Acute kidney injury (AKI) is common in patients with acute coronary syndrome (ACS). However, understanding its prevalence, risk factors and prognosis remains incomplete. We identified 21328 patients admitted for chest pain to a regional hospital in 2021; 6685 had confirmed ACS. AKI episodes were identified by the serum creatinine criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) AKI guideline. The rates of recovery and inpatient, 30-day and 90-day mortality rates were analyzed. Multi-variable analysis showed that ACS was independently associated with AKI (adjusted odds ratio [OR] 2.327; 95% confidence interval [CI] 2.130-2.542; p < 0.0001). Subgroup analysis showed that ACS was independently associated with AKI on admission (adjusted OR 2.516, 95% CI 2.305-2.746, p < 0.0001) but not new-onset AKI during hospitalization. Other factors associated with AKI were similar between patients with and without ACS. AKI in patients with ACS had similar rate of recovery as those without ACS (p = 0.4). Multi-variable logistic regression showed that both ACS types in AKI were associated with higher inpatient, 30-day and 90-day mortality rates, and they had a synergistic effect. Other factors associated with inpatient, 30-day and 90-day mortality rates of patients with AKI were similar between patients with and without ACS. We conclude that ACS was associated with a higher incidence of AKI, and the risk was mainly associated with AKI on admission. The recovery rates from AKI were similar between patients with and without ACS, but the presence of AKI and ACS synergistically increased the inpatient, 30-day and 90-day mortality rates.

Previous studies demonstrated that CNS4, a glutamate concentration biased N-methyl-D-aspartate receptor modulator, produces central analgesic and stress mitigating effects in mice. To translate these findings to a nonrodent species, we evaluated the pharmacokinetics (PK) and safety of CNS4 in 21 adult beagle dogs. A custom formulation was developed for subcutaneous (SC) delivery, and an initial 2 dose PK study (5 and 10 mg/kg) was conducted. CNS4 achieved rapid absorption, with Tmax values of 1.50 ± 0.87 hour (5 mg/kg) and 1.67 ± 0.58 hour (10 mg/kg). Pharmacokinetics were comparable across the limited doses studied, and apparent volumes of distribution for the extravascular route were 33.5 ± 12.5 and 25.6 ± 3.67 L/kg, respectively. To assess oral feasibility, a 50 mg/kg dose of CNS4 suspended in 0.5% carboxymethyl cellulose was first tested in mice and then in dogs. Oral administration in dogs resulted in rapid absorption, with a Tmax of ∼1 hour, comparable to the SC route. Systemic tolerability was assessed in an acute toxicity study involving 4 groups (vehicle, 5, 10, and 25 mg/kg SC) of dogs. No changes in behavior, food intake, or body weight were observed over 14 days. Hematology, lipid panels, and electrolyte measurements collected on days 0 (predose), 7, and 14 revealed no significant CNS4 related abnormalities. Together, these findings demonstrate that CNS4 has an acceptable safety profile and predictable PK across SC and oral administration routes in dogs. This first-in-dog evaluation supports further development of CNS4 as a potential non opioid analgesic and stress mitigating therapeutic agent. SIGNIFICANCE STATEMENT: N-methyl-D-aspartate receptor subtypes are attractive therapeutic targets for chronic pain and post-traumatic stress disorder because of their critical role in emotional memory formation. This translational pharmacology study demonstrates the safety and predictable pharmacokinetics of a centrally acting analgesic and stress mitigating N-methyl-D-aspartate receptor modulator (CNS4) in dogs after single dose subcutaneous and oral administration.

Spinal cord stimulation (SCS) represents an established neuromodulatory intervention for refractory neuropathic pain (NP), yet the cellular mechanisms underlying its anti-inflammatory effects remain incompletely defined. The activation of astrocytes, especially polarization into the A1-like phenotype, is crucial for the persistence of central sensitization. This study aimed to investigate whether the analgesic effects of SCS are associated with modulation of astrocyte activation and calcium ions (Ca2+) / calcineurin (CaN) / nuclear factors of activated T cells 4 (NFAT4) pathway signaling in the spinal dorsal horn. In a rat model of chronic constriction injury (CCI), the present study found that SCS significantly ameliorated mechanical allodynia and reduced spinal levels of proinflammatory cytokines. Furthermore, SCS suppressed spinal dorsal horn astrocyte activation and attenuated their polarization toward the A1-like phenotype. In association with these changes, SCS reduced CCI-induced spinal Ca2+ elevation, downregulated CaN and NFAT4 expression, and decreased NFAT4 nuclear translocation. In vitro experiments further demonstrated that inhibition of CaN or NFAT4 similarly attenuated astrocyte activation, A1-like polarization, and proinflammatory cytokine release. The findings suggest that the analgesic effect of SCS in NP is associated with suppression of Ca2+/CaN/NFAT4 pathway signaling and attenuation of neurotoxic A1-like astrocyte polarization and neuroinflammation. This study supports the involvement of an astrocyte-related Ca2+/CaN/NFAT4 signaling axis in the biological effects of SCS and provides a potential therapeutic target for improving neuromodulation-based pain management. Graphical Abstract. Spinal cord stimulation alleviates neuropathic pain and is associated with reduced Ca2+/CaN/NFAT4 pathway signaling, astrocyte activation, and A1-like polarization in the spinal dorsal horn. Spinal cord stimulation reverses the activation of the Ca2+/CaN/NFAT4 signaling pathway in spinal dorsal horn caused by peripheral nerve injury, thereby inhibiting NFAT4 nuclear translocation. This suppresses A1-like astrocyte polarization and proinflammatory cytokine release, alleviating neuropathic pain.

Oral lichen planus (OLP) causes chronic pain and functional limitations. In a randomized, placebo-controlled crossover trial of ibuprofen gargle, short-term analgesia on the visual analog scale (VAS) was not statistically significant, although patient-perceived functional gains were suggested. This study aimed to characterize the long-term patient-centered response patterns to ibuprofen gargling using predefined responder definitions. We performed a secondary exploratory analysis of a single-center trial and its long-term extensions (jRCTs051220009 and jRCTs051220010). Twenty-four participants were followed up on day 176. Endpoints combined within-day analgesia on VAS at 0, 5, and 15 min (VAS0, VAS5, VAS15) with multidimensional symptoms from the 10-item Patient-Reported Oral Mucositis Symptom (PROMS) scale. Time-to-first achievement (TFA) was summarized, and responses were evaluated descriptively and visually. Overall PROMS response (Definition C) occurred in 21/24 participants (median TFA, 5 d). Domain-level responders were frequent (e.g., pain domain D 20/24, eating domain F 18/24; both median 5 d). In contrast, fewer participants met VAS-based endpoints: A 16/24 (between-day VAS) and B 17/24 (within-day VAS) over the observation period. Visual summaries suggested that improvements tended to emerge early and were sustained or recurrent across subsequent weeks in some participants. Although immediate analgesia was modest, this exploratory analysis indicated that regular use of ibuprofen gargling may be associated with early and durable improvements in patient-reported symptoms and function in OLP. These exploratory findings suggest that patient-centered endpoints may be useful for evaluating topical NSAIDs, and should be examined in future studies with larger sample sizes.

Adenylyl cyclase 1 (AC1) plays an integral role in the excitatory signaling in the anterior cingulate cortex underlying chronic pain pathophysiology. Upon chronic nociceptive input, sustained Ca2+/calmodulin (CaM)-stimulated AC1 activity leads to the development of chronic pain. In this study, we characterize our recently reported series of pyrazolopyrimidinone amine analogs that selectively inhibit Ca2+/CaM-stimulated AC1 activity. Lead compounds AC10136A, AC10142A, and AC10172A exhibited potent AC1 inhibition (IC50 = 140-290 nM) and complete selectivity over AC2, AC5, and AC8. All compounds showed high therapeutic indices (>300) and minimal cytotoxicity up to 100 μM. Lead compounds displayed no functional agonism at κ-opioid receptor. Further, compounds prevented and reversed μ-opioid receptor-mediated heterologous sensitization of AC1, highlighting potential utility in mitigating opioid-induced dependence. Further, chronic treatment with lead compounds failed to induce opioid-like adaptations, such as heterologous sensitization, and did not modulate expression of AC1. Mechanistic studies revealed that inhibition is Ca2+/CaM dependent but independent of Gαs, suggesting preferential targeting of the active AC1 conformation. In mice, AC10142A demonstrated analgesic efficacy in the complete Freund adjuvant model of chronic inflammatory pain. Acute and repeated dosing at 48-120 h after complete Freund adjuvant treatment increased mechanical paw withdrawal thresholds and sustained analgesia over this repeated dosing. By targeting Ca2+/CaM-bound AC1, these inhibitors preferentially inhibit increased AC1 activity to its normal activity, demonstrating a state-dependent mechanism ideal for chronic pain treatment. Together, these findings establish AC10136A, AC10142A, and AC10172A as potent, selective, and well-tolerated AC1 inhibitors, with promising therapeutic potential for chronic pain and potentially opioid use disorder. SIGNIFICANCE STATEMENT: Adenylyl cyclase 1 (AC1) plays a key role in chronic pain sensitization and opioid use disorder, making it a promising therapeutic target. Selective pyrazolopyrimidinone amine inhibitors of AC1 potently block Ca2+/calmodulin-dependent activation (with IC50 values of 140-290 nM), exhibit excellent in vitro safety profiles, prevent μ-opioid receptor-mediated AC1 sensitization in vitro, and demonstrate robust antiallodynic effects in vivo, positioning this compound series as a compelling nonopioid strategy for managing chronic pain and potentially addressing opioid use disorder.

Early detection of consciousness in critically ill patients with severe brain injuries can profoundly impact prognostication and clinical care decisions. Advanced multimodal protocols to detect signs of consciousness include standardized behavioral assessments, task-based functional magnetic resonance imaging (fMRI), and task-based electroencephalography (EEG). However, these approaches have limited diagnostic sensitivity because patients may lack auditory function, attention, language, or other cognitive capacities required to perform a task or process a sensory stimulus, even if they are conscious. Transcranial magnetic stimulation EEG (TMS-EEG) has the potential to overcome these limitations by directly engaging corticothalamic circuits to compute the perturbational complexity index (PCI), an emerging indicator of consciousness. To date, TMS-EEG studies have focused on patients in the subacute or chronic stage of recovery from severe brain injury. Here, we report the proof-of-concept application of TMS-EEG for a critically ill patient in the acute stage of brain injury, in which multimodal assessments suggested a vegetative state/unresponsive wakefulness syndrome. We demonstrate that TMS-EEG may detect signs of consciousness that elude current advanced evaluations, showing the feasibility of TMS-EEG as part of a multimodal protocol for assessing consciousness in the intensive care unit.

Background Mycetoma is a chronic, progressively destructive infection that can result in severe disability and limb loss. In Ethiopia, diagnostic capacity and access to effective treatment remain limited, and the burden of mycetoma is poorly characterized. Recent clinical observations from the Afar Region suggest a high frequency of advanced disease and amputation, yet systematic evidence on the burden is lacking. This study aimed to describe the clinical burden of mycetoma, diagnostic and treatment practices, care-seeking patterns, and the extent of limb amputation at Dubti General Hospital in Afar region, northeastern Ethiopia. We conducted a facility-based retrospective review of all patients with a clinical diagnosis of mycetoma managed at Dubti General Hospital between September 2020 and August 2025. Demographic characteristics, clinical presentation, diagnostic investigations, treatment modalities, disability status, and surgical outcomes were summarized descriptively. Factors associated with delayed presentation (>12 months from symptom onset) were assessed using multivariable logistic regression. A total of 143 patients were identified, with a mean age of 30.9 years (SD ± 11.7); 79% were male, 85.3% resided in rural areas, and 46% were pastoralists. All cases involved the lower limb and presented with localized swelling. Pain (90.9%), warmth (54.5%), sinus formation (42.7%), and discharge (40.6%) were common. Diagnosis relied primarily on clinical assessment alone (58.7%), with limited use of imaging and biopsy. The mean duration of illness before first presentation was 33.8 months (SD ± 29), and 89.5% of patients presented after more than 12 months of symptoms. Compared with farmers, merchants had lower odds of delayed presentation (AOR = 0.89, 95% CI: 0.27-0.59). Nineteen patients (13.3%) underwent limb amputation, accounting for 23.5% of all orthopaedic amputations performed at the hospital during the study period. Disability at presentation was frequent, with 14.0% of patients experiencing severe motor impairment. Mycetoma in Afar predominantly affects young rural men and presents almost exclusively with advanced lower-limb disease. Profound diagnostic limitations, delayed care-seeking, and restricted surgical options contribute to poor outcomes. Integrating mycetoma into national neglected tropical disease strategies, strengthening early detection and diagnostic services, ensuring consistent access to essential medications, and expanding limb-sparing surgical capacity are critical to reducing preventable disability and aligning Ethiopia's response with global NTD control targets.

Sickle cell disease (SCD) causes significant morbidity and mortality, affecting approximately 100,000 people in the United States. Chronic pain negatively impacts quality of life and is estimated to occur in 30% to 40% of adolescents and adults with SCD. As a result, patients often rely on opioids for pain control. Management of pain and opioid use is further complicated when patients with SCD become pregnant. Patients with SCD face an increased risk of maternal and perinatal complications compared to the nonpregnant sickle cell population. In the SCD population, buprenorphine is thought to be a safer alternative than full mu opioid agonists like oxycodone. However, there is scant literature on the use of buprenorphine for pain in SCD patients who become pregnant. We present buprenorphine initiation for pain in two pregnant patients with SCD on chronic opioids. The buprenorphine transition was started by the inpatient palliative care team and continued by the outpatient palliative providers. As the patients' pregnancies progressed, we encountered challenges with continuing buprenorphine for pain in SCD. Neither patient remained on buprenorphine for the full duration of their pregnancy. We describe the challenges and lessons we learned in these cases.