AOP report: Development of an adverse outcome pathway for deposition of energy leading to learning and memory impairment.

Understanding radiation-induced non-cancer effects on the central nervous system (CNS) is essential for the risk assessment of medical (e.g., radiotherapy) and occupational (e.g., nuclear workers and astronauts) exposures. Herein, the adverse outcome pathway (AOP) approach was used to consolidate relevant studies in the area of cognitive decline for identification of research gaps, countermeasure development, and for eventual use in risk assessments. AOPs are an analytical construct describing critical events to an adverse outcome (AO) in a simplified form beginning with a molecular initiating event (MIE). An AOP was constructed utilizing mechanistic information to build empirical support for the key event relationships (KERs) between the MIE of deposition of energy to the AO of learning and memory impairment through multiple key events (KEs). The evidence for the AOP was acquired through a documented scoping review of the literature. In this AOP, the MIE is connected to the AO via six KEs: increased oxidative stress, increased deoxyribonucleic acid (DNA) strand breaks, altered stress response signaling, tissue resident cell activation, increased pro-inflammatory mediators, and abnormal neural remodeling that encompasses atypical structural and functional alterations of neural cells and surrounding environment. Deposition of energy directly leads to oxidative stress, increased DNA strand breaks, an increase of pro-inflammatory mediators and tissue resident cell activation. These KEs, which are themselves interconnected, can lead to abnormal neural remodeling impacting learning and memory processes. Identified knowledge gaps include improving quantitative understanding of the AOP across several KERs and additional testing of proposed modulating factors through experimental work. Broadly, it is envisioned that the outcome of these efforts could be extended to other cognitive disorders and complement ongoing work by international radiation governing bodies in their review of the system of radiological protection.

Automatic ploidy prediction and quality assessment of human blastocysts using time-lapse imaging.

Assessing fertilized human embryos is crucial for in vitro fertilization, a task being revolutionized by artificial intelligence. Existing models used for embryo quality assessment and ploidy detection could be significantly improved by effectively utilizing time-lapse imaging to identify critical developmental time points for maximizing prediction accuracy. Addressing this, we develop and compare various embryo ploidy status prediction models across distinct embryo development stages. We present BELA, a state-of-the-art ploidy prediction model that surpasses previous image- and video-based models without necessitating input from embryologists. BELA uses multitask learning to predict quality scores that are thereafter used to predict ploidy status. By achieving an area under the receiver operating characteristic curve of 0.76 for discriminating between euploidy and aneuploidy embryos on the Weill Cornell dataset, BELA matches the performance of models trained on embryologists' manual scores. While not a replacement for preimplantation genetic testing for aneuploidy, BELA exemplifies how such models can streamline the embryo evaluation process.

The independent and combined effects of aerobic exercise intensity and dose differentially increase post-exercise cerebral shear stress and blood flow.

This research examined the impact of aerobic exercise intensity and dose on acute post-exercise cerebral shear stress and blood flow. Fourteen young adults (27 ± 5 years of age, eight females) completed a maximal oxygen uptake ( V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ ) treadmill test followed by three randomized study visits: treadmill exercise at 30% of V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ for 30 min, 70% of V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ for 30 min and 70% of V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ for a duration that resulted in caloric expenditure equal to that in the 30% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ visit (EqEE). A venous blood draw and internal carotid artery (ICA) ultrasound were collected before and immediately following exercise. ICA diameter and blood velocity were determined using automated edge detection software, and blood flow was calculated. Using measures of blood viscosity, shear stress was calculated. Aerobic exercise increased ICA shear stress (time: P = 0.005, condition: P = 0.012) and the increase was greater following exercise at 70% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (∆4.1 ± 3.5 dyn/cm2) compared with 30% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (∆1.1 ± 1.9 dyn/cm2; P = 0.041). ICA blood flow remained elevated following exercise (time: P = 0.002, condition: P = 0.010) with greater increases after 70% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (Δ268 ± 150 mL/min) compared with 30% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (∆125 ± 149 mL/min; P = 0.041) or 70% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ EqEE (∆127 ± 177 mL/min; P = 0.004). Therefore, aerobic exercise resulted in both intensity- and dose-dependent effects on acute post-exercise ICA blood flow whereby vigorous intensity exercise provoked a larger increase in ICA blood flow compared to light intensity exercise when performed at a higher dose.

FDA Breakthrough Therapy Designation Reduced Late-Stage Drug Development Time.

The Food and Drug Administration's (FDA's) breakthrough therapy designation (BTD) program was created to increase patient access to safe and effective therapies by supporting the efficient clinical development of qualifying, clinically meaningful therapies. Using a new data set of key development milestones for drugs approved between 2006 and 2020, including both BTD drugs and a set of comparator drugs identified by FDA experts, we estimated the BTD program's impact on time spent in late-stage clinical development, measured as the elapsed time between a drug's end-of-Phase-II meeting with regulators and its approval for marketing. Our analysis suggests that the BTD program lowers late-stage clinical development time by 30 percent. Our findings provide insight into future regulatory and innovation policies aimed at driving efficiency in medical product development to ensure timely patient access to the most clinically meaningful therapies.

A longitudinal study of breastfeeding relationships at home during the COVID-19 pandemic: A grounded theory method.

AIMS: To describe the process of breastfeeding relationships among stay-at-home mother and infant dyads at 1, 3, 5 and 6 months. DESIGN: A longitudinal qualitative online survey design was used. METHODS: Data were obtained at 1, 3, 5 and 6 months from 26 breastfeeding mothers who stayed home with their infants and directly breastfed at least once a day for the first 6 months between June 2022 and August 2023. Mothers' written responses to 3 open-ended questions were analysed to assess breastfeeding experiences at home, thoughts/comments while directly breastfeeding and breastfeeding concerns/problems and strategies they used. Based on grounded theory, inductive content analysis was used to analyse the data. Trustworthiness of results was established by coding to consensus, formal peer debriefing and maintaining an audit trail. RESULTS: 'Breastfeeding Relationships at Home,' the core construct, was identified and organized the process of breastfeeding relationships into 5 domains: (1) mothers' emotional well-being while breastfeeding, (2) infant-led feeding, (3) alternatives to breastfeeding, (4) evaluation of breastfeeding and (5) changes in breastfeeding as infants grow older. CONCLUSION: Breastfeeding is not simply about feeding breast milk but also involves nurturing and developing a relationship between mother and infant. Across the domains, mutual responsiveness, a central element of the breastfeeding relationship was clear. Mothers who were committed to breastfeeding with embedded infant suckling reached emotional well-being in return for their engagement which has potential to reduce maternal stress and prevent postpartum depression. IMPACT: Findings from the current study add to nurses' knowledge about the relationship building process between stay-at-home mothers and their infants in the first 6 months of breastfeeding during the COVID-19 pandemic. Nurses must remain sensitive to aid the development of breastfeeding relationships in the home environment to maximize mutual responsiveness. PATIENT OR PUBLIC CONTRIBUTION: No patients or public involved.

Cardiac Extracorporeal Membrane Oxygenation in Community Cardiac Surgery Program: Are the Results Comparable?

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) outcomes in small centers are commonly considered less favorable than in large-volume centers. New ECMO protocols and procedures were established in our regional community hospital system as part of a cardiogenic shock initiative. This retrospective study aims to evaluate the outcomes of veno-arterial extracorporeal membrane oxygenation (VA ECMO) and extracorporeal cardiopulmonary resuscitation (ECPR) in a community hospital system with cardiac surgery capability and assess whether protocol optimization and cannulation standards result in comparable outcomes to larger centers whether the outcomes of this new ECMO program at the community hospital setting were comparable to the United States averages. METHODS: Our regional system comprises five hospitals with 1500 beds covering southwestern New Jersey, with only one of these hospitals having cardiac surgery and ECMO capability. In May 2021, the new ECMO program was initiated. Patients were screened by a multidisciplinary call, cannulated by our ECMO team, and subsequently treated by the designated team. We reviewed our cardiac ECMO outcomes over two years, from May 2021 to April 2023, in patients who required ECMO due to cardiogenic shock or as a part of extracorporeal cardiopulmonary resuscitation (ECPR). RESULTS: A total of 60 patients underwent cardiac ECMO, and all were VA ECMO, including 18 (30%) patients who required ECPR for cardiac arrest. The overall survival rate for our cardiac ECMO program turned out to be 48% (29/60), with 50% (22/42) in VA ECMO excluding ECPR and 39% (7/18) in the ECPR group. The hospital survival rate for the VA ECMO and ECPR groups was 36% (15/42) and 28% (5/18), respectively. The ELSO-reported national average for hospital survival is 48% for VA ECMO and 30% for ECPR. Considering these benchmarks, the hospital survival rate of our program did not significantly lag behind the national average. CONCLUSIONS: With protocol, cannulation standards, and ECMO management optimized, the VA ECMO results of a community hospital system with cardiac surgery capability were not inferior to those of larger centers.

Move and Thrive: Development of an Adolescent Friendly and Inclusive Online Fitness Resource.

While physical activity (PA) is a strong protective factor for adolescents, many youth experience discrimination and intimidation in traditional fitness spaces. This is especially true for youth of color, youth in larger bodies, and transgender youth. This manuscript describes the development of Move and Thrive, an online resource for PA promotion designed specifically for adolescents prioritizing inclusivity and diversity. Working with Community and Youth Advisory Boards, we developed guiding principles of Move and Thrive: to create resources that are 1) youth and community driven; 2) inclusive of diverse representation; 3) body and weight neutral; 4) trauma informed; and 5) accessible. We developed a guide for PA instructors to use trauma informed approaches; avoid mention of weight talk or physical appearance; use gender inclusive language; and offer multiple options to improve accessibility. Specific care was taken to hire instructors diverse in body size, race, ethnicity, and gender identity. The first iteration of Move and Thrive was launched in March 2021, and the current resource contains 72 PA videos. Over the course of 12 months, the site had more than the site had over 9,000 views in over 40 countries, including six continents. Users have reported high levels of satisfaction with Move and Thrive, and physicians have responded enthusiastically to sharing Move and Thrive as a free resource for adolescents. University of Minnesota Move and Thrive Project is currently available on an ad-free YouTube Channel. We believe that Move and Thrive has the potential to reach populations historically excluded from PA resources.

Analysis of the first ten years of FDA's rare pediatric disease priority review voucher program: designations, diseases, and drug development.

BACKGROUND: The Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) Program was enacted in 2012 to support the development of new products for children. Prior to requesting a voucher, applicants can request RPD designation, which confirms their product treats or prevents a rare disease in which the serious manifestations primarily affect children. This study describes the trends and characteristics of these designations. Details of RPD designations are not publicly disclosable; this research represents the first analysis of the RPD designation component of the program. RESULTS: We used an internal US Food and Drug Administration database to analyze all RPD designations between 2013 and 2022. Multiple characteristics were analyzed, including the diseases targeted by RPD designation, whether the product targeted a neonatal disease, product type (drug/biologic), and the level of evidence (preclinical/clinical) to support designation. There were 569 RPD designations during the study period. The top therapeutic areas were neurology (26%, n = 149), metabolism (23%, n = 131), oncology (18%, n = 105). The top diseases targeted by RPD designation were Duchenne muscular dystrophy, neuroblastoma, and sickle cell disease. Neonatology products represented 6% (n = 33), over half were for drug products and 38% were supported by clinical data. CONCLUSIONS: The RPD PRV program was created to encourage development of new products for children. The results of this study establish that a wide range of diseases have seen development-from rare pediatric cancers to rare genetic disorders. Continued support of product development for children with rare diseases is needed to find treatments for all children with unmet needs.

Orphan Drug Label Expansions: Analysis Of Subsequent Rare And Common Indication Approvals.

The Orphan Drug Act of 1983 was enacted to provide financial incentives to stimulate drug development for rare diseases. In recent years, concerns have been raised regarding these orphan drugs, including how many are being approved for both rare and common diseases and the number of subsequent indication approvals. Policy makers have suggested modifications to the Orphan Drug Act's incentives to address these concerns. In this study we investigated the approval "family trees" of orphan drugs. We found that 491 novel orphan drugs were approved between 1990 and 2022. To date, 65 percent have been approved for a single rare disease, 15 percent have been approved for multiple rare diseases, and 20 percent have been approved for both rare and common diseases. Ten percent of orphan drugs received a subsequent indication approval for a pediatric population of an orphan disease. Revenue estimates from 2021 show that one-third of the drugs approved for both rare and common indications and 6 percent of rare-only drugs were among the 200 top-selling drugs worldwide. The results have implications for the possible externalities of modifying the incentives of the Orphan Drug Act, such as a potential decrease in the initiation of programs to develop pediatric rare disease drugs.

Investigating the fundamental levels of a signature pedagogy in nursing education: A scoping review.

BACKGROUND: A signature pedagogy is a unique approach that provides a blueprint for curricular decision-making, as it reflects how we teach (surface structures), why we teach (deep structures), and what we believe are vital concepts or values all learners should embody (implicit structures). OBJECTIVE: To investigate what is known from the existing literature about a signature pedagogy to support undergraduate nursing education. DESIGN: This scoping review adopted Arksey and O'Malley's framework to guide the analysis of data. Two electronic databases were used to explore studies on educational strategies, content, and values published in Arabic, English, Filipino, French, Portuguese, and Spanish between 1972 and 2022. RESULTS: A total of 258 articles were included in this review. The analysis revealed that the majority of articles were at the surface (n = 189), followed by the deep (n = 123), with the least number examining the implicit level (n = 90) associated with signature pedagogy levels. Results reflect a limited focus on implicit level; the core concepts and values that all learners should understand and grasp for their future practice to construct their professional identity and engage in healthcare transformation. CONCLUSIONS: The findings from this scoping review, should not be an isolated movement within nursing education. The first step is to engage in discourse amongst all stakeholders, educational and healthcare nurse leaders, regarding the state of the profession. As a profession we need to understand what is the preferred future of nursing and what are the necessary educational processes to ensure the profession is actualizing their mandate. A call to action to develop a unique signature pedagogy should provide synergy between education and practice to enhance learner's competencies as a future professional.

Determining Commonalities in the Experiences of Patients with Rare Diseases: A Qualitative Analysis of US Food and Drug Administration Patient Engagement Sessions.

BACKGROUND: Rare diseases are estimated to affect more than one in ten Americans. However, most patients with a rare disease face significant emotional, physical, and social challenges. To better understand the burden of disease and unmet needs, the US Food and Drug Administration (FDA) conducts and supports multiple patient engagement platforms. We analyzed summaries from these discussions to identify commonalities among patients with disparate rare diseases, the results of which could inform priorities for cross-disease policies and medical product development. METHODS: We conducted a qualitative analysis of patient engagement session summaries to investigate shared experiences across rare diseases. Cross-disease similarities were identified within four dimensions: product development/regulatory, clinical/physical, social/psychological, and economic/financial. Summaries from 29 rare diseases were included in our analyses. RESULTS: Within the product development/regulatory dimension, we observed that patients and caregivers across rare diseases shared the desire for development of medical products that cured their disease or improved their overall quality of life. In the clinical/physical dimension, we found that patients had numerous common symptoms, including pain and fatigue. In the social/psychological dimension, we observed significant negative impact on mental health. Within the economic/financial dimension, patients and caregivers shared that disease burden caused significant financial hardships. CONCLUSION: We found remarkable similarities among patients with rare diseases across all four dimensions. Our results indicate that, even among rare diseases with diverse etiologies, patients share numerous commonalties due to their diseases: a lack of effective treatment options, certain physical symptoms, mental health challenges, and financial concerns.

Rifampin-Associated Renal Failure.

Rifampin is an effective and widely used for the treatment of both active and latent tuberculosis. Although significant side effects are rare, severe side effects such as acute renal failure have been reported in the literature, usually secondary to acute interstitial nephritis. We report a case of rifampin-induced acute renal failure due to heme pigment-related injury in a patient who was receiving daily rifampin as therapy for latent tuberculosis. The patient case illustrates considering rifampin as a potential cause of acute renal failure when no other cause is identified.

Automatic Ploidy Prediction and Quality Assessment of Human Blastocyst Using Time-Lapse Imaging.

Assessing fertilized human embryos is crucial for in vitro-fertilization (IVF), a task being revolutionized by artificial intelligence and deep learning. Existing models used for embryo quality assessment and chromosomal abnormality (ploidy) detection could be significantly improved by effectively utilizing time-lapse imaging to identify critical developmental time points for maximizing prediction accuracy. Addressing this, we developed and compared various embryo ploidy status prediction models across distinct embryo development stages. We present BELA (Blastocyst Evaluation Learning Algorithm), a state-of-the-art ploidy prediction model surpassing previous image- and video-based models, without necessitating subjective input from embryologists. BELA uses multitask learning to predict quality scores that are used downstream to predict ploidy status. By achieving an AUC of 0.76 for discriminating between euploidy and aneuploidy embryos on the Weill Cornell dataset, BELA matches the performance of models trained on embryologists' manual scores. While not a replacement for preimplantation genetic testing for aneuploidy (PGT-A), BELA exemplifies how such models can streamline the embryo evaluation process, reducing time and effort required by embryologists.

Cerebral hemodynamics comparison using transcranial doppler ultrasound and 4D flow MRI.

Introduction: Age-related changes in cerebral hemodynamics are controversial and discrepancies may be due to experimental techniques. As such, the purpose of this study was to compare cerebral hemodynamics measurements of the middle cerebral artery (MCA) between transcranial Doppler ultrasound (TCD) and four-dimensional flow MRI (4D flow MRI). Methods: Twenty young (25 ± 3 years) and 19 older (62 ± 6 years) participants underwent two randomized study visits to evaluate hemodynamics at baseline (normocapnia) and in response to stepped hypercapnia (4% CO2, and 6% CO2) using TCD and 4D flow MRI. Cerebral hemodynamic measures included MCA velocity, MCA flow, cerebral pulsatility index (PI) and cerebrovascular reactivity to hypercapnia. MCA flow was only assessed using 4D flow MRI. Results: MCA velocity between the TCD and 4D flow MRI methods was positively correlated across the normocapnia and hypercapnia conditions (r = 0.262; p = 0.004). Additionally, cerebral PI was significantly correlated between TCD and 4D flow MRI across the conditions (r = 0.236; p = 0.010). However, there was no significant association between MCA velocity using TCD and MCA flow using 4D flow MRI across the conditions (r = 0.079; p = 0.397). When age-associated differences in cerebrovascular reactivity using conductance were compared using both methodologies, cerebrovascular reactivity was greater in young adults compared to older adults when using 4D flow MRI (2.11 ± 1.68 mL/min/mmHg/mmHg vs. 0.78 ± 1.68 mL/min/mmHg/mmHg; p = 0.019), but not with TCD (0.88 ± 1.01 cm/s/mmHg/mmHg vs. 0.68 ± 0.94 cm/s/mmHg/mmHg; p = 0.513). Conclusion: Our results demonstrated good agreement between the methods at measuring MCA velocity during normocapnia and in response to hypercapnia, but MCA velocity and MCA flow were not related. In addition, measurements using 4D flow MRI revealed effects of aging on cerebral hemodynamics that were not apparent using TCD.

A comprehensive study of the rare diseases and conditions targeted by orphan drug designations and approvals over the forty years of the Orphan Drug Act.

BACKGROUND: Rare diseases affect more than 30 million Americans. The passage of the Orphan Drug Act (ODA) in the United States in 1983 represented a launching point for a rare disease drug development revolution for these patients. Financial incentives provided by the ODA through its Orphan Drug Designation Program, in addition to remarkable scientific advances over the past 40 years, have led to hundreds of drug approvals for rare diseases. Our research examines the rare diseases that have been targeted by orphan drug designations and subsequent approvals since the law was enacted. METHODS: Using an internal FDA database, we classified and analyzed all orphan drug designations and approvals from 1983 to 2022 by disease and therapeutic area. RESULTS: Over the 40 years of the ODA, 6,340 orphan drug designations were granted, representing drug development for 1,079 rare diseases. Additionally, 882 of those designations resulted in at least one FDA approval for use in 392 rare diseases. Much of this development has been concentrated in oncology as seven of the top ten most designated and approved diseases were rare cancers. CONCLUSIONS: Researchers have estimated that there may be 7000-10,000 rare diseases that have been identified and described. Based on our study, we can conclude that around 5% of rare diseases have an FDA-approved drug and up to 15% of rare diseases have at least one drug that has been developed and shown promise in their treatment, diagnosis or prevention. Funding of basic and translational science for rare disease drug development should continue in order to bring therapies to the millions of affected patients who remain without treatment options.

The severity of COVID-19 across the spectrum of HIV.

PURPOSE OF REVIEW: We review the intersection between the HIV and COVID-19 pandemics, particularly the impact of HIV infection on the development of severe COVID-19. RECENT FINDINGS: Studies early in the COVID-19 pandemic did not find a clear link between HIV infection and increased COVID-19 severity or mortality. People with HIV (PWH) were more likely to have severe COVID-19, but much of the risk for worse outcomes was related to high rates of comorbidities and social determinants of health. Although comorbidities and social determinants of health are certainly critically important reasons for severe COVID-19 among PWH, recent large studies have found HIV infection - particularly when the CD4 cell count is low or HIV RNA is not suppressed - is an independent risk factor for COVID-19 severity. The link between HIV and severe COVID-19 highlights the need to diagnose and treat HIV as well as the importance of COVID-19 vaccination and treatment among PWH. SUMMARY: People with HIV have faced increased challenges during the COVID-19 pandemic because of high rates of comorbidities and social determinants of health as well as the impact of HIV on COVID-19 severity. Information on the intersection of the two pandemics has been crucial to improving care for people with HIV.

Removing neonicotinoid seed treatments has negligible effects on refuge function and crop protection in transgenic maize targeting western corn rootworm (Coleoptera: Chrysomelidae).

Nearly all maize seed sold in the United States includes a neonicotinoid seed treatment (NST), meant to protect seedlings against early-season insect pests. For key pests, including western corn rootworm (Diabrotica virgifera virgifera LeConte) (D.v.v), insecticidal proteins derived from Bacillus thuringiensis (Bt) are expressed in plant tissues as alternatives to soil-applied insecticides. Insect resistance management (IRM) plans use non-Bt "refuges" to encourage survival of Bt-susceptible D.v.v., which maintains susceptible alleles in the population. In non-cotton producing regions, IRM guidelines require a minimum 5% blended refuge for maize expressing more than 1 trait targeting D.v.v. Prior work has shown that 5% blends yield insufficient proportions of refuge beetles to contribute reliably to IRM. Whether NSTs interfere with survivorship of refuge beetles is unknown. Our objective was to determine whether NSTs affect proportions of refuge beetles, and secondarily, to determine whether NSTs provide agronomic advantages over Bt seed alone. To reveal host plant type (i.e., Bt or refuge), we used a stable isotope (15N) to mark refuge plants in plots with 5% seed blends. To assess refuge performance between treatments, we compared proportions of beetles from respective natal hosts. In all site-years, NSTs showed inconsistent effects on proportions of refuge beetles. Treatment comparisons showed inconsistent agronomic benefits of NSTs when combined with Bt traits. Our results demonstrate that NSTs have a negligible impact on refuge performance and reinforces the assertion that 5% blends are serving little benefit for IRM. Plant stand and yield were not improved by NSTs.