Citations

Background PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome is diagnosed clinically. Adult-onset PFAPA syndrome is rare and often has a more diverse clinical presentation that its childhood counterpart. This is the first reported case of adult-onset PFAPA syndrome with complete response to lingual tonsillectomy. Case Summary A 41-year-old man was evaluated for periodic fevers associated with uvulitis, cervical lymphadenitis, pharyngitis, and lower extremity rash. He had a variable response to steroids and was intolerant of colchicine. Laboratory workup revealed intermittent elevation of erythrocyte sedimentation rate and C-reactive protein level. Computed tomography neck and laryngoscopy confirmed adenoidal and lingual tonsillar hypertrophy. He underwent adenoidectomy and lingual tonsillectomy with resolution of symptoms. Conclusions Hypertrophy of the remaining lymphoid structures within Waldeyer's ring may be associated with remote recurrence of PFAPA syndrome after tonsillectomy. Lingual tonsillectomy may be an alternative treatment strategy in select patients with PFAPA, prominent lingual hypertrophy, and incomplete response to steroids.

The importance of canonical versus noncanonical mechanisms for the generation of angiotensins remains a major challenge that, in part, is heavily swayed by the relative efficacy of therapies designed to inhibit renin, ACE (angiotensin-converting enzyme), or the Ang II (Angiotensin II) receptor. Ang (1–12) (angiotensin [1-12]) is an Ang II forming substrate serving as a source for Ang II–mediated tissue actions. This study identifies for the first time the presence of Ang (1–12) in the blood of 52 normal (22 women) and 19 (13 women) patients with hypertension not receiving antihypertensive medication at the time of the study. Normal subjects of comparable ages and body habitus had similar circulating plasma Ang (1–12) concentrations (women: 2.02±0.62 [SD] ng/mL; men 2.05±0.55 [SD] ng/mL, P >0.05). The higher values of plasma Ang (1–12) concentrations in hypertensive men (2.51±0.49 ng/mL, n=6) and women (2.33±0.63 [SD] ng/mL, n=13) were statistically significant ( P <0.02) and correlated with elevated plasma renin activity, systolic and pulse pressure, and plasma concentrations of NT-proBNP (N-terminal prohormone BNP). The increased plasma Ang (1–12) in patients with hypertension was not mirrored by similar changes in plasma angiotensinogen and Ang II concentrations. The first identification of an age-independent presence of Ang (1–12) in the blood of normotensive subjects and patients with hypertension, irrespective of sex, implicates this non-renin dependent substrate as a source for Ang II production in the blood and its potential contribution to the hypertensive process.

AbstractBackgroundHypertension is a major risk factor for cardiovascular and cerebrovascular disease including stroke, small vessel disease, and dementia. The Systolic blood PRessure INTervention (SPRINT) randomized trial prospectively evaluated the effects of intensive systolic blood pressure (SBP) control (target SBP<120mmHg) versus standard control (SBP<140mmHg) on cardiovascular outcomes in individuals without baseline diabetes or stroke, and included cerebral blood flow (CBF) measurements. Previous studies with much smaller sample sizes and shorter duration suggested stable CBF in response to intensive treatment (SBP<125mmHg) [1], but long term effects are unknown. We evaluated the long‐term effects of intensive blood pressure treatment on CBF.MethodWhole brain CBF was measured at 3T using pseudocontinuous arterial spin labeled (ASL) perfusion MRI at baseline and after 3.9±0.3 years. Total white matter lesion (WML) load was measured from Fluid Attenuated Inversion Recovery T2 MRI. Data from 324 subjects with adequate ASL scan quality acquired from 6 sites were included.ResultDemographics and scanner specific CBF values are provided in Table 1. The intensive treatment group was older (p=0.01), but was otherwise similar to the standard group at baseline. There was a significant effect on the longitudinal CBF change (p=0.006) of the intensive treatment (5.7% increase) compared to the standard treatment (4.0% decrease, Fig 1). Secondary analysis showed a significant increase in age‐adjusted fractional CBF for the intensive treatment group (p<0.001) with no change (p=0.24) in the standard treatment group. Change in CBF was not associated with change in WML.ConclusionSustained intensive antihypertensive treatment does not reduce whole brain CBF, in fact it showed an increase in whole brain CBF relative to standard therapy. While improved CBF might contribute to the reduced WML progression observed in the intensive‐therapy group versus standard therapy in SPRINT[2], we did not observe a direct correlation between CBF changes and WML changes. References: (1) Croall et al. JAMA‐Neurol,2018; (2) Nasrallah et al., JAMA‐Neurol, 2019.

Abstract The development and implementation of clinical decision support (CDS) that trains itself and adapts its algorithms based on new data—here referred to as Adaptive CDS—present unique challenges and considerations. Although Adaptive CDS represents an expected progression from earlier work, the activities needed to appropriately manage and support the establishment and evolution of Adaptive CDS require new, coordinated initiatives and oversight that do not currently exist. In this AMIA position paper, the authors describe current and emerging challenges to the safe use of Adaptive CDS and lay out recommendations for the effective management and monitoring of Adaptive CDS.

Abstract Introduction Statin-associated side effects prevent a substantial proportion of patients from being adequately treated with statin therapy and achieving adequate LDL-C reductions. Phase 3 trials showed that inclisiran, a new siRNA, durably lowers LDL-C by ≥50% on top of maximally tolerated statin therapy. Purpose To evaluate inclisiran's tolerability and LDL-C lowering effects among individuals who were not receiving statin therapy mainly because of statin intolerance. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) with LDL-C &gt;70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. The primary efficacy endpoints were % change in LDL-C from baseline to Day 510 and time adjusted % change in LDL-C from baseline after Day 90 and up to Day 540. Absolute LDL-C reductions were secondary endpoints. This analysis included individuals who were not on statin therapy at baseline. Results The trials included 252 (7.9% of the pooled trial populations; mean age 68; male 62%; lipid-lowering therapy 28%). AE rates and LDL-C reductions are shown in the Table. Overall, 12 (4.7%) patients had myalgia (4.8% in the inclisiran groups, 4.7% in the placebo groups). There were 8 discontinuations in the inclisiran groups (6.5%) and 3 in the placebo groups (2.3%). The placebo-adjusted mean reduction in LDL-C at Day 510 was 45.8%, an absolute reduction of 68.0 mg/dL (p&lt;0.0001). Conclusion Among statin intolerant individuals in ORION-10 and 11, inclisiran potently and durably lowered LDL-C with an adverse event profile comparable to placebo. Inclisiran may represent a new and potent therapeutic option for patients with elevated LDL-C unable to tolerate statins. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

Abstract Introduction Inclisiran, an investigational siRNA, has been shown to effectively and durably lower LDL-C in Phase 3 trials. Inter-individual variability in LDL-C reductions has been documented for statin therapy and ezetimibe. Purpose To evaluate the inter-individual variability in LDL-C lowering with inclisiran. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) who had LDL-C &gt;70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. Co-primary endpoints were the LDL-C reduction from baseline to Day 510 and the time adjusted average % change in LDL-C reduction after Day 90 and up to Day 540. Measures of response variability were pre-specified secondary endpoints. This analysis examines the inter-individual variability of LDL-C reductions at day 510 using pooled data from both trials. Results The analysis included 3178 individuals (92% on statins). At Day 90, 97% of inclisiran-treated patients had an LDL-C reduction. At Day 510, the median percent reduction in LDL-C levels from baseline was 57.3% in the inclisiran group (interquartile range, 44%-70%). An LDL-C reduction ≥50% was reached by 1359 (86.6%) inclisiran-treated patients versus 97 (6.2%) placebo patients at any visit (odds ratio [OR] 97.6, 95% confidence interval [CI] 76–126). An LDL-C reduction ≥30% was reached by 1523 (97.0%) inclisiran-treated patients versus 371 (23.7%) placebo patients (OR 104.5, 95% CI 76–143). At Day 510, 921 patients (65.1%) in the inclisiran group had a reduction ≥50% in LDL-C compared to 34 patients (2.4%) in the placebo group, and 1228 (86.8%) had a reduction ≥30% compared to 148 (10.5%), respectively. Among placebo-treated patients, there was a substantial proportion with notable increases in LDL-C at Day 510 (figure). Conclusion In Phase 3 trials, inclisiran on top of maximally tolerated statins provided reliable, consistent and durable reductions in LDL-C. A large percentage of subjects randomized to inclisiran achieved substantial reductions (&gt;50%) in LDL-C and nearly all achieved at least a 30% reduction suggesting inclisiran is potentially a promising novel therapy for patients needing sustained LDL-C reductions. Waterfall plot of pooled trials Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company