The Patterns of Morphological Change During Intracerebral Hemorrhage Expansion: A Multicenter Retrospective Cohort Study

Objectives: Hemorrhage expansion (HE) is a common and serious condition in patients with intracerebral hemorrhage (ICH). In contrast to the volume changes, little is known about the morphological changes that occur during HE. We developed a novel method to explore the patterns of morphological change and investigate the clinical significance of this change in ICH patients.Methods: The morphological changes in the hematomas of ICH patients with available paired non-contrast CT data were described in quantitative terms, including the diameters of each hematoma in three dimensions, the longitudinal axis type, the surface regularity (SR) index, the length and direction changes of the diameters, and the distance and direction of movement of the center of the hematoma. The patterns were explored by descriptive analysis and difference analysis in subgroups. We also established a prognostic nomogram model for poor outcomes in ICH patients using both morphological changes and clinical parameters.Results: A total of 1,094 eligible patients from four medical centers met the inclusion criteria. In 266 (24.3%) cases, the hematomas enlarged; the median absolute increase in volume was 14.0 [interquartile range (IQR), 17.9] mL. The initial hematomas tended to have a more irregular shape, reflected by a larger surface regularity index, than the developed hematomas. In subtentorial and deep supratentorial hematomas, the center moved in the direction of gravity. The distance of center movement and the length changes of the diameters were small, with median values of less than 4 mm. The most common longitudinal axis type was anterior–posterior (64.7%), and the axis type did not change between initial and repeat imaging in most patients (95.2%). A prognostic nomogram model including lateral expansion, a parameter of morphological change, showed good performance in predicting poor clinical outcomes in ICH patients.Conclusions: The present study provides a morphological perspective on HE using a novel automatic approach. We identified certain patterns of morphological change in HE, and we believe that some morphological change parameters could help physicians predict the prognosis of ICH patients.

Effects and Mechanism of Salvianolic Acid B on the Injury of Human Renal Tubular Epithelial Cells Induced by Iopromide

With the increasing application of medical imaging contrast materials, contrast-induced nephropathy (CIN) has become the third major cause of iatrogenic renal insufficiency. CIN is defined as an absolute increase in serum creatinine levels of at least 0.50 mg/dl or an increase >25% of serum creatinine from baseline after exposure to contrast. In this study, the protective effects of salvianolic acid B (Sal B) were detected in human renal tubular epithelial cells (HK-2) exposed to iopromide. The results showed that different concentrations of Sal B counteract the loss of cell viability induced by iopromide, and reduce cell apoptosis, the reactive oxygen species (ROS) levels, and the levels of endoplasmic reticulum stress (ERS)–related and apoptosis-related proteins such as p-IRE-1α, p-eIF-2α/eIF-2α, p-JNK, CHOP, Bax/Bcl-2, and cleaved caspase-3. In addition, Sal B at a concentration of 100 μmol/L inhibited ERS and reduced cell damage to a similar extent as the ERS inhibitor 4-PBA. Importantly, treatment with Sal B could abolish the injury induced by ERS agonist tunicamycin, increasing cell viability and the mitochondrial membrane potential, as well as significantly reducing ROS levels and the expression of Bax/Bcl-2, cleaved-caspase-3, GRP78, p-eIF2α, p-JNK, and CHOP. These results suggested that the protective effect of Sal B against HK-2 cell injury induced by iopromide may be related to the inhibition of ERS.

Inhalable, Spray-Dried Terbinafine Microparticles for Management of Pulmonary Fungal Infections: Optimization of the Excipient Composition and Selection of an Inhalation Device

Terbinafine is a broad-spectrum antifungal agent with therapeutic potential against pulmonary aspergillosis. The main aim of the current study was to investigate the potential of l-leucine, alone and in combination with mannitol, to improve the performance of spray-dried terbinafine microparticles for inhalation. The study also aimed to investigate the potential of the low resistance Cyclohaler® and the high resistance Handihaler® as inhalation devices for spray-dried microparticles. To this end, eight powder inhalation formulations of terbinafine were prepared by nano spray drying via a factorial experimental design. The formulations were evaluated in vitro for their potential to deliver the antifungal drug to the lungs using the Cyclohaler® and the Handihaler®. Leucine was superior as an excipient to mannitol and to mixtures of leucine and mannitol. Using leucine as an excipient resulted in formulations with fine particle fractions of up to 60.84 ± 0.67% w/w and particle mass median aerodynamic diameters of down to 1.90 ± 0.20 μm, whereas using mannitol as an excipient resulted in formulations with fine particle fractions of up to 18.75 ± 3.46% w/w and particle mass median aerodynamic diameters of down to 6.79 ± 0.82 μm. When leucine was used as an excipient, using 50% w/w rather than 25% w/w ethanol in water as a spray solvent enhanced the dispersibility of the particles, with a mean absolute increase in the formulation fine particle fraction of 9.57% w/w (95% confidence interval = 6.40–12.73% w/w). This was potentially underlain by enrichment of the particle surfaces with leucine. The Cyclohaler® outperformed the Handihaler® as an inhalation device for the developed formulations, with a mean absolute increase in the fine particle fraction of 9.17% w/w (95% confidence interval = 8.17–10.16% w/w).

Circulating Chromogranin B Is Associated With Left Ventricular Functional Recovery After Successful Recanalization of Chronic Total Occlusion

Background: Chromogranin B (CgB) is increased in heart failure and proportionate to disease severity. We investigated whether circulating CgB level is associated with left ventricular (LV) functional recovery potential after successful recanalization of chronic total occlusion (CTO).Methods: Serum levels of CgB were assayed in 53 patients with stable angina with LV functional recovery [an absolute increase in LV ejection fraction (EF) of ≥5%] and 53 age- and sex-matched non-recovery controls after successful recanalization of CTO during 12-month follow-up.Results: We found that CgB level was significantly lower in the recovery group than in the non-recovery group (593 [IQR 454–934] vs. 1,108 [IQR 696–2020] pg/ml, P < 0.001), and that it was inversely correlated with changes in LVEF (Spearman's r = −0.31, P = 0.001). Receiver operating characteristic (ROC) analysis showed that the area under the curve of CgB for predicting LVEF improvement was 0.76 (95% CI 0.664–0.856), and that the optimal cutoff value was 972.5 pg/ml. In multivariate analyses, after adjusting for confounding factors, high CgB level remained an independent determinant of impaired LV functional recovery after CTO recanalization. LV functional improvement appeared to be more responsive to CgB in patients with poor than with good coronary collaterals.Conclusions: Elevated circulating CgB level confers an increased risk of impaired LV functional recovery after successful recanalization of CTO in patients with stable coronary artery disease.

A Contemporary View on the Anatomy of Parotid Gland

One of the up-to-date issues of contemporary medicine is the study of the features of individual anatomical structure variability of various organs. In recent years, the incidence of parotid gland diseases has been rising. This phenomenon can be associated with an absolute increase in this organ pathologies incidence as well as with the development of additional methods of examination and visualization of the gland. Most pathologies of major salivary glands, in particular the parotid gland, require surgical treatment. Knowledge of topographical relationship of the parotid gland with the adjacent vessels and nerve trunks is utterly necessary for planning and performing surgical interventions and reconstructive operations in the parotid region. According to the statistics, surgical interventions on the parotid gland take the leading place among the causes of damage to the facial nerve branches. This fact may also prove a large variation in the syntopy of the facial nerve and the parotid gland. The paper reviews the data of native and foreign literature on the anatomy of parotid gland and the place of radiation research methods in the study of its topographical and anatomical features. The analysis revealed a wide range of anatomical norm of parotid gland in many parameters, including shape, linear size, blood supply, and topographical features. The practice of using anthropometric studies aimed at structuring the existing knowledge and narrowing the borders of anatomical norm for various organs proved to be successful. However, in the pool of scientific papers, we have not found similar studies concerning parotid gland. The facts mentioned above make the background and justify further studies of parotid gland in the context of normal individual variability.

Excess mortality by individual and spousal education for recent and long-term widowed

Objectives The loss of a spouse is followed by a dramatic but short-lived increase in the mortality risk of the survivor. Contrary to expectations, several studies have found this increase to be larger among those with high education. Having a spouse with high education is associated with lower mortality which suggests that losing a spouse with high education means the loss of a stronger protective factor than losing a spouse with low education. This may disproportionately affect the high educated because of educational homogamy. Methods We use Swedish total population registers to construct an open cohort of 1,842,487 married individuals aged 60 to 89 during 2007—2016, observing 239,276 transitions into widowhood and 277,946 deaths. We use Poisson regression to estimate relative and absolute mortality risks by own and spousal education among the married, recent, and long-term widows. Results We find an absolute increase in mortality risk, concentrated to the first six months of widowhood across all educational strata. The relative increase in mortality risk is larger in higher educational strata. Losing a spouse with high education is associated with higher excess mortality, which attenuates this difference. Discussion When considering the timing and the absolute level of excess mortality we find that the overall patterns of excess mortality are similar across educational strata. We argue that widowhood has a dramatic impact on health, regardless of education.

Changes in diabetes prescription patterns following Affordable Care Act Medicaid expansion

IntroductionMost patients with diabetes mellitus are prescribed medications to control their blood glucose. The implementation of the Affordable Care Act (ACA) led to improved access to healthcare for patients with diabetes. However, impact of the ACA on prescribing trends by diabetes drug category is less clear. This study aims to assess if long-acting insulin and novel agents were prescribed more frequently following the ACA in states that expanded Medicaid compared with non-expansion states.Research design and methodsIn this analysis of a natural experiment, prescriptions reimbursed by Medicaid (US public insurance) for long-acting insulins, metformin, and novel agent medications (DPP4 inhibitors, sodium/glucose cotransporter 2 inhibitor antagonists, and glucagon-like peptide-1 receptor agonists) from 2012 to 2017 were obtained from public records. For each medication category, we performed difference-in-differences (DID) analysis modeling change in rate level from pre-ACA to post-ACA in Medicaid expansion states relative to Medicaid non-expansion states.ResultsExpansion and non-expansion states saw a decline in both metformin and long-acting insulin prescriptions per 100 enrollees from pre-ACA to post-ACA. These decreases were larger in non-expansion states relative to expansion states (metformin: absolute DID = +0.33, 95% CI=0.323 to 0.344) and long-acting insulin (absolute DID: +0.11; 95% CI=0.098 to 0.113). Novel agent prescriptions in expansion states (+0.08 per 100 enrollees) saw a higher absolute increase per 100 Medicaid enrollees than in non-expansion states (absolute DID= +0.08, 95% CI=0.079 to 0.086).ConclusionsThere was a greater absolute increase for prescriptions of novel agents in expansion states relative to non-expansion states after accounting for number of enrollees. Reducing administrative barriers and improving the ability of providers to prescribe such newer therapies will be critical for caring for patients with diabetes—particularly in Medicaid non-expansion states.

Associations of hypoglycemia, glycemic variability and risk of cardiac arrhythmias in insulin-treated patients with type 2 diabetes: a prospective, observational study

Background Insulin-treated patients with type 2 diabetes (T2D) are at risk of hypoglycemia, which is associated with an increased risk of cardiovascular disease and mortality. Using a long-term monitoring approach, we investigated the association between episodes of hypoglycemia, glycemic variability and cardiac arrhythmias in a real-life setting. Methods Insulin-treated patients with T2D (N = 21, [mean ± SD] age 66.8 ± 9.6 years, BMI 30.1 ± 4.5 kg/m2, HbA1c 6.8 ± 0.4% [51.0 ± 4.8 mmol/mol]) were included for a one-year observational study. Patients were monitored with continuous glucose monitoring ([mean ± SD] 118 ± 6 days) and an implantable cardiac monitor (ICM) during the study period. Results Time spend in hypoglycemia was higher during nighttime than during daytime ([median and interquartile range] 0.7% [0.7–2.7] vs. 0.4% [0.2–0.8]). The ICMs detected 724 episodes of potentially clinically significant arrhythmias in 12 (57%) participants, with atrial fibrillation and pauses accounting for 99% of the episodes. No association between hypoglycemia and cardiac arrhythmia was found during daytime. During nighttime, subject-specific hourly incidence of cardiac arrhythmias tended to increase with the occurrence of hypoglycemia (incident rate ratio [IRR] 1.70 [95% CI 0.36–8.01]) but only slightly with increasing time in hypoglycemia (IRR 1.04 [95% CI 0.89–1.22] per 5 min). Subject-specific incidence of cardiac arrhythmias during nighttime increased with increasing glycemic variability as estimated by coefficient of variation whereas it decreased during daytime (IRR 1.33 [95% CI 1.05–1.67] and IRR 0.77 [95% CI 0.59–0.99] per 5% absolute increase, respectively). Conclusions Cardiac arrhythmias were common in insulin-treated patients with T2D and were associated with glycemic variability, whereas arrhythmias were not strongly associated with hypoglycemia. Trial registration: NCT03150030, ClinicalTrials.gov, registered May 11, 2017. https://clinicaltrials.gov/ct2/show/NCT03150030

Treatment with IMR-687, a Highly Selective PDE9 Inhibitor, Increases HbF and Reduces VOCs in Adults with Sickle Cell Disease in a Long-Term, Phase 2a, Open-Label Extension Study

Introduction IMR-687 (tovinontrine) is a highly selective phosphodiesterase 9 (PDE9) inhibitor being developed as an orally administered therapy for patients with sickle cell disease (SCD) and beta-thalassemia. IMR-687 increases intracellular cGMP levels and has been shown in preclinical studies to increase fetal hemoglobin (HbF) expression and reduce hemolysis and sickling of RBCs, which can lead to painful vaso-occlusive crisis (VOC). In a Phase 2a, randomized, double-blind, placebo-controlled study of adult patients with SCD (N=93) (NCT03401112), IMR-687 was generally well-tolerated as a monotherapy and in combination with hydroxyurea (HU) (European Hematology Association Annual Congress 2021, Abstract S263). IMR-687 treatment with 50-200 mg once daily (N=63) for up to 6 months, as compared with placebo (N=30), resulted in a 40% lower mean annualized rate of VOCs, 38% lower mean annualized rate of VOC-related hospitalizations, and increased median time to first VOC (169 days vs 87 days, respectively, p=0.029). Improvements were also observed in patient-reported outcomes regarding pain episode severity (ASCQ-Me) and percentage of RBCs containing HbF (F-cells). Methods A Phase 2a open-label extension (OLE) study (NCT04053803) is ongoing to assess the long-term safety and benefit of IMR-687 administered to adult subjects with SCD for up to 4 years. Secondary long-term pharmacokinetic (PK) and pharmacodynamic (PD) parameters are also being examined. The use of background HU is permitted. The Safety Review Committee meets regularly and ad hoc as necessary. Subjects were eligible upon completion of the Phase 2a parent study (16 or 24 weeks depending on the assigned treatment arm and without early withdrawal) and if they met all inclusion and exclusion criteria. For subjects without treatment interruption, baseline values from the parent study were used, as appropriate. The dose of IMR-687 initially administered in the OLE study was 200 mg as a once daily oral dose. The dose of IMR-687 is planned to be increased to 300 or 400 mg daily, depending on the subject's weight. Subjects are evaluated every 4-6 months for safety, PK and PD parameters (including HbF, F-cells, hemoglobin [Hb] and other biomarkers) as well as incidence of VOCs. Results As of a data cut-off of 12-May-2021, 24 subjects were enrolled in the OLE study, 17 of which had a treatment interruption between the parent and OLE studies, and 7 subjects had direct roll-over to the OLE study. Seventeen of the OLE subjects were treated with IMR-687 monotherapy and 7 subjects were treated with combination IMR-687 + HU. IMR-687 continued to be well-tolerated in the OLE study (N=24). There were no treatment-related serious adverse events (SAEs), and the most common (≥10%) AEs were headache (21% of subjects), back pain (17%) and nausea (13%). There were 3 (13%) subjects with VOC-related hospitalizations. Annualized VOC rate was analyzed for 18 subjects treated for at least 200 days in the OLE study. Subjects who were previously in the active treatment arm in the parent study (N=13) maintained a low mean annualized VOC rate while continuing IMR-687 in the OLE study (1.35/yr [parent] and 1.85/yr [OLE]); subjects previously treated with placebo (N=5) had a 39% reduction in VOC rate when switched to IMR-687 (4.71/yr [parent] vs 2.89/yr [OLE]) (Figure 1). Of 15 subjects with evaluable PD data at 8 months, 7 (47%) subjects had a ≥ 6% absolute increase in F-cells, and 4 of 11 (36%) subjects had a ≥ 3% absolute increase in HbF (Figure 2). Updated data for subjects completing 12 months in the OLE study will be presented. Conclusions Consistent with the parent study, preliminary results from the ongoing Phase 2a OLE study demonstrate that daily dosing of 200 mg IMR-687 was well-tolerated with longer-term treatment as a monotherapy or in combination with HU. IMR-687 treatment reduced the annualized rate of VOCs and increased HbF (%) and F-cells (%). Based on these encouraging data, a Phase 2b study (NCT04474314) is ongoing to further explore IMR-687 at doses up to 400 mg daily as a disease-modifying therapy for SCD. Figure 1 Figure 1. Disclosures Barysauskas: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Yen: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Tang: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Ballal: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Attie: Imara Inc.: Current Employment, Current equity holder in publicly-traded company.

Absolute Increase in the Number and Proportion of Peripheral Eosinophils Associated With Immune Checkpoint Inhibitor Treatment in Non-small Cell Lung Cancer Patients

Background/Aim: To clarify the clinical significance of the absolute increase in the number and proportion of peripheral eosinophils associated with immune checkpoint inhibitor (ICPI) treatment in non-small cell lung cancer (NSCLC) patients. Patients and Methods: We performed a retrospective study, by reviewing the medical charts of 191 patients who were treated with ICPI monotherapy and 80 patients treated with the combination of ICPI and chemotherapy during the period from February 2016 and April 2021. Results: In patients treated with ICPI monotherapy, there was a significant difference in time to treatment failure (TTF) between the two groups divided by eosinophils ≥ or <10%. Similarly, a significant difference was found in TTF between the two groups divided by eosinophils ≥ or <1,500/μl. Factors related to both an increase in the number and percentage of peripheral eosinophils were “immune-related adverse effects (irAE) that did not lead to discontinuation of administration". Conclusion: Some patients with irAE might have a 'favorable' absolute increase in peripheral eosinophils.