Citations

The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 μM CQ had no effect on cell viability; however, 100 μM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.

AbstractExtracorporeal membrane oxygenation (ECMO) employs vascular cannulation and a gas exchange circuit to provide support to patients with severely compromised cardiopulmonary function. ECMO is often the last intervention taken before death and thus presents a unique challenge to medical examiners. This study describes the characteristics of decedents on ECMO at the time of death, including clinical indications, types of circuit configurations, causes and manners of death, gross findings at autopsy, and therapeutic complications. Files of a regional medical examiner office within an academic medical center were searched for the period between 2013 and 2019. Nineteen cases were identified with a median age of 36 years. The circumstances surrounding the initial presentation included: sudden death, trauma, substance abuse, homicide, therapeutic complication, work‐related injury, drowning, and hypothermia. The underlying causes of death included injury‐related, as well as respiratory and cardiac‐related natural diseases. The time spent on ECMO varied from less than 1 h to 10 months. Complications encountered due to ECMO included cannulation site bleeding, pneumohemopericardium, retroperitoneal hematoma, limb ischemia, clotting, and cannula dislodgement. The patient population likely to receive ECMO has significant overlap with death circumstances likely to be reported to the medical examiner. As ECMO therapy has become increasingly available, it is of importance for medical examiners and death investigators to be familiar with the procedure as well as its limitations. Familiarity with ECMO and its sequelae allows for the proper documentation of postmortem findings and fosters an informed determination of the cause and manner of death.

Abstract Background: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. Methods: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer–specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer–specific mortality, and somatic mutations. Results: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer–specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07–3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer–specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. Conclusions: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer–specific mortality and specific somatic mutated genes. Impact: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.

AbstractGain of 1q22 at diagnosis portends poorer outcomes in multiple myeloma (MM), but the prognostic significance of acquired 1q22 gain is unknown. We identified 63 MM patients seen at Mayo Clinic from 1/2004 to 12/2019 without 1q22 gain at diagnosis who acquired it during follow up and compared them to 63 control patients who did not acquire 1q22 gain with similar follow up. We also compared outcomes in the acquired 1q22 gain group with outcomes in 126 patients with 1q22 gain present at diagnosis. The incidence of acquired 1q22 gain was 6.1% (median follow‐up 6.8 years); median time to acquisition was 5.0 years (range: 0.7–11.5 years). Abnormalities on baseline fluorescence in situ hybridization (FISH) included trisomies (54%) and monosomy 13 (39%); 16 (25%) had high‐risk (HR) translocations or del(17p). Median progression‐free survival with front line therapy was 29.5 months in patients with acquired 1q22 gain, versus 31.4 months in control patients (p = .34) and 31.2 months in patients with de novo 1q22 gain (p = .04). Median overall survival (OS) from diagnosis was 10.9 years in patients with acquired 1q22 gain, versus 13.0 years in control patients (p = .03) and 6.3 years in patients with de novo 1q22 gain (p = .01). Presence of HR FISH at baseline increased risk of 1q22 gain acquisition. We demonstrate that acquisition of 1q22 gain is a significant molecular event in MM, associated with reduced OS. Among HR patients for whom this clonal evolution is determined, a risk‐adapted approach and/or clinical trial should be considered.

Background: Obesity is a risk factor for complications in breast reconstruction. Thus, implant-based immediate breast reconstruction in obese women may be controversial. The authors analyzed obese patients who underwent skin-sparing mastectomy using Wise-pattern incisions (Goldilocks procedure) and compared outcomes between two groups: Goldilocks with immediate breast reconstruction and Goldilocks only. Methods: A retrospective review was performed of patients with a body mass index of 30 kg/m2 or higher who underwent the Goldilocks procedure at the Mayo Clinic Health System from 2012 to 2019. Data were extracted from electronic medical records. Minor complications (partial-thickness wound dehiscence or flap necrosis, or tissue expander/implant malposition) and major complications (full-thickness wound dehiscence or flap necrosis, capsular contracture, tissue expander/implant explantation, or unplanned reoperation or readmission) were compared between groups. Patient-reported outcomes using BREAST-Q questionnaires were also assessed. Results: One hundred five patients (181 breasts) were included. Mean ± SEM age and body mass index were 57.1 ± 10.4 years and 37.9 ± 5.8 kg/m2 for the Goldilocks-only group and 51.5 ± 1.1 years and 35.5 ± 0.4 kg/m2 for the Goldilocks with immediate breast reconstruction group, respectively. Median follow-up time was 15.1 months (interquartile range, 10.0 to 28.6 months). Overall, 96 breasts underwent the Goldilocks-only procedure and 85 Goldilocks with immediate breast reconstruction. Multivariable analyses revealed a higher rate of minor complications (adjusted hazard ratio, 2.83; 95 percent CI, 1.22 to 7.02) and major complications (adjusted hazard ratio, 2.26; 95 percent CI, 1.25 to 4.24) in the Goldilocks with immediate breast reconstruction group compared with the Goldilocks-only group, at any given time. Patient satisfaction was not statistically different between groups. Conclusions: The Goldilocks procedure is a feasible breast reconstructive option in obese patients; however, when it is performed with immediate breast reconstruction, it is associated with higher rates of complications. For patients with a body mass index of 40 kg/m2 or greater, the authors recommend the Goldilocks-only procedure or delayed reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Abstract Background Annually in the United States (US), an estimated 80–90,000 patients are diagnosed with acute pericarditis and 15–30% experience recurrent pericarditis (RP), resulting in increased morbidity and reduced health-related quality of life (HRQoL). Treatment options include non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine. Corticosteroids (CS) are often added to the treatment plan in RP despite CS-associated adverse events and inherent potentiation of recurrence with long-term treatment. A recent Phase 3 clinical trial RHAPSODY (NCT03737110) demonstrated efficacy and safety of rilonacept, an interleukin-1 α and β cytokine trap, in patients with RP. RHAPSODY data helped support FDA approval of the first therapy for RP. With the emergence of this targeted therapy, there is increased interest to learn more about this disease with the goal to better inform treatment and management decisions and improve long-term outcomes. Purpose RESONANCE Registry aims to evaluate the natural history of RP by collecting retrospective and prospective, longitudinal physician- and patient-reported outcomes data in real-world clinical practice across the US. Methods RP patients with active disease (recurrence within 3 years) will have both retrospective and prospective data collected (Figure 1) for as long as their RP is managed up to 5 years. For patients with inactive disease (no recurrence within 3 years), data collection will be retrospective (Figure 2). Up to 500 patients in the US are planned for enrollment at pediatric and adult medical centers, with the potential for expansion to European sites. Additionally, patients will be recruited through a novel, internet-based technology platform and screened for eligibility at a “decentralized” trial site. The registry will include variables obtained from health records, including baseline characteristics and medical history, as well as patient reported outcome (PRO) measures collected every 3 months. The RESONANCE protocol is designed to include a broad population of pediatric and adult patients, regardless of etiology or treatment course, including patients treated with rilonacept. Data will be analyzed to understand disease heterogeneity, variability in treatment and management, and impact on HRQoL. The protocol and Case Report Forms (CRFs) were developed in collaboration with physicians, patients, and patient advocates. Conclusions Registries utilize real-world data to fill knowledge gaps in the management of less common diseases such as RP. The RESONANCE Registry is the first RP registry designed to collect data across a broad range of patients regardless of treatment. The registry will also serve as a connection point for physicians to further educate and empower patients with information about their disease. In addition, PRO data may enable greater insights into the understanding of the burden of RP from the patient's perspective. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Kiniksa Pharmaceuticals

Abstract Background Recurrent pericarditis (RP) patients report that painful, debilitating flares negatively impact their health-related quality of life (HRQoL). RHAPSODY, the Phase 3 trial of rilonacept (IL-1α/IL-1β cytokine trap), included a daily pain diary and patient-reported outcome SF-36v2 to measure HRQoL throughout the trial. Purpose The purpose of this research is to evaluate the effect of rilonacept on HRQoL in relation to changes in pain for RP patients who have a recurrence. Methods RHAPSODY enrolled 86 patients with acute symptomatic RP to receive weekly rilonacept for a 12-week run-in (RI) period and randomized 61 patients (1:1) to receive placebo (n=31) or continue rilonacept (n=30) for the event-driven randomized-withdrawal (RW) period. Patients on placebo who experienced a qualifying recurrence during RW (return of pericarditis pain and increase in C-reactive protein) were rescued with bailout rilonacept. Patients reported daily pericarditis pain electronically, using a 0–10 numeric rating scale (NRS), and completed the SF-36v2 at study visits prior to clinician interaction. Scores from RI Baseline (BL), RI Week 12 (RW BL), Recurrence visit, and RW up to Week 24 (or end of study; EOS) were evaluated for patients who experienced recurrence in RW. Analyses exclude one patient randomized to placebo who had a recurrence after Week 24 of the RW period. Results Analyses focused on the 22 of 30 patients (73%) in the placebo group who experienced a recurrence before Week 24 of RW (median time from RW BL to recurrence: 8.6 weeks). During RI, daily pain scores decreased while on rilonacept (Cohen's effect size [ES] d=−2.0), and SF-36v2 scores improved, with scores at RI BL (Fig. 1 red line) below the general population average of 50 and near or above average at RI Week 12 (Fig. 1 blue line); ES were all large (d>0.8), ranging from 0.917 (Mental Component Summary) to 2.021 (Bodily Pain). At recurrence, pain scores increased (d=6.5; Fig. 2) and SF-36v2 scores were below the population average (Fig. 1 orange line), with largest reductions between RI Week 12 (RW BL) and recurrence for Bodily Pain (−13.4) and Physical Component Summary (−10.6). Following rilonacept bailout, average pain decreased (d=−2.1; Fig. 2), and by RW Week 24/EOS, SF-36v2 scores returned to similar levels as at the end of the RI period (Fig. 1 green line). Conclusion Impaired RI BL SF-36v2 scores indicate negative impact of RP on HRQOL in RP patients. While receiving rilonacept, HRQoL scores improved to near or above population averages, in conjunction with patient-reported pain. After discontinuing rilonacept during RW, HRQoL scores worsened at recurrence and improved upon receipt of bail-out rilonacept, similar to pain. These results provide support for the broader benefit of rilonacept treatment beyond pain, when administered on top of conventional therapies and as mono-therapy, providing evidence of its potential to improve HRQoL in this patient population. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Kiniksa Pharmaceuticals, Ltd.

Objective Mild aortic valve stenosis (AS) and aortic valve (AV) sclerosis are associated with diastolic dysfunction and increased mortality in the general population. This study specifically investigated the impact of mild AV disease in heart failure with preserved ejection fraction (HFpEF). Methods Consecutive patients hospitalised with HFpEF (n=370) underwent assessment of cardiac structure and function and long-term clinical follow-up. Results In the study cohort, 111 had mild AS (30%), 104 AV sclerosis (28%) and 155 a non-calcified AV (42%). Mild-to-moderate AV regurgitation (AR) was present in 64 (17%). Compared with patients with a normal AV, those with AV disease were older, with worse renal function and more atrial fibrillation. E/e′ increased from non-calcified AV to AV sclerosis to mild AS (13.8 (10.8–16.8) vs 15.0 (10.9–20.0) vs 18.0 (12.7–23.3), respectively; p<0.001)). Left ventricular diastolic pressure–volume relationships were shifted leftwards in patients with AS and AV sclerosis, but not influenced by AR. The left ventricular end-diastolic volume normalised at 20 mm Hg was 117±34 mL, 106±30 mL and 112±30 mL in non-calcified AV, AV sclerosis and mild AS, respectively (p=0.023), while 112±32 mL in mild-to-moderate AR. Over 30 months (IQR, 8–61 months), 247 patients died (67%). The presence of mild AV disease was associated with increased mortality, but this was no longer significant after adjusting for age and sex. Conclusions Low-grade AV disease is common among patients hospitalised for HFpEF and is associated with older age, atrial arrhythmia, renal dysfunction, higher left heart filling pressures and increased left ventricular chamber stiffness.