Citations

OBJECTIVE Cervical spondylotic myelopathy (CSM) can be associated with urinary dysfunction, leading to an inability or marked difficulty with micturition. This study aimed to evaluate the urinary dysfunction, long-term prognosis, and recovery in patients with CSM following surgical intervention. METHODS The CSM cases of the Quality Outcomes Database SpineCORe study group were analyzed. Urinary control was assessed using the modified Japanese Orthopaedic Association (mJOA) urinary function subscore. Improvement was defined as a minimum improvement of 1 point in the mJOA urinary function subscore at the 2-year follow-up. Univariate and multivariable analyses were conducted as appropriate. RESULTS Of 1141 patients, 772 (67.7%) patients were identified with a minimum 2-year follow-up mJOA score, and 249 (32.3%) of these patients reported baseline urinary dysfunction. Of those 249 patients with baseline urinary control problems, 193 (77.5%) had improvement in urinary function postoperatively, and more women than men had improved urinary control after CSM surgery (54.9% vs 45.1%, p = 0.03). Apart from sex, demographic characteristics of patients who experienced urinary function improvement versus those who did not were similar. Patients who experienced urinary function improvement had lower overall baseline mJOA scores (10.2 vs 13, p < 0.01). Both cohorts reported similar rates of postoperative satisfaction (North American Spine Society scores of 1 and 2) (89.1% vs 85.9%, p = 0.26). CONCLUSIONS Among the one-third of patients with CSM experiencing urinary dysfunction, nearly 78% achieve improved urinary function at the 2-year postoperative follow-up. Women are more likely to experience improvement in this function. Patients with and without improvements in urinary function are equally satisfied with their surgery and report similar outcomes on long-term follow-up.

Alcohol use disorder (AUD) is the most prevalent substance use disorder. Excessive alcohol consumption leads to a range of health issues. We set out to identify inflammatory markers linked to alcohol consumption, which might ultimately offer novel insight into genetic underpinnings and have implications for alcohol-associated disease. Alcohol consumption and blood-based multi-omics data were collected by The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence study. Plasma samples from patients with AUD were used for proteomics analysis using the OLINK “Explore Inflammation” panel (n=410). Liver enzymes were also measured. A genome-wide association study (GWAS) was performed to explore the relationship between genetic variants and plasma TREM2 levels. Our findings show thatplasma triggering receptor expressed on myeloid cells 2 (TREM2), a key gene associated with neurodegenerative disease, was the most significant signal correlated with alcohol consumption, and has also been associated with liver enzyme levels in patients with AUD. We identified the rs7232 single nucleotide polymorphism (SNP) in MS4A6A as a key genetic variant associated with plasma TREM2 levels, with the minor allele (A) linked to higher TREM2 levels and increased alcohol consumption, particularly in men. Furthermore, MA4A6A is an ethanol-responsive gene in a SNP-dependent manner, and the variant genotype of the rs7232 SNP was associated with lower expression for MA4A6A due to proteasome-mediated protein degradation. In summary, this study provides insight into the relationship between plasma TREM2 levels, alcohol consumption, and liver function in AUD patients, shedding light on genetic factors underlying alcohol-related diseases.

Migraine is one of the most prevalent and disabling neurological diseases, significantly affecting quality of life and productivity, as well as contributing to substantial societal costs. Recent innovations, including calcitonin gene-related peptide (CGRP) pathway inhibitors and onabotulinumtoxinA, have transformed migraine prevention by offering high efficacy and excellent tolerability, thus improving adherence. Clinical trials and real-world studies show that significant reductions in migraine frequency and, in some cases, complete migraine freedom is achievable. In this Position Statement, we advocate for raising the standards of migraine prevention by setting ambitious treatment goals aimed at optimal outcomes, such as migraine freedom or very low number of days with migraine or moderate/severe headache. We emphasize the importance of addressing residual migraine burden, highlighting that achieving a ≥50% reduction in monthly migraine days, although often considered a successful response, may not fully restore quality of life. Relying solely on percentage-based improvements can obscure the persisting impact of residual burden. This Position Statement does not want to change the standards for clinical trials but aims primarily at real-world clinical practice and proposes a shift from percentage-based measures of success to absolute goals while on treatment. We outline a framework that categorizes outcomes into four tiers: migraine freedom (no days with migraine or moderate-to-severe headache), optimal control (less than four days with migraine or moderate-to-severe headache), modest control (four to six days with migraine or moderate-to-severe headache) and insufficient control (more than days with migraine or moderate-to-severe headache). Focusing on residual burden while on treatment aims to further improve patient quality of life and drive innovation in preventive therapies and non-pharmacological approaches. By advocating for higher standards, this Position Statement, is not aimed primarily to drive reimbursement policies for migraine preventive treatments, but seeks to inspire clinicians, researchers and policymakers to prioritize ambitious goals in migraine prevention, ultimately enhancing patient outcomes and reducing the broader societal and economic impact of this debilitating condition.

OBJECTIVE It is not clear whether smoking impacts patient-reported outcomes (PROs) in patients with cervical spondylotic myelopathy (CSM). The aim of this study was to explore the impact of smoking status on baseline symptom severity and the rate of achieving satisfaction and the minimal clinically important differences (MCIDs) for PROs in patients with CSM. METHODS This study was an analysis of the prospective Quality Outcomes Database CSM module. Patients aged ≥ 18 years diagnosed with primary CSM who underwent elective surgery were included. PROs (visual analog scale [VAS] neck and arm pain, Neck Disability Index [NDI], modified Japanese Orthopaedic Association [mJOA], and EQ-5D scores and North American Spine Society [NASS] patient satisfaction) were collected at baseline and 24 months of follow-up. RESULTS Of the 1141 patients with CSM, 202 (17.7%) were smokers and 939 (82.3%) were nonsmokers. Compared with the nonsmokers, smokers were younger (56.3 ± 11.3 years vs 61.5 ± 11.7 years, p < 0.01) and had a lower BMI (29.3 ± 6.8 vs 30.3 ± 6.3, p = 0.04). A higher proportion of smokers had depression, anxiety, and chronic obstructive pulmonary disease (all p < 0.01). At baseline, smokers had worse pain (VAS neck pain score: 6.0 ± 3.2 vs 5.1 ± 3.3; VAS arm pain score: 5.7 ± 3.2 vs 4.7 ± 3.5), disability (NDI score: 45.2 ± 20.0 vs 37.1 ± 20.6), myelopathy (mJOA score: 11.5 ± 2.9 vs 12.2 ± 2.8), and quality of life (EQ-5D score: 0.51 ± 0.23 vs 0.57 ± 0.22) (all p < 0.01). At the 24-month follow-up, a higher proportion of smokers achieved the MCID in mJOA (69.4% vs 56.6%, p < 0.01) compared with nonsmokers. However, after accounting for significant covariates, there was no significant difference in the baseline disease severity. There was also no difference between the PROs at the 24-month follow-up. The two groups also achieved similar MCIDs for most PROs and were similarly satisfied (NASS score of 1 or 2: smoker 81.2% vs nonsmoker 84.6%, p = 0.29) 24 months after surgery. CONCLUSIONS Smokers and nonsmokers with CSM had similar baseline disease severity and 24-month PROs. They also achieved similar rates of MCIDs for PROs and satisfaction after surgery. Numerous previous studies have documented the association between tobacco usage and inferior clinical outcomes after spine surgery. However, in the context of severe and debilitating spinal disorders such as cervical myelopathy, meaningful and impactful improvements are still seen in properly selected patients.

Abstract Opioid use disorder (OUD) affects over 40 million people worldwide, creating significant social and economic burdens. Medication for opioid use disorder (MOUD) is often considered the primary treatment approach for OUD. MOUD, including methadone, buprenorphine, and naltrexone, is effective for some, but its benefits may be limited by poor adherence to treatment recommendations. Immunopharmacotherapy offers an innovative approach by using vaccines to generate antibodies that neutralize opioids, blocking them from crossing the blood-brain barrier and reducing their psychoactive effects. To date, only 3 clinical trials for opioid vaccines have been published. While these studies demonstrated the potential of opioid vaccines for relapse prevention, there is currently no standardized protocol for evaluating their effectiveness. We have reviewed recent preclinical studies that demonstrated the efficacy of vaccines targeting opioids, including heroin, morphine, oxycodone, hydrocodone, and fentanyl. These studies showed that vaccines against opioids reduced drug reinforcement, decreased opioid-induced antinociception, and increased survival rates against lethal opioid doses. These studies also demonstrated the importance of vaccine formulation and the use of adjuvants in enhancing antibody production and specificity. Finally, we highlighted the strengths and concerns associated with the opioid vaccine treatment, including ethical considerations.

ABSTRACT There is an increasing need for biomarkers of senescent cell burden to facilitate the selection of participants for clinical trials. p16 Ink4a is encoded by the CDKN2A locus, which produces five variant transcripts in humans, two of which encode homologous p16 proteins: p16 Inka4a , encoded by p16_variant 1 , and p16ɣ, encoded by p16_variant 5. While distinct quantitative polymerase chain reaction primers can be designed for p16_variant 5, primers for p16_variant 1 also measure p16_variant 5 ( p16_variant 1 + 5 ). In a recent clinical trial evaluating the effects of the senolytic combination, dasatinib + quercetin (D + Q), on bone metabolism in postmenopausal women, we found that women in the highest tertile for T‐cell expression of p16_variant 5 had the most robust skeletal responses to D + Q. Importantly, the assessment of p16_variant 5 was more predictive of these responses than p16_variant 1 + 5 . Here, we demonstrate that in vitro, p16_variant 1 + 5 increased rapidly (Week 1) following the induction of DNA damage, whereas p16_variant 5 increased later (Week 4), suggesting that p16_variant 5 becomes detectable only when the abundance of senescent cells reaches some threshold. Further analysis identified a SASP panel in plasma that performed as well in identifying postmenopausal women with a positive skeletal response to D + Q. Collectively, our findings provide further support for the T‐cell p16_variant 5 assay as a biomarker for selecting participants in clinical trials of senolytic interventions. In addition, our data indicate that correlated plasma SASP markers could be used in lieu of the more technically challenging T‐cell p16 assay. Trial Registration: ClinicalTrials.gov identifier: NCT04313634.