Citations

Abstract Introduction Risk of sudden death in multiple system atrophy (SuD-MSA) is greatest during sleep. Mechanisms underlying SuD-MSA may involve impaired brainstem arousal and cardiovascular responses to hypercapnia in MSA patients. We hypothesized that nocturnal arousal-related tachycardia events are reduced in MSA patients. We analyzed whether nocturnal pulse event frequency was altered in patients with MSA compared to patients with sleep disordered breathing without MSA utilizing portable overnight oximetry. Methods We retrospectively analyzed 46 probable MSA and 46 age-sex matched patients with sleep disordered breathing (SDB) without MSA, excluding patients receiving cardioactive medications. Nocturnal oxyhemoglobin desaturation indices (ODI) and pulse event indices (PEI) were automatically recorded for all patients using portable overnight oximetry. We calculated a PEI/ODI ratio to determine the relationship between probable breathing-related arousals and pulse rate change. Cardiovagal function was assessed by heart rate to deep breathing and Valsalva ratio in patients with MSA and Composite Autonomic Severity Score was assigned. Group comparisons were made with non-parametric tests. Multivariable regression explored relationships between oximetry variables and clinical characteristics. Results Average age at overnight oximetry was 62.9 ± 7.7 years. Total respiratory events between MSA patients compared with OSA controls were similar (95.0 ± 118.6 vs 73.5± 54.2, p=0.61). Total pulse events were lower in MSA than OSA controls without MSA (25.5±44.2 vs 111.6±120.2, p<0.001), as were pulse events per hour (3.1 ± 5.3 vs. 12.8 ± 10.8, p <0.001). The ratio of PEI/ODI was lower in MSA than OSA patients without MSA (p<0.001). Twelve (26%) MSA patients had zero pulse rate events, while all OSA patients without MSA had at least 1 pulse rate event (p<0.001). The number of pulse events was not associated with severity of cardiovagal dysfunction on daytime autonomic function testing. Conclusion Patients with MSA have fewer pulse rate events when compared with SDB patients without MSA, despite similar overall respiratory event frequency. The number of pulse events was not explained by severity of daytime autonomic dysfunction in those with MSA. Whether nocturnal pulse event response to sleep disordered breathing is a marker of disease severity or plays a role in SuD-MSA deserves further study. Support (If Any)

Importance Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate. Objective: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. Design, setting and participants: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres. Exposures Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months. Main outcomes and measures: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2–3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy). Results Forty-six participants (mean age, 44.1 years (range, 18–68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of −29.6% (95% CI, −39.6% to −19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, −27%; 95% CI, −38.7% to −15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, −30.8%; IQR, −47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention. Conclusion In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis. Trial registration number NCT02961374 .

Abstract Cellular senescence contributes to tissue homeostasis and age-related pathologies. However, how senescence is initiated in damaged cells remains vague. Here, we discover that irreparable stresses induce transient biogenesis of cilia, which are used by stressed cells to directly communicate with the promyelocytic leukemia nuclear bodies (PML-NBs), the validated stress signaling hub, to initiate senescence responses. Mechanistically, a ciliary ARL13B-ARL3 GTPase cascade negatively regulates the association of transition fiber protein FBF1 and SUMO-conjugating enzyme UBC9. Irreparable stresses downregulate the ciliary ARLs to release UBC9, which SUMOylates FBF1 at the ciliary base. SUMOylated FBF1 then translocates to PML-NBs to promote PML-NB-dependent senescence initiation. Remarkably, Fbf1 suppression effectively subdues global senescence burden and prevents associated health-span decline in irradiation-treated mice. Collectively, our findings assign primary cilia a central role in inducing senescence program and identify them as promising targets to dampen senescence-associated detrimental damage in future senotherapy strategies.

ABSTRACT Background The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages. Objective To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence‐based and consensus‐based methodology. Methods We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference. Results The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow. Conclusions This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Abstract Background Neuromodulators have proven efficacy in reducing facial rhytides and have also been reported to improve jawline contour and the appearance of platysmal bands. Lifting effects of the tail of the eyebrow are expected outcomes when targeting the lateral periorbital region, underscoring the versatility of neuromodulator treatments. Objectives The aim of this study was to analyze the clinical effectiveness of a novel neuromodulator-based injection algorithm with regards to its ability to reposition the middle and lower facial soft tissues. Methods Seventy-five study participants (8 males, 67 females) with a mean [standard deviation] age of 37.5 [8.5] years were injected with neuromodulators in the subdermal plane of the mandibular soft tissues following a standardized algorithm. Live rating of clinical appearance was performed, as well as volume change and skin vector displacement measured by 3-dimensional imaging at baseline, Day 14, and Day 30. Results Three-dimensional volume analysis revealed an increase in midfacial volume by 0.46 mL, and a decrease of the lower facial volume by 0.30 mL compared with baseline. Additionally, an improvement of midfacial fullness (by 0.13) and jawline contour (by 0.44) was reported on clinical rating scales at Day 30 compared with baseline. Conclusions Facial soft tissues can be repositioned during the 30-day follow-up period following a neuromodulator treatment; this was reflected through an increase in midfacial volume as well as through a decrease in lower facial volume. The novel injection algorithm presented can provide a safe and effective option for patients desiring improvement of midfacial fullness and jawline contour with neuromodulator treatment alone. Level of Evidence: 4

Background. There is a paucity of data on the impact of cytomegalovirus (CMV) serostatus and CMV infection on outcomes in facial vascularized composite allotransplantation. Methods. This international, multicenter, retrospective cohort study presents data on CMV and basic transplant-related demographics, including pretransplant viral D/R serostatus, and duration of antiviral prophylaxis. CMV-related complications (viremia, disease), allograft-related complications (rejection episodes, loss), and mortality were analyzed. Results. We included 19 patients, 4 of whom received CMV high-risk transplants (D+/R−). CMV viremia was noted in 6 patients (all 4 D+/R− patients and 2 D−/R+), mostly within the first-year posttransplant, shortly after discontinuation of antiviral prophylaxis (median 2 mo). CMV disease occurred in 2 D+/R− patients. The high-risk group experienced relatively more rejection episodes per month follow-up. None of D+/R− patients suffered allograft loss due to rejection (longest follow-up: 121 mo). Conclusions. D+/R− patients were at increased risk of CMV-related complications. Although a higher number of rejections was noted in this group, none of the D+/R− patients lost their allograft or died because of CMV or rejection. Thus, CMV D+/R− face transplantation can likely be safely performed with prophylaxis, active surveillance, and prompt treatment.