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Abstract Introduction There are overlapping features between inflammatory myopathies and muscular dystrophies, particularly laminopathies. Key features that characterize laminopathies include axial and proximal weakness, contractures, and cardiac abnormalities. Methods/Results A 12‐year‐old girl diagnosed with juvenile dermatomyositis as a child presented with cardiac failure and was found to have an LMNA likely pathogenic variant, with a phenotype most consistent with Emery–Dreifuss muscular dystrophy type 2. Discussion The spectrum of clinical features of LMNA‐related muscular dystrophies can mimic or present with inflammatory myopathy‐like features. Early identification of LMNA‐related muscular dystrophies is crucial to ensure appropriate cardiac screening and prevent devastating cardiac complications.

Introduction: Published data investigating a time-dependent effect of initiation of antiarrhythmic therapy for shockable in-hospital cardiac arrest (IHCA) is lacking. We aimed to evaluate the association between time of intravenous amiodarone or lidocaine administration and return of spontaneous circulation (ROSC) in patients with IHCA caused by ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT). Methods: This was a retrospective, multi-center, single health system, observational cohort study of patients with an IHCA caused by VF/pVT and who received amiodarone or lidocaine during 2014–2024. The primary outcome was ROSC, and the secondary outcome was survival to hospital discharge. A multivariable logistic regression model was constructed to evaluate the association between (1) time to drug administration and (2) drug administration prior to the second defibrillator shock on both survival outcomes. Results: A total of 88 patients with a shockable IHCA were identified. Longer time to amiodarone or lidocaine administration was associated with lower likelihood of ROSC (adjusted odds ratio [aOR] 0.91; 95% CI: 0.83–0.99, P = 0.04) but not with survival to discharge (aOR 0.99; CI 0.90–1.10P = 0.90). Administration of antiarrhythmic therapy prior to the second defibrillator shock was associated with higher likelihood of ROSC (aOR 6.48; CI 2.08–20.21, P = 0.001) and survival to discharge (aOR 2.82; CI 1.03–7.77, P = 0.04). Conclusion: Early administration of amiodarone or lidocaine, particularly prior to the second defibrillator shock, was associated with an increased odds of survival outcomes in IHCA with shockable rhythms.

It is well established that hearing loss can lead to widespread plasticity within the central auditory pathway, which is thought to contribute to the pathophysiology of audiological conditions such as tinnitus and hyperacusis. Emerging evidence suggests that hearing loss can also result in plasticity within brain regions involved in higher-level cognitive functioning like the prefrontal cortex; findings which may underlie the association between hearing loss and cognitive impairment documented in epidemiological studies. Using the 40-Hz auditory steady state response to assess sound-evoked gamma oscillations, we previously showed that noise-induced hearing loss results in impaired gamma phase coherence within the prefrontal but not the auditory cortex. To determine whether region-specific structural or molecular changes accompany this differential plasticity following hearing loss, in the present study we utilized Golgi-Cox staining to assess dendritic organization and synaptic density, as well as Western blotting to measure changes in synaptic signaling proteins in these cortical regions. We show that following noise exposure, impaired gamma phase coherence within the prefrontal cortex is accompanied by alterations in pyramidal cell dendritic morphology and decreased expression of proteins involved in GABAergic (GAD65) and glutamatergic (NR2B) neurotransmission; findings that were not observed in the auditory cortex, where gamma phase coherence remained unchanged post-noise exposure. In contrast to the noise-induced effects we observed in the prefrontal cortex, plasticity in the auditory cortex was characterized by an increase in NR2B suggesting increased excitability, as well as increases in the synaptic proteins PSD95 and synaptophysin within the auditory cortex. Overall, our results highlight the disparate effect of noise-induced hearing loss on auditory and higher-level brain regions as well as potential structural and molecular mechanisms by which hearing loss may contribute to impaired cognitive and sensory functions mediated by the prefrontal and auditory cortices.

Solid tumors generally exhibit chromosome copy number variation, which is typically caused by chromosomal instability (CIN) in mitosis. The resulting aneuploidy can drive evolution and associates with poor prognosis in various cancer types as well as poor response to T-cell checkpoint blockade in melanoma. Macrophages and the SIRPα-CD47 checkpoint are understudied in such contexts. Here, CIN is induced in poorly immunogenic B16F10 mouse melanoma cells using spindle assembly checkpoint MPS1 inhibitors that generate persistent micronuclei and diverse aneuploidy while skewing macrophages toward a tumoricidal ‘M1-like’ phenotype based on markers and short-term anti-tumor studies. Mice bearing CIN-afflicted tumors with wild-type CD47 levels succumb similar to controls, but long-term survival is maximized by SIRPα blockade on adoptively transferred myeloid cells plus anti-tumor monoclonal IgG. Such cells are the initiating effector cells, and survivors make de novo anti-cancer IgG that not only promote phagocytosis of CD47-null cells but also suppress tumor growth. CIN does not affect the IgG response, but pairing CIN with maximal macrophage anti-cancer activity increases durable cures that possess a vaccination-like response against recurrence.

Modeling of infectious diseases at the livestock-wildlife interface is a unique subset of mathematical modeling with many innate challenges. To ascertain the characteristics of the models used in these scenarios, a scoping review of the scientific literature was conducted. Fifty-six studies qualified for inclusion. Only 14 diseases at this interface have benefited from the utility of mathematical modeling, despite a far greater number of shared diseases. The most represented species combinations were cattle and badgers (for bovine tuberculosis, 14), and pigs and wild boar [for African (8) and classical (3) swine fever, and foot-and-mouth and disease (1)]. Assessing control strategies was the overwhelming primary research objective (27), with most studies examining control strategies applied to wildlife hosts and the effect on domestic hosts (10) or both wild and domestic hosts (5). In spatially-explicit models, while livestock species can often be represented through explicit and identifiable location data (such as farm, herd, or pasture locations), wildlife locations are often inferred using habitat suitability as a proxy. Though there are innate assumptions that may not be fully accurate when using habitat suitability to represent wildlife presence, especially for wildlife the parsimony principle plays a large role in modeling diseases at this interface, where parameters are difficult to document or require a high level of data for inference. Explaining observed transmission dynamics was another common model objective, though the relative contribution of involved species to epizootic propagation was only ascertained in a few models. More direct evidence of disease spill-over, as can be obtained through genomic approaches based on pathogen sequences, could be a useful complement to further inform such modeling. As computational and programmatic capabilities advance, the resolution of the models and data used in these models will likely be able to increase as well, with a potential goal being the linking of modern complex ecological models with the depth of dynamics responsible for pathogen transmission. Controlling diseases at this interface is a critical step toward improving both livestock and wildlife health, and mechanistic models are becoming increasingly used to explore the strategies needed to confront these diseases.

Abstract Grinding stones and ground stone implements are important technological innovations in later human evolution, allowing the exploitation and use of new plant foods, novel tools (e.g., bone points and edge ground axes) and ground pigments. Excavations at the site of Madjedbebe recovered Australia’s (if not one of the world’s) largest and longest records of Pleistocene grinding stones, which span the past 65 thousand years (ka). Microscopic and chemical analyses show that the Madjedbebe grinding stone assemblage displays the earliest known evidence for seed grinding and intensive plant use, the earliest known production and use of edge-ground stone hatchets (aka axes), and the earliest intensive use of ground ochre pigments in Sahul (the Pleistocene landmass of Australia and New Guinea). The Madjedbebe grinding stone assemblage reveals economic, technological and symbolic innovations exemplary of the phenotypic plasticity of Homo sapiens dispersing out of Africa and into Sahul.

In an effort to help elucidate the neural mechanisms underlying tinnitus in humans, researchers have often relied on animal models; a preclinical approach which ultimately required that behavioral paradigms be designed to reliably screen animals for tinnitus. Previously, we developed a two-alternative forced-choice (2AFC) paradigm for rats that allowed for the simultaneous recording of neural activity at the very moments when they were reporting the presence/absence of tinnitus. Because we first validated our paradigm in rats experiencing transient tinnitus following a high-dose of sodium salicylate, the present study now sought to evaluate its utility to screen for tinnitus caused by intense sound exposure; a common tinnitus-inducer in humans. More specifically, through a series of experimental protocols, we aimed to (1) conduct sham experiments to ensure that the paradigm was able to correctly classify control rats as not having tinnitus, (2) confirm the time course over which the behavioral testing could reliably be performed post-exposure to assess chronic tinnitus, and (3) determine if the paradigm was sensitive to the variable outcomes often observed after intense sound exposure (e.g., hearing loss with our without tinnitus). Ultimately, in accordance with our predictions, the 2AFC paradigm was indeed resistant to false-positive screening of rats for intense sound-induced tinnitus, and it was able to reveal variable tinnitus and hearing loss profiles in individual rats following intense sound exposure. Taken together, the present study documents the utility of our appetitive operant conditioning paradigm to assess acute and chronic sound-induced tinnitus in rats. Finally, based on our findings, we discuss important experimental considerations that will help ensure that our paradigm is able to provide a suitable platform for future investigations into the neural basis of tinnitus.

Hearing loss is a chronic health condition that affects millions of people worldwide. In addition to age-related hearing impairment, excessive noise exposure is a leading cause of hearing loss. Beyond the devastating effects of hearing impairment itself, epidemiological studies have identified hearing loss as a major risk factor for age-related cognitive decline, including dementia. At present, we currently lack a full understanding of the brain regions and underlying molecular changes that are responsible for mediating the link between hearing loss and cognitive impairment across aging. In the present study, we exposed 6-month-old rats to an occupational-like noise (100 dB SPL, 4 h/day × 30 days) or sham exposure and investigated both hippocampal-dependent (i.e., spatial learning and memory, assessed using the Morris water maze) and striatal-dependent (i.e., visuomotor associative learning, assessed using an operant-conditioning task) cognitive function across aging at 7, 10, and 13 months of age. We also investigated brain region-specific changes in microglial expression following noise/sham exposure in order to assess the potential contribution of this cell type to noise-induced cognitive impairments. Consistent with human studies, the occupational-like noise exposure resulted in high-frequency hearing loss, evidenced by a significant increase in hearing thresholds at 20 kHz. Ultimately, our results suggest that not all higher-level cognitive tasks or their associated brain regions appear to be equally susceptible to noise-induced deficits during aging, as the occupational-like noise exposure caused an age-dependent deficit in spatial but not visuomotor associative learning, as well as altered microglial expression in the hippocampus but not the striatum. Interestingly, we found no significant relationships between spatial learning ability and the level of hearing loss or altered microglial density in the hippocampus following noise exposure, suggesting that other changes in the brain likely contribute to hippocampal-dependent cognitive dysfunction following noise exposure. Lastly, we found that a subset of younger animals also showed noise-induced deficits in spatial learning; findings which suggest that noise exposure may represent an increased risk for cognitive impairment in vulnerable subjects. Overall, our findings highlight that even a mild occupational-like noise exposure earlier in adulthood can have long lasting implications for cognitive function later in life.

Abstract Background Only a few small studies have previously reported episodes of hypoglycemia in children with neuromuscular diseases; however, there has been no broader investigation into the occurrence of hypoglycemia in children with congenital muscle disease (CMD). Methods Pediatric patients enrolled in the CMD International Registry (CMDIR) with a history of hypoglycemia were included in this retrospective review. Hypoglycemic episodes and associated clinical and biochemical characteristics were characterized. Results Ten patients with CMD (5 with LAMA2-related muscular dystrophy) reported at least one episode of hypoglycemia beginning at an average age of 3.5 years. Predominant symptoms included altered mental status and nausea/vomiting, and laboratory studies demonstrated metabolic acidosis and ketonuria, consistent with ketotic hypoglycemia. Conclusion Patients with CMD may have an increased risk of hypoglycemia during fasting, illness, or stress due to their relatively low muscle mass and hence, paucity of gluconeogenic substrate. Clinicians should therefore maintain a high index of suspicion for hypoglycemia in this high-risk patient population and caregivers should routinely be trained to recognize and treat hypoglycemia.

A hallmark of Alzheimer's, Huntington's and similar diseases is the assembly of proteins into amyloids rather than folding into their native state. There is an increasing appreciation that amyloids, under specific conditions, may be non-pathogenic. Here we show that amyloids form as a normal part of Xenopus oocyte development. Amyloids are detectable in the cytosol and the nucleus using an amyloid binding dye and antibodies that recognize amyloid structure. In the cytosol, yolk platelets are amyloid reactive, as are a number of yet to be characterized particles. In the nucleus, we find particles associated with transcription by RNA polymerase I, II and III and RNA processing contain amyloids. Nuclear amyloids remain intact for hours following isolation; however, RNase treatment rapidly disrupts nuclear amyloids.

For many proteins, aggregation is one part of a structural equilibrium that can occur. Balancing productive aggregation versus pathogenic aggregation that leads to toxicity is critical and known to involve adenosine triphosphate (ATP) dependent action of chaperones and disaggregases. Recently a second activity of ATP was identified, that of a hydrotrope which, independent of hydrolysis, was sufficient to solubilize aggregated proteins in vitro. This novel function of ATP was postulated to help regulate proteostasis in vivo. We tested this hypothesis on aggregates found in Xenopus oocyte nucleoli. Our results indicate that ATP has dual roles in the maintenance of protein solubility. We provide evidence of endogenous hydrotropic action of ATP but show that hydrotropic solubilization of nucleolar aggregates is preceded by a destabilizing event. Destabilization is accomplished through an energy dependent process, reliant upon ATP and one or more soluble nuclear factors, or by disruption of a co-aggregate like RNA.