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Stimuli that evoke pain stimulate the sympathetic nervous system leading to downstream vascular and hemodynamic adjustments. In clinical populations and older individuals, the perception of pain is associated with cardiovascular responses (e.g., heart rate, blood pressure, and arterial stiffness). However, there are extensive inter‐individual differences in the perception of pain, pain perception may be influenced by age, and it’s unclear if pain is associated with cardiovascular responses in younger adults. PURPOSE Therefore, we sought to determine whether heart rate, blood pressure, and arterial stiffness responses to sympathoexcitatory stimuli were associated with perceived pain, in apparently healthy young adults METHODS 17 young adults (21.6±3.9 yrs; BMI: 24.4±2.8 kg/m 2 ;Mean±SD) participated in this investigation. Following 10‐min of supine rest, we measured heart rate (HR) and mean arterial pressure (MAP), via pulse wave analysis (PWA), and arterial stiffness via carotid‐femoral pulse wave velocity (cf‐PWV). Measures were obtained in duplicate then averaged for analysis. Participants then performed a 3‐min isometric handgrip exercise (HG) at 30% of maximum voluntary contraction, which was immediately followed by 3‐min of brachial cuff‐occlusion at 240mmHg. Perceived pain was assessed via visual analog scale (0‐10; 0=no pain, 10=most pain) at the first minute of each stimulus. HR and MAP were assessed at minute two and arterial stiffness was acquired in the final minute of each stimulus. Associations between perceived pain scores during HG and cuff‐occlusion with percent change in cardiovascular responses were assessed using Spearman’s correlations (α=0.05) RESULTS During HG, significant (P<0.01) increases in HR (pre: 63±6 vs. post: 78±11 bpm; 23±15 %), MAP (pre: 86±9 vs. post: 105±14 mmHg; 22±10 %), and cf‐PWV (pre: 6.5±1.7 vs. post: 7.2±1.0 m/s; 13±26 %) were observed. During cuff‐occlusion, relative to pre, significant (P<0.05) increases in MAP (post: 100±13 mmHg; 18±15%) and cf‐PWV (post: 7.2±1.4 m/s; 14±13%), but not (P>0.05) HR (post: 64±7 bpm; 7±6%) were observed. Perceived pain during cuff‐occlusion (3.73±1.79 A.U.) was significantly greater (P=0.01) than during HG (1.88±1.20 A.U.). While no relationships were observed between perceived pain and cardiovascular responsiveness during HG (P>0.05) with HR (r=0.28; P=0.28), BP (r=0.45; P=0.07), or cf‐PVW (r=0.28; P=0.28), perceived pain was associated with increases in BP (r=0.57; P=0.02) and cf‐PWV (r=0.55; P=0.02;), but not HR (r=0.19; P=0.47), during cuff‐occlusion. CONCLUSIONS While pain during HG was not associated with cardiovascular responses, significantly greater cuff‐occlusion evoked pain was associated with cardiovascular responsiveness. Our data suggests that the relation between perceived pain and cardiovascular responsiveness to sympathoexcitatory stimuli exists in younger adults, although additional data in larger cohorts and using varied stimuli are warranted.

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.

Influenza is an important cause of hospitalization due to lower respiratory tract involvement for which there is no specific antiviral treatment with proven efficacy. We conducted a double-blind, randomized, placebo-controlled trial to assess the tolerability and efficacy of nebulized zanamivir (16 mg four times a day) in combination with rimantadine compared to rimantadine with nebulized saline for treating influenza in adults hospitalized with influenza. Twenty patients tolerated the inhaled zanamivir (ZNV) plus rimantadine without decline in peak expiratory flow rates compared to the 21 who received inhaled saline. The study was terminated early because the approval of ZNV made further enrolment untenable. No significant differences were observed in the proportion of patients shedding virus by treatment day 3 (57% ZNV plus rimantadine, 67% placebo plus rimantadine), or in the durations of hospitalization and supplemental oxygen use. More ZNV plus rimantadine recipients exhibited no or mild cough on day 3 of treatment (94 vs 55%, P=0.01). Two rimantadine-resistant viruses emerged during rimantadine monotherapy; no ZNV resistance was observed. Nebulized ZNV appears to be well tolerated in this hospitalized population but further studies are needed to assess its efficacy.

AbstractMicroglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single‐cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single‐cell microglia transcriptomes. We discovered microglial co‐expression network modules associated with age, sex, and APOE‐ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single‐cell transcriptomes revealed significant overlap between age‐associated module genes and both pro‐inflammatory and disease‐associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta‐analyses with published bulk and single‐cell microglial datasets further supported our findings. Thus, these data represent a well‐characterized human microglial transcriptome resource and highlight age, sex, and APOE‐related microglial immunometabolism perturbations with potential relevance in neurodegeneration.

PURPOSE The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II studies of molecularly targeted therapies on the basis of detection of predefined genetic alterations. Patients with tumors harboring mutations or fusions driving activation of the mitogen-activated protein kinase (MAPK) pathway were treated with the MEK inhibitor selumetinib. METHODS Patients received selumetinib twice daily for 28-day cycles until disease progression or intolerable toxicity. The primary end point was objective response rate; secondary end points included progression-free survival and tolerability of selumetinib. RESULTS Twenty patients (median age: 14 years) were treated. All were evaluable for response and toxicities. The most frequent diagnoses were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7). Twenty-one actionable mutations were detected: hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1 (n = 7), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease including two patients with HGG ( NF1 mutation, six cycles; KRAS mutation, 12 cycles). Six-month progression-free survival was 15% (95% CI, 4 to 34). Five patients (25%) experienced a grade 3 or higher adverse event that was possibly or probably attributable to study drug. CONCLUSION A national histology-agnostic molecular screening strategy was effective at identifying children and young adults eligible for treatment with selumetinib in the first Pediatric MATCH treatment arm to be completed. MEK inhibitors have demonstrated promising responses in some pediatric tumors (eg, low-grade glioma and plexiform neurofibroma). However, selumetinib in this cohort with treatment-refractory tumors harboring MAPK alterations demonstrated limited efficacy, indicating that pathway mutation status alone is insufficient to predict response to selumetinib monotherapy for pediatric cancers.

Abstract Background Mammographic breast density (MBD) decline post-tamoxifen initiation is a favorable prognostic factor in estrogen receptor (ER)–positive breast cancer (BC) and has potential utility as a biomarker of tamoxifen response. However, the prognostic value of MBD decline may vary by molecular characteristics among ER–positive patients. Methods We investigated associations between MBD decline (≥10% vs &lt;10%) and breast cancer–specific mortality (BCSM) among ER–positive breast cancer patients aged 36-87 years at diagnosis treated with tamoxifen at Kaiser Permanente Northwest (1990-2008). Patients who died of BC (case patients; n = 62) were compared with those who did not (control patients; n = 215) overall and by tumor molecular characteristics (immunohistochemistry [IHC]–based subtype [luminal A–like: ER–positive/progesterone receptor [PR]–positive/HER2–negative/low Ki67; luminal B–like: ER–positive and 1 or more of PR–negative, HER2–positive, high Ki67] and modified IHC [mIHC]–based recurrence score of ER/PR/Ki67). Percent MBD was measured in the unaffected breast at baseline mammogram (mean = 6 months before tamoxifen initiation) and follow-up (mean = 12 months post-tamoxifen initiation). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models. All statistical tests were 2-sided. Results MBD decline was statistically significantly associated with reduced risk of BCSM overall (OR = 0.38, 95% CI = 0.15 to 0.92). This association was, however, stronger among women with aggressive tumor characteristics including luminal B–like (OR = 0.17, 95% CI = 0.04 to 0.73) vs A–like (OR = 0.74, 95% CI = 0.19 to 2.92); large (OR = 0.26, 95% CI = 0.08 to 0.78) vs small (OR = 0.41, 95% CI = 0.04 to 3.79) tumors; PR–negative (OR = 0.02, 95% CI = 0.001 to 0.37) vs PR–positive (OR = 0.50, 95% CI = 0.18 to 1.40) disease; and high (OR = 0.25, 95% CI = 0.07 to 0.93) vs low (OR = 0.44, 95% CI = 0.10 to 2.09) mIHC3 score. Conclusion The findings support MBD decline as a prognostic marker of tamoxifen response among patients with aggressive ER–positive BC phenotypes, for whom understanding treatment effectiveness is critical.

Introduction: Excessive bodyweight, often associated with dyslipidemia, may affect the pharmacology of drugs. Inclisiran, a small interfering RNA targeting PCSK9 hepatic mRNA, is an effective LDL-C lowering agent with twice-yearly subcutaneous dosing (after the initial and 3-month doses). Aim: To analyze the efficacy and safety of inclisiran in patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalent across body mass index (BMI) strata. Methods: In this post hoc analysis from ORION-9 (NCT03397121), ORION-10 (NCT03399370) and ORION-11 (NCT03400800), eligible patients were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo at baseline, Day 90 and 6-monthly thereafter. Analyses were stratified by baseline BMI: <25, 25-<30, 30-<35 or ≥35 kg/m 2 . Percentage change in atherogenic lipids from baseline at Day 510 was evaluated. Safety was assessed over 540 days. Results: Baseline demographic and clinical characteristics including atherogenic lipid levels were mostly balanced between the treatment arms and across the BMI strata ( Table ). Percentage change in atherogenic lipids from baseline at Day 510 was significantly greater with inclisiran vs placebo within each BMI stratum ( Table ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms and were reported more frequently with increasing BMI strata (data not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs placebo similarly across strata, but all were mild or moderate. Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained lipid lowering in patients, irrespective of their baseline BMI, and was generally well tolerated.

Introduction: Disorders of glucose metabolism increase in prevalence globally and contribute to excess risk of ASCVD, necessitating intensive lipid lowering. Aim: To analyze efficacy and safety of inclisiran (small interfering RNA targeting hepatic PCSK9 mRNA) across the strata of glycemic disorders. Methods: In this post hoc, pooled analysis of ORION-10 and ORION-11, 3174 patients (pts) with ASCVD/ASCVD risk equivalent (including diabetes mellitus [DM]) were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo (pbo) at baseline (BL), Day (D) 90, and 6-monthly thereafter. Analyses were stratified by BL glycemic status (normoglycemia, pre-DM or DM). LDL-C percentage (%) change from BL to D510 and time-adjusted % change from D90 to D540 were evaluated. Safety was assessed over 540 days. Results: BL characteristics were generally balanced between the treatment arms across the glycemic strata ( Table 1 ). LDL-C % change and time-adjusted % change were greater with inclisiran vs pbo and were similar across all strata ( Table 2 ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms; TEAEs were reported more frequently in pts with vs without glycemic disorders (not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs pbo across the strata but all were mild or moderate ( Table 2 ). Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering irrespective of BL glycemic status, and was generally well tolerated.

Introduction: Primary prevention implantable cardioverter defibrillators (ICDs) reduce mortality in select patients with left ventricular systolic dysfunction (LVSD). The occurrence of device therapies after ICD implantation in contemporary clinical practice is not well described, especially in patient subgroups designated in the Centers for Medicare and Medicaid Services (CMS) 2005 Coverage with Evidence Development (CED). Methods: The Longitudinal Study of ICDs assessed rates and correlates of device therapies (overall and those requiring shock) up to 3 years post-implant among 2540 patients with LVSD receiving first-time primary prevention ICDs in 7 US health care systems from 2006-2009. Implant data from the National Cardiovascular Data Registry ICD Registry were linked to electronic longitudinal health care system data and a novel centrally adjudicated repository of device therapies abstracted from medical records. Proportional hazard models evaluated associations with device therapies by appropriateness, adjusted for demographic and clinical factors. Results: Subjects were 26% women, 35% <65 years old, and 59% non-Hispanic white. Over a mean 26 months, 738 (29.1%) received at least 1 therapy (median 2). Estimated 3-year risk of any device therapy was 36% (24% appropriate, 12% inappropriate); for therapy requiring shock, corresponding values were 24%, 14%, 9%. The rate of appropriate therapy was higher in men than women (adjusted hazard ratio 1.84, 95% confidence interval 1.43-2.35). The rate of inappropriate therapy was higher for subjects <65 than for those >=65 years (1.40, 1.04-1.88), and lower among 2009 implants compared to 2006 (0.66, 0.46-0.95). Regarding the 3 CMS CED patient subgroups, neither ejection fraction nor heart failure symptom severity was associated with device therapy; for LVSD etiology, the rate of inappropriate therapy was nominally but not significantly higher among subjects with non-ischemic cardiomyopathy of < 9 months duration (1.38, 0.88-2.18). Conclusions: In a representative cohort of primary prevention ICD patients in usual care, rates of device therapies were somewhat lower than in landmark trials, differed by some patient characteristics, but did not differ meaningfully for CMS CED subgroups.