The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.

Direct synthesis of multi-contrast brain MR images from MR multitasking spatial factors using deep learning.

PURPOSE: To develop a deep learning method to synthesize conventional contrast-weighted images in the brain from MR multitasking spatial factors. METHODS: Eighteen subjects were imaged using a whole-brain quantitative T1 -T2 -T1ρ MR multitasking sequence. Conventional contrast-weighted images consisting of T1 MPRAGE, T1 gradient echo, and T2 fluid-attenuated inversion recovery were acquired as target images. A 2D U-Net-based neural network was trained to synthesize conventional weighted images from MR multitasking spatial factors. Quantitative assessment and image quality rating by two radiologists were performed to evaluate the quality of deep-learning-based synthesis, in comparison with Bloch-equation-based synthesis from MR multitasking quantitative maps. RESULTS: The deep-learning synthetic images showed comparable contrasts of brain tissues with the reference images from true acquisitions and were substantially better than the Bloch-equation-based synthesis results. Averaging on the three contrasts, the deep learning synthesis achieved normalized root mean square error = 0.184 ± 0.075, peak SNR = 28.14 ± 2.51, and structural-similarity index = 0.918 ± 0.034, which were significantly better than Bloch-equation-based synthesis (p < 0.05). Radiologists' rating results show that compared with true acquisitions, deep learning synthesis had no notable quality degradation and was better than Bloch-equation-based synthesis. CONCLUSION: A deep learning technique was developed to synthesize conventional weighted images from MR multitasking spatial factors in the brain, enabling the simultaneous acquisition of multiparametric quantitative maps and clinical contrast-weighted images in a single scan.

The Use of Authorized Concealment to Minimize Nocebo Side Effects: A Survey of US Public Attitudes.

INTRODUCTION: To minimize nocebo effects, it may be possible to employ authorized concealment, in which clinicians tell patients about the nocebo phenomenon and ask if they would prefer not to be informed about mild treatment side effects. OBJECTIVE: The objective of the study was to understand public evaluations of authorized concealment for reducing nocebo effects. METHODS: An online cross-sectional survey was completed by a demographically diverse US national community sample between June 2 and 6, 2023. Participants were 1,012 adults residing in 48 states, ages ranging from 18 to 94 (mean = 43.2), 65.4% regularly taking medication, and 66.6% reporting a chronic physical or mental health condition. After learning about nocebo effects, participants rated and estimated their likelihood of consenting to four potential methods for authorized concealment of mild side effects. The four methods were ranked for preference and ranked again with the options of (1) receiving all side-effect information and (2) having the opportunity to select among disclosure methods. RESULTS: A majority of participants (86.2%) positively endorsed at least one authorized concealment method and 88.2% estimated they would consent to at least one method. Authorized concealment in which individuals learned only the most common side effects or had side-effect information available online received more positive ratings and rankings. A final ranking yielded preferences for receiving all side-effect information (30.4%) and having the opportunity to select side-effect disclosure method (31.8%). CONCLUSIONS: Our study suggests that many in the public could be open to authorized concealment for mild side effects when it is explained in reference to nocebo effects.

Multiparametric mapping in the brain from conventional contrast-weighted images using deep learning.

PURPOSE: To develop a deep-learning-based method to quantify multiple parameters in the brain from conventional contrast-weighted images. METHODS: Eighteen subjects were imaged using an MR Multitasking sequence to generate reference T1 and T2 maps in the brain. Conventional contrast-weighted images consisting of T1 MPRAGE, T1 GRE, and T2 FLAIR were acquired as input images. A U-Net-based neural network was trained to estimate T1 and T2 maps simultaneously from the contrast-weighted images. Six-fold cross-validation was performed to compare the network outputs with the MR Multitasking references. RESULTS: The deep-learning T1 /T2 maps were comparable with the references, and brain tissue structures and image contrasts were well preserved. A peak signal-to-noise ratio >32 dB and a structural similarity index >0.97 were achieved for both parameter maps. Calculated on brain parenchyma (excluding CSF), the mean absolute errors (and mean percentage errors) for T1 and T2 maps were 52.7 ms (5.1%) and 5.4 ms (7.1%), respectively. ROI measurements on four tissue compartments (cortical gray matter, white matter, putamen, and thalamus) showed that T1 and T2 values provided by the network outputs were in agreement with the MR Multitasking reference maps. The mean differences were smaller than ± 1%, and limits of agreement were within ± 5% for T1 and within ± 10% for T2 after taking the mean differences into account. CONCLUSION: A deep-learning-based technique was developed to estimate T1 and T2 maps from conventional contrast-weighted images in the brain, enabling simultaneous qualitative and quantitative MRI without modifying clinical protocols.

New Constraint on the Local Relic Neutrino Background Overdensity with the First KATRIN Data Runs.

We report on the direct search for cosmic relic neutrinos using data acquired during the first two science campaigns of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity molecular tritium gas source are analyzed by a high-resolution MAC-E filter around the end point at 18.57 keV. The analysis is sensitive to a local relic neutrino overdensity ratio of η<9.7×10^{10}/α (1.1×10^{11}/α) at a 90% (95%) confidence level with α=1 (0.5) for Majorana (Dirac) neutrinos. A fit of the integrated electron spectrum over a narrow interval around the end point accounting for relic neutrino captures in the tritium source reveals no significant overdensity. This work improves the results obtained by the previous neutrino mass experiments at Los Alamos and Troitsk. We furthermore update the projected final sensitivity of the KATRIN experiment to η<1×10^{10}/α at 90% confidence level, by relying on updated operational conditions.

Incidence of spontaneous intracranial hypotension in a community: Beverly Hills, California, 2006-2020.

BACKGROUND: Spontaneous intracranial hypotension is diagnosed with an increasing frequency, but epidemiologic data are scarce. The aim of this study was to determine the incidence rate of spontaneous intracranial hypotension in a defined population. METHODS: Using a prospectively maintained registry, all patients with spontaneous intracranial hypotension residing in Beverly Hills, California, evaluated at our Medical Center between 2006 and 2020 were identified in this population-based incidence study. Our Medical Center is a quaternary referral center for spontaneous intracranial hypotension and is located within 1.5 miles from downtown Beverly Hills. RESULTS: A total of 19 patients with spontaneous intracranial hypotension were identified. There were 12 women and seven men with a mean age of 54.5 years (range, 28 to 88 years). The average annual incidence rate for all ages was 3.7 per 100,000 population (95% confidence interval [CI]: 2.0 to 5.3), 4.3 per 100,000 for women (95% CI, 1.9 to 6.7) and 2.9 per 100,000 population for men (95% CI, 0.8 to 5.1). CONCLUSION: This study, for the first time, provides incidence rates for spontaneous intracranial hypotension in a defined population.

Current Practice Diagnosing Brain Death Is Not Consistent With Legal Statutes Requiring the Absence of All Brain Function.

The legal standard for the determination of death by neurologic criteria in the United States is laid out in the Uniform Determination of Death Act (UDDA), which requires the irreversible cessation of all functions of the entire brain. Most other nations endorse a "whole-brain" standard as well. However, current practice in the determination of death by neurologic criteria is not consistent with this legal standard, because some patients who are diagnosed as brain-dead, in fact retain some brain function, or retain the capacity for the return of some brain function. In response, the American Academy of Neurology published updated guidelines, which assert that hypothalamic function is consistent with the neurological standard enshrined in the UDDA. Others have suggested that it is an open question whether the hypothalamus and pituitary are part of "the entire brain," as delineated in the UDDA. While we agree that determination of death practices are worthy of continued dialogue and refinement in practice that dialogue must adhere to reasonable standards of logic and scientific accuracy.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Challenge Experiments in Nonhuman Primates: An Ethical Perspective.

The coronavirus disease 2019 (COVID-19) pandemic has stimulated massive investment in biomedical research with the aims of understanding the disease and developing effective vaccine and therapeutic interventions. What role should animal research play in this scientific endeavor? Both the urgency to evaluate candidate interventions for human use and growing societal concern about ethical treatment of (nonhuman) animals put into question the justifiability of animal research as a precursor to clinical trials. Yet forgoing animal research in the rush to undertake human testing might expose human research participants to unacceptable risks. In this article, we apply a recently developed framework of principles for animal research ethics in exploring ethical questions raised by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection challenge experiment involving rhesus macaques, which evaluated the protective efficacy of the mRNA-1273 vaccine that was recently approved for emergency use. Our aim is to illuminate the ethical issues while introducing, and illustrating the use of, the framework.

Rural-urban and racial/ethnic trends and disparities in early-onset and average-onset colorectal cancer.

BACKGROUND: Incidence rates (IRs) of early-onset colorectal cancer (EOCRC) are increasing, whereas average-onset colorectal cancer (AOCRC) rates are decreasing. However, rural-urban and racial/ethnic differences in trends by age have not been explored. The objective of this study was to examine joint rural-urban and racial/ethnic trends and disparities in EOCRC and AOCRC IRs. METHODS: Surveillance, Epidemiology, and End Results data on the incidence of EOCRC (age, 20-49 years) and AOCRC (age, ≥50 years) were analyzed. Annual percent changes (APCs) in trends between 2000 and 2016 were calculated jointly by rurality and race/ethnicity. IRs and rate ratios were calculated for 2012-2016 by rurality, race/ethnicity, sex, and subsite. RESULTS: EOCRC IRs increased 35% from 10.44 to 14.09 per 100,000 in rural populations (APC, 2.09; P < .05) and nearly 20% from 9.37 to 11.20 per 100,000 in urban populations (APC, 1.26; P < .05). AOCRC rates decreased among both rural and urban populations, but the magnitude of improvement was greater in urban populations. EOCRC increased among non-Hispanic White (NHW) populations, although rural non-Hispanic Black (NHB) trends were stable. Between 2012 and 2016, EOCRC IRs were higher among all rural populations in comparison with urban populations, including NHW, NHB, and American Indian/Alaska Native populations. By sex, rural NHB women had the highest EOCRC IRs across subgroup comparisons, and this was driven primarily by colon cancer IRs 62% higher than those of their urban peers. CONCLUSIONS: EOCRC IRs increased in rural and urban populations, but the increase was greater in rural populations. NHB and American Indian/Alaska Native populations had particularly notable rural-urban disparities. Future research should examine the etiology of these trends.

Bound on 3+1 Active-Sterile Neutrino Mixing from the First Four-Week Science Run of KATRIN.

We report on the light sterile neutrino search from the first four-week science run of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are analyzed by a high-resolution MAC-E filter down to 40 eV below the endpoint at 18.57 keV. We consider the framework with three active neutrinos and one sterile neutrino. The analysis is sensitive to the mass, m_{4}, of the fourth mass state for m_{4}^{2}≲1000 eV^{2} and to active-to-sterile neutrino mixing down to |U_{e4}|^{2}≳2×10^{-2}. No significant spectral distortion is observed and exclusion bounds on the sterile mass and mixing are reported. These new limits supersede the Mainz results for m_{4}^{2}≲1000 eV^{2} and improve the Troitsk bound for m_{4}^{2}<30 eV^{2}. The reactor and gallium anomalies are constrained for 100<Δm_{41}^{2}<1000 eV^{2}.

Allocating a COVID-19 Vaccine: Balancing National and International Responsibilities.

Policy Points In this paper we propose a middle-ground policy for the distribution of an effective COVID-19 vaccine, between a cosmopolitan approach that rejects entirely nation-state priority and unbridled vaccine nationalism that disregards obligations to promote an equitable global allocation of an effective vaccine over time. Features of the COVAX partnership, a collaboration among the Global Alliance for Vaccines and Immunizations (GAVI), the Coalition for Epidemic Preparedness Innovations (CEPI), and the World Health Organization (WHO) to develop and distribute COVID-19 vaccines make it an appropriate framework for a middle-ground policy.

Spontaneous spinal cerebrospinal fluid-venous fistulas in patients with orthostatic headaches and normal conventional brain and spine imaging.

OBJECTIVE: To determine the occurrence of cerebrospinal fluid (CSF)-venous fistulas, a type of spinal CSF leak that cannot be detected with routine computerized tomography myelography, among patients with orthostatic headaches but normal brain and spine magnetic resonance imaging. BACKGROUND: Spontaneous spinal CSF leaks cause orthostatic headaches but their detection may require sophisticated spinal imaging techniques. METHODS: A prospective cohort study of patients with orthostatic headaches and normal brain and conventional spine imaging who underwent digital subtraction myelography (DSM) to look for CSF-venous fistulas, between May 2018 and May 2020, at a quaternary referral center for spontaneous intracranial hypotension. RESULTS: The mean age of the 60 consecutive patients (46 women and 14 men) was 46 years (range, 13-83 years), who had been suffering from orthostatic headaches between 1 and 180 months (mean, 43 months). DSM demonstrated a spinal CSF-venous fistula in 6 (10.0%; 95% confidence interval [CI]: 3.8-20.5%) of the 60 patients. The mean age of these five women and one man was 50 years (range, 41-59 years). Spinal CSF-venous fistulas were identified in 6 (19.4%; 95% CI: 7.5-37.5%) of 31 patients with spinal meningeal diverticula but in none (0%; 95% CI: 0-11.9%) of the 29 patients without spinal meningeal diverticula (p = 0.024). All CSF-venous fistulas were located in the thoracic spine. All patients underwent uneventful surgical ligation of the fistula. Complete and sustained resolution of symptoms was obtained in five patients, while in one patient, partial recurrence of symptoms was noted 3 months postoperatively. CONCLUSION: Concerns about a spinal CSF leak should not be dismissed in patients suffering from orthostatic headaches when conventional imaging turns out to be normal, even though the yield of identifying a CSF-venous fistula is low.

Discovery of soluble epoxide hydrolase inhibitors through DNA-encoded library technology (ELT).

Inhibition of soluble epoxide hydrolase (sEH) has recently emerged as a new approach to treat cardiovascular disease and respiratory disease. Inhibitors based on 1,3,5-triazine chemotype were discovered through affinity selection against two triazine-based DNA-encoded libraries. The structure and activity relationship study led to the expansion of the original 1,4-cycloalkyl series to related aniline, piperidine, quinoline, aryl-ether and benzylic series. The 1,3-cycloalkyl chemotype led to the discovery of a clinical candidate (GSK2256294) for COPD.

Liberty and Protection of Society During a Pandemic: Revisiting John Stuart Mill.

John Stuart Mill's classic text, On Liberty, maps the scope and limits on individual freedom. His "harm principle"-that liberty can be legitimately restricted by government or society only to prevent harm to others-has had a great influence on contemporary public health ethics. This essay examines Mill's philosophy of liberty as it pertains to public health interventions in response to the coronavirus pandemic. Particular applications include examination of face masks, lockdowns, and mandatory vaccination.

The Legality and Ethics of Mandating COVID-19 Vaccination.

In light of ongoing concerns in the US that COVID-19 vaccine uptake is stagnating and that cases remain high amongst the unvaccinated, there is growing interest in increasing uptake by mandating vaccination. COVID-19 vaccine mandates must be understood and assessed in terms of who is requiring vaccination and who is required to be vaccinated. This essay considers the legal and ethical implications of states mandating vaccination for children and adults, as well as of employers mandating vaccines for employees. We conclude that COVID-19 vaccine mandates are legally and ethically permissible.

Three-dimensional simultaneous brain T1 , T2 , and ADC mapping with MR Multitasking.

PURPOSE: To develop a simultaneous T1 , T2 , and ADC mapping method that provides co-registered, distortion-free images and enables multiparametric quantification of 3D brain coverage in a clinically feasible scan time with the MR Multitasking framework. METHODS: The T1 /T2 /diffusion weighting was generated by a series of T2 preparations and diffusion preparations. The underlying multidimensional image containing 3 spatial dimensions, 1 T1 weighting dimension, 1 T2 -preparation duration dimension, 1 b-value dimension, and 1 diffusion direction dimension was modeled as a 5-way low-rank tensor. A separate real-time low-rank model incorporating time-resolved phase correction was also used to compensate for both inter-shot and intra-shot phase inconsistency induced by physiological motion. The proposed method was validated on both phantom and 16 healthy subjects. The quantification of T1 /T2 /ADC was evaluated for each case. Three post-surgery brain tumor patients were scanned for demonstration of clinical feasibility. RESULTS: Multitasking T1 /T2 /ADC maps were perfectly co-registered and free from image distortion. Phantom studies showed substantial quantitative agreement ( R2=0.999 ) with reference protocols for T1 /T2 /ADC. In vivo studies showed nonsignificant T1 (P = .248), T2 (P = .97), ADC (P = .328) differences among the frontal, parietal, and occipital regions. Although Multitasking showed significant differences of T1 (P = .03), T2 (P < .001), and ADC (P = .001) biases against the references, the mean bias estimates were small (ΔT1 % < 5%, ΔT2 % < 7%, ΔADC% < 5%), with all intraclass correlation coefficients greater than 0.82 indicating "excellent" agreement. Patient studies showed that Multitasking T1 /T2 /ADC maps were consistent with the clinical qualitative images. CONCLUSION: The Multitasking approach simultaneously quantifies T1 /T2 /ADC with substantial agreement with the references and is promising for clinical applications.

Bioethics as a Vocation.

This essay offers practical guidance for the activity of bioethics scholarship in the form of maxims or rules of thumb, explicated by the author's work in bioethics research, mentoring, peer review, and journal editing. It is organized into three sections: (1) education, (2) seeking ideas for projects, and (3) writing papers.

Revisiting the Distinction and the Connection Between Research and Practice.

The Belmont Report addresses the distinction between practice and research as guidance for which activities should be evaluated prospectively by a research ethics committee. This essay argues that the distinction between clinical practice and clinical research has a more fundamental significance for understanding the ethics of clinical research. After discussing the important connections between clinical research and clinical practice, the essay examines in detail ethically significant differences between these two sorts of activities. This sets the stage for a critique of clinical equipoise, widely regarded as a fundamental principle of clinical research ethics.

Improved Upper Limit on the Neutrino Mass from a Direct Kinematic Method by KATRIN.

We report on the neutrino mass measurement result from the first four-week science run of the Karlsruhe Tritium Neutrino experiment KATRIN in spring 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are energy analyzed by a high-resolution MAC-E filter. A fit of the integrated electron spectrum over a narrow interval around the kinematic end point at 18.57 keV gives an effective neutrino mass square value of (-1.0_{-1.1}^{+0.9}) eV^{2}. From this, we derive an upper limit of 1.1 eV (90% confidence level) on the absolute mass scale of neutrinos. This value coincides with the KATRIN sensitivity. It improves upon previous mass limits from kinematic measurements by almost a factor of 2 and provides model-independent input to cosmological studies of structure formation.

Drug screening assay based on the interaction of intact Keap1 and Nrf2 proteins in cancer cells.

BACKGROUND: The Nrf2-Keap1 interaction is the major regulatory pathway for cytoprotective responses against oxidative and electrophilic stresses. Keap1, a substrate protein of a Cul3-dependent E3 ubiquitin ligase complex, is a negative regulator of Nrf2. The use of chemicals to regulate the interaction between Keap1 and Nrf2 has been proposed as a strategy for the chemoprevention of degenerative diseases and cancers. RESULTS: The interactions between Keap1 and Nrf2 in vitro and in vivo were investigated using fluorescence resonance energy transfer (FRET) and bimolecular fluorescence complementation (BiFC) strategies in our study. Nrf2 with its N-terminal fused to eGFP and Keap1 with its C-terminal fused to mCherry were expressed and purified in vitro. When purified eGFP-Nrf2 and Keap1-mChrry proteins were mixed together, a strong FRET signal could be detected, indicating an efficient energy transfer from eGFP to mCherry. Moreover, the FRET was detected in vivo using confocal microscopy in colon cancer HCT-116 cells that were co-transfected with eGFP-Nrf2 and Keap1-mCherry. Finally, using an eGFP BiFC approach, the Keap1-Nrf2 interaction was also detected in MCF7 cells by transfecting eGFP N-terminal fused to Nrf2 (eN158-Nrf2) and eGFP C-terminal fused to Keap1 (eC159-Keap1). Using the BiFC and FRET systems, we demonstrated that the prototypical Nrf2-activiting compound tBHQ and the antitumor drug F-dUrd might interfere with the intracellular interaction between Keap1 and Nrf2 whereas the 5-Fu have little role in activating the protective response of Nrf2 pathway in cancer cells. CONCLUSIONS: By analyzing the perturbation of the energy transfer between the donor and acceptor fluorophores and the bimolecular fluorescence complementation of eGFP, we can screen potential inhibitors for the interaction between Keap1 and Nrf2.