recruited to measure demographic information and homesickness. and tested for reliability and validity. Patterns and influences of homesickness among Chinese elderly were explored through latent profile analysis and One-way ANOVA on the basis of EHQ. Results: A three-factor structure was verified in the 19-item elderly homesickness questionnaire (EHQ), namely "positive contact", "refusal to separate" and "homesickness behavior". The EHQ reports high validity and reliability. Chinese elderly had a high degree of homesickness, and homesickness among Chinese elderly varied significantly across variables such as age, occupation, and education level. Four homesickness patterns were found in Chinese elderly, named low homesick group, moderate homesick group, middle-high homesick group, and high homesick group. Coming from rural/urban areas and living with grandchildren are factors that affect classification. Conclusion: The present study reveals the high validity and reliability of the EHQ among Chinese elderly. The Chinese elderly reported high levels of homesickness, which varied significantly across levels of demographic factors. Four patterns of homesickness were found among the Chinese elderly, coming from rural/urban areas and living with grandchildren are the factors that affect classification. There may be a masking of the male contribution to the main effect due to the larger female sample.

Latent Network Analysis of Executive Functions Across Development.

Executive functions (EFs) are crucial for academic achievement, physical health, and mental well-being. Previous studies using structural equation models revealed EFs' developmental organization, evolving from one factor in childhood to three factors in adults: inhibition, cognitive flexibility, and updating. Recent network model studies confirmed this differentiation from childhood to adulthood. Reanalyzing previously published data from 1019 children (aged 7.8 to 15.3; 50.4% female; 59.1% White, 15.0% Latinx, 14.3% Bi-racial, 6.7% African American, 4.2% Asian American, 0.6% Other), this study compared three analytical methods to explore EF development: structural equation model, network model, and the novel latent variable network model. All approaches supported fine-grained EF-specific trajectories and differentiation throughout development, with inhibition being central in childhood and updating in early adolescence.

The temporospatial relationship between mouse dental pulp stem cells and tooth innervation.

Background/purpose: Dental pulp stem cells (DPSCs) exhibit versatile differentiation capabilities, including neural differentiation, prompting the hypothesis that they may be implicated in the neurodevelopment of teeth. This study aimed to explore the temporospatial dynamics between DPSCs and tooth innervation, employing immunofluorescence staining and fluorescent dye injections to investigate the distribution of DPSCs, neural stem cells (NSCs), nerve growth cones, and sensory nerves in developing mouse tooth germs at various stages. Materials and methods: Immunofluorescence staining targeting CD146, Nestin, and GAP-43, along with the injection of AM1-43 fluorescent dye, were utilized to observe the distribution of DPSCs, NSCs, nerve growth cones, and sensory nerves in mouse tooth germs at different developmental stages. Results: Positive CD146 immunostaining was observed in microvascular endothelial cells and pericytes within and around the tooth germ. The percentage of CD146-positive cells remained consistent between 4-day-old and 8-day-old second molar tooth germs. Conversely, Nestin expression in odontoblasts and their processes decreased in 8-day-old tooth germs compared to 4-day-old ones. Positive immunostaining for GAP-43 and AM1-43 fluorescence revealed the entry of nerve growth cones and sensory nerves into the pulp in 8-day-old tooth germs, while these elements were confined to the dental follicle in 4-day-old germs. No co-localization of CD146-positive DPSCs with nerve growth cones and sensory nerves was observed. Conclusion: DPSCs and NSCs were present in dental pulp tissue before nerves penetrated the pulp. The decline in NSCs after nerve entry suggests a potential role for DPSCs and NSCs in attracting neural growth and/or differentiation within the pulp.

The addition of mammalian cell culture medium impacts nanoparticle toxicity in zebrafish.

Engineered nanomaterials (ENMs) are ubiquitous in contemporary applications, yet their environmental and human health impacts remain inadequately understood. This study addresses the challenge of identifying potential risks associated with ENM exposure by highlighting the significant variability in existing research methodologies. Without a systematic collection of toxicological data that encompasses standardized materials, relevant platforms, and assays, the task of identifying potential risks linked to ENM exposure becomes an intricate challenge. In vitro assessments often use media rich in ionic species, such as RPMI and fetal bovine serum (FBS). Zebrafish embryos, known to develop normally in low-ionic environments, were exposed to Cerium Oxide, Zinc Oxide, and Graphene Oxides in different media at varying concentrations. Here, we discovered that zebrafish embryos tolerated a mix of 80 % RPMI, 2 % FBS, and 1 % antibiotic cocktail. The results revealed that adverse effects observed in zebrafish with certain nanomaterials in Ultra-Pure (UP) water were mitigated in cell culture medium, emphasizing the importance of revisiting previously considered non-toxic materials in vitro. The zebrafish results underscore the importance of utilizing a multidimensional in vivo platform to gauge the biological activity of nanomaterials accurately.

Therapeutic development targeting host heparan sulfate proteoglycan in SARS-CoV-2 infection.

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an urgent need for effective therapeutic options. SARS-CoV-2 is a novel coronavirus responsible for the COVID-19 pandemic that has resulted in significant morbidity and mortality worldwide. The virus is known to enter host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, and emerging evidence suggests that heparan sulfate proteoglycans (HSPGs) play a crucial role in facilitating this process. HSPGs are abundant cell surface proteoglycan present in many tissues, including the lung, and have been shown to interact directly with the spike protein of SARS-CoV-2. This review aims to summarize the current understanding of the role of HSPGs in SARS-CoV-2 infection and the potential of developing new therapies targeting HSPGs.

Early-life contact with non-maternal adult cows and a pasture-based rearing environment influence behavioural responses of dairy heifers to novelty.

The complexity experienced in early life can affect trait development of individuals, including sociability and fearfulness. The modern dairy calf's rearing environment often lacks environmental and social complexity. This study examined the effects of early-life, non-maternal adult contact and access to a physically complex environment on the responses of dairy heifers to several stressors, including restraint, social isolation, and novelty at 18 months of age. From the age of 2-13 weeks, 60 dairy heifers (Bos taurus) were reared according to one of three treatments applied to 20 calves each: (1) Hand-reared at pasture in groups of ten, with three unrelated dry cows (+S); (2) Hand-reared at pasture in groups of ten (-S); or (3) Hand-reared in sheds in groups of 10-12 as a commercial control (CC). At 13 weeks, all treatment groups were mixed and managed at pasture as a single herd. At 18 months, the responses of 50 heifers to restraint in a crush, social isolation and a novel object were observed (+S = 16, -S = 17, CC = 17). Treatment did not influence responses to restraint or social isolation, but influenced some indicators of fearfulness during exposure to a novel object. Six +S heifers interacted with the novel object compared to 0 -S and one CC, and CC heifers spent around 50% more time in vigilance than +S or -S heifers. Dairy heifers provided with early-life social enrichment in the form of non-maternal adult contact may have reduced fear of novelty. The implications for lifelong ability to adapt to novel situations, such as entry into the milking herd, should be assessed.

Development and Validation of a Symptom Scale for Indian Patients With Medically Unexplained Physical Symptoms.

Introduction Patients with medically unexplained physical symptoms (MUPS) account for a substantial proportion of patients visiting the outpatient department. Diagnosis of MUPS is a challenge for most physicians. An accurate diagnosis relies on obtaining a detailed history from patients regarding the nature of their symptoms, their onset, and any associated aggravating or relieving factors. This study aims to develop a symptom scale for Indian patients with MUPS. Methods The study had a mixed-method study design. Phase 1 involved designing the questionnaire using qualitative techniques, such as literature reviews, focus-group discussions, expert evaluation, and pre-testing of a Hindi and English language Likert-rated interviewer-administered scale. In phase 2, the construct validity of the questionnaire was established using quantitative approaches among 116 patients diagnosed with MUPS. Results The final questionnaire consists of 38 items, with good internal consistency (Cronbach 𝛂 = 0.916). Confirmation sampling adequacy for factor analysis was done using the Kaiser-Meyer-Olkin test (KMO value = 0.792) and Bartlett's test of sphericity (p < 0.001). The newly developed scale showed a Pearson correlation coefficient of 0.568 (p < 0.001) with Patient Health Questionnaire (PHQ)-15 scores. Conclusion A reliable and valid tool has been developed to assess patients' symptoms with MUPS in English and Hindi languages. This questionnaire can be used for assessment, screening, and diagnostic purposes as well as to chart longitudinal changes in patients with MUPS.

Anti-psychotic Nature of Antibiotics: Vancomycin and Omadacycline Combination Ameliorating Stress in a Zebrafish Model.

Background Stress affects mental health significantly and is a ubiquitous feature of contemporary living. Among the possible antibiotics are omadacycline and vancomycin, whose anti-inflammatory properties have also been thoroughly documented in recent research. The goal of the current study was to examine their complex involvement in the brain's stress response circuits and how they modulate stress. An established model organism that provides a useful platform for examining stress-induced behaviors and possible therapeutic approaches is the zebrafish. To investigate how dopamine affects the stress response, we used a zebrafish model that was exposed to stress. Methodology For three minutes, zebrafish were continually subjected to chasing stress. They were then given antibiotic combinations of 50 µg/mL each of vancomycin and omadacycline at various ratios of 1:1, 3:1, and 3:1. Behavior alterations, including freezing bouts, top-bottom ratios, and latency periods, were analyzed and contrasted with control groups. ImageJ software was utilized to analyze the video footage of the fish. Results The study showed that the combination of omadacycline and vancomycin greatly reduced the behaviors in zebrafish caused by stress. They chose their concentration (50 µg/mL) according to the lethal concentration 50% result. By shortening the latency time and increasing the intensity of breezing sessions, these chemicals restored almost normal activity. There was statistical significance in the outcomes. The results show that the combination of vancomycin and omadacycline may have an anti-psychotic impact on zebrafish behaviors brought on by stress. Their control of stress reactions is consistent with their known roles in the reward and stress circuits of the brain. These results emphasize the complex interactions between neurotransmitter systems and the control of stress, highlighting the therapeutic potential of dopamine in the treatment of stress-related mental illnesses. Conclusions The combination of vancomycin and omadacycline has been shown to have anti-psychotic effects, which presents potential opportunities for the development of new treatment strategies for mental diseases associated with stress. To fully understand the specific processes underpinning their involvement in stress management and how they relate to mental illnesses in humans, more investigation is necessary.

An Enhanced Agile V-Model: Conformance to regulatory bodies and experiences from model's adoption to medical device development.

Context: Medical devices fall under the broad topic encompass everything from basic hardware to integrated software systems. The integration of software into hardware devices is not simple due to requirements of regional regulatory bodies. Therefore, medical businesses need to oversee not only the creation of devices but also the observance of guidelines and standards established by regulatory bodies. While plan-driven methodologies prevented software from evolving or changing, agile methodologies have inherent characteristics of insufficient planning and documentation. Objectives: The objective of our research is to propose a suitable process model for medical device development, keeping in mind the regulatory requirements. Methods: First, based on the detailed analysis of literature and McHughs proposed model, we suggested the Enhanced Agile V-Model (EAV), which combines plan-driven and agile approaches. Second, we mapped the proposed model to the MDEVSPICE framework to confirm that it adhered to the rules outlined in the standard IEC62304. Finally, the proposed model is evaluated through implication to case study of wave therapeutic medical device. Results: The support of both agile and waterfall approach in EAV model helps in accommodating new requirements in the medical devices and the proposed systems engineering approach helps in hardware and software integration. The mapping of the EAV model to the MDEVSPICE shows complete compliance. Moreover, the implication of the proposed model has been clearly shown statistically and successfully implemented in our case study. Further, device usability and efficiency metrics showed confidence of P < 0.05 and for device safety and efficiency, we conducted an experiment which shows significant improvement in selected parameters. Conclusion: The proposed model shows conformance to regulatory standards, and successfully implemented in development of wave therapeutic device. However, its applicability to more compact and straightforward medical products is unknown and can be determined by using this model to analyze the performance of other medical products.

Detection of newly synthesized RNA reveals transcriptional reprogramming during ZGA and a role of Obox3 in totipotency acquisition.

Zygotic genome activation (ZGA) after fertilization enables the maternal-to-zygotic transition. However, the global view of ZGA, particularly at initiation, is incompletely understood. Here, we develop a method to capture and sequence newly synthesized RNA in early mouse embryos, providing a view of transcriptional reprogramming during ZGA. Our data demonstrate that major ZGA gene activation begins earlier than previously thought. Furthermore, we identify a set of genes activated during minor ZGA, the promoters of which show enrichment of the Obox factor motif, and find that Obox3 or Obox5 overexpression in mouse embryonic stem cells activates ZGA genes. Notably, the expression of Obox factors is severely impaired in somatic cell nuclear transfer (SCNT) embryos, and restoration of Obox3 expression corrects the ZGA profile and greatly improves SCNT embryo development. Hence, our study reveals dynamic transcriptional reprogramming during ZGA and underscores the crucial role of Obox3 in facilitating totipotency acquisition.

Protective Factors in the Context of Childhood Bereavement: Youth Gratitude, Future Orientation, and Purpose in Life.

The objective of the study was to examine potential associations between positive youth development constructs (gratitude, future orientation, purpose in life) and psychological functioning (posttraumatic stress symptoms, depressive symptoms, maladaptive grief reactions) among bereaved youth and test whether these associations vary by age. A diverse sample of 197 clinic-referred bereaved youth (56.2% female; M = 12.36, SD = 3.18; 36.1% Hispanic, 23.7% White, 20.1% Black, 11.9% Multiracial, and 8.2% another race/ethnicity) completed self-report measures of psychological functioning and positive youth development constructs. Linear regression models indicated that gratitude and purpose were associated with lower posttraumatic stress and depressive symptoms among bereaved youth. Future orientation was associated with higher posttraumatic stress symptoms. Results were consistent across age. If replicated longitudinally, gratitude and purpose may be important protective factors against negative mental health outcomes in the aftermath of losing a loved one.