A Systematic Approach to the Evaluation of the Coronary Microcirculation Using Bolus Thermodilution: CATH CMD.

Coronary microvascular dysfunction (CMD) can cause myocardial ischemia in patients presenting with angina without obstructive coronary artery disease (ANOCA). Evaluating for CMD by using the thermodilution technique offers a widely accessible means of assessing microvascular resistance. Through this technique, 2 validated indices, namely coronary flow reserve and the index of microcirculatory resistance, can be computed, facilitating investigation of the coronary microcirculation. The index of microcirculatory resistance specifically estimates minimum achievable microvascular resistance within the coronary microcirculation. We aim to review the bolus thermodilution method, outlining the fundamental steps for conducting measurements and introducing an algorithmic approach (CATH CMD) to systematically evaluate the coronary microcirculation. Embracing a standardized approach, exemplified by the CATH CMD algorithm, will facilitate adoption of this technique and streamline the diagnosis of CMD.

SCAI Expert Consensus Statement on the Management of Calcified Coronary Lesions.

The prevalence of calcification in obstructive coronary artery disease is on the rise. Percutaneous coronary intervention of these calcified lesions is associated with increased short-term and long-term risks. To optimize percutaneous coronary intervention results, there is an expanding array of treatment modalities geared toward calcium modification prior to stent implantation. The Society for Cardiovascular Angiography and Interventions, herein, puts forth an expert consensus document regarding methods to identify types of calcified coronary lesions, a central algorithm to help guide use of the various calcium modification strategies, tips for when using each treatment modality, and a look at future studies and trials for treating this challenging lesion subset.

Inter-individual variability in neural response to low doses of LSD.

The repeated use of small doses of psychedelics (also referred to as "microdosing") to facilitate benefits in mental health, cognition, and mood is a trending practice. Placebo-controlled studies however have largely failed to demonstrate strong benefits, possibly because of large inter-individual response variability. The current study tested the hypothesis that effects of low doses of LSD on arousal, attention and memory depend on an individual's cognitive state at baseline. Healthy participants (N = 53) were randomly assigned to receive repeated doses of LSD (15 mcg) or placebo on 4 occasions divided over 2 weeks. Each treatment condition also consisted of a baseline and a 1-week follow-up visit. Neurophysiological measures of arousal (resting state EEG), pre-attentive processing (auditory oddball task), and perceptual learning and memory (visual long-term potentiation (LTP) paradigm) were assessed at baseline, dosing session 1 and 4, and follow-up. LSD produced stimulatory effects as reflected by a reduction in resting state EEG delta, theta, and alpha power, and enhanced pre-attentive processing during the acute dosing sessions. LSD also blunted the induction of LTP on dosing session 4. Stimulatory effects of LSD were strongest in individuals with low arousal and attention at baseline, while inhibitory effects were strongest in high memory performers at baseline. Decrements in delta EEG power and enhanced pre-attentive processing in the LSD treatment condition were still present during the 1-week follow-up. The current study demonstrates across three cognitive domains, that acute responses to low doses of LSD depend on the baseline state and provides some support for LSD induced neuroadaptations that sustain beyond treatment.

Frozen Shoulder and the Risk of Parkinson's Disease: A Danish Registry-Based Cohort Study.

Background: Frozen shoulder may be an early preclinical symptom of Parkinson's disease (PD). Objective: To examine PD risk after frozen shoulder diagnosis and to evaluate this disorder as a possible manifestation of parkinsonism preceding the clinical recognition of PD and possible target for screening. Methods: Danish population-based medical registries were used to identify patients aged ≥40 years with a first-time frozen shoulder diagnosis (1995-2016). A comparison cohort was randomly selected from the general population matched on age and sex. To address detection bias and the specificity of frozen shoulder diagnosis, we performed a sensitivity analysis, using similar matching criteria to select a cohort of patients with back pain diagnosis. The outcome was incident PD. Cumulative incidences and adjusted hazard ratios (HRs) were estimated with 95% confidence intervals (CIs). Results: We identified 37,041 individuals with frozen shoulder, 370,410 general population comparators, and 111,101 back pain comparators. The cumulative incidence of PD at 0-22 years follow-up was 1.51% in the frozen shoulder cohort, 1.03% in the general population cohort, and 1.32% in the back pain cohort. For frozen shoulder versus general population, adjusted HRs were 1.94 (CI: 1.20-3.13) at 0-1 years and 1.45 (CI: 1.24-1.70) at 0-22 years follow-up. For frozen shoulder versus back pain, adjusted HRs were 0.89 (CI: 0.54-1.46) and 1.01 (CI: 0.84-1.21), respectively. Conclusion: Patients with frozen shoulder had an increased PD risk compared with the general population, although the absolute risks were low. Frozen shoulder might sometimes represent early manifestations of PD. Detection bias probably cannot account for the increased PD risk during the long-term follow-up.

Social support and ideal cardiovascular health in urban Jamaica: A cross-sectional study.

Recent studies have suggested that high levels of social support can encourage better health behaviours and result in improved cardiovascular health. In this study we evaluated the association between social support and ideal cardiovascular health among urban Jamaicans. We conducted a cross-sectional study among urban residents in Jamaica's south-east health region. Socio-demographic data and information on cigarette smoking, physical activity, dietary practices, blood pressure, body size, cholesterol, and glucose, were collected by trained personnel. The outcome variable, ideal cardiovascular health, was defined as having optimal levels of ≥5 of these characteristics (ICH-5) according to the American Heart Association definitions. Social support exposure variables included number of friends (network size), number of friends willing to provide loans (instrumental support) and number of friends providing advice (informational support). Principal component analysis was used to create a social support score using these three variables. Survey-weighted logistic regression models were used to evaluate the association between ICH-5 and social support score. Analyses included 841 participants (279 males, 562 females) with mean age of 47.6 ± 18.42 years. ICH-5 prevalence was 26.6% (95%CI 22.3, 31.0) with no significant sex difference (male 27.5%, female 25.7%). In sex-specific, multivariable logistic regression models, social support score, was inversely associated with ICH-5 among males (OR 0.67 [95%CI 0.51, 0.89], p = 0.006) but directly associated among females (OR 1.26 [95%CI 1.04, 1.53], p = 0.020) after adjusting for age and community SES. Living in poorer communities was also significantly associated with higher odds of ICH-5 among males, while living communities with high property value was associated with higher odds of ICH among females. In this study, higher level of social support was associated with better cardiovascular health among women, but poorer cardiovascular health among men in urban Jamaica. Further research should explore these associations and identify appropriate interventions to promote cardiovascular health.

Neuroinflammation generated by HIV-infected microglia promotes dysfunction and death of neurons in human brain organoids.

Despite the success of combination antiretroviral therapy (ART) for individuals living with HIV, mild forms of HIV-associated neurocognitive disorder (HAND) continue to occur. Brain microglia form the principal target for HIV infection in the brain. It remains unknown how infection of these cells leads to neuroinflammation, neuronal dysfunction, and/or death observed in HAND. Utilizing two different inducible pluripotent stem cell-derived brain organoid models (cerebral and choroid plexus [ChP] organoids) containing microglia, we investigated the pathogenic changes associated with HIV infection. Infection of microglia was associated with a sharp increase in CCL2 and CXCL10 chemokine gene expression and the activation of many type I interferon stimulated genes (MX1, ISG15, ISG20, IFI27, IFITM3 and others). Production of the proinflammatory chemokines persisted at low levels after treatment of the cell cultures with ART, consistent with the persistence of mild HAND following clinical introduction of ART. Expression of multiple members of the S100 family of inflammatory genes sharply increased following HIV infection of microglia measured by single-cell RNA-seq. However, S100 gene expression was not limited to microglia but was also detected more broadly in uninfected stromal cells, mature and immature ChP cells, neural progenitor cells and importantly in bystander neurons suggesting propagation of the inflammatory response to bystander cells. Neurotransmitter transporter expression declined in uninfected neurons, accompanied by increased expression of genes promoting cellular senescence and cell death. Together, these studies underscore how an inflammatory response generated in HIV-infected microglia is propagated to multiple uninfected bystander cells ultimately resulting in the dysfunction and death of bystander neurons.

Mammalian RNAi represses pericentromeric lncRNAs to maintain genome stability.

Mammalian pericentromeric tandem repeats produce long noncoding RNAs (lncRNAs) that are dysregulated in cancer and linked to genomic instability. Identifying the basic molecular characteristics of these lncRNAs and their regulation is important to understanding their biological function. Here, we determine that the Argonaute (Ago) proteins of the RNA interference (RNAi) pathway directly and uniformly repress bidirectional pericentromeric lncRNAs in a Dicer-dependent manner in mouse embryonic and adult stem cells. Ago-dependent and Dicer-dependent autoregulatory small RNAs were identified within pericentromeric lncRNA degradation intermediates. We develop an RNase H cleavage assay to determine the relative proportions and lengths of the pericentromeric lncRNA targets. We find that 5'-phosphate and non-polyadenylated bidirectional pericentromeric lncRNAs are expressed at similar proportions. These lncRNAs can span up to 9 repeats, with transcription from the reverse strand template yielding the longer products. Using pericentromeric repeat RNA reporters, we determine that Ago represses pericentromeric lncRNAs after S phase transcription. Upon loss of Ago, pericentromeric lncRNA dysregulation results in delayed cell cycle progression, a defective mitotic spindle assembly checkpoint (SAC) and genomic instability. These results show that an evolutionarily conserved Ago activity at pericentromeres contributes to mammalian genome stability.

Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

INOCA: Ischemia in non-obstructive coronary arteries.

This article provides a summary of the clinical spectrum of no obstructive coronary arteries. We describe the pathologies, invasive and noninvasive assessment, and management strategies.

Outcomes and Long-Term Survival of Adolescent and Young Adult Patients Admitted to the Intensive Care Unit Following Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Experience of 152 Patients.

BACKGROUND AND OBJECTIVES: Prognostic factors reliably predicting outcomes for critically ill adolescent and young adult (AYA) patients undergoing allogeneic hematopoietic cell transplantation (allo-HSCT) are lacking. We assessed transplant and intensive care unit (ICU)-related factors impacting patient outcomes. PATIENTS AND METHODS: AYA patients who underwent allo-HSCT and required ICU admission at a Tertiary care Centre, during the period of 2003-2013, were included in this retrospective review. This was a non-interventional study. Only outcomes after the first allo-HSCT and index ICU admissions were analyzed. Disease-, transplant-, and ICU-related variables were analyzed to identify risk factors predictive of survival. RESULTS: Overall, 152 patients were included (males, 60.5%); median age at transplantation was 24 years (interquartile range [IQR] 18-32.5); median age at admission to the ICU was 25.8 years (IQR 19-34). Eighty-four percent underwent transplantation for a hematological malignancy; 129 (85%) received myeloablative conditioning. Seventy-one percent of ICU admissions occurred within the first year after allo-HSCT. ICU admission was primarily due to respiratory failure (47.3%) and sepsis (43.4%). One hundred and three patients (68%) died within 28 days of ICU admission. The 1- and 5-year overall survival rates were 19% and 17%, respectively. Main causes for ICU-related death were refractory septic shock with multiorgan failure (n = 49, 32%) and acute respiratory distress syndrome (ARDS) (n = 39, 26%). Univariate analysis showed that ICU mortality was associated with an Acute Physiology and Chronic Health Evaluation (APACHE) II score >20, a sequential organ failure assessment (SOFA score) > 12, a high lactate level, anemia, thrombocytopenia, leukopenia, hyperbilirubinemia, a high international normalized ratio (INR) and acute graft-versus-host disease (GVHD). Multivariate analysis identified thrombocytopenia, high INR, and acute GVHD as independent predictors of mortality. CONCLUSIONS: In AYA allo-HSCT patients admitted to the ICU, mortality remains high. Higher SOFA and APACHE scores, the need for organ support, thrombocytopenia, coagulopathy, and acute GVHD predict poor outcomes.

Systems analysis of innate and adaptive immunity in Long COVID.

Since the onset of the COVID-19 pandemic, significant progress has been made in developing effective preventive and therapeutic strategies against severe acute SARS-CoV-2 infection. However, the management of Long COVID (LC), an infection-associated chronic condition that has been estimated to affect 5-20% of individuals following SARS-CoV-2 infection, remains challenging due to our limited understanding of its mechanisms. Although LC is a heterogeneous disease that is likely to have several subtypes, immune system disturbances appear common across many cases. The extent to which these immune perturbations contribute to LC symptoms, however, is not entirely clear. Recent advancements in multi-omics technologies, capable of detailed, cell-level analysis, have provided valuable insights into the immune perturbations associated with LC. Although these studies are largely descriptive in nature, they are the crucial first step towards a deeper understanding of the condition and the immune system's role in its development, progression, and resolution. In this review, we summarize the current understanding of immune perturbations in LC, covering both innate and adaptive immune responses, and the cytokines and analytes involved. We explore whether these findings support or challenge the primary hypotheses about LC's underlying mechanisms. We also discuss the crosstalk between various immune system components and how it can be disrupted in LC. Finally, we emphasize the need for more tissue- and subtype-focused analyses of LC, and for enhanced collaborative efforts to analyze common specimens from large cohorts, including those undergoing therapeutic interventions. These collective efforts are vital to unravel the fundaments of this new disease, and could also shed light on the prevention and treatment of the larger family of chronic illnesses linked to other microbial infections.

Acute Coronary Syndrome in Women: An Update.

PURPOSE OF REVIEW: The goal of this manuscript is to provide a concise summary of recent developments in the approach to and treatment of women with acute coronary syndrome (ACS). RECENT FINDINGS: This review covers terminology updates relating to ACS and myocardial injury and infarction. Updates on disparities in recognition, treatments, and outcomes of women with ACS due to atherosclerotic coronary artery disease are covered. Other causes of ACS, including spontaneous coronary artery dissection and myocardial infarction with non-obstructive coronary artery disease are discussed, given the increased frequency in women compared with men. The review summarizes the latest on the unique circumstance of ACS in women who are pregnant or post-partum, including etiologies, diagnostic approaches, medication safety, and revascularization considerations. Compared with men, women with ACS have unique risk factors, presentations, and pathophysiology. Treatments known to be effective for men with atherosclerosis-related ACS are also effective for women; further work remains on reducing the disparities in diagnosis and treatment. Implementation of multimodality imaging will improve diagnostic accuracy and allow for targeted medical therapy in the setting of myocardial infarction with non-obstructive coronary artery disease.

Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells.

The latent reservoir of HIV persists for decades in people living with HIV (PWH) on antiretroviral therapy (ART). To determine if persistence arises from the natural dynamics of memory CD4+ T cells harboring HIV, we compared the clonal dynamics of HIV proviruses to that of memory CD4+ T cell receptors (TCRß) from the same PWH and from HIV-seronegative people. We show that clonal dominance of HIV proviruses and antigen-specific CD4+ T cells are similar but that the field's understanding of the persistence of the less clonally dominant reservoir is significantly limited by undersampling. We demonstrate that increasing reservoir clonality over time and differential decay of intact and defective proviruses cannot be explained by mCD4+ T cell kinetics alone. Finally, we develop a stochastic model of TCRß and proviruses that recapitulates experimental observations and suggests that HIV-specific negative selection mediates approximately 6% of intact and 2% of defective proviral clearance. Thus, HIV persistence is mostly, but not entirely, driven by natural mCD4+ T cell kinetics.

Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2.

Long COVID (LC) occurs after at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, yet its etiology remains poorly understood. We used 'omic" assays and serology to deeply characterize the global and SARS-CoV-2-specific immunity in the blood of individuals with clear LC and non-LC clinical trajectories, 8 months postinfection. We found that LC individuals exhibited systemic inflammation and immune dysregulation. This was evidenced by global differences in T cell subset distribution implying ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. LC individuals displayed increased frequencies of CD4+ T cells poised to migrate to inflamed tissues and exhausted SARS-CoV-2-specific CD8+ T cells, higher levels of SARS-CoV-2 antibodies and a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Our analysis suggested an improper crosstalk between the cellular and humoral adaptive immunity in LC, which can lead to immune dysregulation, inflammation and clinical symptoms associated with this debilitating condition.

Synthesis of 6,8-diaminopurines via acid-induced cascade cyclization of 5-aminoimidazole precursors and preliminary anticancer evaluation.

Inspired by the pharmacological interest generated by 6-substituted purine roscovitine for cancer treatment, 5-aminoimidazole-4-carboxamidine precursors containing a cyanamide unit were prepared by condensation of 5-amino-N-cyanoimidazole-4-carbimidoyl cyanides with a wide range of primary amines. When these amidine precursors were combined with acids, a fast cascade cyclization occurred at room temperature, affording new 6,8-diaminopurines with the N-3 and N-6 substituents changed relatively to the original positions they occupied in the amidine and imidazole moieties of precursors. The efficacy and wide scope of this method was well demonstrated by an easy and affordable synthesis of 22 6,8-diaminopurines decorated with a wide diversity of substituents at the N-3 and N-6 positions of the purine ring. Preliminary in silico and in vitro assessments of these 22 compounds were carried out and the results showed that 13 of these tested compounds not only exhibited IC50 values between 1.4 and 7.5 µM against the colorectal cancer cell line HCT116 but also showed better binding energies than known inhibitors in docking studies with different cancer-related target proteins. In addition, good harmonization observed between in silico and in vitro results strengthens and validates this preliminary evaluation, suggesting that these novel entities are good candidates for further studies as new anticancer agents.

Any infection among patients with hip fracture: Predictive ability of Charlson, Elixhauser, Rx-Risk, and Nordic comorbidity indices.

BACKGROUND: In studies on infection after hip fracture surgery, a common and serious complication, it remains unknown which comorbidity index is best for case-mix confounder adjustment. We evaluated the predictive ability of Charlson Comorbidity Index (CCI), Elixhauser Comorbidity Index (ECI), Rx-Risk Index (Rx-Risk), and Nordic Multimorbidity Index (NMI) for any infection up to 1 year from discharge after hip fracture surgery. METHODS: Using Danish medical registries, we included 92,600 patients (mean age 83 years) surgically treated for hip fracture between 2004 and 2018. Comorbidity-index scores were calculated using prevalence of diagnosis codes, prescription codes, or both. Lookback periods of 1, 5, and 10 years were applied. Logistic regression was used to calculate c-index to assess discrimination of comorbidity indices individually and in combination with a base model of age and sex. Outcome was any infection (not only surgical site infection) in-hospital and 1 year after discharge. RESULTS: At 10-year lookback period, the c-index for individual comorbidity indices for in-hospital infections varied from 0.53 to 0.56, similar to base model alone (0.56). The predictive ability of comorbidity indices in combination with base model varied from 0.56 to 0.57. Within 1 year after discharge, NMI in combination with base model had best predictive ability for infection (c-index = 0.62), followed by CCI and ECI (c-index = 0.60) and Rx-Risk (c-index = 0.58). Discrimination was similar for all lookback periods. CONCLUSIONS: Comorbidity indices have low predictive ability for any infection up to 1 year after hip fracture surgery, similar to that of age and sex alone. For case-mix adjustment, evaluated comorbidity indices are of equal value.