The fentanyl era has produced recurrent community observations of people remaining upright or semi-upright in sustained forward flexion of the head and trunk with intermittent nodding, colloquially referred to as the "fentanyl nod" or "fentanyl fold." Yet the motor state producing this appearance has never been measured directly. We conducted a structured narrative review spanning axial postural-control and reticulospinal neurophysiology, mu-opioid pharmacology, fentanyl-associated rigidity, alpha-2 adulterants, and observations from supervised consumption settings, and integrated these literatures into a testable framework. We introduce opioid flexion phenotype as a descriptive term for the observed configuration, deliberately holding it apart from any diagnostic or mechanistic claim. We advance disproportionate impairment of axial antigravity control as the primary hypothesis, set against three alternatives the evidence does not yet exclude: generalized sedation with loss of postural support; flexor-predominant rigidity or dystonia; and a mixed or fluctuating motor state. The hypothesis predicts that axial extensor activity will be reduced beyond that expected for the level of arousal at comparable ventilation, without increased flexor co-contraction or passive resistance. The rigidity literature prevents visual flexion from being equated with hypotonia, while alpha-2 agonists such as xylazine and medetomidine are better understood as state-dependent modifiers because they may deepen sedation, alter postural support or attenuate an established rigidity state. Persistent flexion after naloxone is non-specific and does not identify either co-exposure or motor mechanism. Discrimination among the accounts requires concurrent assessment of axial muscle activity, passive tone, arousal, ventilation, kinematics, toxicological exposure and longitudinal response. The immediate clinical and harm reduction implications are mechanism-independent: forward flexion should prompt assessment for toxicity rather than dismissal as sleep or voluntary posture; ventilation, not posture, governs urgency and naloxone titration in suspected opioid overdose; and neither appearance nor naloxone response identifies the underlying motor state. The flexed presentation has been read confidently as sedation, hypotonia and rigidity; none of these interpretations is yet warranted, and the instruments needed to adjudicate among them exist, while the observational protocol does not.

The substantial weight loss achieved with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin agonists has transformed the management of obesity and cardiometabolic risk. However, the accompanying reduction in lean mass has raised concerns regarding potential sarcopenia and impaired physical function, particularly in older adults. These concerns have become increasingly relevant as incretin-based therapies assume a central role in cardiovascular prevention. Importantly, reductions in lean mass measured by dual-energy X-ray absorptiometry and other body-composition techniques do not necessarily reflect deterioration in muscle quality, strength, or functional capacity. We propose that a substantial proportion of the observed decline in lean mass represents a physiological adaptation to the reduced mechanical loading associated with marked weight loss. Obesity imposes chronic biomechanical overload on weight-bearing musculature, promoting compensatory increases in muscle mass. Conversely, successful weight reduction lowers mechanical demands and may induce adaptive remodeling of antigravity muscles toward a new equilibrium appropriate for a lighter body. This interpretation is supported by established principles of unloading physiology derived from studies of immobilization, bed rest, and microgravity, as well as by emerging concepts linking body-weight sensing to musculoskeletal adaptation. We present a conceptual framework in which energy deficit, improvements in tissue composition, and mechanical unloading act as complementary contributors to lean mass reduction during GLP-1 RAs therapy. We also propose testable predictions that may help distinguish adaptive remodeling from pathological muscle loss (Fig. 1). From a cardiovascular prevention perspective, the key question may not be whether lean mass decreases during successful obesity treatment, but whether these changes impair physical function or diminish the substantial cardiometabolic benefits of weight reduction. Recognizing mechanical unloading as an underappreciated explanatory framework for interpreting lean mass loss during incretin-based therapy may improve risk-benefit assessment and redirect attention toward clinically meaningful outcomes, including muscle strength, physical performance, mobility, and cardiovascular health.

Insulin resistance is important in the cause of type 2 diabetes mellitus (T2DM), but traditional markers for obesity are not enough to explain metabolic risk. The idea for this review stems from an interest in understanding the interplay between ectopic fat accumulation and activity of skeletal muscle with gravitational loading in precipitating insulin resistance and a 'Gravity-Muscle-Ectopic Fat Axis' as an integrative framework. We conducted a literature search using a narrative review approach in PubMed, Scopus, Web of Science, and Google Scholar. We identified and screened published studies from 2018 to 2026 and synthesized up to 40 high-quality, representative articles. We critically analyzed the evidence on ectopic fat, Skeletal Muscle Metabolism, anti-gravity muscle activity, Exercise interventions, and glucose homeostasis. Ectopic deposition of fat in skeletal muscle, pancreas, and liver is thought to be associated with insulin resistance and impaired pancreatic β-cell function. Ectopic fat and insulin sensitivity are tightly linked, and metabolic health is closely tied to both. Skeletal muscle has emerged as a key regulator of glucose homeostasis, and emerging evidence suggests that gravitational loading and anti-gravity muscle activation may contribute to more favorable ectopic fat distribution and improved metabolic regulation. This Gravity-Muscle-Ectopic Fat Axis offers a new conceptual model that connects muscle activity, ectopic fat loss, and insulin sensitivity. Addressing muscle health and ectopic fat may be promising strategies for preventing and treating insulin resistance (IR) and T2DM.

Abnormal synergies coexist with primary motor impairments (weakness and spasticity) after stroke. They are observed during voluntary movements and are characterized by stereotyped movement patterns, a loss of independent joint control, and abnormal muscle coordination (eg, involuntary activation of distal muscles led by proximal joint movement). The structure and expression of abnormal synergies, however, are highly context-dependent (eg, influenced by gravity, body posture, and task constraints) and are not homogeneous across patients. Current evidence suggests that abnormal synergies are pathophysiologically related to damage to corticospinal tracts, upregulation of brainstem pathways (particularly the medial reticulospinal tract, but also involves the vestibulospinal tract), and maladaptive changes in spinal circuitry. These same mechanisms may overlap with those underlying spasticity and weakness. Spasticity is believed to result from overexcitability of descending excitatory brainstem pathways, the reticulospinal tract in particular, and the consequent exaggerated stretch reflexes, while muscle weakness is attributed to the reduction in corticospinal output. Recent research and clinical observations have advanced our understanding of abnormal synergies. Post-stroke abnormal synergies are not fixed motor impairments. A new framework is proposed that suggests post-stroke abnormal synergies could constitute the behavioral expression of primary impairments, including weakness and spasticity, arising from their interactions with environmental constraints, particularly antigravity control mechanisms. The term "synergy" has been used across various frameworks, with different definitions and quantification approaches. Identifying appropriate methods to quantify abnormal synergies is therefore essential to investigate their relationship with spasticity and muscle weakness, and evaluate potential abnormal synergy improvements following interventions, even if they primarily target other motor impairments.

MEGF10 biallelic variants cause early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD), congenital myopathies with cores, and later-onset myopathies with respiratory failure. As MEGF10 plays a key role in satellite cells proliferation and differentiation, these disorders are considered primary Satellite Cell-opathies. We present clinical, genetic, and laboratory findings from three patients with MEGF10-related myopathy from two families: a 6-year-old boy with EMARDD, and two siblings with a milder myopathy with respiratory involvement. Patient 1, male, showed decreased fetal movements and profound neonatal hypotonia with respiratory failure, requiring tracheostomy soon after birth. At 6 years, he had lack of head and trunk control, scoliosis, and upper limbs antigravity movements. Muscle MRI revealed mild-to-moderate, symmetrical fibro-fatty replacement affecting scapular, paravertebral, gluteal and adductor muscles, with bilateral absence of the semimembranosus. Muscle biopsy revealed a reduction of Pax7-positive satellite cells. Genetic studies disclosed the novel homozygous MEGF10 c.337T>C, p.(Cys113Arg) variant. Patient 2 is a 24-year-old woman with myopathic facies, progressive axial and generalized weakness, and thoracolumbar scoliosis at 11 years, leading to progressive respiratory involvement necessitating tracheostomy at 14 years. Her 17-year-old brother, patient 3, experienced a threatened abortion and perinatal complications consisting of neonatal hypoxia, right arm monoplegia, and clavicle fracture, followed by motor delay, scoliosis and progressive respiratory dysfunction, requiring non-invasive ventilation at 16 years. P2 and P3 harbour the novel homozygous c.917G>C, p. (Arg306Pro) MEGF10 pathogenic variant. We describe three new patients with MEGF10-related myopathy, showing severe but variable clinical expression, associated with two novel variants.

Background: Early recovery after total hip (THA) and total knee arthroplasty (TKA) is often limited by pain and impaired antigravity function. Mechano-acoustic vibration therapy (VT) may enhance neuromuscular activation and analgesia, but evidence in arthroplasty is scarce. Methods: A total of 380 patients aged ≥65 years were retrospectively identified within 3 ± 1 days after primary unilateral total hip arthroplasty (THA) or total knee arthroplasty (TKA). All patients underwent standard inpatient physiotherapy; in the VT group, mechano-acoustic vibration therapy (ViSS®, 30 min/day for 5 days at 200-300 Hz) was added as an adjunct treatment, whereas the control group received standard physiotherapy alone. Pain (VAS, McGill), muscle strength (MRC), thigh circumferences, and 10 s Sit-to-Stand were assessed at baseline (T0), end of treatment (T1), and 3-day follow-up (T2). Results: VT produced large, early and sustained improvements in both cohorts. In THA patients, VAS decreased from 7.1 ± 1.1 to 3.8 ± 0.6 at T1 and 3.0 ± 0.7 at T2 and Sit-to-Stand repetitions increased from 3.7 ± 1.9 to 6.3 ± 1.7 at T2, with significant gains in strength and circumferences. TKA VT patients showed similar patterns. Control groups reported smaller pain reductions and no clinically relevant changes in the reported outcomes. Conclusions: integrating a short cycle of mechano-acoustic VT into early inpatient rehabilitation after THA or TKA significantly enhances pain relief and restoration of antigravity function compared with standard physiotherapy alone. VT represents a promising adjunct to conventional rehabilitation strategies and may contribute to optimizing postoperative recovery pathways in major joint replacement.

BACKGROUND Cervical spinal epidural abscesses are uncommon; ventral lesions are rare, often arising from contiguous spondylodiscitis. Atypical presentations without cranial nerve involvement or altered consciousness are easily misattributed to intracranial diseases, delaying care. CASE REPORT We report the case of a 51-year-old man with poorly controlled hypertension and recent heroin use who developed progressive back and neck pain along with 3 days of fever, followed by rapidly progressive asymmetric weakness. Neurological examination revealed a paradoxical T4/T5 sensory level with preserved mentation and cranial nerve function, an important bedside clue suggesting a spinal process despite an initial stroke workup. Cervical gadolinium-enhanced magnetic resonance imaging (MRI) later revealed a long-segment ventral-dorsal C2-C7 epidural abscess with compressive myelopathy and C4-C6 spondylodiscitis; blood cultures grew methicillin-resistant Staphylococcus aureus. The patient underwent urgent C3-C7 decompressive laminectomy with abscess drainage, followed by 6 weeks of pathogen-directed intravenous antibiotics. Adjunctive hyperbaric oxygen therapy and intravascular laser irradiation of the blood were initiated; repetitive transcranial magnetic stimulation was instituted as a rehabilitative neuromodulation strategy. Bacteremia cleared and inflammatory markers normalized; motor function improved from flaccid quadriplegia to partial antigravity strength in the selected muscle groups, although he still needed to use a wheelchair at discharge. CONCLUSIONS This case emphasizes that a thoracic sensory level with fever and preserved consciousness should prompt early spinal MRI. Standard surgical antimicrobial therapy remains important, and carefully selected adjuncts (eg, adjunctive hyperbaric oxygen therapy, intravascular laser irradiation of the blood, and repetitive transcranial magnetic stimulation) may be considered to support infection control and neurorecovery.

We report a case in which a girl diagnosed with HNRNPU-associated neurodevelopmental disorder presented with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and generalized hypotonia accompanied by chorea-like involuntary movements. On the first day of hospitalization, she presented with fever and generalized clonic seizures. Twenty four hours later, she continued to experience impaired consciousness and generalized hypotonia. Her consciousness improved gradually, but chorea-like involuntary movements of the limbs were observed. From the seventh day of hospitalization, the patient repeatedly experienced difficulty in making eye contact for 20-30 s for 2-3 days. Brain MRI with diffusion-weighted imaging revealed hyperintensity from the bilateral frontal cortex to subcortical white matter and the bilateral caudate nuclei. This patient presented with chorea-like involuntary movements and generalized hypotonia, and was unable to perform antigravity movements. HNRNPU-related neurodevelopmental disorders often present with congenital hypotonia. When affected children develop acute encephalopathy associated with basal ganglia lesions, the synergistic effect of these conditions may exacerbate the hypotonia.