Are Patients With Cancer Best Managed in a Clinical Trial?

This Viewpoint analyzes how the NCCN's boxed statement that all cancer is best managed in a clinical trial cannot be applied to all patients and calls for its removal from its clinical practice guidelines.

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.

Profession-based manual therapy nomenclature: exploring history, limitations, and opportunities.

OBJECTIVE: The International Consortium on Manual Therapies (ICMT) is a grassroots interprofessional association open to any formally trained practitioner of manual therapy (MT) and basic scientists promoting research related to the practice of MT. Currently, MT research is impeded by professions' lack of communication with other MT professions, biases, and vernacular. Current ICMT goals are to minimize these barriers, compare MT techniques, and establish an interprofessional MT glossary. METHODS: Practitioners from all professions with training in manual therapies were encouraged by e-mail and website to participate (www.ICMTConferene.org). Video conferences were conducted at least bimonthly for 2.5 years by profession-specific and interprofessional focus groups (FGs). Members summarized scopes of practice, technique descriptions, associated mechanisms of action (MOA), and glossary terms. Each profession presented their work to the interprofessional FG to promote dialogue, understanding and consensus. Outcomes were reported and refined at numerous public events. RESULTS: Focus groups with representatives from 5 MT professions, chiropractic, massage therapy, osteopathic, physical therapy and structural integration identified 17 targeting osseous structures and 49 targeting nonosseous structures. Thirty-two techniques appeared distinct to a specific profession, and 13 were used by more than 1. Comparing descriptions identified additional commonalities. All professions agreed on 4 MOA categories for MT. A glossary of 280 terms and definitions was consolidated, representing key concepts in MT. Twenty-one terms were used by all MT professions and basic scientists. Five terms were used by MT professions exclusive of basic scientists. CONCLUSION: Outcomes suggested a third to a half of techniques used in MT are similar across professions. Additional research is needed to better define the extent of similarity and how to consistently identify those approaches. Ongoing expansion and refinement of the glossary is necessary to promote descriptive clarity and facilitate communication between practitioners and basic scientists.

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.

The Impact of School Infrastructure and Teachers' Human Capital on Academic Performance in Brazil.

To improve one of the lowest rates of literacy and numeracy in the world, the government of Brazil has targeted public education reform, given the strong link between an educated population and economic growth. This study examines the academic performance of the Brazilian public primary school system. It addresses the empirical shortcomings of prior research to examine the dynamics of the relationship between academic performance scores and several demographic and institutional variables, such as socioeconomic characteristics, variations in school infrastructure and school complexity, and teachers' human capital. We employed quantile regression to explore the determinants of academic performance across 35,490 schools in rural and urban environments in Brazil. The dependent variable in our analysis captures the academic performance score, as measured by Brazil's education authorities, of each school in our dataset. The model includes several education-related indices used in prior research and, as explanatory factors, measures of teachers' human capital and the students' socioeconomic level, which synthesizes information on parents' education and household income. The results suggest that several institutional variables, including access to school libraries, computer facilities, projectors, and televisions, are positively and significantly related to the academic performance of primary students in Brazil's system of public education. Furthermore, students' socioeconomic level is positively associated with their academic performance.

Opportunistic CT Screening-Machine Learning Algorithm Identifies Majority of Vertebral Compression Fractures: A Cohort Study.

Vertebral compression fractures (VCF) are common in patients older than 50 years but are often undiagnosed. Zebra Medical Imaging developed a VCF detection algorithm, with machine learning, to detect VCFs from CT images of the chest and/or abdomen/pelvis. In this study, we evaluated the diagnostic performance of the algorithm in identifying VCF. We conducted a blinded validation study to estimate the operating characteristics of the algorithm in identifying VCFs using previously completed CT scans from 1200 women and men aged 50 years and older at a tertiary-care center. Each scan was independently evaluated by two of three neuroradiologists to identify and grade VCF. Disagreements were resolved by a senior neuroradiologist. The algorithm evaluated the CT scans in a separate workstream. The VCF algorithm was not able to evaluate CT scans for 113 participants. Of the remaining 1087 study participants, 588 (54%) were women. Median age was 73 years (range 51-102 years; interquartile range 66-81). For the 1087 algorithm-evaluated participants, the sensitivity and specificity of the VCF algorithm in diagnosing any VCF were 0.66 (95% confidence interval [CI] 0.59-0.72) and 0.90 (95% CI 0.88-0.92), respectively, and for diagnosing moderate/severe VCF were 0.78 (95% CI 0.70-0.85) and 0.87 (95% CI 0.85-0.89), respectively. Implementing this VCF algorithm within radiology systems may help to identify patients at increased fracture risk and could support the diagnosis of osteoporosis and facilitate appropriate therapy. © 2023 Amgen, Inc. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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.

Postoperative Spinal Cerebrospinal Fluid-Venous Fistulas Associated With Dural Tears in Patients With Intracranial Hypotension or Superficial Siderosis-A Digital Subtraction Myelography Study.

BACKGROUND: Postoperative spinal cerebrospinal fluid (CSF) leaks are common but rarely cause extensive CSF collections that require specialized imaging to detect the site of the dural breach. OBJECTIVE: To investigate the use of digital subtraction myelography (DSM) for patients with extensive extradural CSF collections after spine surgery. METHODS: A retrospective review was performed to identify a consecutive group of patients with extensive postoperative spinal CSF leaks who underwent DSM. RESULTS: Twenty-one patients (9 men and 12 women) were identified. The mean age was 46.7 years (range, 17-75 years). The mean duration of the postoperative CSF leak was 3.3 years (range, 3 months to 21 years). MRI showed superficial siderosis in 6 patients. DSM showed the exact location of the CSF leak in 19 (90%) of the 21 patients. These 19 patients all underwent surgery to repair the CSF leak, and the location of the CSF leak could be confirmed intraoperatively in all 19 patients. In 4 (19%) of the 21 patients, DSM also showed a CSF-venous fistula at the same location as the postoperative dural tear. CONCLUSION: In this study, DSM had a 90% detection rate of visualizing the exact site of the dural breach in patients with extensive postoperative spinal CSF leaks. The coexistence of a CSF-venous fistula in addition to the primary dural tear was present in about one-fifth of patients. The presence of a CSF-venous fistula should be considered if CSF leak symptoms persist in spite of successful repair of a durotomy.

Framed and Reframed! The Art of Using Cognitive Behavioral Techniques to Combat Burnout.

The incidence of burnout among radiologists has been increasing exponentially, largely attributed to increased work volumes, expectations for more rapid turn-around times and decreasing interpersonal interactions. While personal wellness activities have been described in the literature, there is little information on the role of cognitive behavioral therapy strategies to mitigate burnout. This manuscript will describe the value of naming automatic negative emotions which can lead to burnout and will provide an overview of strategies that can be used to combat them, using cognitive behavioral therapy techniques.

The reversible impairment of behavioral variant frontotemporal brain sagging syndrome: Challenges and opportunities.

Introduction: Due to loss of brain buoyancy, spontaneous spinal cerebrospinal fluid (CSF) leaks cause orthostatic headaches but also can cause symptoms indistinguishable from behavioral variant frontotemporal dementia (bvFTD) due to severe brain sagging (including the frontal and temporal lobes), as visualized on brain magnetic resonance imaging. However, the detection of these CSF leaks may require specialized spinal imaging techniques, such as digital subtraction myelography (DSM). Methods: We performed DSM in the lateral decubitus position under general anesthesia in 21 consecutive patients with frontotemporal dementia brain sagging syndrome (4 women and 17 men; mean age 56.2 years [range: 31-70 years]). Results: Nine patients (42.8%) were found to have a CSF-venous fistula, a recently discovered type of CSF leak that cannot be detected on conventional spinal imaging. All nine patients underwent uneventful surgical ligation of the fistula. Complete or near-complete and sustained resolution of bvFTD symptoms was obtained by all nine patients, accompanied by reversal of brain sagging, but in only three (25.0%) of the twelve patients in whom no CSF-venous fistula could be detected (P = 0.0011), and who were treated with non-targeted therapies. Discussion: Concerns about a spinal CSF leak should not be dismissed in patients with frontotemporal brain sagging syndrome, even when conventional spinal imaging is normal. However, even with this specialized imaging the source of the loss of spinal CSF remains elusive in more than half of patients.

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.

Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials: A Systematic Review and Meta-analysis.

Importance: Adverse events (AEs) after placebo treatment are common in randomized clinical drug trials. Systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide especially because concern about AEs is reported to be a reason for vaccination hesitancy. Objective: To compare the frequencies of AEs reported in the placebo groups of COVID-19 vaccine trials with those reported in the vaccine groups. Data Sources: For this systematic review and meta-analysis, the Medline (PubMed) and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched systematically using medical subheading terms and free-text keywords for trials of COVID-19 vaccines published up to July 14, 2021. Study Selection: Randomized clinical trials of COVID-19 vaccines that investigated adults aged 16 years or older were selected if they assessed solicited AEs within 7 days of injection, included an inert placebo arm, and provided AE reports for both the vaccine and placebo groups separately. Full texts were reviewed for eligibility by 2 independent reviewers. Data Extraction and Synthesis: Data extraction and quality assessment were performed independently by 2 reviewers, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline and using the Cochrane risk-of-bias tool. Meta-analyses were based on random-effects models. Main Outcomes and Measures: The primary outcomes were the proportions of placebo recipients reporting overall, systemic, and local (injection-site) AEs as well as logarithmic odds ratios (ORs) to evaluate group differences. Outcomes were tested for significance using z tests with 95% CIs. Results: Twelve articles with AE reports for 45 380 participants (22 578 placebo recipients and 22 802 vaccine recipients) were analyzed. After the first dose, 35.2% (95% CI, 26.7%-43.7%) of placebo recipients experienced systemic AEs, with headache (19.3%; 95% CI, 13.6%-25.1%) and fatigue (16.7%; 95% CI, 9.8%-23.6%) being most common. After the second dose, 31.8% (95% CI, 28.7%-35.0%) of placebo recipients reported systemic AEs. The ratio between placebo and vaccine arms showed that nocebo responses accounted for 76.0% of systemic AEs after the first COVID-19 vaccine dose and for 51.8% after the second dose. Significantly more vaccine recipients reported AEs, but the group difference for systemic AEs was small after the first dose (OR, -0.47; 95% CI, -0.54 to -0.40; P < .001; standardized mean difference, -0.26; 95% CI, -0.30 to -0.22) and large after the second dose (OR, -1.36; 95% CI, -1.86 to -0.86; P < .001; standardized mean difference, -0.75; 95% CI, -1.03 to -0.47). Conclusions and Relevance: In this systematic review and meta-analysis, significantly more AEs were reported in vaccine groups compared with placebo groups, but the rates of reported AEs in the placebo arms were still substantial. Public vaccination programs should consider these high rates of AEs in placebo arms.

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.

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.

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.

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.