Nonalcoholic Fatty Liver Disease (NAFLD) is a growing health epidemic in developed countries with increased prevalence in obese and diabetic populations. Exercise is an established and essential component of lifestyle modification for NAFLD disease management. Despite numerous studies reporting exercise-mediated improvements in NAFLD, there remains a large gap in our knowledge of how to optimize exercise prescriptions and whether the benefits of exercise extend beyond improvements in liver fat. In this review, we summarize studies that have investigated the independent effects of exercise training on liver enzymes, hepatic fat, and histologic markers in NAFLD. Overall, 12-weeks of aerobic, resistance, the combination of aerobic and resistance, and novel training modalities, including acceleration and hybrid training, significantly improve liver enzymes and hepatic fat. The greatest benefits in NAFLD may occur through the combination of aerobic and resistance training that targets both cardiorespiratory fitness, and mediators of skeletal muscle, known as myokines. Understanding the role of myokines in the beneficial effects of exercise in NAFLD may identify future therapeutic targets that can be modified with tailored exercise prescriptions.

Importance Acute musculoskeletal pain is challenging to treat in the Emergency Department (ED), a novel setting to incorporate nonpharmacologic interventions, such as acupuncture, to reduce chronic pain. Objective Determine effectiveness of ED acupuncture for treating acute musculoskeletal pain. Design Pragmatic two-stage adaptive randomized clinical trial over one year. Stage 1 identified whether auricular acupuncture (AA) or peripheral acupuncture (PA) was more feasible and efficacious in the ED. Stage 2 assessed effectiveness of selected ED acupuncture intervention(s) on 1-hour pain reduction compared to no acupuncture (NA). Setting Academic tertiary-care ED. Participants Adults with acute (≤7 days) musculoskeletal pain in neck, back and/or extremities. Of 911 patients screened, 491 met inclusion criteria, 247 enrolled, 11 withdrew, and 236 were randomized (68 NA, 84 AA, 84 PA). Interventions AA places ear needles based on battlefield acupuncture. PA places needles in head, neck, and extremity sites distal to pain. Acupuncture was delivered by licensed acupuncturists. All three arms received usual care from blinded ED providers. Main Outcomes Primary outcome: 11-point Numeric pain rating scale at 1-hour. Secondary outcomes: Satisfaction with treatment; ED opioids given. Results Interim analysis at end of Stage 1 found both acupuncture styles similarly feasible and efficacious, so Stage 2 continued all three arms with unequal allocation (from 1:1:1 to 1:2:2 NA:AA:PA). All three arms had similar demographics (mean age 46.1 years ±16.5 SD, 56.2% female, and 53.6% Black), ED baseline pain scores (AA 7.0 ± 2.3, PA 7.2 ± 2.3, NA 6.9 ± 2.2) and pre-baseline ED administration of opioid and non-opioid analgesics. Both AA (2.1 ± 2.9) and PA (1.6 ± 2.0) produced significantly greater 1-hour pain reductions than NA (0.4 ± 1.9). Conclusions and Relevance Two different styles of ED acupuncture effectively reduce acute musculoskeletal pain better than usual care alone. Acupuncture is feasible, acceptable, and effective for treating pain in historically underserved populations in the emergency department setting. Clinicaltrials.gov registration Emergency Department Acupuncture for Acute Musculoskeletal Pain Management ID#: NCT04290741; URL: https://clinicaltrials.gov/ct2/show/NCT04290741 Question What is the effectiveness of acupuncture for reducing acute musculoskeletal pain in an emergency department (ED) population? Findings In this pragmatic randomized clinical trial of 236 adults, ED patients receiving auricular acupuncture had a mean (± SD) pain score reduction of 2.1 ± 2.9 points, those receiving peripheral acupuncture had a reduction of 1.6 ± 2.0 points, while those who did not receive acupuncture had no change in pain (0.4 ± 1.9), which was a significant difference between no acupuncture and both acupuncture groups. Meaning Acupuncture can be added to usual care to effectively improve acute musculoskeletal pain in the ED.

DYRK1A syndrome is a rare, severe neurodevelopmental disorder (NDD) characterized by intellectual disability, impaired speech development, microcephaly, craniofacial dysmorphisms, autism spectrum syndrome, and anxious/stereotypical behaviors. 1 DYRK1A syndrome is caused by disruptions to the DYRK1A gene located at chromosomal region 21q22.13, [1][2][3] which encodes for dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). DYRK1A is a highly dosage-sensitive gene. 4,5 DYRK1A syndrome is one of the most frequent monogenic causes of intellectual disability (affecting around 0.3% to 0.5% of cases). 1,[6][7][8] DYRK1A syndrome was first identified as a unique syndrome in 2008-2011, 2,3 but knowledge of the disorder has expanded rapidly. To date, over 260 unique cases of DYRK1A syndrome have been described in the literature [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] and the DYRK1A Syndrome International Association maintains a registry of over 970 patients representing 61 countries. 24 In 2024-2025, Frontiers in Neuroscience hosted a research topic: Advances in DYRK1A Syndrome: Underlying Mechanisms, Disease Models, and Novel Therapeutic Approaches. Its goals were to encourage publications that 1) explore the biological mechanisms of DYRK1A in cellular systems; 2) investigate domains such as skeletal health and executive functioning; and 3) advance translational opportunities. The five articles collected here advance these goals through clinical, mechanistic, and conceptual contributions.Cisternas et al. 25 provide a comprehensive review of the role of DYRK1A dosage in the neuronastrocyte axis, framing DYRK1A as having a Goldilocks zone. DYRK1A is central to neuronal morphogenesis and synaptic transmission, by acting as a checkpoint that ensures the proper number of neurons and astrocytes have differentiated at each stage of development. DYRK1A is thought to influence the astrocytes' neuroprotective activity by modulating astrocyte reactivity and glutamate excitotoxicity and viability. Cisternas et al. integrate the existing literature to hypothesize potential molecular mechanisms by which aberrant phosphorylation of DYRK1A substrates contribute to astrocyte pathology: impairing astrocyte reactivity, decreasing astrocytic uptake of glutamate to cause excitotoxicity, disrupting astrocyte regulation of appropriate Aꞵ levels, and contributing to tau hyperphosphorylation and aggregation. The review underscores the need for integrating the existing knowledge of DYRK1A in over-and under-expression disease contexts, so that we can advance the rational design of therapies tailored to target DYRK1A-subtrate interactions in both neurons and astrocytes.Courraud et al. 26 used IP-MS to map the DYRK1A interactome in human neural stem cells (hNSCs). They identified 35 DYRK1A interactors, 20 of which were novel. Overall, there was significant enrichment in proteins involved in cell cycle regulation and ubiquitination -notably, members of the anaphase-promoting complex and RNF114 (ZNF313). To investigate the consequences of DYRK1A loss on the transcriptome, Courraud et al. conducted siRNA knock down (KD) of DYRK1A in hNSCs and performed mRNA sequencing. They identified 91 significantly differentially expressed genes, with negative enrichment of genes related to the extracellular matrix and calcium binding, and upregulation of members of the early growth factor family and their downstream targets. DYRK1A-KD hNSCs leads to decreased proliferation and ERK activation. Importantly, Courraud et al. identified DCAF7, GSPT1, and PTBP2 as novel candidate genes for involvement in NDDs. Altogether, this study underscores DYRK1A's molecular role in development and highlights common molecular pathways between DYRK1A syndrome and other NDDs.Le May et al. 27 describe 11 individuals initially suspected of nucleotide excision repair (NER) disorders-Cockayne syndrome (CS) and trichothiodystrophy -who were ultimately diagnosed with DYRK1A syndrome. Shared features were microcephaly, intellectual disability, feeding difficulties, ataxic gait, and deep-set eyes. However, all these patients displayed features that are not typical in NER disorders: severe language impairment, febrile seizures, and anxious or autistic behaviors. Further, all 11 patients were found to be indistinguishable from the previously published cases in DYRK1A syndrome as measured on a 20-point clinical DYRK1A scale. After UV exposure, DYRK1A patient fibroblasts did not exhibit CS-like NER defects, nor did they show the CS transcriptional signature: ATF3 upregulation and ATF3-dependent gene downregulation. Crucially, DYRK1A itself is an ATF3-dependent gene downregulated in CS cells; therefore, the authors postulate that these disorders may have a common underlying cellular pathophysiology. Based on their findings, Le May and colleagues strongly advise that the differential diagnosis for clinicians suspecting patients of NER disorders includes DYRK1A syndrome.Otte and Roper 28 review skeletal phenotypes across human case reports and mouse models of DYRK1A syndrome and Down syndrome. They outline similar clinical skeletal phenotypes, including short stature, craniofacial dysmorphology, microcephaly, fetal growth restriction, and dental abnormalities. Mouse models of these disorders exhibit skeletal deficits analogous to humans, including craniofacial dysmorphisms, abnormal dentition, and a lowered body mass index. Interestingly, the authors reported potential sex differences in the Dyrk1a+/-mouse, showing reduced trabecular bone thickness, density, and area in male mice but not in females.Finally, the authors list potential pathways by which DYRK1A dysregulation impacts skeletal health, including PI3K/AKT/mTOR, NGF, and REST. Overall, this review emphasizes that DYRK1A mouse models are an important research tool to characterize the skeletal anomalies in DYRK1A syndrome. This understanding will aid in future...