Attenuating midline thalamus bursting to mitigate absence epilepsy.

Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain-of-function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK-D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, a stimulant medication, or physical perturbation also effectively suppresses MLT bursting and prevents absence seizures. These findings suggest that the MLT is a promising target for clinical interventions. Our diverse approaches offer valuable insights for developing next generation therapeutics to treat absence epilepsy.

Volumetric Analysis: Effect on Diagnosis and Management of Indeterminate Solid Pulmonary Nodules in Routine Clinical Practice.

OBJECTIVE: To evaluate the effect of volumetric analysis on the diagnosis and management of indeterminate solid pulmonary nodules in routine clinical practice. METHODS: This was a retrospective study with 107 computed tomography (CT) cases of solid pulmonary nodules (range, 6-15 mm), 57 pathology-proven malignancies (lung cancer, n = 34; metastasis, n = 23), and 50 benign nodules. Nodules were evaluated on a total of 309 CT scans (average number of CTs/nodule, 2.9 [range, 2-7]). CT scans were from multiple institutions with variable technique. Nine radiologists (attendings, n = 3; fellows, n = 3; residents, n = 3) were asked their level of suspicion for malignancy (low/moderate or high) and management recommendation (no follow-up, CT follow-up, or care escalation) for baseline and follow-up studies first without and then with volumetric analysis data. Effect of volumetry on diagnosis and management was assessed by generalized linear and logistic regression models. RESULTS: Volumetric analysis improved sensitivity (P = 0.009) and allowed earlier recognition (P < 0.05) of malignant nodules. Attending radiologists showed higher sensitivity in recognition of malignant nodules (P = 0.03) and recommendation of care escalation (P < 0.001) compared with trainees. Volumetric analysis altered management of high suspicion nodules only in the fellow group (P = 0.008). κ Statistics for suspicion for malignancy and recommended management were fair to substantial (0.38-0.66) and fair to moderate (0.33-0.50). Volumetric analysis improved interobserver variability for identification of nodule malignancy from 0.52 to 0.66 (P = 0.004) only on the second follow-up study. CONCLUSIONS: Volumetric analysis of indeterminate solid pulmonary nodules in routine clinical practice can result in improved sensitivity and earlier identification of malignant nodules. The effect of volumetric analysis on management recommendations is variable and influenced by reader experience.

Actin cytoskeletal regulation of ciliogenesis in development and disease.

Primary cilia are antenna-like sensory organelles that are evolutionarily conserved in nearly all modern eukaryotes, from the single-celled green alga, Chlamydomonas reinhardtii, to vertebrates and mammals. Cilia are microtubule-based cellular projections that have adapted to perform a broad range of species-specific functions, from cell motility to detection of light and the transduction of extracellular mechanical and chemical signals. These functions render cilia essential for organismal development and survival. The high conservation of cilia has allowed for discoveries in C. reinhardtii to inform our understanding of the basic biology of mammalian primary cilia, and to provide insight into the genetic etiology of ciliopathies. Over the last two decades, a growing number of studies has revealed that multiple aspects of ciliary homeostasis are regulated by the actin cytoskeleton, including centrosome migration and positioning, vesicle transport to the basal body, ectocytosis, and ciliary-mediated signaling. Here, we review actin regulation of ciliary homeostasis, and highlight conserved and divergent mechanisms in C. reinhardtii and mammalian cells. Further, we compare the disease manifestations of patients with ciliopathies to those with mutations in actin and actin-associated genes, and propose that primary cilia defects caused by genetic alteration of the actin cytoskeleton may underlie certain birth defects.

Description of the local hemodynamic environment in intracranial aneurysm wall subdivisions.

Intracranial aneurysms (IAs) pose severe health risks influenced by hemodynamics. This study focuses on the intricate characterization of hemodynamic conditions within the IA walls and their influence on bleb development, aiming to enhance understanding of aneurysm stability and the risk of rupture. The methods emphasized utilizing a comprehensive dataset of 359 IAs and 213 IA blebs from 268 patients to reconstruct patient-specific vascular models, analyzing blood flow using finite element methods to solve the unsteady Navier-Stokes equations, the segmentation of aneurysm wall subregions and the hemodynamic metrics wall shear stress (WSS), its metrics, and the critical points in WSS fields were computed and analyzed across different aneurysm subregions defined by saccular, streamwise, and topographical divisions. The results revealed significant variations in these metrics, correlating distinct hemodynamic environments with wall features on the aneurysm walls, such as bleb formation. Critical findings indicated that regions with low WSS and high OSI, particularly in the body and central regions of aneurysms, are prone to conditions that promote bleb formation. Conversely, areas exposed to high WSS and positive divergence, like the aneurysm neck, inflow, and outflow regions, exhibited a different but substantial risk profile for bleb development, influenced by flow impingements and convergences. These insights highlight the complexity of aneurysm behavior, suggesting that both high and low-shear environments can contribute to aneurysm pathology through distinct mechanisms.

The Importance of Monitoring Non-clonal Chromosome Aberrations (NCCAs) in Cancer Research.

Cytogenetic analysis has traditionally focused on the clonal chromosome aberrations, or CCAs, and considered the large number of diverse non-clonal chromosome aberrations, or NCCAs, as insignificant noise. Our decade-long karyotype evolutionary studies have unexpectedly demonstrated otherwise. Not only the baseline of NCCAs is associated with fuzzy inheritance, but the frequencies of NCCAs can also be used to reliably measure genome or chromosome instability (CIN). According to the Genome Architecture Theory, CIN is the common driver of cancer evolution that can unify diverse molecular mechanisms, and genome chaos, including chromothripsis, chromoanagenesis, and polypoidal giant nuclear and micronuclear clusters, and various sizes of chromosome fragmentations, including extrachromosomal DNA, represent some extreme forms of NCCAs that play a key role in the macroevolutionary transition. In this chapter, the rationale, definition, brief history, and current status of NCCA research in cancer are discussed in the context of two-phased cancer evolution and karyotype-coded system information. Finally, after briefly describing various types of NCCAs, we call for more research on NCCAs in future cytogenetics.

The New Era of Cancer Cytogenetics and Cytogenomics.

The promises of the cancer genome sequencing project, combined with various -omics technologies, have raised questions about the importance of cancer cytogenetic analyses. It is suggested that DNA sequencing provides high resolution, speed, and automation, potentially replacing cytogenetic testing. We disagree with this reductionist prediction. On the contrary, various sequencing projects have unexpectedly challenged gene theory and highlighted the importance of the genome or karyotype in organizing gene network interactions. Consequently, profiling the karyotype can be more meaningful than solely profiling gene mutations, especially in cancer where karyotype alterations mediate cellular macroevolution dominance. In this chapter, recent studies that illustrate the ultimate importance of karyotype in cancer genomics and evolution are briefly reviewed. In particular, the long-ignored non-clonal chromosome aberrations or NCCAs are linked to genome or chromosome instability, genome chaos is linked to genome reorganization under cellular crisis, and the two-phased cancer evolution reconciles the relationship between genome alteration-mediated punctuated macroevolution and gene mutation-mediated stepwise microevolution. By further synthesizing, the concept of karyotype coding is discussed in the context of information management. Altogether, we call for a new era of cancer cytogenetics and cytogenomics, where an array of technical frontiers can be explored further, which is crucial for both basic research and clinical implications in the cancer field.

Tracking Karyotype Changes in Treatment-Induced Drug-Resistant Evolution.

Karyotype coding, which encompasses the complete chromosome sets and their topological genomic relationships within a given species, encodes system-level information that organizes and preserves genes' function, and determines the macroevolution of cancer. This new recognition emphasizes the crucial role of karyotype characterization in cancer research. To advance this cancer cytogenetic/cytogenomic concept and its platforms, this study outlines protocols for monitoring the karyotype landscape during treatment-induced rapid drug resistance in cancer. It emphasizes four key perspectives: combinational analyses of phenotype and karyotype, a focus on the entire evolutionary process through longitudinal analysis, a comparison of whole landscape dynamics by including various types of NCCAs (including genome chaos), and the use of the same process to prioritize different genomic scales. This protocol holds promise for studying numerous evolutionary aspects of cancers, and it further enhances the power of karyotype analysis in cancer research.

The Digital World of Cytogenetic and Cytogenomic Web Resources.

The dynamic growth of technological capabilities at the cellular and molecular level has led to a rapid increase in the amount of data on the genes and genomes of organisms. In order to store, access, compare, validate, classify, and understand the massive data generated by different researchers, and to promote effective communication among research communities, various genome and cytogenetic online databases have been established. These data platforms/resources are essential not only for computational analyses and theoretical syntheses but also for helping researchers select future research topics and prioritize molecular targets. Furthermore, they are valuable for identifying shared recurrent genomic patterns related to human diseases and for avoiding unnecessary duplications among different researchers. The website interface, menu, graphics, animations, text layout, and data from databases are displayed by a front end on the screen of a monitor or smartphone. A database front-end refers to the user interface or application that enables accessing tabular, structured, or raw data stored in the database. The Internet makes it possible to reach a greater number of users around the world and gives them quick access to information stored in databases. The number of ways of presenting this data by front-ends increases as well. This requires unifying the ways of operating and presenting information by front-ends and ensuring contextual switching between front-ends of different databases. This chapter aims to present selected cytogenetic and cytogenomic Internet resources in terms of obtaining the needed information and to indicate how to increase the efficiency of access to stored information. Through a brief introduction of these databases and by providing examples of their usage in cytogenetic analyses, we aim to bridge the gap between cytogenetics and molecular genomics by encouraging their utilization.

Studying the Dynamics of Tunneling Tubes and Cellular Spheres.

Cancer cytogenetic analyses often involve cell culture. However, many cytogeneticists overlook interesting phenotypes associated with cultured cells. Given that cytogeneticists need to focus more on phenotypes to comprehend the genotypes, the biological significance of seemingly trivial cellular variations deserves attention. One example is the formation of cellular tunneling tubes (TTs) in cultured cancer cells, which likely play a role in cell-to-cell communication and material transport. In this chapter, we describe protocols for studying these TTs as well as cellular spheres. In addition to diverse chromosomal variants, these different types of variations should be considered for understanding cancer heterogeneity and dynamics, as they illustrate the importance of various forms of fuzzy inheritance.

Evaluating the Clinical Relevance of Antibodies against Non-Human Leukocyte Antigen in Kidney Transplantation.

Introduction: Kidney transplantation is the preferred modality of kidney replacement therapy for eligible patients with end-stage kidney disease (ESKD), given that it has been found to reduce mortality rates, improve quality of life, and is cost-effective compared to dialysis. Recent advancements in human leukocyte antigen (HLA) typing and donor-specific antibody (DSA) detection have helped to reduce the risk of rejection, but antibody-mediated rejection (AMR) can still occur without DSA. Previous studies suggest that rejection can be attributed to antibodies against Non-Human Leucocyte Antigens (non-HLAs). We aimed to acquire further understanding of the prevalence and distribution of non-HLA antibodies in our local population and attempt to correlate these findings with graft outcomes, as well as assess whether non-HLA antibodies can be utilized to determine graft impairment and dysfunction. Methods: We conducted a retrospective study involving kidney transplant recipients between January 2010 and December 2020. All included individuals were aged over 18 and underwent kidney-alone transplants; were ABO- and HLA-compatible; and were matched at A, B, and DR loci (mismatch 0:0:0). HLA testing was negative at the time of transplantation. The samples from both cases of early graft rejection and the control group were tested for non-HLA antibodies using One Lambda LABScreenTM, Autoantibody kit groups 1, 2, and 3, as well as the Immucor LIFECODES non-HLA autoantibody assay. Results: A total of 850 kidney transplant recipients were included, in which 12 patients experienced early graft rejection within the first month post transplant and 18 patients who did not experience graft rejection were selected as study controls. Our study reported no correlation between the total burden of non-HLA antibodies and early rejection, most likely as the result of a small sample size. Nevertheless, a sub-analysis revealed that specific high-frequency pre-transplant non-HLA antibodies such as GSTT, CXCL11, CXCL10, and HNR, detected by LIFECODES, were associated with rejection (Fisher's exact test with Bonferroni correction, p < 0.001). Most pre-transplant non-HLA antibody levels were reduced after transplantation, which was attributed to immunosuppression. Conclusion: The 'high frequency' non-HLA antibodies displayed an association with graft rejection, though the overall associations between the burden of non-HLA antibodies and rejection episodes remain inconclusive. Further work is needed to establish the rebound phenomenon of non-HLA antibodies, the development of de novo non-HLA antibodies in the long run, and their implications on graft survival.

Comparing the effectiveness of letrozole versus methotrexate for treatment of ectopic pregnancy: A randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of two different regimens of Letrozole, an aromatase inhibitor, in the management of ectopic pregnancy compared to methotrexate. STUDY DESIGN: This randomized controlled trial was conducted on 88 women diagnosed with ectopic pregnancy with a baseline level of serum beta-human chorionic gonadotropin under 3000 mIU/mL between June 30, 2023, and December 30, 2023, at the Department of Obstetrics and Gynecology of the Vali-e-Asr Hospital affiliated with Tehran University of Medical Sciences. Participants were allocated into either methotrexate (n = 43), 5-day course Letrozole (n = 24), or 10-day course Letrozole (n = 21) treatments. The methotrexate group received a single dose of 50 mg/m2 dosage intramuscular methotrexate. The 5-day Letrozole group received a 2.5 mg Letrozole tablet three times daily for 5 days, whereas the 10-day Letrozole group received a 2.5 mg Letrozole tablet twice daily for 10 days. The primary outcome was the treatment response, defined as the achievement of a negative serum beta-human chorionic level without the need for additional methotrexate treatment or surgery. The secondary outcomes were the need for additional methotrexate dose or laparoscopic surgery intervention. The trial protocol was prospectively registered in ClinicalTrials.gov with code NCT05918718. RESULTS: The treatment response rates in methotrexate, 5-day Letrozole, and 10-day Letrozole groups were 76.7 %, 75.0 %, and 90.5 %, respectively, with no significant differences between the groups (P-value = 0.358). A total of 10 (23.3 %) patients from the methotrexate group, 3 (12.5 %) from the 5-day Letrozole group, and 2 (9.5 %) from the 10-day Letrozole group required an additional methotrexate dose, with no significant differences between the groups (P-value = 0.307). Furthermore, only 3 (12.5 %) patients, all from the 5-day Letrozole group, were suspected of tubal rupture and underwent surgery (P-value = 0.016). CONCLUSION: Our findings suggest Letrozole as a safe alternative to methotrexate in treating stable ectopic pregnancies, with a favorable treatment response rate. However, there is still a need for future larger studies to determine the applicability of Letrozole in the EP management. Also, the non-significant higher effectiveness of the 10-day Letrozole regimen than the 5-day Letrozole group underscores the need for future research to determine the optimal Letrozole regimen for the management of ectopic pregnancy.

Themis: advancing precision oncology through comprehensive molecular subtyping and optimization.

Recent advances in tumor molecular subtyping have revolutionized precision oncology, offering novel avenues for patient-specific treatment strategies. However, a comprehensive and independent comparison of these subtyping methodologies remains unexplored. This study introduces 'Themis' (Tumor HEterogeneity analysis on Molecular subtypIng System), an evaluation platform that encapsulates a few representative tumor molecular subtyping methods, including Stemness, Anoikis, Metabolism, and pathway-based classifications, utilizing 38 test datasets curated from The Cancer Genome Atlas (TCGA) and significant studies. Our self-designed quantitative analysis uncovers the relative strengths, limitations, and applicability of each method in different clinical contexts. Crucially, Themis serves as a vital tool in identifying the most appropriate subtyping methods for specific clinical scenarios. It also guides fine-tuning existing subtyping methods to achieve more accurate phenotype-associated results. To demonstrate the practical utility, we apply Themis to a breast cancer dataset, showcasing its efficacy in selecting the most suitable subtyping methods for personalized medicine in various clinical scenarios. This study bridges a crucial gap in cancer research and lays a foundation for future advancements in individualized cancer therapy and patient management.

Distribution of rupture sites and blebs on intracranial aneurysm walls suggests distinct rupture patterns in ACom and MCA aneurysms.

The mechanisms behind intracranial aneurysm formation and rupture are not fully understood, with factors such as location, patient demographics, and hemodynamics playing a role. Additionally, the significance of anatomical features like blebs in ruptures is debated. This highlights the necessity for comprehensive research that combines patient-specific risk factors with a detailed analysis of local hemodynamic characteristics at bleb and rupture sites. Our study analyzed 359 intracranial aneurysms from 268 patients, reconstructing patient-specific models for hemodynamic simulations based on 3D rotational angiographic images and intraoperative videos. We identified aneurysm subregions and delineated rupture sites, characterizing blebs and their regional overlap, employing statistical comparisons across demographics, and other risk factors. This work identifies patterns in aneurysm rupture sites, predominantly at the dome, with variations across patient demographics. Hypertensive and anterior communicating artery (ACom) aneurysms showed specific rupture patterns and bleb associations, indicating two pathways: high-flow in ACom with thin blebs at impingement sites and low-flow, oscillatory conditions in middle cerebral artery (MCA) aneurysms fostering thick blebs. Bleb characteristics varied with gender, age, and smoking, linking rupture risks to hemodynamic factors and patient profiles. These insights enhance understanding of the hemodynamic mechanisms leading to rupture events. This analysis elucidates the role of localized hemodynamics in intracranial aneurysm rupture, challenging the emphasis on location by revealing how flow variations influence stability and risk. We identify two pathways to wall failure-high-flow and low-flow conditions-highlighting the complexity of aneurysm behavior. Additionally, this research advances our knowledge of how inherent patient-specific characteristics impact these processes, which need further investigation.

The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.

Evaluation of a Novel Dermal Cooling System for the Treatment of Benign Pigmented Lesions in Asians.

OBJECTIVE: Our study aimed to evaluate the efficacy of this novel dermal cooling system (DCS) in reducing pigmentation in benign pigmented lesions in Asian patients and its potential side effects. METHODS: It was a prospective open-label single-center study. Asian patients, with the presence of benign pigmented lesions mainly including lentigines, melasma, nevus spilus, ephelides, café au lait, and seborrheic keratosis were recruited for a novel DCS. The DCS provided localized cooling of the epidermal layer below freezing but was less intense than cryotherapy. Each patient received DCS at Week 0 and repeated at 4-week intervals up to 10 sessions. Global aesthetic improvement scores (GAIS) by blinded physicians and subjects were recorded at 2, 6, and 12 months posttreatment follow-up. RESULTS: Eighty-one patients were recruited with a total of 305 sessions performed and 1716 lesion sites treated. At 2-month posttreatment, 76.5% and 58.6% treatment sites showed obvious to marked improvement respectively and the improvement sustained at 6 and 12 months. Only minor adverse events were reported. Erythema and edema were the most commonly anticipated effects immediately after treatment. The pain was minimal. Postinflammatory hyperpigmentation was only reported in 2.2% (38/1716) treated sites. CONCLUSION: To our knowledge, this study was the first study to demonstrate that this novel DCS was an effective, safe, and well-tolerated treatment for benign pigmented lesions in Asians.

SOFIA Aspiration System as first-line Technique (SOFAST): a prospective, multicenter study to assess the efficacy and safety of the 6 French SOFIA Flow Plus aspiration catheter for endovascular stroke thrombectomy.

BACKGROUND: Mechanical thrombectomy (MT) is the standard of care for acute ischemic stroke (AIS) patients with large vessel occlusion (LVO). The SOFAST study collected clinical evidence on the safety and efficacy of the 6 French SOFIA Flow Plus aspiration catheter (SOFIA 6F) when used as first-line treatment. METHODS: This was a prospective, multicenter investigation to assess the safety and efficacy of SOFIA 6F used for first-line aspiration. Anterior circulation LVO stroke patients were enrolled. The primary endpoint was the final modified Thrombolysis in Cerebral Infarction (mTICI)≥2b rate. Secondary endpoints included first-pass and first-line mTICI≥2b rates, times from arteriotomy to clot contact and mTICI≥2b, and 90-day modified Rankin Scale (mRS)≤2. First-line and final mTICI scores were adjudicated by an independent imaging core lab. Safety events were assessed by an independent clinical events adjudicator. RESULTS: A total of 108 patients were enrolled across 12 centers from July 2020 to June 2022. Median age was 67 years, median National Institutes of Health Stroke Scale (NIHSS) was 15.5, and 56.5% of patients received intravenous thrombolytics. At the end of the procedure, 97.2%, 85.2%, and 55.6% of patients achieved mTICI≥2b, ≥2c, and 3, respectively. With SOFIA 6F first-line aspiration, 87.0%, 79.6%, and 52.8% achieved mTICI≥2b, ≥2c, and 3, respectively. After the first pass, 75.0%, 70.4%, and 50.9% achieved mTICI≥2b, ≥2c, and 3, respectively. Median times from arteriotomy to clot contact and successful revascularization were 12 and 17 min, respectively. At 90 days, 66.7% of patients achieved mRS≤2. CONCLUSIONS: First-line aspiration with SOFIA 6F is safe and effective with high revascularization rates and short procedure times.

Wavefront curvature analysis derived from preprocedural imaging can identify the critical isthmus in patients with postinfarcted ventricular tachycardia.

BACKGROUND: Where activation wavefront curvature is convexly shaped, functional conduction block can occur. OBJECTIVE: The purpose of this study was to determine whether left ventricular (LV) wall thickness determined from contrast-enhanced computed tomography (CT) is useful in localizing such areas in clinical postinfarction reentrant ventricular tachycardia (VT). METHODS: We evaluated data from 6 patients who underwent catheter ablation for postinfarction VT. CT imaging with inHEART processing was conducted 1-3 days before electrophysiological (EP) study to determine LV wall thickness (T). Activation wavefront curvature was approximated as ΔT/T, where ΔT represents wall thickness change. During EP study, bipolar LV VT electrograms were acquired using a high-density mapping catheter, and activation times were determined. Maps of T, ΔT/T, and VT activation were subsequently compared using statistical analyses. RESULTS: Two of 6 cases exhibited dual circuit morphologies, resulting in a total of 8 VT morphologies analyzed. The LV wall near the VT isthmus location tended to be thin, on the order of a few hundred micrometers. Regions of largest ΔT/T partially coincided with the lateral isthmus boundaries where electrical conduction block occurred during VT. ΔT/T at the boundaries, measured from imaging, was significantly larger compared to values at the isthmus midline and to the global LV mean value (P <.001). CONCLUSION: Wavefront curvature measured by ΔT/T and caused by source-sink mismatch is dependent on ventricular wall thickness. Areas of high wavefront curvature partly coincide with and may be helpful in locating the VT isthmus in infarct border zones using preprocedural imaging analysis.

High-performance GeSi/Ge multi-quantum well photodetector on a Ge-buffered Si substrate.

This work demonstrates a high-performance photodetector with a 4-cycle Ge0.86Si0.14/Ge multi-quantum well (MQW) structure grown by reduced pressure chemical vapor deposition techniques on a Ge-buffered Si (100) substrate. At -1 V bias, the dark current density of the fabricated PIN mesa devices is as low as 3 mA/cm2, and the optical responsivities are 0.51 and 0.17 A/W at 1310 and 1550 nm, respectively, corresponding to the cutoff wavelength of 1620 nm. At the same time, the device has good high-power performance and continuous repeatable light response. On the other hand, the temperature coefficient of resistance (TCR) of the device is as high as -5.18%/K, surpassing all commercial thermal detectors. These results indicate that the CMOS-compatible and low-cost Ge0.86Si0.14/Ge multilayer structure is promising for short-wave infrared and uncooled infrared imaging.

Individualized Dose-Response to Statins Associated with Cardiovascular Disease Outcomes.

Background: Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using three distinct pharmacological properties: (1) E0 (baseline LDL-C), (2) ED50 (potency: median dose achieving 50% reduction in LDL-C); and (3) Emax (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown. Objective: We analyze the relationship between ED50 and Emax with real-world cardiovascular disease outcomes. Method: We leveraged de-identified electronic health record data to identify individuals exposed to multiple doses of the three most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal healthcare. We derived ED50 and Emax to quantify the relationship with a composite outcome of ASCVD events and all-cause mortality. Results: We estimated ED50 and Emax for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED50 and Emax are independently associated with the primary endpoint. Hazard ratios were 0.85 (p < 0.01), 0.83 (p < 0.01), and 0.87 (p = 0.10) for ED50 and 1.13 (p < 0.001), 1.06 (p < 0.001), and 1.15 (p = 0.009) for Emax in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively. Conclusion: The class-wide association of ED50 and Emax with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.

Factors Associated with Obstetric Anal Sphincter Injury During Vacuum-Assisted Vaginal Delivery.

INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injury (OASI) is a major complication associated with vacuum-assisted vaginal delivery (VAVD). The aim of this study was to evaluate risk factors related to vacuum extraction that are associated with OASI. METHODS: This was a case-control study performed at a tertiary university teaching hospital. Included were patients aged 18-45 years who had a singleton pregnancy resulting in a live, term, VAVD. The study group consisted of women diagnosed with OASI following vacuum extraction. The control group included women following VAVD without OASI. Matching at a ratio of 1:2 was performed. Groups were compared regarding demographic, obstetric. and labor-related parameters, specifically focusing on variables related to the vacuum procedure itself. RESULTS: One hundred and ten patients within the study group and 212 within the control group were included in the final analysis. Patients in the OASI group were more likely to undergo induction of labor, use of oxytocin during labor, increased second stage of labor, higher likelihood of the operator being a resident, increased number of pulls, procedure lasting under 10 min, occipito-posterior head position at vacuum initiation, episiotomy, increased neonatal head circumference, and birthweight. Multivariate logistic regression analysis revealed that increased week of gestation (OR 1.67, 95% CI 1.25-2.22, p < 0.001), unsupervised resident performing the procedure (OR 4.63, 95% CI 2.17-9.90), p < 0.001), indication of VAVD being fetal distress (OR 2.72, 95% CI 1.04-7.10, p = 0.041), and length of procedure under 10 min (OR 4.75, 95% CI 1.53-14.68, p = 0.007) were associated with OASI. Increased maternal age was associated with lower risk of OASI (OR 0.9, 95% CI 0.84-0.98, p = 0.012). CONCLUSIONS: When performing VAVD, increased week of gestation, unsupervised resident performing the procedure, fetal distress as vacuum indication, and vacuum procedure under 10 min were associated with OASI. In contrast, increased maternal age was shown to be a protective factor.