Citations

AbstractMetabolic syndrome (MetS) is a prevalent comorbidity in patients with chronic pain conditions. Emerging evidence suggests that the relationship between MetS and chronic pain is bidirectional. This interplay involves complex mechanisms, including proinflammatory mediators in nociceptive modulation and pain‐induced lifestyle changes affecting metabolic function. This scoping review examines the association between MetS and chronic pain. We conducted a scoping review, including 28 studies. This review followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses Extension for Scoping Reviews guidelines. We included observational studies (cross‐sectional, case–control, and cohort studies) from the following databases: Ovid MEDLINE, EMBASE, Cochrane Central, Cochrane Database of Systematic Reviews, and Scopus. We identified studies on migraine (n = 9), spinal pain (n = 8), general chronic pain (n = 4), fibromyalgia syndrome (n = 3), carpal tunnel syndrome (n = 1), osteoarthritis (n = 1), shoulder pain (n = 1), and neuropathic pain (n = 1). Most studies used a cross‐sectional design and standard criteria to define MetS, with some exceptions. Individuals with MetS and spinal pain, fibromyalgia, or general chronic pain showed higher pain scores and increased functional limitations. MetS was common in patients with migraine, but its effect on pain severity was inconclusive. The relationship between MetS and other pain conditions requires further investigation to clarify the association and potential mechanisms. MetS is prevalent in patients with chronic pain and is associated with worse pain and functional outcomes. Health care providers should acknowledge the wide spectrum of MetS beyond obesity. This understanding may help identify those at risk for more severe chronic pain.

Background Neuropsychiatric symptoms (NPS) are frequent in Alzheimer's disease (AD) dementia, but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co-occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). NPS trajectories over disease course in these subgroups is not well understood. Objective We investigated changes in NPS severity over time, at two time points, comparing clinicopathologically defined cohorts of AD (without LB), ADLB, DLB, and controls. Methods Cases with two available Neuropsychiatric Inventory-Questionnaire (NPIQ), at the time of enrollment and within 2.5 years of death, were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Differences and rate of change in NPIQ scores were compared between AD (n = 75), ADLB (n = 48) DLB (n = 65), and controls (n = 32) with covariates for age, sex, and cognition. Results First NPIQ scores were highest in ADLB when compared to AD (p = 0.04) and controls (p = 0.01) but not different from DLB. A significant increase in NPS severity was observed in DLB and AD (p < 0.001) over a mean follow up time of 4.9 ± 3.0 years, and the rate of change was significantly greater in DLB when compared to other groups. Final NPIQ scores were highest in DLB when compared to AD (p = 0.03) but not ADLB, and in DLB, ADLB, and AD than controls ( all p < 0.001). Conclusions Early NPS burden as well as NPS severity progression rate, independently of cognitive status, might be useful clinical metrics and may help predict underlying pathological diagnoses.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and comprehensive care of patients with MDS based on a review of recent clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts is convened at least on an annual basis. During the annual meeting, the panel evaluates new and emerging data to inform their recommendations. These NCCN Guidelines Insights review the recent updates, including treatment recommendations both for lower-risk and higher-risk MDS, preference stratification of therapeutic agents, and emerging data on novel therapeutics.

Objective To examine comfort (C) and threshold (T) levels in adult cochlear implant (CI) recipients over the first 18 months postactivation. Study Design Retrospective review of longitudinal CI programming data. Setting Tertiary academic center. Patients A total of 480 CIs among 428 adult CI recipients. Interventions Cochlear implantation with Cochlear Ltd. devices with subsequent programming to behavioral standards using Custom Sound® fitting software. Main Outcome Measures Charge levels needed to achieve C and T levels were measured longitudinally using Custom Sound®, from time of activation to a minimum of 6 and a maximum of 18 months postactivation. Charge (nC) levels were calculated as the product of pulse width (μs) and current amplitude (μA) to standardize among implant models. Changes in C and T charge levels over time were evaluated using repeated-measures analysis of variance. Results When considering the entire electrode, the largest increases were seen at 1 month postactivation, and C and T charge levels did not increase significantly after 6 and 12 months, respectively. These findings were consistent across patient age at implantation and sex. When considering proximal electrodes only, C and T levels did not increase significantly after 6 months. In distal electrodes only, C levels did not increase significantly after 6 months, but T levels continued to demonstrate small, but statistically significant increases up to 18 months postactivation. Conclusions Across the entire electrode, we observed the largest changes in C and T charge levels at 1 month postactivation. Small increases in C and T levels continued out to 6 and 12 months, respectively, but may be of limited clinical significance. The stability of programming levels over time may support selective de-escalation of CI follow-up after the initial postactivation period, but, given small yet persistent increases with time, most notably in the distal electrodes, alternatives for follow-up or remote programming may still be encouraged.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an increasing incidence and extremely dismal prognosis. Discovery and mechanistic understanding of the genetic and epigenetic drivers of PDAC is therefore of critical importance. Here, we uncover serine protease inhibitor Kazal type 1 (SPINK1) as a putative determinant of clinical progression and demonstrate that it can have a non-canonical function as a regulator of epigenomic states of PDAC cells and associated extensive changes in gene expression. We show that SPINK1 expression, which varies in PDAC, is associated with key aggressive phenotypic cancer states and is correlated with the expression of stemness markers both in vitro and in patient samples. Mechanistically, our results strongly suggest that SPINK1 acts through a new signaling axis, by interacting with COL18A1 in the Golgi apparatus, promoting endostatin release and eventually inducing extensive histone H3 modifications. These results reveal a new function of SPINK1 in PDAC and suggest a potential therapeutic route to combat PDAC aggressiveness by targeting the SPINK1-COL18A1-endostatin signaling.

Importance High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. Objective To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). Design, Setting, and Participants The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (&amp;lt;60 years vs ≥60 years) and disease duration (&amp;lt;6 months vs ≥6 months). Interventions A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. Main Outcomes and Measures The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. Results A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Conclusions and Relevance Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (&amp;lt;60 years or ≥60 years) and disease duration (recent [&amp;lt;6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P &amp;gt;.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Abstract Purpose: Germline alterations in homologous recombination repair (gHRR) genes affect the pathogenesis, treatment options, and survival of patients with cancer. However, distinct gHRR gene alterations may differentially affect treatment response and oncogenic signaling. In this study, we interrogated genomic and transcriptomic data and assessed clinical outcomes of patients with gHRR mutations across four BRCA-associated cancers (breast, ovarian, pancreatic, and prostate cancers) to identify therapeutic vulnerabilities. Experimental Design: We assessed 24,309 patients undergoing matched tumor/normal next-generation DNA and RNA sequencing. Annotated gHRR gene variants [germline BRCA1, germline BRCA2, germline PALB2, germline ATM (gATM), and germline CHEK2] were analyzed. HRs were used to assess survival outcomes comparing germline versus sporadic groups. Somatic alterations and their frequencies were compared across gHRR-altered groups. Differential gene expression and gene set enrichment analysis were used to compare transcriptomic profiles. Results: Somatic TP53 mutations were depleted in gATM carriers (P &lt; 0.05) across all four BRCA-associated cancers by up to 2.5-fold. Tumors with germline BRCA1/2 mutations were associated with improved survival in patients with ovarian cancer and had consistent enrichment of TP53 mutations in all four cancers. gATM mutations displayed elevated p53 transcriptional activity in all four cancers, with significance reached in breast and prostate cancers (P &lt; 0.01). In breast, ovarian, and prostate cancers, gATM tumors demonstrated significantly increased inflammatory pathways (P &lt; 0.001). Finally, using gene dependency data, we found that cell lines that were highly dependent on ATM were co-dependent on canonical p53 function. Conclusions: gATM-associated cancers seem to require intact p53 activity and this synthetic essentiality may be used to guide targeted therapies that perturb canonical TP53 function.

Abstract Objective: To retrospectively observe procalcitonin (PCT) and antibiotic ordering practices in patients hospitalized with community-acquired pneumonia (CAP). Design: Retrospective, exact matched, multicenter cohort study from October 1, 2018 – March 31, 2023. Setting: All hospitals across the Mayo Clinic Enterprise. Participants: Adult patients with CAP, identified using pneumonia diagnosis codes and receipt of systemic antibiotics with an indication of “respiratory tract infection” within 48 hours of hospitalization. Methods: PCT testing within the first 7 days of hospitalization was compared to non-PCT care (nPCT). The primary outcomes were treatment duration, antibiotic days of therapy (DOT), and length of stay (LOS). Results: 15364 patients met inclusion criteria. PCT testing occurred in 42.4% (6515/15364) of encounters, totaling 8214 PCT results. 12880 unique patient encounters were matched 1:1, 6440 in each group. Treatment duration was longer in the PCT group compared to the nPCT group (5.1 vs 4.6 days, respectively, P < 0.001). Patients in the PCT group also received more DOT (8.6 vs 7.6 DOT, P < 0.001) and had a longer LOS (6.8 vs 5.9 days, P < 0.001), respectively. There was no difference in 30-day all-cause mortality or C. difficile infection between groups. In a sensitivity analysis of nPCT patients compared to those with a peak value <0.25 ng/mL (i.e. normal result) there was no difference in treatment duration (4.6 days nPCT vs 4.7 days normal PCT, P = 0.104) or LOS (5.9 days nPCT vs 6.0 days normal PCT, P = 0.134). Conclusion: PCT testing in patients hospitalized with CAP was not associated with reduced antimicrobial utilization, LOS, or 30-day all-cause mortality.

Background Intra-articular corticosteroid (IACS) injection and peri-articular corticosteroid injection are commonly used to treat musculoskeletal conditions. Results vary by musculoskeletal region, but most studies report short-term benefit with mixed results on long-term relief. Publications showed adverse events from single corticosteroid injections. Recommended effective doses were lower than those currently used by clinicians. Methods Development of the practice guideline for joint injections was approved by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine and the participating societies. A Corticosteroid Safety Work Group coordinated the development of three guidelines: peripheral nerve blocks and trigger points; joints; and neuraxial, facet, and sacroiliac joint injections. The topics included safety of the technique in relation to landmark-guided, ultrasound-guided, or radiology-aided injections; effect of the addition of the corticosteroid on the efficacy of the injectate; and adverse events related to the injection. Experts on the topics were assigned to extensively review the literature and initially develop consensus statements and recommendations. A modified version of the US Preventive Services Task Force grading of evidence and strength of recommendation was followed. A modified Delphi process was adhered to in arriving at a consensus. Results This guideline focuses on the safety and efficacy of corticosteroid joint injections for managing joint chronic pain in adults. The joints that were addressed included the shoulder, elbow, hand, wrist, hip, knee, and small joints of the hands and feet. All the statements and recommendations were approved by all participants and the Board of Directors of the participating societies after four rounds of discussion. There is little evidence to guide the selection of one corticosteroid over another. Ultrasound guidance increases the accuracy of injections and reduces procedural pain. A dose of 20 mg triamcinolone is as effective as 40 mg for both shoulder IACS and subacromial subdeltoid bursa corticosteroid injections. The commonly used dose for hip IACS is 40 mg triamcinolone or methylprednisolone. Triamcinolone 40 mg is as effective as 80 mg for knee IACS. Overall, IACS injections result in short-term pain relief from a few weeks to a few months. The adverse events include an increase in blood glucose, adrenal suppression, detrimental effect on cartilage lining the joint, reduction of bone mineral density, and postoperative joint infection. Conclusions In this practice guideline, we provided specific recommendations on the role of corticosteroids in joint, bursa, and peritendon injections for musculoskeletal pain.