Financial barriers, facilitators, and strategies among syringe services programs in the U.S., and their impact on implementation and health outcomes.

Syringe Services Programs (SSPs) provide evidence-based services like drug use equipment to prevent infectious disease, overdose prevention education, and naloxone distribution to people who use drugs (PWUD). However, inadequate funding threatens provision of these interventions. This study aimed to document how the current funding landscape impacted determinants of SSP implementation, particularly describing financial and staffing barriers, facilitators, and proposed strategies, using qualitative methods informed by three implementation research frameworks. We interviewed 20 leaders of SSPs in the United States using a semi-structured interview guide. Participants described how structural stigma against PWUD led to insufficient and restrictive funding, and burdensome reporting for SSPs. This resulted in harming program implementation outcomes like reach, fidelity, and sustainability. Inadequate funding also led to insufficient staffing and subsequent staff stress, burnout, and turnover. Taken together, these barriers threatened the implementation of evidence-based interventions that SSPs provided, ultimately harming their ability to effectively address health outcomes like infectious disease transmission and opioid overdose mortality within their communities. Interviewees described how upstream policy strategies like political advocacy might address structural stigma at the federal level. Participants also highlighted state-level efforts like harm reduction-centered funding, technical assistance and capacity-building, and clearinghouse programs that may facilitate better implementation and health outcomes. A more robust understanding of the relationship between financial barriers, facilitators, and strategies on implementation and health outcomes represents a novel and vital area of research within harm reduction literature.

Comparing harm reduction and overdose response services between community-based and public health department syringe service programmes using a national cross-sectional survey.

Background: Syringe services programmes (SSPs) are an evidence-based strategy to reduce infectious diseases and deliver overdose prevention interventions for people who use drugs. They face regulatory, administrative, and funding barriers that limit their implementation in the US, though the federal government recently began providing funding to support these efforts. In this study we aim to understand whether the organisational characteristics of SSPs are associated with the provision of syringe and other overdose response strategies. Methods: We examine four outcomes using the National Survey of Syringe Services Programs (NSSSP) (N = 472): syringe distribution, naloxone distribution, fentanyl test strip (FTS) availability, and buprenorphine implementation. These outcomes are assessed across three organizational categories of SSPs-those operated by public health departments (DPH), community-based organizations (CBOs) with government funding, and CBOs without government funding-while adjusting for community-level confounders. Findings: The proportion of SSPs by organizational category was 36% DPH, 42% CBOs with government funding, and 22% CBOs without government funding. Adjusting for community-level differences, we found that CBO SSPs with government funding had significantly higher provision of all four syringe and overdose response services as compared to DPH SSPs and across three of the four services as compared to CBO SSPs without government funding. CBO SSPs without government funding still had significantly higher provision of three of the four services as compared to programmes maintained by the DPH. Interpretation: CBO SSPs have strong potential to expand overdose response services nationally, particularly if provided with sustained and adequate funding. Communities should aim to provide funding that does not hinder SSP innovation so they can remain flexible in responding to local needs. Funding: This study was supported by Arnold Ventures (20-05172).

Funding and Delivery of Syringe Services Programs in the United States, 2022.

Objectives. To describe the current financial health of syringe services programs (SSPs) in the United States and to assess the predictors of SSP budget levels and associations with delivery of public health interventions. Methods. We surveyed all known SSPs operating in the United States from February to June 2022 (n = 456), of which 68% responded (n = 311). We used general estimating equations to assess factors influencing SSP budget size and estimated the effects of budget size on multiple measures of SSP services. Results. The median SSP annual budget was $100 000 (interquartile range = $20 159‒$290 000). SSPs operating in urban counties and counties with higher levels of opioid overdose mortality had significantly higher budget levels, while SSPs located in counties with higher levels of Republican voting in 2020 had significantly lower budget levels. SSP budget levels were significantly and positively associated with syringe and naloxone distribution coverage. Conclusions. Current SSP funding levels do not meet minimum benchmarks. Increased funding would help SSPs meet community health needs. Public Health Implications. Federal, state, and local initiatives should prioritize sustained SSP funding to optimize their potential in addressing multiple public health crises. (Am J Public Health. 2024;114(4):435-443. https://doi.org/10.2105/AJPH.2024.307583).

Vulnerability to environmental and climatic health provocations among women and men hospitalized with chronic heart disease: insights from the RESILIENCE TRIAL cohort.

AIMS: We aimed to recruit a representative cohort of women and men with multi-morbid chronic heart disease as part of a trial testing an innovative, nurse-co-ordinated, multi-faceted intervention to lower rehospitalization and death by addressing areas of vulnerability to external challenges to their health. METHODS AND RESULTS: The prospective, randomized open, blinded end-point RESILIENCE Trial recruited 203 hospital inpatients (mean age 75.7 ± 10.2 years) of whom 51% were women and 94% had combined coronary artery disease, heart failure, and/or atrial fibrillation. Levels of concurrent multi-morbidity were high (mean Charlson Index of Comorbidity Score 6.5 ± 2.7), and 8.9% had at least mild frailty according to the Rockwood Clinical Frailty Scale. Including the index admission, 19-20% of women and men had a pre-existing pattern of seasonally linked hospitalization (seasonality). Detailed phenotyping revealed that 48% of women and 40% of men had ≥3 physiological factors, and 15% of women and 16% of men had ≥3 behavioural factors likely to increase their vulnerability to external provocations to their health. Overall, 61-62% of women and men had ≥4 combined factors indicative of such vulnerability. Additional factors such as reliance on the public health system (63 vs. 49%), lower education (30 vs. 14%), and living alone (48 vs. 29%) were more prevalent in women. CONCLUSION: We successfully recruited women and men with multi-morbid chronic heart disease and bio-behavioural indicators of vulnerability to external provocations to their health. Once completed, the RESILIENCE TRIAL will provide important insights on the impact of addressing such vulnerability (promoting resilience) on subsequent health outcomes. REGISTRATION: ClinicalTrials.org: NCT04614428.

Updates on syringe coverage and service uptake among needle and syringe programs in the United States, 2019-2020.

BACKGROUND: As injection drug use has increased in the US, so too has the prevalence of receptive syringe sharing. Since the 1980s, Needle and Syringe Programs (NSPs) have been an important source of clean injection equipment and disposal of used syringes. This study reports national syringe coverage and examines the impact of program attributes on organizational-level service uptake, defined as number of syringes distributed per participant contact per year. METHODS: In 2019 and 2020, we administered an annual cross-sectional survey to NSPs operating in the US (n = 260). A national estimate of coverage was calculated by dividing the total number of syringes distributed by the 2019 and 2020 population estimate of people who inject drugs (PWID). Frequency distributions and percentages were calculated for categorical variables (e.g., funding, census region, distribution policy/modality), and median and interquartile ranges (IQR) were calculated for continuous variables (e.g., participant contacts, syringes distributed). Bivariate and multivariable mixed effects logistic regression models were used to estimate the odds ratio associated with organizational characteristics on increasing service uptake at the NSP level. RESULTS: From 2019 to 2020, the total number of participant contacts by NSPs increased from 871,976 to 898,891, and the number of syringes distributed increased from 92,648,529 to 113,071,748. The national coverage estimate increased from 29.5 (95 % CI = 15.0, 58.2) to 35.8 (95 % CI = 18.2, 70.6) syringes per PWID. Fifty-eight percent of NSPs increased service uptake in 2020 as compared to the previous year. NSPs that received government funding and NSPs that changed to a less restrictive syringe distribution policy were more likely to increase service uptake (aOR 1.80, 95 % CI = 1.01, 3.22 and aOR 3.33, 95 % CI = 1.11, 9.94, respectively). Syringe distribution modalities also diversified, with more NSPs reaching participants via backpacking/outreach, fixed site pop-ups, mobile delivery, mail-based delivery, leaving supplies out, and secondary distribution. CONCLUSION: Both governmental investment in harm reduction programming and needs-based distribution of syringes increased service uptake and thus should be expanded and sustained to reduce harms associated with injection drug use.

Systems analysis and improvement approach to improve naloxone distribution within syringe service programs: study protocol of a randomized controlled trial.

BACKGROUND: More than half a million Americans died of an opioid-related overdose between 1999 and 2020, the majority occurring between 2015 and 2020. The opioid overdose mortality epidemic disproportionately impacts Black, Indigenous, and people of color (BIPOC): since 2015, overdose mortality rates have increased substantially more among Black (114%) and Latinx (97%) populations compared with White populations (32%). This is in part due to disparities in access to naloxone, an opioid antagonist that can effectively reverse opioid overdose to prevent death. Our recent pilot work determined that many barriers to naloxone access can be identified and addressed by syringe service programs (SSPs) using the Systems Analysis and Improvement Approach to Naloxone distribution (SAIA-Naloxone). This randomized controlled trial will test SAIA-Naloxone's ability to improve naloxone distribution in general and among BIPOC specifically. METHODS: We will conduct a trial with 32 SSPs across California, randomly assigning 16 to the SAIA-Naloxone arm and 16 to receive implementation as usual. SAIA-Naloxone is a multifaceted, multilevel implementation strategy through which trained facilitators work closely with SSPs to (1) assess organization-level barriers, (2) prioritize barriers for improvement, and (3) test solutions through iterative change cycles until achieving and sustaining improvements. SSPs receiving SAIA-Naloxone will work with a trained facilitator for a period of 12 months. We will test SAIA-Naloxone's ability to improve SSPs' naloxone distribution using an interrupted time series approach. Data collection will take place during a 3-month lead-in period, the 12-month active period, and for an additional 6 months afterward to determine whether impacts are sustained. We will use a structured approach to specify SAIA-Naloxone to ensure strategy activities are clearly defined and to assess SAIA-Naloxone fidelity to aid in interpreting study results. We will also assess the costs associated with SAIA-Naloxone and its cost-effectiveness. DISCUSSION: This trial takes a novel approach to improving equitable distribution of naloxone amid the ongoing epidemic and associated racial disparities. If successful, SAIA-Naloxone represents an important organizational-level solution to the multifaceted and multilevel barriers to equitable naloxone distribution.

Renin-angiotensin-aldosterone system dynamics after targeted blood pressure control using angiotensin II or norepinephrine in cardiac surgery: mechanistic randomised controlled trial.

BACKGROUND: The role of the renin-angiotensin-aldosterone axis in vasoplegia after cardiac surgery remains unclear. We tested the hypothesis that, compared with norepinephrine, infusion of angiotensin II titrated to achieve similar mean arterial pressure (MAP) would suppress plasma renin concentration (PRC) while maintaining aldosterone levels. METHODS: In a double-blind, randomised controlled trial, subjects received either an infusion of angiotensin II or norepinephrine to maintain MAP 70-80 mm Hg from induction of anaesthesia. We compared PRC, aldosterone, dipeptidyl peptidase-3, and angiotensin-converting enzyme 2 activity between treatment groups, before surgery, on ICU admission, and 24 h after surgery. RESULTS: In 60 patients (11.7% female; mean age 68 yr [11 yr]), norepinephrine increased median PRC at ICU admission (median difference [MD] 46 [inter-quartile range, IQR, 3-88] µU ml-1; P<0.001) but angiotensin II did not (MD -3 [IQR -62 to 35] µU ml-1; P=0.36). Aldosterone levels increased with both. The aldosterone:PRC ratio did not change with norepinephrine (MD -0.01 [IQR -0.14 to 0.03] µU ml-1 per ng dl-1, P=0.76) but increased with angiotensin II (MD 0.05 [IQR 0.004-0.26] µU ml-1 per ng dl-1, P<0.001). The upper quartile of PRC before surgery was associated with higher vasopressor requirements when norepinephrine was used to maintain MAP, but not angiotensin II. Dipeptidyl peptidase-3 levels and angiotensin-converting enzyme 2 activities were similar at all time points. CONCLUSIONS: Angiotensin II suppressed renin release while maintaining aldosterone levels compared with norepinephrine. Higher plasma renin concentration before surgery was associated with greater vasopressor requirement for norepinephrine, but not angiotensin II. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry-ACTRN12621000195853 23/02/2021.

Global coagulation assays in patients with chronic kidney disease and their role in predicting thrombotic risk.

BACKGROUND: Despite cardiovascular diseases and thrombosis being major causes of death in patients with chronic kidney disease (CKD), there remains no effective biomarker to predict thrombotic risk in this population. OBJECTIVE: To evaluate global coagulation assays in patients with CKD and correlate the biomarkers to clinical outcomes. MATERIAL AND METHODS: Patients with eGFR<30 mL/min/1.73m2 were recruited (n = 90) in this prospective observational study. Blood samples were collected for global coagulation assays, including thromboelastography, calibrated automated thrombogram (CAT), overall hemostatic potential (OHP) and tissue factor pathway inhibitor (TFPI). RESULTS: Following adjustment for age and gender, CKD subjects (mean age 66 years, 36 % female) had increased maximum amplitude on thromboelastography (70.1 vs 60.2 mm, p < 0.001), higher peak thrombin (233.2 vs 219.7 mm, p = 0.030) and increased OHP (16.1 vs 6.4 units, p < 0.001) compared to healthy controls (n = 153). TFPI was also increased in CKD patients (36.4 vs 14.5 ng/mL, p < 0.001). Compared to hemodialysis patients (n = 43), peritoneal-dialysis patients (n = 25) had more hypercoagulable parameters. Thirty-five CKD patients reported thrombotic complications - key predictors included dialysis, higher fibrinogen, reduced endogenous thrombin potential, elevated D-dimer and increased TFPI. Using the dialysis cohort, the predictive risk model based on the key predictors performed better than Framingham heart score and number of cardiovascular risk factors (Harrell's C-stat 0.862 vs 0.585 vs 0.565). CONCLUSION: CKD appears to confer a hypercoagulable state compared to healthy controls. Interestingly, reduced thrombin generation and raised TFPI was paradoxically associated with increased thrombotic risks, highlighting possible complex compensatory mechanisms within the coagulation system, which may be important in predicting clinical outcomes.

Optimizing naloxone distribution to prevent opioid overdose fatalities: results from piloting the Systems Analysis and Improvement Approach within syringe service programs.

BACKGROUND: Opioid overdose fatalities are preventable with timely administration of naloxone, an opioid antagonist, during an opioid overdose event. Syringe service programs have pioneered naloxone distribution for potential bystanders of opioid overdose. The objective of this study was to pilot test a multi-component implementation strategy-the systems analysis and improvement approach for naloxone (SAIA-Naloxone)-with the goal of improving naloxone distribution by syringe service programs. METHODS: Two syringe service programs participated in a 6-month pilot of SAIA-Naloxone, which included (1) analyzing program data to identify gaps in the naloxone delivery cascade, (2) flow mapping to identify causes of attrition and brainstorm programmatic changes for improvement, and (3) conducting continuous quality improvement to test and assess whether modifications improve the cascade. We conducted an interrupted time series analysis using 52 weeks of data before and 26 weeks of data after initiating SAIA-Naloxone. Poisson regression was used to evaluate the association between SAIA-Naloxone and the weekly number of participants receiving naloxone and number of naloxone doses distributed. RESULTS: Over the course of the study, 11,107 doses of naloxone were distributed to 6,071 participants. Through SAIA-Naloxone, syringe service programs prioritized testing programmatic modifications to improve data collection procedures, proactively screen and identify naloxone-naïve participants, streamline naloxone refill systems, and allow for secondary naloxone distribution. SAIA-Naloxone was associated with statistically significant increases in the average number of people receiving naloxone per week (37% more SPP participants; 95% CI, 12% to 67%) and average number of naloxone doses distributed per week (105% more naloxone doses; 95% CI, 79% to 136%) beyond the underlying pre-SAIA-Naloxone levels. These initial increases were extended by ongoing positive changes over time (1.6% more SSP participants received naloxone and 0.3% more naloxone doses were distributed in each subsequent week compared to the weekly trend in the pre-SAIA Naloxone period). CONCLUSIONS: SAIA-Naloxone has strong potential for improving naloxone distribution from syringe service programs. These findings are encouraging in the face of the worsening opioid overdose crisis in the United States and support testing SAIA-Naloxone in a large-scale randomized trial within syringe service programs.

Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: It is uncertain whether hormone therapy should be used for the primary prevention of chronic conditions such as heart disease, osteoporosis, or some types of cancers. Objective: To update evidence for the US Preventive Services Task Force on the benefits and harms of hormone therapy in reducing risks for chronic conditions. Data Sources: PubMed/MEDLINE, Cochrane Library, EMBASE, and trial registries from January 1, 2016, through October 12, 2021; surveillance through July 2022. Study Selection: English-language randomized clinical trials and prospective cohort studies of fair or good quality. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; meta-analyses when at least 3 similar studies were available. Main Outcomes and Measures: Morbidity and mortality related to chronic conditions; health-related quality of life. Results: Twenty trials (N = 39 145) and 3 cohort studies (N = 1 155 410) were included. Participants using estrogen only compared with placebo had significantly lower risks for diabetes over 7.1 years (1050 vs 903 cases; 134 fewer [95% CI, 18-237]) and fractures over 7.2 years (1024 vs 1413 cases; 388 fewer [95% CI, 277-489]) per 10 000 persons. Risks per 10 000 persons were statistically significantly increased for gallbladder disease over 7.1 years (1113 vs 737 cases; 377 more [95% CI, 234-540]), stroke over 7.2 years (318 vs 239 cases; 79 more [95% CI, 15-159]), venous thromboembolism over 7.2 years (258 vs 181 cases; 77 more [95% CI, 19-153]), and urinary incontinence over 1 year (2331 vs 1446 cases; 885 more [95% CI, 659-1135]). Participants using estrogen plus progestin compared with placebo experienced significantly lower risks, per 10 000 persons, for colorectal cancer over 5.6 years (59 vs 93 cases; 34 fewer [95% CI, 9-51]), diabetes over 5.6 years (403 vs 482 cases; 78 fewer [95% CI, 15-133]), and fractures over 5 years (864 vs 1094 cases; 230 fewer [95% CI, 66-372]). Risks, per 10 000 persons, were significantly increased for invasive breast cancer (242 vs 191 cases; 51 more [95% CI, 6-106]), gallbladder disease (723 vs 463 cases; 260 more [95% CI, 169-364]), stroke (187 vs 135 cases; 52 more [95% CI, 12-104]), and venous thromboembolism (246 vs 126 cases; 120 more [95% CI, 68-185]) over 5.6 years; probable dementia (179 vs 91 cases; 88 more [95% CI, 15-212]) over 4.0 years; and urinary incontinence (1707 vs 1145 cases; 562 more [95% CI, 412-726]) over 1 year. Conclusions and Relevance: Use of hormone therapy in postmenopausal persons for the primary prevention of chronic conditions was associated with some benefits but also with an increased risk of harms.

Somatic Mosaic Mutation Gradient Detected in Trace Brain Tissue From Stereo-EEG Depth Electrodes.

BACKGROUND AND OBJECTIVES: Mosaic pathogenic variants restricted to brain are increasingly recognized as a cause of focal epilepsies. We aimed to identify a mosaic pathogenic variant and its anatomical gradient in brain DNA derived from trace tissue on explanted stereo-electroencephalography (SEEG) electrodes. MATERIAL AND METHODS: We studied a patient with non-lesional multifocal epilepsy undergoing pre-surgical evaluation with SEEG. Following explantation, electrodes were divided into 3 pools based on their brain location (right posterior quadrant, left posterior quadrant, hippocampus/temporal neocortex). Tissue from each pool was processed and DNA whole genome amplified prior to high-depth exome sequencing. Droplet digital PCR was performed to quantify mosaicism. Brain-specific GFAP protein assay enabled cell-of-origin analysis. RESULTS: We demonstrated a mosaic gradient for a novel pathogenic KCNT1 loss-of-function variant, c.530G>A, p.W177X, predicted to lead to nonsense-mediated decay. Strikingly, the mosaic gradient correlated strongly with the SEEG findings as the highest mutant allele fraction was in the right posterior quadrant, reflecting the most epileptogenic region on EEG studies. Elevated GFAP level indicated enrichment of brain-derived cells in SEEG cell suspension. CONCLUSIONS: This study demonstrates proof-of-concept that mosaic gradients of pathogenic variants can be established using trace tissue from explanted SEEG electrodes.

Plasma Angiotensin Converting Enzyme 2 (ACE2) Activity in Healthy Controls and Patients with Cardiovascular Risk Factors and/or Disease.

Angiotensin converting enzyme 2 (ACE2) is an endogenous negative regulator of the renin-angiotensin system, a key factor in the development of cardiovascular disease (CVD). ACE2 is also used by SARS-CoV-2 for host cell entry. Given that COVID-19 is associated with hypercoagulability, it is timely to explore the potential relationship between plasma ACE2 activity and the coagulation profile. In this cross-sectional study, ACE2 activity and global coagulation assays (GCA) including thromboelastography, thrombin, and fibrin generation were measured in adult healthy controls (n = 123; mean age 41 ± 17 years; 35% male) and in patients with cardiovascular risk factors and/or disease (n = 258; mean age 65 ± 14 years; 55% male). ACE2 activity was significantly lower in controls compared to patients with cardiovascular risk factors and/or disease (median 0.10 (0.02, 3.33) vs. 5.99 (1.95, 10.37) pmol/mL/min, p < 0.001). Of the healthy controls, 48% had undetectable ACE2 activity. Controls with detectable ACE2 had lower maximum amplitude (p < 0.001). In patients with cardiovascular risk factors and/or disease, those in the 3rd tertile were older and male (p = 0.002), with a higher Framingham grade and increased number of cardiovascular risk factors (p < 0.001). In conclusion, plasma ACE2 activity is undetectable to very low in young healthy controls with minimal clinically relevant associations to GCA. Patients with cardiovascular risk factors and/or disease have increased plasma ACE2 activity, suggesting that it may be an important biomarker of endothelial dysfunction and atherosclerosis.

Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2.

Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens.

Measurement Error-Corrected Estimation of Clinically Significant Change Trajectories for Interventions Targeting Comorbid PTSD and Substance Use Disorders in OEF/OIF Veterans.

In randomized control trials (RCTs), a focus on average differences between treatment arms often limits our understanding of whether individuals show clinically significant improvement or deterioration. The present study examined differences in individual-level clinical significance trajectories between Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE) and Relapse Prevention (RP). Eighty-one treatment-seeking veterans with a comorbid PTSD/SUD diagnosis were randomized to COPE or RP; data from an additional n = 48 patients who did not meet criteria for both disorders was used to establish a normative threshold. A newly developed, modernized approach to the Jacobson and Truax (1991) clinically significant change framework, using (a) moderated nonlinear factor analysis (MNLFA) scale scoring and (b) measurement error-corrected multilevel modeling (MEC-MLM) was used; this approach was compared to other approaches using conventional total scores and/or assuming no measurement error. Using a conventional approach to estimating the Reliable Change Index (RCI) yielded no differences between COPE and RP in the percentage of patients achieving statistically significant improvement (SSI; 88.9% for both groups). However, under MNLFA/MEC-MLM, higher percentages of patients receiving COPE (75.0%) achieved SSI compared to RP (40.7%). Findings suggest that, even though COPE and RP appear to reduce the same number of PTSD symptoms, MNLFA scoring of outcome measures gives greater weight to interventions that target and reduce "hallmark" PTSD symptoms.

Plasma Neurofilament Light Chain and Clinical Diagnosis in Frontotemporal Dementia Syndromes.

BACKGROUND: Frontotemporal dementia (FTD) syndromes, mimics, phenocopy (phFTD), and slowly progressive behavioral variant FTD (bvFTD) can be difficult to distinguish clinically. Biomarkers such as neurofilament light chain (NfL) may be helpful. OBJECTIVE: To study plasma NfL levels in people with FTD syndromes and determine if plasma NfL can distinguish between FTD syndromes and phFTD. METHODS: Plasma NfL levels were estimated using both Simoa® Quanterix HD-X™ and SR-X™ machines grouped via final diagnosis after investigation and review. RESULTS: Fifty participants were studied: bvFTD = 20, semantic variant FTD (svFTD) = 11, non-fluent variant FTD (nfvFTD) = 9, FTD with motor neuron disease (MND) = 4, phFTD = 2, slow progressors = 3, FTD mimic = 1, mean age 67.2 (SD 8.4) years. NfL levels were significantly higher in the FTD group compared to phenocopy group (p = 0.003). Median NfL (IQR) pg/mL was comparable in the FTD syndromes: bvFTD 41.10 (50.72), svFTD 44.38 (16.61), and nfvFTD 42.61 (22.93), highest in FTD with MND 79.67 (45.32) and lowest in both phFTD 13.99 (0.79) and slow progressors 17.97 (3.62). CONCLUSION: Plasma NfL appears to differentiate FTD syndromes and mimics. However, a lower NfL may predict a slower, but not necessarily absence of neurodegeneration, and therefore appears limited in distinguishing slow progressors from FTD phenocopies. Larger numbers of patients from all clinical groups are required to strengthen diagnostic utility.

Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.

A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-ß) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-ß, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5-81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.

Retinal microvascular function predicts chronic kidney disease in patients with cardiovascular risk factors.

BACKGROUND AND AIMS: Endothelial dysfunction is a precursor to atherosclerosis and is implicated in the coexistence between cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined whether retinal microvascular dysfunction is present in subjects with renal impairment and predictive of long-term CKD progression in patients with CVD. METHODS: In a single centre prospective observational study, 253 subjects with coronary artery disease and CVD risk factors underwent dynamic retinal vessel analysis. Retinal microvascular dysfunction was quantified by measuring retinal arteriolar and venular dilatation in response to flicker light stimulation. Serial renal function assessment was performed over a median period of 9.3 years using estimated GFR (eGFR). RESULTS: Flicker light-induced retinal arteriolar dilatation (FI-RAD) was attenuated in patients with baseline eGFR <90 mL/min/1.73 m2, compared to those with normal renal function (eGFR ≥90 mL/min/1.73 m2) (1.0 [0.4-2.1]% vs. 2.0 [0.8-3.6]%; p < 0.01). In patients with normal renal function, subjects with the lowest FI-RAD responses exhibited the greatest annual decline in eGFR. In uni- and multivariable analysis, among subjects with normal renal function, a 1% decrease in FI-RAD was associated with an accelerated decline in eGFR of 0.10 (0.01, 0.15; p = 0.03) and 0.07 mL/min/1.73 m2 per year (0.00, 0.14; p = 0.06), respectively. FI-RAD was not predictive of CKD progression in subjects with baseline eGFR <90 mL/min/1.73 m2. CONCLUSIONS: Retinal arteriolar endothelial dysfunction is present in patients with CVD who have early-stage CKD, and serves as an indicator of long-term CKD progression in those with normal renal function.

Corrigendum: Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2.

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Angiotensin-Converting Enzyme 2 Activity Is Associated With Embolic Stroke of Undetermined Source.

[Figure: see text].