Nanoscale Chemical Imaging of Amyloid Fibrils in Water Using Total-Internal-Reflection Tip-Enhanced Raman Spectroscopy.

Total-internal-reflection tip-enhanced Raman spectroscopy (TIR-TERS) imaging of amyloid-ß (Aß1-42-L34T) fibrils is performed with nanoscale spatial resolution in water, using TERS tips fabricated by bipolar electrodeposition. Ideal experimental parameters are corroborated by both theoretical simulations and TIR-TERS measurements. TIR-TERS imaging reveals the predominant parallel ß-sheet secondary structure of Aß1-42-L34T fibrils as well as the nanoscale spatial distribution of tyrosine, histidine, and phenylalanine aromatic amino acids. Their proportion in TERS spectra can be qualitatively explained by the combined effect of their localization in the Aß1-42-L34T fibril structure and their molecular orientation with respect to the excitation laser light polarization. Conclusions drawn from the TERS experiments in water corroborate and significantly enrich our previous study in ambient air, thus confirming that hydration has only a marginal impact on the structure of such amyloid fibrils. This first TIR-TERS study in liquid opens fascinating perspectives for future applications in biology.

Better Care, Same Cost - Reducing Unplanned Care for Multi-visit Patients: A Payer-Provider Model.

IMPORTANCE: Many interventions implemented for multi-visit patients (MVP) have been developed to address patient-centric needs of these individuals and reduce unplanned care for ambulatory-sensitive conditions. More rigorous research is needed to better understand the impact of these interventions on changes in care utilization including unplanned care. OBJECTIVE: To evaluate the impact of the Enhanced Care Program (ECP), a payer-provider collaborative model, on unplanned care use and cost of care. DESIGN: Using propensity methods, a comparison group was constructed using insurer membership files. Comparisons were performed using a difference-in-differences analysis. PARTICIPANTS: Patients enrolled in ECP through December 2019 were considered eligible for the study (n = 357). All patients had five or more ED visits in the past year or two or more inpatient hospitalizations in the past year prior to enrollment. EXPOSURES: ECP is a high-intensity outpatient intervention intended to reduce avoidable unplanned care such as ED visits and inpatient hospital stays through home visits, chronic/acute disease management, and intensive care coordination. MAIN MEASURES: The primary outcomes of interest were events per 100 members per year of ED use with return to home, unplanned inpatient and observational status admissions, and unplanned behavioral health inpatient admission, and cost of care per member per month. KEY RESULTS: Overall total unplanned care encounters were significantly reduced with a difference-in-difference of 320 unplanned care encounters per 100 members per year in the intervention group (p < 0.05). The ECP group showed statistically significant decreases in costs of unplanned ED, unplanned observation admission, and unplanned inpatient behavioral medicine costs, but statistically significant increases in overall pharmacy costs and lab costs. Changes in total costs of care for the ECP group were not statistically different than the control group (p = 0.55). CONCLUSIONS: ECP showed significant reduction of unplanned care for MVP patients.

Borane-catalysed C2-selective indole reductive functionalisation.

Indolines are common motifs within pharamceuticals and natural products. Boron catalysis enables the chemoselective allylation of indoles to give allylic indolines in excellent diastereoselectivity. Mechanistic studies revealed in situ formation of the allylic borane, allylation of the imine tautomer of the indole and B-N/B-H transborylation for catalytic turnover.

Distinct mucosal endotypes as initiators and drivers of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a potentially devastating autoimmune disease. The great majority of patients with RA are seropositive for anti-citrullinated protein antibodies (ACPAs), rheumatoid factors, or other autoantibodies. The onset of clinically apparent inflammatory arthritis meeting classification criteria (clinical RA) is preceded by ACPA seropositivity for an average of 3-5 years, a period that is designated as 'at-risk' of RA for ACPA-positive individuals who do not display signs of arthritis, or 'pre-RA' for individuals who are known to have progressed to developing clinical RA. Prior studies of individuals at-risk of RA have associated pulmonary mucosal inflammation with local production of ACPAs and rheumatoid factors, leading to development of the 'mucosal origins hypothesis'. Recent work now suggests the presence of multiple distinct mucosal site-specific mechanisms that drive RA evolution. Indicatively, subsets of individuals at-risk of RA and patients with RA harbour a faecal bacterial strain that has exhibited arthritogenic activity in animal models and that favours T helper 17 (TH17) cell responses in patients. Periodontal inflammation and oral microbiota have also been suggested to promote the development of arthritis through breaches in the mucosal barrier. Herein, we argue that mucosal sites and their associated microbial strains can contribute to RA evolution via distinct pathogenic mechanisms, which can be considered causal mucosal endotypes. Future therapies instituted for prevention in the at-risk period, or, perhaps, during clinical RA as therapeutics for active arthritis, will possibly have to address these individual mechanisms as part of precision medicine approaches.

Diblock Rings as Topological Adhesives at Immiscible Polymer Interfaces.

Disparate polymers often do not mix well, and the resulting immiscible interfaces are mechanically weaker than the bulk, which is undesirable for many technological applications. Large-scale molecular simulations are performed to demonstrate the effectiveness of diblock ring polymers as a new type of adhesive for immiscible polymer interfaces. The peak stress σp and the failure strain γp upon shear deformation approach the bulk values with increasing diblock ring length and coverage. Breaking the diblock rings into pairs of diblock linear chains creates a reference system for comparison. The diblock rings increase both σp and γp compared to the diblock linear chains at the same coverage. Further topological analysis based on the Gauss Linking Number reveals that the threading of diblock rings by linear chains from the two opposite sides is the key mechanism for stronger adhesion, which is analogous to the hook-and-loop process in Velcro tape.

OCT-based comparative evaluation of culprit lesion morphology in very young versus older adult patients with STEMI.

Background: The clinical and pathophysiological characteristics of coronary artery disease in very young adults are poorly described. Aims: Using optical coherence tomography (OCT), we compared culprit lesion morphology in very young adult patients (≤35 years) versus older adult patients (>60 years) with ST-segment elevation myocardial infarction (STEMI). Methods: Culprit lesion morphology was classified as plaque rupture, plaque erosion, or calcified nodule. Thrombus age was subclassified into acute (intraluminal thrombus with surface irregularity) or subacute (mostly mural thrombus with a smooth surface). Results: A total of 61 patients who underwent thrombolysis within 24 hours from symptom onset were included, with 38 (59.7%) subjects ≤35 years and 23 (40.3%) subjects >60 years of age. As an underlying mechanism of STEMI thrombosis, plaque erosion was more common in very young patients (52.6% vs 21.7%; p=0.02) while plaque rupture was more common in elderly patients (65.2% vs 36.8%; p=0.03). Acute or subacute thrombus was identified in 68.9% (42/61) of patients, with red thrombus being more frequent in very young patients. In the entire patient cohort, acute thrombus was more frequent in plaque rupture compared with plaque erosion (62.0% vs 28.0%; p=0.01), whereas subacute thrombus was more common in plaque erosion versus plaque rupture (52.0% vs 10.3%; p=0.0008). Conclusions: OCT showed that plaque erosion and plaque rupture were the most common underlying STEMI mechanisms in very young patients and older patients, respectively, and that subjects with plaque erosion had greater evidence of subacute thrombus.

Measuring Topological Constraint Relaxation in Ring-Linear Polymer Blends.

Polymers are an effective test bed for studying topological constraints in condensed matter due to a wide array of synthetically available chain topologies. When linear and ring polymers are blended together, emergent rheological properties are observed as the blend can be more viscous than either of the individual components. This emergent behavior arises since ring-linear blends can form long-lived topological constraints as the linear polymers thread the ring polymers. Here, we demonstrate how the Gauss linking integral can be used to efficiently evaluate the relaxation of topological constraints in ring-linear polymer blends. For majority-linear blends, the relaxation rate of topological constraints depends primarily on reptation of the linear polymers, resulting in the diffusive time τ_{d,R} for rings of length N_{R} blended with linear chains of length N_{l} to scale as τ_{d,R}∼N_{R}^{2}N_{L}^{3.4}.

Understanding the Sequelae of Invasive Meningococcal Disease in the United States.

Invasive meningococcal disease (IMD) is an uncommon but serious and potentially fatal condition that can result in reduced life expectancy and a broad spectrum of sequelae, many of which may be lifelong and devastating for those who survive the acute disease period. In the United States of America (USA), vaccination is available against the five meningococcal serogroups (A, B, C, W, and Y), but meningococcal vaccination rates among healthy USA adolescents and individuals at high risk because of medical conditions are low, rendering them vulnerable to IMD and its sequelae. Despite the severity of the disease, the clinical impact and rates of IMD sequelae in the USA are poorly understood, as USA-specific data are limited, and the methodology of existing research is heterogenous. This commentary presents clinical experts' perspectives on IMD sequelae based on the available published evidence and direct clinical experience. Among sequelae previously identified in a global systematic literature review, 16 conditions were considered as related to IMD by the present authors. These sequelae include short- and long-term physical, neurological, and emotional consequences that impose a substantial humanistic burden on survivors and their caregivers and result in considerable healthcare and societal costs. This commentary highlights existing knowledge gaps concerning IMD sequelae, including the unclear relationship between IMD and mental health disorders, the contribution of sequelae to the disease burden, prevalence of late-onset sequelae among survivors, and timing of the development of sequelae in different age groups. Addressing these knowledge gaps can inform decisions regarding clinical management in the post-acute period and help quantify the impact of prevention through meningococcal vaccination.

Invasive meningococcal disease is uncommon but life-threatening. Those who survive may have lasting conditions, also known as sequelae, that negatively impact their health. In this commentary, expert physicians used previous publications to identify 16 sequelae of invasive meningococcal disease, many of which, including loss of limbs, blindness, and intellectual disabilities, can severely affect the lives of survivors and their caregivers. It is important to better understand how sequelae affect patients and the cost of living with these conditions for the healthcare system and society. This information would help policymakers make decisions on preventing invasive meningococcal disease with vaccination and managing its sequelae.

A solution NMR methodology enabling the elucidation of small molecule phospholipid membrane adhesion and passive permeation parameters.

Quantifying small molecule uptake across a biological membrane of a target cell is crucial for the development of efficacious and selective drugs. However, current methods to obtaining such data are not trivial. Herein, we present an accessible, higher-throughput (20 minutes), 1H NMR spectroscopy assay, which enables the quantification of small molecule phospholipid passive membrane permeation and membrane adhesion parameters.

Impact of Lipidic Plaque on In-Stent and Stent Edge-Related Events After PCI in Myocardial Infarction: A PROSPECT II Substudy.

BACKGROUND: Lipid content in untreated nonobstructive coronary artery lesions is associated with adverse clinical outcomes, and residual in-stent or stent edge lipid may worsen outcomes after percutaneous coronary intervention (PCI). METHODS: Near-infrared spectroscopy-intravascular ultrasound was performed before and after PCI in patients with myocardial infarction. We evaluated the impact of lipid assessed by near-infrared spectroscopy (maximal lipid core burden index over 4 mm [maxLCBI4mm]) along with intravascular ultrasound information including residual plaque burden on in-stent or edge-related major adverse cardiac events (MACE) in de novo PCI-treated culprit coronary artery lesions. The primary end point was culprit lesion-related MACE (CL-MACE), defined as cardiac death, myocardial infarction, or unstable or progressive angina either requiring revascularization or with rapid lesion progression and classified as in-stent or stent edge-related. RESULTS: During a median follow-up of 3.8 years, 25 CL-MACE (11 stent edge-related, 13 in-stent, and 1 in-lesion without a stent) occurred in 1041 PCI-treated lesions in 768 patients. Pre-PCI or post-PCI measures of lipid content were not related to in-stent CL-MACE. However, stent edge-related CL-MACE was increased if both the post-PCI stent edge maxLCBI4mm was greater than the upper quartile (108.7) and the stent edge plaque burden was >50% (adjusted odds ratio, 4.11 [95% CI, 1.12-15.2]; P=0.03). CONCLUSIONS: In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), CL stent implantation leaving behind greater stent edge-related lipid and uncovered plaque burden was associated with an increased risk of stent edge-related CL-MACE during follow-up. In contrast, CL lipid content was not related to in-stent CL-MACE. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02171065.

Large Field-of-View Intravascular Ultrasound for Mitral and Tricuspid Valve-in-Valve Guidance: A Pilot Study.

Background: Actual expansion of a transcatheter heart valve (THV) might differ from nominal, particularly during nonaortic valve-in-valve for a degenerated bioprosthetic surgical heart valve (SHV). This pilot study compared THV expansion measured using large-field-of-view intravascular ultrasound (IVUS) vs. multi-slice computed tomography (MSCT) and assessed the correlation between THV dimensions and transvalvular gradients. Methods: Fourteen patients were successfully treated with mitral/tricuspid valve-in-valve SAPIEN 3 implantation sized using the true SHV inner diameter; all 14 had baseline MSCT and transvalvular gradients measured at baseline, postprocedure, and at discharge. Periprocedural IVUS (in 6 patients using a Philips 10MHz Vision PV035) was compared with postprocedural MSCT (in 9 patients) with offline measurements performed at 1-mm steps along the THV height. Overall, 190 MSCT and paired 124 IVUS cross-sections were analyzed. Results: There was very good agreement between IVUS THV dimensions and corresponding MSCT measurements (intraclass correlation coefficient ≥0.986 and p < 0.001). IVUS measured THV expansion (percent of the nominal cross-sectional area) was smaller within the inflow and middle of the THV overlapping the ring (85.9% ± 11.3%, 83.8% ± 11.8%) than within the outflow (98.8% ± 12.7%). The residual mean transvalvular gradient increased from periprocedural to predischarge (3.5 ± 2.0 vs. 6.3 ± 1.7 mmHg, p < 0.001). The only independent predictor of predischarge maximal transvalvular gradient was the smallest minimal inner THV frame diameter (r2 = 0.67), predicted by true SHV internal diameter (Beta = 0.066, 95% CI = 0.015-0.117, r2 = 0.49, p = 0.037). Conclusions: This pilot study is the first to report the feasibility of a large field-of-view IVUS for periprocedural measurement of actual THV expansion when deployed valve-in-valve. Minimal inner THV stent frame dimensions correlate with increased postprocedural transvalvular gradients.

Past, present, and future policy considerations regarding meningococcal vaccination in the United States.

INTRODUCTION: In 2005, the United States Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination against invasive meningococcal disease (IMD) caused by serogroups A, C, W, and Y (MenACWY) for all 11-12-year-olds, as well as 2-10-year-olds at high risk. In 2010, a booster dose was recommended for all 16-year-olds, as well as for high-risk patients every 3-5 years. In 2015, optional (as opposed to routine) vaccination against meningococcal serogroup B (MenB) at the preferred age of 16-18 years was recommended (Category B, later changed to shared clinical decision-making). In 2023, a vaccine (MenABCWY) against the five serogroups primarily responsible for IMD in the U.S. became available. AREAS COVERED: This review summarizes the evolution of public policy that led to each milestone vaccine recommendation, reviews epidemiologic data published following the recommendations, and discusses the current state of meningococcal immunization policy. EXPERT OPINION: The use of MenABCWY has the potential to consolidate policy, improve coverage rates for the five serogroups, address disparities in vaccination coverage, and simplify vaccine delivery.

Limitations of Separating Athletes into High or Low-Risk Groups based on a Cut-Off. A Clinical Commentary.

Background: Athlete injury risk assessment and management is an important, yet challenging task for sport and exercise medicine professionals. A common approach to injury risk screening is to stratify athletes into risk groups based on their performance on a test relative to a cut-off threshold. However, one potential reason for ineffective injury prevention efforts is the over-reliance on identifying these 'at-risk' groups using arbitrary cut-offs for these tests and measures. The purpose of this commentary is to discuss the conceptual and technical issues related to the use of a cut-off in both research and clinical practice. Clinical Question: How can we better assess and interpret clinical tests or measures to enable a more effective injury risk assessment in athletes? Key Results: Cut-offs typically lack strong biologic plausibility to support them; and are typically derived in a data-driven manner and thus not generalizable to other samples. When a cut-off is used in analyses, information is lost, leading to potentially misleading results and less accurate injury risk prediction. Dichotomizing a continuous variable using a cut-off should be avoided. Using continuous variables on its original scale is advantageous because information is not discarded, outcome prediction accuracy is not lost, and personalized medicine can be facilitated. Clinical Application: Researchers and clinicians are encouraged to analyze and interpret the results of tests and measures using continuous variables and avoid relying on singular cut-offs to guide decisions. Injury risk can be predicted more accurately when using continuous variables in their natural form. A more accurate risk prediction will facilitate personalized approaches to injury risk mitigation and may lead to a decline in injury rates. Level of Evidence: 5.

Controlled and sequential single-electron reduction of the uranyl dication.

A flexible tripodal pyrrole-imine ligand (H3L) has been used to facilitate the controlled and sequential single-electron reductions of the uranyl dication from the U(VI) oxidation state to U(V) and further to U(IV), processes that are important to understanding the reduction of uranyl and its environmental remediation. The uranyl(VI) complexes UO2(HL)(sol) (sol = THF, py) were straightforwardly accessed by the transamination reaction of H3L with UO2{N(SiMe3)2}2(THF)2 and adopt 'hangman' structures in which one of the pyrrole-imine arms is pendant. While deprotonation of this arm by LiN(SiMe3)2 causes no change in uranyl oxidation state, single-electron reduction of uranyl(VI) to uranyl(V) occurred on addition of two equivalents of KN(SiMe3)2 to UO2(HL)(sol). The potassium cations of this new [UVO2(K2L)]2 dimer were substituted by transmetalation with the appropriate metal chloride salt, forming the new uranyl(V) tetra-heterometallic complexes, [UVO2Zn(L)(py)2]2 and [UVO2Ln(Cl)(L)(py)2]2 (Ln = Y, Sm, Dy). The dimeric uranyl(V)-yttrium complex underwent further reduction and chloride abstraction to form the tetrametallic U(IV) complex [UIVO2YIII(py)]2, so highlighting the adaptability of this ligand to stabilise a variety of different uranium oxidation states.

Practices and outcomes of rotational atherectomy in China: The Rota China registry.

BACKGROUND: Rotational atherectomy (RA) remains an integral tool for the treatment of severe coronary calcified lesions despite emergence of newer techniques. We aimed to evaluate the contemporary clinical practices and outcomes of RA in China. METHODS: The Rota China Registry (NCT03806621) was an investigator-initiated, prospective, multicenter registry based on China Rota Elite Group. Consecutive patients treated with RA were recruited. A pre-designed, standardized protocol was recommended for the RA procedure. The primary safety endpoint was major adverse cardiovascular events (MACE: composite of cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) at 30 days. The primary efficacy endpoint was procedural success. RESULTS: Between July 2018 and December 2020, 980 patients were enrolled at 19 sites in China. Mean patient age was 68.4 years, and 61.4% were men. Radial access was used in 79.1% patients, and 32.7% procedures were guided by intravascular imaging. A total of 22.6% procedures used more than 1 burr, and the maximal burr size was ≥1.75 mm in 24.4% cases, with burr upsizing in 19.3% cases, achieving a final burr-to-artery ratio of 0.52. Procedural success was achieved in 91.1% of patients, and the rate of 30-day and 1-year MACE was 4.9% and 8.2%, respectively. Multivariable analysis identified the total lesion length (HR 1.014, 95% CI: 1.002-1.027; p = 0.021) as predictor of 30-day MACE, and renal insufficiency (HR 1.916, 95% CI: 1.073-3.420; p = 0.028) as predictor of 1-year MACE. CONCLUSIONS: In this contemporary prospective registry in China, the use of RA was effective in achieving high procedural success rate with good short- and long-term outcomes in patients with severely calcified lesions.

Experience and perspective with intravascular imaging and invasive coronary physiology: Insights from allied health professionals.

BACKGROUND: Although intravascular imaging (IVI) and invasive coronary physiology (ICP) are utilized in percutaneous coronary intervention (PCI) with robust positive clinical evidence, their adoption in cardiac catheterization laboratories (CCLs) is still limited. AIMS: The aim of our survey was to assess the perspectives on the experiences of allied health professionals in CCLs' utility of IVI and ICP. METHODS: An anonymous online survey was conducted through multiple channels, including the Cardiovascular Research Technologies (CRT) 2023 Nurses and Technologists Symposium, social media, Cath Lab Digest link, and field requests, leading to diverse representation of allied health professionals. RESULTS: A total of 101 CCL members participated in the survey. First, 59% of responders noted an increased use of IVI in their institutions over recent years. For those experiencing an increase, 49% credited training, 45% emerging evidence, and 34% attributed new CCL members. Barriers to IVI usage were perceived increased procedure time (58%), staff resistance (56%), procedural cost (48%), and difficulty interpreting findings (44%). Regarding ICP, 61% reported using it in approximately 25% to 75% of cases, while 10% utilized it in 75% to 100% of CCL procedures. Interpreting ICP results was mixed, with 56% confident in interpreting all ICP results and 6% unable to interpret any ICP results. CONCLUSION: Our findings highlight opportunities for increasing routine utilization of IVI and ICP in the CCL through allied health professionals. By providing education and training, we can elevate familiarity with the equipment and subsequently build a CCL culture that advocates for both IVI and ICP.

Sex and outcomes after stenting and endarterectomy in asymptomatic severe carotid stenosis patients.

OBJECTIVES: To determine if sex was an effect modifier in a pooled analysis of asymptomatic patients from CREST and ACT I. MATERIALS AND METHODS: We analyzed data from 2544 patients aged <80 with ≥70 % asymptomatic carotid stenosis randomized to CAS or CEA (nCREST = 1091; nACT-1 = 1453). The pre-specified primary endpoint in both trials was any stroke, myocardial infarction or death during the peri-procedural period, or ipsilateral stroke within 4 years of randomization. The secondary endpoint was any stroke or death during the peri-procedural period, or ipsilateral stroke within 4 years of randomization. RESULTS: There was no significant difference in the frequency of events for men or women between CAS and CEA for the primary or secondary endpoints. When assessing for an interaction of sex and risks between procedures, the treatment-by-sex interaction was not significant for either primary or secondary endpoints in the four-year period or the peri-procedural period. However, women had significantly fewer post-procedural events (ipsilateral stroke) with CAS than CEA (HR = 0.33, 95 % CI: 0.09-1.18) compared to men (HR = 2.09, 95 % CI: 0.78-5.61), p = 0.02 for interaction. CONCLUSIONS: In this large, pooled analysis of asymptomatic patients comparing CAS to CEA, sex did not act as an effect modifier of treatment differences in the four-year primary stroke-MI-or-death endpoint or the secondary stroke-or-death endpoint. However, during the post-procedural period men treated with CAS were at higher risk than their female counterparts.