ANZACS-QI Heart Failure Registry: a new approach using age-stratified sampling of hospital discharges to guide quality improvement (ANZACS-QI 79).

Heart failure is a major healthcare problem in New Zealand. The Acute Decompensated Heart Failure (ADHF) Registry was introduced in 2015, and has identified the need for quality improvement strategies to improve care of patients hospitalised with heart failure. In this paper, we describe the implementation of the revised ANZACS-QI Heart Failure Registry, which has a primary aim to support evidence-based management of and quality improvement measures for patients who are hospitalised with heart failure in New Zealand. Taking the learnings from the initial experience with the ADHF Registry, the revised ANZACS-QI Heart Failure Registry i) utilises age-stratified sampling of hospital discharge coding to identify a representative heart failure cohort, ii) utilises existing ANZACS-QI infrastructure for data-linkage to reduce the burden of manual data entry, iii) receives governance from the Heart Failure Working Group, and iv) focusses on established quality improvement indicators for heart failure management.

Exposure to toxic chemical elements among people living with HIV/AIDS in Northern Tanzania.

Environmental exposure to toxic chemicals including cadmium (Cd), lead (Pb), and mercury (Hg), are known risk factors for cardiovascular (CVD) and kidney disease. In people living with HIV (PLWH), CVD and kidney disease are the leading cause of death. Neither traditional risk factors nor markers of HIV infection fully explain such an increased risk. It is of paramount importance to establish the epidemiology of toxic chemicals exposure in PLWH, to inform screening and prevention interventions in this vulnerable population. This cross-sectional study compares toxic chemical levels (T-Cd, T-Pb, and T-Hg) among PLWH and HIV-uninfected adults in Northwestern Tanzania. A total of 495 PLWH and 505 HIV-uninfected subjects were analyzed. Spearman's rank correlations were used to examine the relationship between toxic chemical elements by HIV status. Linear regression models were used to determine the association between exposures and outcomes of interest among study participants. In both PLWH and HIV-uninfected adults, blood T-Cd, T-Pb, and T-Hg levels were frequently found at levels above the reference value of 5, 50, and 20 µg/L, respectively. Overall, factors associated with blood toxic chemical levels included vegetable servings per week, obesity, untreated water sources, use of alcohol, and HIV. Among PLWH, weekly vegetable intake provided a protective effect against T-Cd (Coeff = -0.03, 95%CI = -0.06, -0.01) and T-Pb (Coeff = -0.05, 95%CI = -0.09, -0.01) exposure among PLWH. Alcohol intake (Coeff = 0.10, 95%CI = 0.06, 0.13), obesity (Coeff = 0.08, 95%CI = 0.02, 0.13), longer duration to indoor smoke exposure (Coeff = 0.003, 95%CI = 0.001, 0.004), and HIV infection (Coeff = 0.11, 95%CI = 0.07, 0.15) were associated with increased individuals blood T-Hg levels. Individuals in northwestern Tanzania, including PLWH, have high blood levels for T-Cd, T-Pb, and T-Hg. Factors associated with higher blood levels include water sources, obesity, use of alcohol, exposure to indoor smoke, and HIV infection.

Rates of Choriocapillaris Microvascular Dropout and Macular Structural Changes in Glaucomatous Optic Neuropathy With and Without Myopia.

PURPOSE: To evaluate the association between rates of juxtapapillary choriocapillaris microvasculature dropout (MvD) change and rates of ganglion cell inner plexiform layer (GCIPL) loss in primary open-angle glaucoma (POAG) and glaucoma suspect eyes with and without myopia. DESIGN: Cohort study from clinical trial data METHODS: 238 eyes from 155 POAG and glaucoma suspect patients were stratified into no-myopia (axial length (AL) ≤ 24 mm; n = 78 eyes), mild myopia (24 mm< AL ≤ 26 mm; n = 114 eyes), and high myopia (AL > 26 mm; n = 46 eyes). Eyes with a minimum of 3 visits and 1.5 years of follow-up with both optical coherence tomography angiography (OCT-A) and OCT macula scans were included. Presence, area, and angular circumference of juxtapapillary MvD were evaluated on en face choroidal images and horizontal B-scans obtained from OCT-A imaging. RESULTS: Over the mean follow-up of 4.4 years, the mean MvD area rates of change (95% CI) were largest in high and mild myopia group (0.04 (0.03, 0.05) mm2/year in both groups), followed by the no-myopia group (0.03 (0.02, 0.04) mm2/year). The mean MvD angular circumference rates of change (95% CI) were highest in mild myopia group (8.7o (6.9o, 10.5o)/year) followed by the high myopia and no-myopia groups (8.1o (5.3o, 10.9o)/year, and 7.4o (5.3o, 9.6o)/year, respectively). While the mean global GCIPL thinning rates between eyes with MvD at baseline compared to eyes without were similar in all myopia groups, the rates of MvD area change were significantly faster in all myopia groups with baseline MvD (all p≤0.004). Significant faster rates of MvD angular circumference change were found in the mild myopia group with baseline MvD (p<0.001) only. In multivariable models, the rates of GCIPL thinning over time were significantly associated with rates of MvD angular circumference change and MvD area change (R2=0.33, p<0.001 and R2=0.32, p=0.006, respectively). CONCLUSIONS: Rates of GCIPL thinning were associated with rates of MvD area and angular circumference change over time in myopic POAG eyes. Utilizing OCT-A to detect MvD may provide an additional tool for monitoring macular structural changes in glaucomatous eyes with myopia.

Plasma soluble fms-like tyrosine kinase-1, placental growth factor, and vascular endothelial growth factor system gene variants as predictors of survival in heart failure.

AIMS: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. METHODS AND RESULTS: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy. CONCLUSIONS: Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.

Social factors associated with the risk of glaucoma suspect conversion to glaucoma: analysis of the nationwide All of Us Program.

PURPOSE: To examine social factors associated with the 5-year risk of glaucoma suspects (GS) converting to open-angle glaucoma (OAG). DESIGN: Retrospective cohort analysis. SUBJECTS: We screened for participants diagnosed with GS in the All of Us database. Cases that converted to OAG within 5 years of GS diagnosis (the "conversion group") were compared with control cases that did not convert. METHODS: Demographic, socioeconomic and healthcare utilization data of the cases were extracted and compared between the conversion group and the control group. Multivariable Cox proportional hazards modeling was used to identify potential factors associated with the risk of conversion. MAIN OUTCOME MEASURES: Hazard ratios (HRs) of significant factors associated with the risk of conversion. RESULTS: A total of 5274 GS participants were identified, and 786 (15%) cases converted to OAG within 5-year follow-up. The two groups showed significant differences in age, race, gender, employment status, income/education level, history of intra-ocular surgery, and healthcare utilization patterns. In the multivariable model, African American/Black race (HR [95% confidence interval] =1.70 [1.44-2.00]), older age at GS diagnosis (1.17 [1.09-1.25]), male gender (1.30 [1.13-1.50], no history of recreational drug use (1.23 [1.07-1.42]), history of intra-ocular surgery (1.60 [1.02-1.53]) and having more reasons for delayed healthcare access (2.27 [1.23-4.18]) were associated with a greater hazard of conversion, while being employed (0.71 [0.60-0.86]) was associated with a smaller hazard of conversion (P<0.05 for all). CONCLUSIONS: Several social factors were associated with the conversion from GS to OAG, which may help to identify patients at higher risk of disease progression. Future studies are needed to examine the basis for these findings and the potential interventions that could address them.

Wide-Field Optical Coherence Tomography Imaging Improves Rate of Change Detection in Progressing Glaucomatous Eyes Compared With Standard-Field Imaging.

Purpose: To compare rates of retinal nerve fiber layer change over time in healthy, eyes with nonprogressing glaucoma and eyes with progressing glaucoma using single wide-field (SWF) and optic nerve head (ONH) cube scan optical coherence tomography (OCT) images. Methods: Forty-five eyes of 25 healthy individuals and 263 eyes of 161 glaucoma patients from the Diagnostic Innovations in Glaucoma Study were included. All eyes underwent 24-2 visual field testing and OCT (Spectralis SD-OCT) ONH and macular imaging. SWF images (up to 43° × 28°) were created by stitching together ONH cube scans centered on the optic disc and macular cube scans centered on the fovea. Visual field progression was defined as guided progression analysis likely progression and/or a significant (P < 0.01) mean deviation slope of less than -1.0 dB/year. Mixed effects models were used to compare rates of change. Highly myopic eyes were included. Results: Thirty glaucomatous eyes were classified as progressing. In eyes with glaucoma, mean global rate of change was -1.22 µm/year (P < 0.001) using SWF images and -0.83 µm/year (P = 0.003) using ONH cube scans. Rate of change was significantly greater in eyes with progressing glaucoma compared with eyes with nonprogressing glaucoma (-1.51 µm/year vs. -1.24 µm/year; P = 0.002) using SWF images and was similar using ONH cube scans (P = 0.27). Conclusions: In this cohort that includes eyes with and without high axial myopia, the mean rate of retinal nerve fiber layer thinning measured using SWF images was faster in eyes with progressing glaucoma than in eyes with nonprogressing glaucoma. Wide-field OCT images including the ONH and macula can be effective for monitoring glaucomatous progression in patients with and without high myopia.

Antigen-specific age-related memory CD8 T cells induce and track Alzheimer's-like neurodegeneration.

Cerebral (Aß) plaque and (pTau) tangle deposition are hallmarks of Alzheimer's disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aß/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aß/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T ("hiT") cells act upstream of Aß/pTau after brain injury. Here, we examine whether hiT cells influence sporadic AD-like pathophysiology upstream of Aß/pTau. Examining neuropathology, gene expression, and behavior in our hiT mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. We identify an age-related factor acting upstream of Aß/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.

Utility of an Externalized Temporary Transvenous Implantable Cardioverter-defibrillator System in the Setting of Ventricular Tachycardia Storm and Concurrent Device Infection Requiring Extraction.

With the expanding use of cardiac implantable electronic device (CIED) therapy, intravascular device infections are becoming more common. In the case of transvenous implantable cardioverter-defibrillator (ICD) infections requiring extraction for bacterial clearance, there remains no standard method to deliver temporary ICD therapy following device removal. We present a case of persistent bacteremia complicated by monomorphic ventricular tachycardia (VT) electrical storm where biventricular ICD system extraction was performed and a temporary transvenous dual-coil lead with an externalized ICD generator was used to treat VT episodes prior to the re-implantation of a new permanent system. This case demonstrates the utility of a temporary externalized transvenous ICD system in the successful detection and pace-termination of VT, thereby reducing episodes of painful and potentially harmful external defibrillator shocks during the treatment of CIED infection.

Outcomes comparison of robotic-assisted versus laparoscopic and open surgery for patients undergoing rectal cancer resection with concurrent stoma creation.

BACKGROUND: Despite widespread adoption of robotic-assisted surgery (RAS) in rectal cancer resection, there remains limited knowledge of its clinical advantage over laparoscopic (Lap) and open (OS) surgery. We aimed to compare clinical outcomes of RAS with Lap and OS for rectal cancer. METHODS: We identified all patients aged ≥ 18 years who had elective rectal cancer resection requiring temporary or permanent stoma formation from 1/2013 to 12/2020 from the PINC AI™ Healthcare Database. We completed multivariable logistic regression analysis accounting for hospital clustering to compare ileostomy formation between surgical approaches. Next, we built inverse probability of treatment-weighted analyses to compare outcomes for ileostomy and permanent colostomy separately. Outcomes included postoperative complications, in-hospital mortality, discharge to home, reoperation, and 30-day readmission. RESULTS: A total of 12,787 patients (OS: 5599 [43.8%]; Lap: 2872 [22.5%]; RAS: 4316 [33.7%]) underwent elective rectal cancer resection. Compared to OS, patients who had Lap (OR 1.29, p < 0.001) or RAS (OR 1.53, p < 0.001) were more likely to have an ileostomy rather than permanent colostomy. In those with ileostomy, RAS was associated with fewer ileus (OR 0.71, p < 0.001) and less bleeding (OR 0.50, p < 0.001) compared to Lap. In addition, RAS was associated with lower anastomotic leak (OR 0.25, p < 0.001), less bleeding (OR 0.51, p < 0.001), and fewer blood transfusions (OR 0.70, p = 0.022) when compared to OS. In those patients who had permanent colostomy formation, RAS was associated with fewer ileus (OR 0.72, p < 0.001), less bleeding (OR 0.78, p = 0.021), lower 30-day reoperation (OR 0.49, p < 0.001), and higher discharge to home (OR 1.26, p = 0.013) than Lap, as well as OS. CONCLUSION: Rectal cancer patients treated with RAS were more likely to have an ileostomy rather than a permanent colostomy and more enhanced recovery compared to Lap and OS.

Long-Term Systemic Use of Calcium Channel Blockers and Incidence of Primary Open-Angle Glaucoma.

PURPOSE: To evaluate the association between the systemic use of calcium channel blockers (CCBs) and primary open-angle glaucoma (POAG) using a diverse nationwide dataset. DESIGN: Retrospective cohort study. SUBJECTS: 213 424 individuals aged 40 years and older in the National Institutes of Health All of Us dataset, notable for its demographic, geographic, and medical diversity and inclusion of historically underrepresented populations. Patients with a diagnosis of POAG prior to use of any kind of antihypertensive medication were excluded. METHODS: Bivariate and multivariable regression analyses were performed to evaluate associations between CCB use and POAG. Calcium channel blocker use was further divided into exposure to dihydropyridine CCBs and nondihydropyridine CCBs, and subgroup analyses were performed using chi-square and Fisher tests. MAIN OUTCOME MEASURES: Diagnosis of POAG. RESULTS: Within our cohort, 2772 participants (1.3%) acquired a diagnosis of POAG, while 210 652 (98.7%) did not. Among patients who developed POAG, the mean age was 73.3 years, 52.5% were female, and 48.2% identified as White. Among patients with POAG, 32.6% used 1 or more CCB, 28.2% used a dihydropyridine CCB, and 2.2% used a nondihydropyridine CCB. In bivariate analysis, use of any CCBs was associated with an increased risk of POAG (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.27-1.31, P < 0.001). In multivariable analysis adjusting for age, gender, race, ethnicity, and comorbidities such as diabetes, hyperlipidemia, and hypertension, use of any CCBs remained associated with an increased risk of developing POAG (OR: 1.52, 95% CI: 1.33-1.74, P < 0.001). When stratified by type of CCB, the use of dihydropyridine CCBs (OR: 1.31, 95% CI: 1.14-1.50, P < 0.001) was associated with increased POAG risk. CONCLUSIONS: Use of dihydropyridine CCBs was associated with a significantly higher risk of developing POAG, both before and while adjusting for demographic factors and comorbid medical conditions. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Administration of Bicarbonate Protects Mitochondria, Rescues Retinal Ganglion Cells, and Ameliorates Visual Dysfunction Caused by Oxidative Stress.

Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is a key regulator of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, which is known to protect mitochondria and promote RGC survival. However, the precise molecular mechanisms connecting the sAC-mediated signaling pathway with mitochondrial protection in RGCs against oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress induced by ischemic injury and paraquat administration, we found that administration of bicarbonate, as an activator of sAC, protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death. Notably, the administration of bicarbonate ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.

Smoking data quality of primary care practices in comparison with smoking data from the New Zealand Maori and Pacific abdominal aortic aneurysm screening programme: an observational study.

BACKGROUND: Quality smoking data is crucial for assessing smoking-related health risk and eligibility for interventions related to that risk. Smoking information collected in primary care practices (PCPs) is a major data source; however, little is known about the PCP smoking data quality. This project compared PCP smoking data to that collected in the Maori and Pacific Abdominal Aortic Aneurysm (AAA) screening programme. METHODS: A two stage review was conducted. In Stage 1, data quality was assessed by comparing the PCP smoking data recorded close to AAA screening episodes with the data collected from participants at the AAA screening session. Inter-rater reliability was analysed using Cohen's kappa scores. In Stage 2, an audit of longitudinal smoking status was conducted, of a subset of participants potentially misclassified in Stage 1. Data were compared in three groups: current smoker (smoke at least monthly), ex-smoker (stopped > 1 month ago) and never smoker (smoked < 100 cigarettes in lifetime). RESULTS: Of the 1841 people who underwent AAA screening, 1716 (93%) had PCP smoking information. Stage 1 PCP smoking data showed 82% concordance with the AAA data (adjusted kappa 0.76). Fewer current or ex-smokers were recorded in PCP data. In the Stage 2 analysis of discordant and missing data (N = 313), 212 were enrolled in the 29 participating PCPs, and of these 13% were deceased and 41% had changed PCP. Of the 93 participants still enrolled in the participating PCPs, smoking status had been updated for 43%. Data on quantity, duration, or quit date of smoking were largely missing in PCP records. The AAA data of ex-smokers who were classified as never smokers in the Stage 2 PCP data (N = 27) showed a median smoking cessation duration of 32 years (range 0-50 years), with 85% (N = 23) having quit more than 15 years ago. CONCLUSIONS: PCP smoking data quality compared with the AAA data is consistent with international findings. PCP data captured fewer current and ex-smokers, suggesting ongoing improvement is important. Intervention programmes based on smoking status should consider complementary mechanisms to ensure eligible individuals are not missed from programme invitation.

Association between metformin use with circumpapillary retinal nerve fibre layer thickness and capillary vessel density in glaucoma.

BACKGROUND/AIMS: To investigate the association between use of metformin and circumpapillary retinal nerve fibre layer (cpRNFL) thickness, as well as whole image capillary density (wiCD), in patients with glaucoma. METHODS: This cross-sectional study included patients with glaucoma suspect or primary open-angle glaucoma (POAG) underwent optical coherence tomography angiography imaging. Use and duration of antidiabetic medications were assessed at the time of imaging. Multivariable linear mixed-effect modelling was used to estimate the effect of diabetes medication on wiCD and cpRNFL while controlling for covariates including age, race, body mass index, diagnosis, 24-2 visual field mean deviation, and intraocular pressure, average signal strength index as well as any variables that showed a p <0.1 in the univariable analysis. RESULTS: A total of 577 eyes (330 POAG and 247 glaucoma suspect) of 346 patients were included. Sixty-five patients (23%) had diabetes, of whom 55 (78.5%) used metformin, and 17 (26.2%) used insulin. After adjusting for covariates, the association between metformin use and wiCD (1.56 (95% CI 0.40 to 2.71); p=0.008), duration of metformin use and wiCD (0.12 (95% CI 0.02 to 0.22) per 1 year longer; p=0.037), and metformin use and cpRNFL thickness (5.17 (95% CI 1.24 to 9.10) µm; p=0.010) had statistically significant associations in each model. CONCLUSIONS: Metformin use was associated with higher wiCD and thicker cpRNFL. These findings indicate a potential association, underscoring the need for longitudinal studies to determine if metformin plays a role in the retinal conditions of patients with glaucoma. TRIAL REGISTRATION NUMBER: NCT00221897.

The effects of supplemental instruction derived from peer leaders on student outcomes in undergraduate human anatomy.

Supplemental instruction (SI) confers student success, as represented by grades, knowledge retention, and student engagement. However, studies often report professional, not undergraduate, program findings. To measure these effects, students studying human anatomy at a university in Ontario, Canada, attended structured (peer-assisted) or unstructured (nonpeer-assisted) SI sessions and completed a pre-/post-survey. Fifty-eight learners (39 systems (SYS) and 19 musculoskeletal (MSK) anatomy) completed both surveys and had responses analyzed. Both cohorts, maintained initial perceptions across pre-/post-analyses (MSK p = 0.1376 and SYS p = 0.3521). Resource usage was similar across both cohorts with discrepancies in skeletal model and textbook use. No MSK learner ranked any lab resources as "not at all useful." MSK learners felt more prepared to write a graded assessment (p = 0.0269), whereas SYS learners did not (p = 0.0680). Stratification of learners in MSK and SYS revealed learners spending between 30 and 60 min in SI sessions during the study period had the highest grades compared to students who spent less than 30 (p = 0.0286) or more than 60 (p = 0.0286) min attending SI sessions, respectively. Most learners in MSK (89.4%) and SYS (66%) concluded that they preferred structured over unstructured SI. Sentiment/thematic analysis using a generative AI-driven large language model revealed learners held positive perceptions of SI, emphasizing structured learning, resources, personalized learning, and support offered as the most prevalent themes surrounding SI. Ultimately, this study provides evidence that supports SI for improving student outcomes related to perceived preparedness for completing assessments and preferred teaching/learning styles in undergraduate human anatomy.

Evaluation of left ventricular filling pressure by echocardiography in patients with atrial fibrillation.

BACKGROUND: Echocardiography is widely used to evaluate left ventricular (LV) diastolic function in patients suspected of heart failure. For patients in sinus rhythm, a combination of several echocardiographic parameters can differentiate between normal and elevated LV filling pressure with good accuracy. However, there is no established echocardiographic approach for the evaluation of LV filling pressure in patients with atrial fibrillation. The objective of the present study was to determine if a combination of several echocardiographic and clinical parameters may be used to evaluate LV filling pressure in patients with atrial fibrillation. RESULTS: In a multicentre study of 148 atrial fibrillation patients, several echocardiographic parameters were tested against invasively measured LV filling pressure as the reference method. No single parameter had sufficiently strong association with LV filling pressure to be recommended for clinical use. Based on univariate regression analysis in the present study, and evidence from existing literature, we developed a two-step algorithm for differentiation between normal and elevated LV filling pressure, defining values ≥ 15 mmHg as elevated. The parameters in the first step included the ratio between mitral early flow velocity and septal mitral annular velocity (septal E/e'), mitral E velocity, deceleration time of E, and peak tricuspid regurgitation velocity. Patients who could not be classified in the first step were tested in a second step by applying supplementary parameters, which included left atrial reservoir strain, pulmonary venous systolic/diastolic velocity ratio, and body mass index. This two-step algorithm classified patients as having either normal or elevated LV filling pressure with 75% accuracy and with 85% feasibility. Accuracy in EF ≥ 50% and EF < 50% was similar (75% and 76%). CONCLUSIONS: In patients with atrial fibrillation, no single echocardiographic parameter was sufficiently reliable to be used clinically to identify elevated LV filling pressure. An algorithm that combined several echocardiographic parameters and body mass index, however, was able to classify patients as having normal or elevated LV filling pressure with moderate accuracy and high feasibility.

Interleukin-1ß induces and accelerates human endometrial stromal cell senescence and impairs decidualization via the c-Jun N-terminal kinase pathway.

As the mean age of first-time mothers increases in the industrialized world, inquiries into causes of human reproductive senescence have followed. Rates of ovulatory dysfunction and oocyte aneuploidy parallel chronological age, but poor reproductive outcomes in women older than 35 years are also attributed to endometrial senescence. The current studies, using primary human endometrial stromal cell (ESC) cultures as an in vitro model for endometrial aging, characterize the proinflammatory cytokine, IL-1ß-mediated and passage number-dependent effects on ESC phenotype. ESC senescence was accelerated by incubation with IL-1ß, which was monitored by RNA sequencing, ELISA, immunocytochemistry and Western blotting. Senescence associated secreted phenotype (SASP) proteins, IL-1ß, IL-6, IL-8, TNF-α, MMP3, CCL2, CCL5, and other senescence-associated biomarkers of DNA damage (p16, p21, HMGB1, phospho-γ-histone 2 A.X) were noted to increase directly in response to 0.1 nM IL-1ß stimulation. Production of the corresponding SASP proteins increased further following extended cell passage. Using enzyme inhibitors and siRNA interference, these effects of IL-1ß were found to be mediated via the c-Jun N-terminal kinase (JNK) signaling pathway. Hormone-induced ESC decidualization, classical morphological and biochemical endocrine responses to estradiol, progesterone and cAMP stimulation (prolactin, IGFBP-1, IL-11 and VEGF), were attenuated pari passu with prolonged ESC passaging. The kinetics of differentiation responses varied in a biomarker-specific manner, with IGFBP-1 and VEGF secretion showing the largest and smallest reductions, with respect to cell passage number. ESC hormone responsiveness was most robust when limited to the first six cell passages. Hence, investigation of ESC cultures as a decidualization model should respect this limitation of cell aging. The results support the hypotheses that "inflammaging" contributes to endometrial senescence, disruption of decidualization and impairment of fecundity. IL-1ß and the JNK signaling pathway are pathogenetic targets amenable to pharmacological correction or mitigation with the potential to reduce endometrial stromal senescence and enhance uterine receptivity.