Vertebral pattern and morphology is determined during embryonic segmentation.

BACKGROUND: The segmented nature of the adult vertebral column is based on segmentation of the paraxial mesoderm during early embryogenesis. Disruptions to embryonic segmentation, whether caused by genetic lesions or environmental stress, result in adult vertebral pathologies. However, the mechanisms linking embryonic segmentation and the details of adult vertebral morphology are poorly understood. RESULTS: We induced border defects using two approaches in zebrafish: heat stress and misregulation of embryonic segmentation genes tbx6, mesp-ba, and ripply1. We assayed vertebral length, regularity, and polarity using microscopic and radiological imaging. In population studies, we find a correlation between specific embryonic border defects and specific vertebral defects, and within individual fish, we trace specific adult vertebral defects to specific embryonic border defects. CONCLUSIONS: Our data reveal that transient disruptions of embryonic segment border formation led to significant vertebral anomalies that persist through adulthood. The spacing of embryonic borders controls the length of the vertebra. The positions of embryonic borders control the positions of ribs and arches. Embryonic borders underlie fusions and divisions between adjacent spines and ribs. These data suggest that segment borders have a dominant role in vertebral development.

The Health Benefits, Costs, and Cost-Effectiveness of Ultraorphan Drugs.

OBJECTIVES: To examine ultraorphan drugs in terms of incremental health, costs, and cost-effectiveness compared with more prevalent disease drugs. METHODS: We identified Food and Drug Administration drug approvals from 1999 to 2019. For drugs approved for multiple indications, we considered each drug-indication pair separately. Utilizing Food and Drug Administration's orphan drug designation and US disease prevalence, we categorized drug-indication pairs as: ultraorphan (<10 000 patients), "other" orphan (≥10 000 and <200 000), and nonorphan (≥200 000). We searched the PubMed database for cost-effectiveness analyses and comparative effectiveness studies. We excluded manufacturer-funded studies. We extracted estimates of incremental health gains in terms of quality-adjusted life-years (QALYs) and incremental costs associated with drug-indication pairs compared with the standard of care at the time of their approval. We compared QALY gains, added costs, and incremental cost-effectiveness ratios (ICERs) using the Kruskal-Wallis, Mann-Whitney U (MWU), and Kolmogorov-Smirnov (KS) tests. RESULTS: Median incremental QALYs, costs, and ICERs differed across nonorphan, "other" orphan, and ultraorphan categories (Kruskal-Wallis P < .01). Compared with nonorphan drugs, ultraorphan drugs had larger QALY gains (0.700 vs 0.050, MWU P < .01, KS P < .01), larger costs ($172 231 vs $3360, MWU P < .01, KS P < .01), and larger ICERs ($1 216 184/QALY vs $114 061/QALY, MWU P < .01, KS P <.01). Compared with "other" orphan drugs, ultraorphan drugs had larger QALY gains (0.700 vs 0.310, MWU P =.65, KS P =.32), larger costs ($172 231 vs $69 308, MWU P = .03, KS P = .03), and larger ICERs ($1 216 184/QALY vs $223 472/QALY, MWU P <.01, KS P <.01). CONCLUSIONS: Novel ultraorphan drugs typically offer larger incremental health gains than drugs for more prevalent diseases, but because of their substantial added costs, are typically less cost-effective.

The dynamic feasibility of resisting (R), accepting (A), or directing (D) ecological change.

Ecological transformations are occurring as a result of climate change, challenging traditional approaches to land management decision-making. The resist-accept-direct (RAD) framework helps managers consider how to respond to this challenge. We examined how the feasibility of the choices to resist, accept, and direct shifts in complex and dynamic ways through time. We considered 4 distinct types of social feasibility: regulatory, financial, public, and organizational. Our commentary is grounded in literature review and the examples that exist but necessarily has speculative elements because empirical evidence on this newly emerging management strategy is scarce. We expect that resist strategies will become less feasible over time as managers encounter situations where resisting is ecologically, by regulation, financially, or publicly not feasible. Similarly, we expect that as regulatory frameworks increasingly permit their use, if costs decrease, and if the public accepts them, managers will increasingly view accept and direct strategies as more viable options than they do at present. Exploring multiple types of feasibility over time allows consideration of both social and ecological trajectories of change in tandem. Our theorizing suggested that deepening the time horizon of decision-making allows one to think carefully about when one should adopt different approaches and how to combine them over time.

La viabilidad dinámica de resistir (R), aceptar (A) o dirigir (D) el cambio ecológico Resumen Las transformaciones ecológicas ocurren por el cambio climático, lo que representa un reto para los enfoques tradicionales para decidir en torno a la gestión de tierras. El marco resistir­aceptar­dirigir (RAD) ayuda a los gestores a considerar cómo responder a este reto. Analizamos cómo la viabilidad de las opciones para resistir, aceptar y dirigir cambia de manera compleja y dinámica con el tiempo. Consideramos cuatro tipos distintos de viabilidad: regulatoria, económica, pública y de organización. Nuestro comentario está basado en la revisión bibliográfica y los ejemplos que existen, pero por necesidad tiene elementos especulativos ya que la evidencia empírica sobre esta estrategia emergente de gestión es escasa. Esperamos que las estrategias de resistir se vuelvan menos viables con el tiempo conforme los gestores encuentren situaciones en las que resistir no es viable de forma ecológica, económica, pública o por regulación. Al igual esperamos que cada vez más los marcos regulatorios permitan su uso, si el costo disminuye, y si el público los acepta, los gestores verán cada vez más viables las estrategias de aceptar y dirigir que las que utilizan actualmente. La exploración de varios tipos de viabilidad a lo largo del tiempo permite considerar las trayectorias sociales y ecológicas del cambio en conjunto. Nuestra teoría sugiere que profundizar en el horizonte temporal de las decisiones permite que se analice con cuidado sobre cuando se deben adoptar enfoques diferentes y cómo combinarlos con el tiempo.

Navigating Climate Adaptation on Public Lands: How Views on Ecosystem Change and Scale Interact with Management Approaches.

Managers are increasingly being asked to integrate climate change adaptation into public land management. The literature discusses a range of adaptation approaches, including managing for resistance, resilience, and transformation; but many strategies have not yet been widely tested. This study employed in-depth interviews and scenario-based focus groups in the Upper Gunnison Basin in Colorado to learn how public land managers envision future ecosystem change, and how they plan to utilize different management approaches in the context of climate adaptation. While many managers evoked the past in thinking about projected climate impacts and potential responses, most managers in this study acknowledged and even embraced (if reluctantly) that many ecosystems will experience regime shifts in the face of climate change. However, accepting that future ecosystems will be different from past ecosystems led managers in different directions regarding how to respond and the appropriate role of management intervention. Some felt management actions should assist and even guide ecosystems toward future conditions. Others were less confident in projections and argued against transformation. Finally, some suggested that resilience could provide a middle path, allowing managers to help ecosystems adapt to change without predicting future ecosystem states. Scalar challenges and institutional constraints also influenced how managers thought about adaptation. Lack of institutional capacity was believed to constrain adaptation at larger scales. Resistance, in particular, was considered impractical at almost any scale due to institutional constraints. Managers negotiated scalar challenges and institutional constraints by nesting different approaches both spatially and temporally.

Thymectomy may not be associated with clinical improvement in MuSK myasthenia gravis.

INTRODUCTION: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG. METHODS: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG. RESULTS: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19). DISCUSSION: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019.

Intrinsic network connectivity abnormalities in HIV-infected individuals over age 60.

Individuals infected with HIV are living longer due to effective treatment with combination antiretroviral therapy (cART). Despite these advances, HIV-associated neurocognitive disorders (HAND) remain prevalent. In this study, we analyzed resting state functional connectivity (rs-fc) data from HIV-infected and matched HIV-uninfected adults aged 60 years and older to determine associations between HIV status, neuropsychological performance, and clinical variables. HIV-infected participants with detectable plasma HIV RNA exhibited decreased rs-fc within the salience (SAL) network compared to HIV-infected participants with suppressed plasma HIV RNA. We did not identify differences in rs-fc within HIV-infected individuals by HAND status. Our analysis identifies focal deficits in the SAL network that may be mitigated with suppression of plasma virus. However, these findings suggest that rs-fc may not be sensitive as a marker of HAND among individuals with suppressed plasma viral loads.

Are Drug Novelty Characteristics Associated With Greater Health Benefits?

OBJECTIVE: The aim of this study was to examine the association between characteristics of novel drugs and incremental health gains relative to standard of care, in terms of quality-adjusted life-years (QALYs). METHODS: This study's unit of analysis is the drug-indication pair. For pairs approved by the US FDA from 1999 to 2018, we quantified incremental health gains using QALYs from the published literature and characterized each pair's novelty in terms of a series of six binary (yes/no) characteristics of novel drugs given special consideration by Health Technology Assessment agencies: Novel mechanism of action, Indicated for a rare disease, Indicated for a pediatric population, Treats a serious condition, Offers meaningful improvement over available therapies, and Potential to address unmet clinical needs. We analyzed measures of bivariate association (Mann-Whitney U and Kolmogorov-Smirnov tests) and multivariable regression, accounting for the influence of multiple novelty characteristics simultaneously. RESULTS: Our sample of 146 drugs represents 21% of drugs approved the FDA in the time period (1999-2018). Median and mean QALY gains for 'novel' drug-indication pairs exceeded corresponding QALY gains for non-novel drug-indication pairs. For most comparisons, the bivariate relationships between QALY gains and novelty characteristics were significant at p < 0.05 except for novel mechanism of action (Kolmogorov-Smirnov test) and pediatric indication (both bivariate tests). Multivariable models revealed an independent association between novelty characteristics and QALY gain except for unmet clinical need and indicated for a rare disease. CONCLUSIONS: Drugs with novelty characteristics conferred larger health gains than drugs without these characteristics in bivariate analysis, multivariable models, or both. Future research should examine other aspects of drug novelty, such as patient and health system costs and equitable access.

Utility of Repetitive Nerve Stimulation in the Diagnosis of Myasthenia Gravis in the Inpatient Setting.

Objectives: Sensitivity and specificity of Repetitive Nerve Stimulation (RNS) is typically reported from outpatient centers, and we hypothesized that these values might not apply to hospitalized patients with higher grades of weakness. RNS may be helpful in rapidly confirming diagnosis of myasthenia gravis (MG) in the inpatient setting, as results from confirmatory antibody testing are often delayed. We sought to characterize the sensitivity and specificity of RNS in the inpatient setting to assist in the early diagnosis of MG. Methods: We performed a retrospective analysis of all adult patients who had inpatient RNS at our center from 2016 to 2021. Inclusion criteria included RNS performed at least at one site and a neurological evaluation which prompted an electrodiagnostic study to evaluate for neuromuscular junction (NMJ) pathology. Descriptive statistics and Fisher exact analysis were performed. Results: Of the 32 identified hospitalized patients, 6 had greater than 10% decrement on slow RNS, confirming NMJ dysfunction. Five were diagnosed with MG, and 1 with Lambert-Eaton myasthenic syndrome. Of the 26 patients with normal RNS, 25 ultimately had alternative causes of weakness. One was later diagnosed as seronegative MG based on clinical improvement with acetylcholinesterase inhibitors. In our inpatient population, the overall sensitivity and specificity of RNS were 83.3% and 96.2% respectively. There was a statistically significant association between a positive RNS and diagnosis of MG (P = .0002). Conclusions: RNS is a highly sensitive and specific test for the diagnosis of MG in an inpatient setting, and these results are likely more rapidly available compared to antibody testing.

Disseminated Mycobacterium bovis Infection Complicated by Meningitis and Stroke: A Case Report.

We describe a case of a 19-year-old female presenting with Mycobacterium bovis meningitis, a rarely encountered infection. We discuss the use of pyrosequencing to aid in prompt diagnosis of M. bovis infection, as well as treatment strategies and challenges given the organism's intrinsic resistance to pyrazinamide.

Rescue of Nimodipine-Induced Refractory Vasoplegia With Hydroxocobalamin in Subarachnoid Hemorrhage: A Case Report.

BACKGROUND: We report a case of refractory vasoplegia after nimodipine administration that was unresponsive to triple vasopressor therapy and was rescued by IV hydroxocobalamin. CASE SUMMARY: An 84-year-old male presented comatose from a subarachnoid hemorrhage and developed severe hypotension unresponsive to three vasopressors following a single dose of enteral nimodipine. Multisystem point-of-care ultrasonography ruled out alternate etiologies of shock, indicating that this was likely a vasoplegic state caused by nimodipine. We administered 5 grams of IV hydroxocobalamin over 15 minutes due to the possibility of impaired nitric oxide metabolism as the driver of vasoplegia. This led to immediate improvement in hemodynamics and rapid discontinuation of vasopressors. The patient experienced chromaturia but no other adverse effects due to hydroxocobalamin. CONCLUSIONS: Nimodipine administration is a standard practice for patients with aneurysmal subarachnoid hemorrhage to reduce unfavorable outcomes from cerebral vasospasm. Although mild hypotension is a common side effect of nimodipine, in rare cases, it may become profound, leading to refractory vasoplegia. There is no evidence-base for reversal agents for nimodipine-induced vasoplegia, and this case is the first to demonstrate successful use of hydroxocobalamin as a potential rescue therapy. We also propose an algorithm for treatment of vasoplegia with consideration of medications that act on nitric oxide-mediated vasodilation and their side-effect profiles.

Regional brain volumetric changes despite 2 years of treatment initiated during acute HIV infection.

OBJECTIVE: To assess changes in regional brain volumes after 24 months among individuals who initiated combination antiretroviral therapy (cART) within weeks of HIV exposure. DESIGN: Prospective cohort study of Thai participants in the earliest stages of HIV-1infection. METHODS: Thirty-four acutely HIV-infected individuals (AHI; Fiebig I-V) underwent brain magnetic resonance (MR) imaging and MR spectroscopy at 1.5 T and immediately initiated cART. Imaging was repeated at 24 months. Regional brain volumes were quantified using FreeSurfer's longitudinal pipeline. Voxel-wise analyses using tensor-based morphometry (TBM) were conducted to verify regional assessments. Baseline brain metabolite levels, blood and cerebrospinal fluid biomarkers assessed by ELISA, and peripheral blood monocyte phenotypes measured by flow cytometry were examined as predictors of significant volumetric change. RESULTS: Participants were 31 ±â€Š8 years old. The estimated mean duration of infection at cART initiation was 15 days. Longitudinal analyses revealed reductions in volumes of putamen (P < 0.001) and caudate (P = 0.006). TBM confirmed significant atrophy in the putamen and caudate, and also in thalamic and hippocampal regions. In exploratory post-hoc analyses, higher baseline frequency of P-selectin glycoprotein ligand-1 (PSGL-1)-expressing total monocytes correlated with greater caudate volumetric decrease (ρ = 0.67, P = 0.017), whereas the baseline density of PSGL-1-expressing inflammatory (CD14CD16) monocytes correlated with putamen atrophy (ρ = 0.65, P = 0.022). CONCLUSION: Suppressive cART initiated during AHI may not prevent brain atrophy. Volumetric decrease appears greater than expected age-related decline, although examination of longitudinal change in demographically similar HIV-uninfected Thai individuals is needed. Mechanisms underlying progressive HIV-related atrophy may include early activation and enhanced adhesive and migratory capacity of circulating monocyte populations.

Follow-On Indications for Orphan Drugs Related to the Inflation Reduction Act.

This cohort study assesses rates at which orphan drugs approved by the US Food and Drug Administration were also approved for supplemental (follow-on) indications.

Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years.

BACKGROUND: Current HIV treatments are successful at suppressing plasma HIV RNA to undetectable levels for most adherent patients. Yet, emerging evidence suggests that viral suppression will inadequately control inflammation and mitigate risk for progressive brain injury. We sought to quantify differences in longitudinal brain atrophy rates among older virally suppressed HIV-infected participants compared with that of healthy aging participants. METHODS: We examined longitudinal structural brain magnetic resonance imaging atrophy rates using region of interest assessments and voxel-wise tensor-based morphometry in HIV-infected participants older than 60 years (n = 38) compared with age-matched HIV-uninfected healthy and cognitively normal controls (n = 24). RESULTS: The mean age of participants was 63 years, the mean estimated duration of infection was 21 years, and the median duration of documented viral suppression was 3.2 years. Average proximal and nadir CD4 counts were 550 and 166, respectively; 15/38 (39%) met criteria for HIV-associated neurocognitive disorder. In models adjusting for age and sex, HIV serostatus was associated with more rapid average annualized rates of atrophy in the cerebellum (0.42% vs. 0.02%, P = 0.016), caudate (0.74% vs. 0.03%, P = 0.012), frontal lobe (0.48% vs. 0.01%, P = 0.034), total cortical gray matter (0.65% vs. 0.16%, P = 0.027), brainstem (0.31% vs. 0.01%, P = 0.026), and pallidum (0.73% vs. 0.39%, P = 0.046). Among those with HIV, atrophy rates did not differ statistically by cognitive status. CONCLUSIONS: Despite persistent control of plasma viremia, these older HIV-infected participants demonstrate more rapid progressive brain atrophy when compared with healthy aging. Either HIV or other factors that differ between older HIV-infected participants and healthy controls could be responsible for these differences.

ApoE ε4 Is Associated With Cognition, Brain Integrity, and Atrophy in HIV Over Age 60.

BACKGROUND: There are contradicting reports on the associations between Apolipoprotein E4 (ApoE ε4) and brain outcomes in HIV with some evidence that relationships may be greatest in older age groups. METHODS: We assessed cognition in 76 clinically stable HIV-infected participants over age 60 and genotyped ApoE. Sixty-one of these subjects underwent structural brain magnetic resonance imaging and diffusion tensor imaging. RESULTS: The median age of the participants was 64 years (range: 60-84) and the median estimated duration of HIV infection was 22 years. Apo ε4 carriers (n = 19) were similar to noncarriers (n = 57) in sex (95% vs. 96% male), and education (16.0 vs. 16.2 years) ApoE ε4 carriers demonstrated greater deficits in cognitive performance in the executive domain (P = 0.045) and had reduced fractional anisotropy and increased mean diffusivity throughout large white matter tracts within the brain compared with noncarriers. Tensor-based morphometry analyses revealed ventricular expansion and atrophy in the posterior corpus callosum, thalamus, and brainstem among HIV-infected ApoE ε4 carriers compared with ε4 noncarriers. CONCLUSIONS: In this sample of older HIV-infected individuals, having at least 1 ApoE ε4 allele was associated with decreased cognitive performance in the executive functioning domain, reduced brain white matter integrity, and brain atrophy. Brain atrophy was most prominent in the posterior corpus callosum, thalamus, and brainstem. This pattern of cognitive deficit, atrophy, and damage to white matter integrity was similar to that described in HIV, suggesting an exacerbation of HIV-related pathology; although emergence of other age-associated neurodegenerative disorders cannot be excluded.

Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome.

A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11(+/-)). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2(+)) and fewer dopamine-sensitive (Drd1(+)) neurons in deep layers of cortex. Electrophysiological recordings of Drd2(+) MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11(+/-) mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11(+/-) mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.