Citations

Abstract Introduction: Erythromelalgia is a descriptive term for burning pain and erythema in distal extremities, often worsened by heat and improved by cold. Inherited erythromelalgia has been primarily linked to gain-of-function variants in SCN9A , encoding voltage-gated sodium channel NaV1.7. However, approximately 65% to 85% of patients with erythromelalgia do not have pathogenic SCN9A variants. Objectives: The objective of this study was to uncover and assess gene variants potentially associated with pediatric-onset erythromelalgia. Methods: With IRB approval and informed consent, probands and families with erythromelalgia underwent next-generation sequencing. A list of genes of interest was produced based on Mendelian inheritance models. Selected gene candidates were assessed using the Sequence Kernel Association Test-Optimal (SKAT-O). Results: Sixty-two probands with erythromelalgia and their relatives were included in Mendelian analysis, which identified variants in PR domain zinc finger protein 12 ( PRDM12 ) and dihydropyrimidinase-like protein 2 ( DPYSL2 ). In a targeted 12-gene rare-variant set analysis using SKAT-O, zinc finger homeobox protein 2 ( ZFHX2 ) showed evidence of association ( P = 6.9 × 10 −4 ), surpassing Bonferroni correction for 12 tests (α = 4.17 × 10 −3 ), whereas KIF1B showed only a nominal association signal ( P = 0.03) that did not survive multiple-testing correction. Conclusion: Genes associated with both increased and decreased pain sensitivity are of considerable interest for elucidating pain mechanisms and analgesic development. As rare variants in PRDM12 and DPYSL2 were identified in a pediatric erythromelalgia cohort and a gene-based rare-variant association signal for ZFHX2 was identified, replication and functional validation are needed.

This study is the first to investigate cytokine profiles in women with advanced CKD and low sexual function. We found that lower levels of soluble CD40 ligand were independently linked to higher odds of having low sexual function. Principal component analysis demonstrated that a broader immune activation pattern was associated with higher odds of having low sexual function. Together, these findings suggest that immune signaling patterns may be relevant to sexual health in women with CKD.

Abstract Objectives Fibronodular hepatocellular carcinoma (FN-HCC) is a newly described variant of hepatocellular carcinoma (HCC), with only 29 cases reported. Histologically, it is divided into multiple smaller, well-defined tumor nodules by extensive fibrosis. Its differential diagnosis includes other HCC variants characterized by fibrous stroma, such as fibrolamellar hepatocellular carcinoma and scirrhous hepatocellular carcinoma. Fibronodular hyperplasia may also be considered in the differential diagnosis. We are reporting 7 cases to help better understand this entity. Methods We retrospectively identified 7 cases of FN-HCC and analyzed the clinical and histologic features of each tumor, as well as disease progression and patient prognosis. Results The FN-HCC cases were diagnosed at a median age of 58 years (range, 40-75 years), with a male predilection (n = 6, 86%). Most patients were White (n = 6, 86%), and 1 was African American (n = 1, 14%). Tumors had a mean size of 3.15 cm (range, 1-9 cm) and were mainly located in the right lobe (n = 5, 71%). Background liver was cirrhotic in 6 cases (86%). Five patients were hepatitis C positive (71%). All tumors were surgically removed, with a free resection margin. Among 3 patients with evident vascular invasion, 1 had a positive lymph node. This patient had tumor metastasis 6 years later; otherwise, all patients were disease free on follow-up. Conclusions Our cohort was concordant with published data showing a male predilection, hepatitis C association, and good prognosis when the disease is discovered before metastasis and is surgically excised with negative margins. However, it contradicts the published literature that associates FN-HCC with the absence of advanced fibrosis/cirrhosis.

Abstract Background Women with advanced chronic kidney disease (CKD) encounter reproductive health challenges, including reduced fertility, menstrual irregularity, and sexual dysfunction. This study examined changes in sex hormones in patients with CKD, their correlation with sexual function, and changes after transplant. Methods This study recruited women aged 18–51 years with CKD stages 3b-5 from outpatient clinics and dialysis units. Exclusion criteria included active pregnancy, menopause, prior hysterectomy/bilateral oophorectomy, or use of hormonal contraceptives/therapy. Data were collected at enrollment and at 6 months post-transplant. Results Thirty-eight subjects met eligibility criteria and enrolled in the trial (8 in CKD stage 3b, 10 in CKD stage 4, and 20 in CKD stage 5/5D). Sexual dysfunction (25/38, 65.8%), defined as total female sexual function index score < 26.55, and menstrual irregularities (17/38, 44.7%) were common, with abnormal elevation of luteinizing hormone present in the follicular phase in the majority of patients. There was a significant negative association between total female sexual function index score and prolactin (β = -0.26, P = 0.03) and dehydroepiandrosterone sulfate (β = -0.07, P = 0.01) after adjusting for age. After transplant, there was also a significant improvement in both prolactin and dehydroepiandrosterone sulfate levels, although sexual dysfunction persisted. Conclusions This study highlights the complex interplay between advanced CKD, reproductive endocrinology, and sexual health. Significant hormonal dysregulation and associated reproductive challenges were observed. The prominent role of dehydroepiandrosterone sulfate in sexual dysfunction among women with CKD requires further study.

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

Background/Objectives: Erythromelalgia is a rare condition characterized by burning pain, redness, and warmth primarily in the extremities, usually worsened by heat and alleviated by cold. The objective of this study was to identify the top 10 priorities in pediatric erythromelalgia from multiple perspectives, including clinicians, people with lived experience of childhood-onset erythromelalgia, and their family members. Methods: A modified James Lind Alliance Priority-Setting Process was conducted. The top priorities were identified through four phases: (1) an international online survey to gather priorities, (2) data processing, (3) an interim prioritization online survey, and (4) a virtual workshop to set the final priorities. Results: In phase 1, 185 potential priorities were submitted by 74 respondents (53% patients, 24% family members, and 23% clinicians) that were developed into 68 unique research questions (phase 2). In phase 3, of the 68 questions, 50 were rated for importance by 58 participants (38% patients, 36% family members, and 26% clinicians), reducing the list to 25 questions. In phase 4, the top 10 was reached through consensus by 12 participants (33% patients, 25% family members, and 42% clinicians) across Canada, South Africa, the United States of America, and the United Kingdom. Conclusions: The final priorities focused on the treatment of erythromelalgia, understanding underlying mechanisms, the association of erythromelalgia with various body systems, and generating awareness. This list is the first international patient-centered research agenda for childhood-onset erythromelalgia and a call to action from key partners to improve future research and care.

Background Outcome selection in regional anesthesia and acute pain research is inconsistent, often lacking patient-centered priorities and validated instruments. We aimed to prioritize key outcomes and propose suitable measurement tools to improve the quality, consistency, and relevance of regional anesthesia research. Methods We conducted a multiround Delphi process, including two electronic voting rounds, a multiday in-person meeting, and a patient panel. Experts and patients evaluated existing and proposed outcomes for importance, validity, and relevance. Outcomes reaching ≥70% agreement were prioritized, and appropriate measurement instruments were identified. Results Thirty-two experts and three patients participated. Across three Delphi rounds, 10 outcomes were prioritized for future regional anesthesia research: seven efficacy outcomes (pain scores; opioid consumption; Brief Pain Inventory; functional outcomes; cognitive function; length of stay; block duration); two multidimensional outcomes (quality of recovery and development of a regional anesthesia-specific quality-of-recovery instrument); one safety outcome (chronic postsurgical pain). Patients prioritized cognitive recovery, function, chronic pain, and pain scores. Conclusions This consensus-based, patient-centered framework defines the core priorities for future regional anesthesia and acute pain research. Future work should focus on developing and validating a regional anesthesia-specific quality-of-recovery instrument, refining multidimensional measures such as functional recovery, cognitive outcomes, and the Brief Pain Inventory, and standardizing the reporting of chronic pain and opioid-related outcomes. Adoption of these priorities will enhance methodological consistency, comparability, and patient relevance in future clinical trials.