Class IA Research Articles

Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant.

PIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes.

ITACARE-P/SIGG/SIGOT/SICGE position paper: referral of elderly cardiac patient from geriatrics to cardiac rehabilitation.

Cardiac rehabilitation (CR) is Class IA indication in patients after an acute cardiovascular (CV) event, with efficacy confirmed even in elderly or frail CV patients CV and geriatric outcomes. However, rate of referral and admission to CR of elderly CV patients remains very low. CV patients admitted in geriatric wards are often complex, multimorbid and frail. Therefore, the present position paper addressees their possible referral to CR, since many have various forms of CV diseases amenable to improve with CR. The multidisciplinary and comprehensive model of CR is applicable to these patients where evaluation and interventions should be tailored to the patient functional and clinical status, aiming to appropriate targets. Cardiologist, Geriatrician and other professionals, should synergistically integrate their competences, thus outlining also the new paradigm of "Cardiogeriatric Rehabilitation and Prevention", possibly leading to an increased awareness of the beneficial effect of CR and to an increased referral to CR from Geriatric departments. Operative recommendations are given, based on appropriateness and priority of indications, clinical risk and frailty level, integrating different expertise to reach more effective programs of care.

O USO DOS INIBIDORES DO COTRANSPORTADOR DE SÓDIO-GLICOSE-2 (SGLT2) NA INSUFICIÊNCIA CARDÍACA: UMA REVISÃO BIBLIOGRÁFICA

Heart failure (HF) is not a single pathological diagnosis, but a clinical syndrome caused by a structural and/or functional abnormality of the heart, resulting in elevated intracardiac pressure or inadequate cardiac output at rest or during exercise. It is a common clinical condition found in various healthcare settings, with a vast socio-economic impact. In Brazil, HF is the leading cardiovascular cause of hospital morbidity. Thus, heart failure studies play a crucial role in the development of new drugs, enabling significant improvements in the efficacy, safety and tolerability of treatment, as well as the personalization of care for individual patients. Recent advances in pharmacotherapy have led to the evolution of new therapeutic agents with a decrease in hospitalization and mortality rates in HF. The 2023 update of the European Society of Cardiology (ESC) guidelines recommends (class IA) the administration of sodium-glucose transporter 2 inhibitors (SGLT2i) for patients with heart failure with preserved ejection fraction (HFpEF) and mildly reduced EF (HFpEF). This study aims to analyze the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure. In order to arrive at these topics, articles were collected from the PUBMED and SCIELO databases, and an analysis was carried out based on the material found in order to be able to explain the information relevant to the topic.

2.6-Å resolution cryo-EM structure of a class Ia ribonucleotide reductase trapped with mechanism-based inhibitor N3CDP

Ribonucleotide reductases (RNRs) reduce ribonucleotides to deoxyribonucleotides using radical-based chemistry. For class Ia RNRs, the radical species is stored in a separate subunit (β2) from the subunit housing the active site (α2), requiring the formation of a short-lived α2β2 complex and long-range radical transfer (RT). RT occurs via proton-coupled electron transfer (PCET) over a long distance (~32-Å) and involves the formation and decay of multiple amino acid radical species. Here, we use cryogenic electron microscopy and a mechanism-based inhibitor 2'-azido-2'-deoxycytidine-5'-diphosphate (N3CDP) to trap a wild-type α2β2 complex of Escherichia coli class Ia RNR. We find that one α subunit has turned over and that the other is trapped, bound to β in a midturnover state. Instead of N3CDP in the active site, forward RT has resulted in N2 loss, migration of the third nitrogen from the ribose C2' to C3' positions, and attachment of this nitrogen to the sulfur of cysteine-225. In this study, an inhibitor has been visualized as an adduct to an RNR. Additionally, this structure reveals the positions of PCET residues following forward RT, complementing the previous structure that depicted a preturnover PCET pathway and suggesting how PCET is gated at the α-β interface. This N3CDP-trapped structure is also of sufficient resolution (2.6 Å) to visualize water molecules, allowing us to evaluate the proposal that water molecules are proton acceptors and donors as part of the PCET process.

Awake surgery with mapping-based resection to treat focal epilepsy in eloquent brain areas.

Resective surgery is a potential therapeutic option for select patients with intractable focal epilepsy. However, the presence of ictal onset zones within or surrounding highly functional brain areas presents a surgical challenge, leading to poor seizure and functional outcomes. This report describes our experiences with awake mapping-tailored resection of epileptogenic areas involving eloquent cortices and evaluates their feasibility, tolerance, limitations, and significance. The study included patients who underwent surgery for drug-resistant focal epilepsy at our center under awake conditions. The surgical approach aimed to achieve maximum resection of preoperatively defined epileptogenic zones, considering the boundaries defined by surrounding functional areas. We collected data on preoperative evaluations, intraoperative tests and seizures, postoperative status epilepticus, and neurological functional outcomes. We included 22 patients, 10 of whom had non-lesional epilepsy. Language, motor function, and sensory function were at risk in 19, 9, and 4 patients, respectively. Resection was performed as planned in 14 (63.6%) patients, while modifications were necessary in 8 (36.4%) patients due to functional constraints. The mean follow-up duration was 29.8months. Sixteen (72.7%) patients achieved Engel class Ia outcomes, indicating seizure freedom, while none of the patients experienced clinically significant permanent postoperative neurological deficits. Resective surgery with intraoperative brain mapping under awake conditions was a valid treatment option for achieving a cure in cases of drug-resistant focal epilepsy, even in situations in which the condition is considered inoperable due to the risk of significant postoperative neurological deficits.

Spatial organization of PI3K-PI(3,4,5)P3-AKT signaling by focal adhesions.

The class I phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is a key regulator of cell survival, growth, and proliferation and is among the most frequently mutated pathways in cancer. However, where and how PI3K-AKT signaling is spatially activated and organized in mammalian cells remains poorly understood. Here, we identify focal adhesions (FAs) as subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P3-AKT signaling in human cancer cells containing p110α mutations under basal conditions. We find that class IA PI3Ks are preferentially recruited to FAs for activation, resulting in localized production of PI(3,4,5)P3 around FAs. As the effector protein of PI(3,4,5)P3, AKT1 molecules are dynamically recruited around FAs for activation. The spatial recruitment/activation of the PI3K-PI(3,4,5)P3-AKT cascade is regulated by activated FA kinase (FAK). Furthermore, combined inhibition of p110α and FAK results in a more potent inhibitory effect on cancer cells. Thus, our results unveil a growth-factor independent, compartmentalized organization mechanism for PI3K-PI(3,4,5)P3-AKT signaling.

Thirty days clinical outcomes following stent implantation with aspirin-free prasugrel monotherapy in non-ST segment elevation myocardial infarction. Interim report from ASET-Japan pilot study

Abstract Background Dual antiplatelet therapy with a P2Y12 inhibitor, in addition to aspirin, is the standard therapy after percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) to prevent ischemic cardiovascular events. The Acetyl-Salicylic Elimination Trial (ASET) pilot studies conducted in Japan in patients with NSTE-ACS investigated the safety and feasibility of a low-dose prasugrel monotherapy after PCI. Purpose To ensure the safety of the patients, enrolment in the study was implemented only after confirmation of a successful procedure. The abstract reports our interim analysis, aimed at evaluating preliminary safety and feasibility. Methods The ASET-Japan pilot study was designed to explore the feasibility and safety of a low dose of prasugrel monotherapy (3.75mg/day), without adjunctive aspirin, after optimal PCI using Everolimus eluting stent (EES) in Japanese patients with non-ST-segment elevation acute coronary syndromes. The primary endpoint in the ASET-Japan NSTE-ACS (Phase 2) is a 12-month clinical outcome. The study is currently in the follow-up phase. All the target lesions were treated with a platinum-chromium everolimus-eluting stent. The primary ischemic endpoint was the composite of cardiac death, spontaneous target vessel myocardial infarction, or definite stent thrombosis, and the primary bleeding endpoint was Bleeding Academic Research Consortium types 3 and 5 bleeding up to 12-month. If more than 3 events occurred, trial enrollment would have to be terminated by the data and safety monitoring board. Results One hundred one patients were enrolled after successful index PCI and completed a 30 days follow-up. The mean age was 69.1±12.3 years and 75.2% was male. The mean anatomical SYNTAX score was 7.9±4.7. Unstable angina (UAP) and NSTEMI were seen in 24.8% (25/101) and 75.2% (75/101) patients, respectively. According to the Braunwald classification, 8 percent of the patients were categorised as Class IA UAP, 48% as Class IB, 20% as Class IIB, 4% as Class IIIA and 20% as Class IIIB. In NSTEMI patients, the median (IQR) pre-procedural troponin value (cardiac Troponin T or I) was 2.79 (1.12 – 22.27) times the Upper Limit of Normal. According to the PRECISE DAPT score, 36.6% of patients were categorised as High Bleeding Risk (HBR) with scores above 25. At one month, the primary ischemic endpoints of cardiac death, target-vessel spontaneous MI or definite Stent thrombosis did not occur. Two patients (2.0%) had BARC type 3a bleeding. Conclusion Prasugrel monotherapy in the first 30 days following platinum-chromium everolimus-eluting stent deployment is a feasible and safe strategy in NSTE-ACS patients with simple anatomy and successful PCI.

Transcatheter aortic valve implantation with SAPIEN 3 versus surgical aortic valve replacement in patients with symptomatic severe aortic stenosis at low risk of surgical mortality: a cost-utility analysis for Switzerland.

The 2021 European Society of Cardiology Guidelines on valvular heart disease recommend transcatheter aortic valve implantation (TAVI) for patients with symptomatic severe aortic stenosis at low surgical risk and age ≥75 years who are suitable for a transfemoral approach (recommendation class IA) based on two large randomised controlled trials (PARTNER 3 and Evolut Low Risk) comparing transcatheter aortic valve implantation with surgical aortic valve replacement (SAVR). Whether such an approach is cost-effective in Switzerland remains unclear. The aim of this cost-utility analysis was to compare transcatheter aortic valve implantation with SAPIEN 3 versus surgical aortic valve replacement in symptomatic severe aortic stenosis patients at low risk of surgical mortality from the perspective of Swiss compulsory health insurance using data from the PARTNER 3 trial (reflecting specifically the safety and efficacy of the SAPIEN 3 TAVI device). A previously published two-stage Markov-based model that captured clinical outcomes from the PARTNER 3 trial was adapted from the perspective of the Swiss compulsory health insurance system, using local or geographically close general population mortality and utility data, unit costs and medical resource use from publicly available sources and based on expert opinion. The model had a lifetime horizon with a 3% yearly discounting factor. The cost-utility analysis estimated changes in both direct healthcare costs and health-related quality-adjusted life years for transcatheter aortic valve implantation compared with surgical aortic valve replacement in patients with symptomatic severe aortic stenosis at low risk of surgical mortality. Overall, transcatheter aortic valve implantation with SAPIEN 3 resulted in lifetime costs per patient of CHF 79,534 and quality-adjusted life years per patient of 9.64, compared with surgical aortic valve replacement lifetime costs and quality-adjusted life years per patient of CHF 76,891 and 8.96, respectively. Compared with surgical aortic valve replacement, transcatheter aortic valve implantation was estimated to offer an incremental improvement of +0.68 quality-adjusted life years per patient at an increased cost of +CHF 2643 per patient over a lifetime horizon. The incremental cost-effectiveness ratio was CHF 3866 per quality-adjusted life year gained and remained below CHF 50,000 per quality-adjusted life year gained across several sensitivity analyses. This analysis suggests that transcatheter aortic valve implantation using the SAPIEN 3 device is likely to be a highly cost-effective alternative for symptomatic severe aortic stenosis patients at a low risk of surgical mortality, treated in the contemporary Swiss setting. These findings may help to inform a holistic approach when making policy decisions for the management of this patient group.

Expansion Properties of the Young Supernova Type Iax Remnant Pa 30 Revealed

The recently discovered Pa 30 nebula, the putative type Iax supernova remnant associated with the historical supernova of 1181 AD, shows puzzling characteristics that make it unique among known supernova remnants. In particular, Pa 30 exhibits a complex morphology, with a unique radial and filamentary structure, and it hosts a hot stellar remnant at its center, which displays oxygen-dominated, ultrafast winds. Because of the surviving stellar remnant and the lack of hydrogen and helium in its filaments, it has been suggested that Pa 30 is the product of a failed thermonuclear explosion in a near- or super-Chandrasekhar white dwarf, which created a subluminous transient, a rare subtype of the Ia class of supernovae called type Iax. We present here a detailed study of the 3D structure and velocities of a full radial section of the remnant. The Integral Field Unit observations, obtained with the new red channel of the Keck Cosmic Web Imager spectrograph, reveal that the ejecta are consistent with being ballistic, with velocities close to the free-expansion velocity. Additionally, we detect a large cavity inside the supernova remnant and a sharp inner edge to the filamentary structure, which coincides with the outer edge of a bright ring detected in infrared images. Finally, we detect a strong asymmetry in the amount of ejecta along the line of sight, which might hint at an asymmetric explosion. Our analysis provides strong confirmation that the explosion originated from SN 1181.

2.6-Å resolution cryo-EM structure of a class Ia ribonucleotide reductase trapped with mechanism-based inhibitor N3CDP.

Ribonucleotide reductases (RNRs) reduce ribonucleotides to deoxyribonucleotides using radical-based chemistry. For class Ia RNRs, the radical species is stored in a separate subunit (β2) from the subunit housing the active site (α2), requiring the formation of a short-lived α2β2 complex and long-range radical transfer (RT). RT occurs via proton-coupled electron transfer (PCET) over a long distance (~32-Å) and involves the formation and decay of multiple amino acid radical species. Here, we use cryogenic-electron microscopy and a mechanism-based inhibitor 2'-azido-2'-deoxycytidine-5'-diphosphate (N3CDP) to trap a wild-type α2β2 complex of E. coli class Ia RNR. We find that one α subunit has turned over and that the other is trapped, bound to β in a mid-turnover state. Instead of N3CDP in the active site, forward RT has resulted in N2 loss, migration of the third nitrogen from the ribose C2' to C3' positions, and attachment of this nitrogen to the sulfur of cysteine-225. To the best of our knowledge, this is the first time an inhibitor has been visualized as an adduct to an RNR. Additionally, this structure reveals the positions of PCET residues following forward RT, complementing the previous structure that depicted a pre-turnover PCET pathway and suggesting how PCET is gated at the α-β interface. This N3CDP-trapped structure is also of sufficient resolution (2.6 Å) to visualize water molecules, allowing us to evaluate the proposal that water molecules are proton acceptors and donors as part of the PCET process.

Barriers to Law Enforcement Responsive to the Interests of Victims: A Study on the Practice of Justice for Violent Crimes in the Jurisdiction of Class IA Kupang District Court

Barriers to Law Enforcement Responsive to the Interests of Victims: A Study on the Practice of Justice for Violent Crimes in the Jurisdiction of Class IA Kupang District Court

The Criminal Act of Dissemination of Fake News via Social Media in the Perspective of Individualization of Criminal

This study focuses on 2 (two) main issues. First, how is the judge's decision considered based on the perspective of individualization of punishment? The second main issue is the factors that influence the judge's decision based on the perspective of individualization of punishment for the crime of spreading false news through social media. The implementation of the perspective of individualization of punishment in the Decision of the Jayapura Class IA District Court Number 16/Pid.B/2020/PN Jap is implied in 6 (six) main points of the judge's consideration, namely (1) the indictment and criminal charges of the Public Prosecutor, (2) the defense of the Legal Counsel, (3) evidence in the form of witness statements, both charge witnesses and a de charge witnesses, expert statements, defendant statements, (4) evidence, (5) trial facts, (6) proof of elements of the crime of spreading false news through social media. In addition, 5 (five) factors influence the decision, namely (1) the condition of the perpetrator, (2) the motive of the perpetrator, (3) the impact of the crime committed, (4) the form of the perpetrator's mistake, (5) the purpose of the punishment. Thus, the judicial freedom of judges does not mean that judges abandon the perspective of individualization of punishment this perspective of individualization of punishment provides direction for judges in constructing decisions on criminal cases of spreading fake news through social media, which is fully supported by at least 2 (two) pieces of evidence and the judge's legal conviction (juridische overtuigingen).

How ATP and dATP Act as Molecular Switches to Regulate Enzymatic Activity in the Prototypical Bacterial Class Ia Ribonucleotide Reductase.

Class Ia ribonucleotide reductases (RNRs) are allosterically regulated by ATP and dATP to maintain the appropriate deoxyribonucleotide levels inside the cell for DNA biosynthesis and repair. RNR activity requires precise positioning of the β2 and α2 subunits for the transfer of a catalytically essential radical species. Excess dATP inhibits RNR through the creation of an α-β interface that restricts the ability of β2 to obtain a position that is capable of radical transfer. ATP breaks the α-β interface, freeing β2 and restoring enzyme activity. Here, we investigate the molecular basis for allosteric activity regulation in the well-studied Escherichia coli class Ia RNR through the determination of six crystal structures and accompanying biochemical and mutagenesis studies. We find that when dATP is bound to the N-terminal regulatory cone domain in α, a helix unwinds, creating a binding surface for β. When ATP displaces dATP, the helix rewinds, dismantling the α-β interface. This reversal of enzyme inhibition requires that two ATP molecules are bound in the cone domain: one in the canonical nucleotide-binding site (site 1) and one in a site (site 2) that is blocked by phenylalanine-87 and tryptophan-28 unless ATP is bound in site 1. When ATP binds to site 1, histidine-59 rearranges, prompting the movement of phenylalanine-87 and trytophan-28, and creating site 2. dATP hydrogen bonds to histidine-59, preventing its movement. The importance of site 2 in the restoration of RNR activity by ATP is confirmed by mutagenesis. These findings have implications for the design of bacterial RNR inhibitors.

Mechanical dyssynchrony in patients with chronic heart failure and left bundle branch block

Background. The main problem in patient selection for cardiac resynchronization therapy (CRT) is the lack of unified approaches to the definition of mechanical dyssynchrony (MD) and selection criteria, particularly, in patients with left bundle branch block (LBBB).Aim: To study mechanical dyssynchrony indices and three-dimensional Echo (3DE) criteria of global and local contractility function in patients with chronic heart failure (CHF) and LBBB during different types of isolated left ventricle (LV) pacing.Methodology and Research Methods. The experimental intraoperative study involved 88 points obtained from 12 patients with CRT class IA indications and LBBB. During isolated LV pacing as part of CRT implantation procedure endocardial and epicardial pacing were obtained. Transesophageal Echo (TEE) cineloops recording and paced QRS complex morphology registrations by means of LabSystem Pro Electrophysiological Recording System (Bard Electrophysiology, USA) were performed during each stimulation episode. Philips Qlab 10 software was used for TEE data analysis.Results. The global (3D EF, 23.8 [22; 28.4], GLS, –5.33% [10.90%; –15.4%]) and local contractility (ExсAvg 3.5 [2.1; 5.6]) criteria and dyssyncrony indices (SDI-16, 14.9 [8.9; 23.1]) showed severe systolic dysfunction and intraventricular dyssynchrony – typical signs in this patient group, and differed significantly (3D EF, p = 0.003; GLS, p = 0.004; ExcAvg, p < 0.001; Tmsv-6 SD, р = 0.03) depending on the stimulation method and site. A moderate direct correlation between SDI-16 and the QRS duration (common electical dyssynchrony criterium) and inverse correlation with ExcAvg and 3D LVEF also describes LV response.

Electrocorticography and navigated transcranial magnetic stimulation-tailored supratotal resection for epileptogenic low-grade gliomas.

Epilepsy is commonly associated with low-grade gliomas (LGGs), impacting patients' well-being. While resection is the primary treatment, seizures can persist postoperatively in 27%-55% of cases. The authors aimed to evaluate an electrocorticography (ECoG) and navigated transcranial magnetic stimulation (nTMS)-tailored supratotal resection (ETT-SpTR) for LGG in controlling seizures, preserving neurological function, and enhancing treatment effectiveness. The authors retrospectively analyzed a prospectively enrolled cohort of patients with LGG presenting with epileptic seizures with ictal/interictal activity on electroencephalography (EEG) who underwent resective surgery. The authors performed preoperative nTMS to identify functional cortical areas. ECoG was used to guide the removal of the high-risk epilepsy cortical areas (HREAs). Patients were divided into two groups: group I, the control group, underwent gross-total resection alone, whereas group II patients underwent removal of HREAs identified by ECoG (ETT-SpTR). Resection avoided functionally eloquent areas as identified on nTMS, checked with cortical mapping. Postoperative seizure outcome was assessed using the Engel classification. Fifteen patients who underwent LGG resection between January and July 2023 were included. Among 24 identified nTMS-positive points, none were included in the resection. Overall, 73.3% of patients (11/15) showed positive intraoperative ECoG, with better outcomes in group II (85.7% Engel class IA) than in group I (25% Engel class IA) at the follow-up (p = 0.02, OR 0.5 [95% CI 0.035-7.10], RR 0.19 [95% CI 0.03-1.2]). Seizure control was significantly better in group II, with no notable differences in postoperative transient neurological deficits between the two groups (p = 0.45). No permanent neurological deficits were observed during follow-up. Statistical analysis revealed significant differences between the two groups (p < 0.05). This preliminary study affirms the predictive value of TMS for postoperative neurological status and safety in epileptic patients. Intraoperative ECoG effectively identified peritumoral HREAs. ETT-SpTR significantly improved epileptic outcomes, preserving functions without permanent neurological worsening. Additional resection targets the HREAs in the temporal, frontal, and parietal lobes.

Stability of the Tyrosyl Radical in the Ribonucleotide Reductase Beta Subunit of Arcobacter bivalviorum

Arcobacter spp., such as Arcobacter bivalviorum (A. bivalviorum), are free-living organisms found in diverse environments and associated with animals. They are considered emerging enteropathogens and potential zoonotic agents. Ribonucleotide reductase (RNR) is the key enzyme that is used to convert ribonucleotides into deoxyribonucleoside triphosphates (dNTPs). This process utilises radical-based chemistry and is crucial for DNA biosynthesis and repair. There are three RNR classes, with class I RNR the most studied, present in A. bivalviorum, eukaryotes, and many prokaryotes. Class I RNRs are further divided into three subclasses: Ia, Ib, and Ic. Class Ib RNRs use a dimanganese-oxo centre, unlike class Ia RNRs, which use a diiron-oxo centre. A. bivalviorum possesses a class Ia enzyme that requires a diferric tyrosyl radical cofactor located within its beta (β) subunit. Indeed, both the efficiency and fidelity of DNA synthesis are influenced by the stability of the tyrosyl radical (Y•) in the RNR, which is a critical aspect of its enzymatic function. This study investigates the stability of the Y-radical (Y•) site within the RNR β subunit of A. bivalviorum and the nature of the neighbouring amino acid residues. To achieve these goals, we developed a model of the RNR β subunit of A. bivalviorum, using the RNR β subunit of Aquifex aeolicus as a reference template (7aik.1. A PDB). The results provide some important details about the radical site and its surrounding residues, highlighting the influence of the protein structure on the stability of the radical. These findings may guide the development of novel inhibitors targeting this enzyme in A. bivalviorum.

Analisis Penyerapan Anggaran Operasional dan Pemeliharaan Kantor di Pengadilan Negeri Semarang Kelas IA Khusus

This research aims to analyze the excess realization of operational and office maintenance at the Special Class IA Semarang District Court, with a focus on the causal factors, and how to overcome budget excesses. The research method used is descriptive qualitative with empirical studies at the Special Class IA Semarang District Court. The data collected was RKA-KL (Work Plan and Budget) and LRA (Budget Realization Report) then conducted in-depth interviews after which analysis was carried out to draw conclusions. The results of the research show that several factors that cause excess operational and office maintenance budgets are unrealistic or non-comprehensive budget planning, changes in economic conditions, inefficiencies in project or operational management, lack of control and supervision of expenditure and non-compliance in the implementation of budget policies or lack of coordination. . How to overcome operational budget excesses at the Special Class IA Semarang District Court by strengthening the budget planning process, implementing a strict budget monitoring and control system and increasing the capacity and competence of human resources involved in budget management.

Ertugliflozin to Reduce Arrhythmic Burden in Patients with ICDs/CRT-Ds

BackgroundSodium–glucose cotransporter 2 inhibitors (SGLT2is) have beneficial pleiotropic effects, contributing to improved cardiovascular and renal outcomes for patients with and without diabetes. The impact of SGLT2is on arrhythmic burden remains largely unexplored through randomized trials.MethodsIn this multicenter, double-blind, randomized, placebo-controlled trial, we investigated the effects of ertugliflozin on arrhythmic burden among patients with heart failure with an ejection fraction less than 50%. All patients had an implantable cardioverter–defibrillator (ICD) with or without a cardiac resynchronization therapy device (CRT-D) and were randomized (1:1) to receive either ertugliflozin 5 mg once daily or placebo. The primary end point was the number of incident sustained (>30 seconds) ventricular tachycardia or ventricular fibrillation events from baseline to week 52. Secondary end points included the total number of non-sustained ventricular tachycardias, appropriate ICD therapies, changes in N-terminal pro-brain–type natriuretic peptide (NTproBNP) levels, and the number of heart failure hospitalizations.ResultsRandomization was prematurely terminated, after class IA guideline recommendations were published for SGLT2is in patients with heart failure regardless of the ejection fraction. The final analysis included 46 patients (11% of the originally planned sample size). The yearly rate of the primary end point was 3.5 (95% confidence interval [CI] 2.8 to 4.4) with ertugliflozin compared with 13.3 with placebo (95% CI 11.8 to 14.8; rate ratio 0.16, 95% CI 0.04 to 0.61; P<0.001). There were no apparent differences in appropriate ICD therapies, hospitalizations, NTproBNP levels, or predefined adverse and serious adverse events.ConclusionsErtugliflozin reduced sustained ventricular tachycardia or ventricular fibrillation events in adults with heart failure and an ICD compared with placebo; however, our trial ended early and thus results should be interpreted with caution. (Funded by Investigator-initiated Studies Program of Merck Sharp & Dohme Corp and Pfizer; EudraCT number, 2020-002581-14; ClinicalTrials.gov number NCT04600921.)

Effectiveness of E-Court in Handling Civil Cases in Class IA Religious Court of Ternate

E-Court is a court instrument made by the Indonesian Supreme Court which provides services to society in the forms of online registration, payment, summoning, and courts based on the Supreme Court Decision No. 1 of 2019. Objective: The problems of this research are: (1) How is the effectiveness of the e-Court application in the procedural processes in the Class I A Religious Court of Ternate City and (2) What are the obstacles that influence the application of e-Court in the Class I A Religious Court of Ternate City. Method: This was empirical research which used the statute approach and the case approach. In this research, researchers used the live case study approach which was applied to a legal phenomenon with an ongoing process. Results: showed that the e-Court implementation is effective. Its application is already according to the goal of Article 2 clause (4) of Law No. 48 of 2009 on Judicial Power. The e-Court provides a simpler, quicker, and cheaper form of civil case resolution. The obstacles in e-Court include a lack of human resources, inadequate internet facilities, and social culture. An improvement of the network and socialization on the e-Court implementation under the jurisdiction of the Class I A Religious Court of Ternate are needed. Function: This paper provides information on the effectiveness of the e-Court application. Novelty: This paper provides novelty as no previous research has studied the effectiveness of the e-Court application in the procedural processes in the Class I A Religious Court of Ternate City. E-Court adalah instrumen pengadilan yang dibuat oleh Mahkamah Agung RI yang memberikan pelayanan kepada masyarakat berupa pendaftaran, pembayaran, pemanggilan, dan persidangan secara online berdasarkan Perma No. 1 Tahun 2019. Tujuan: Permasalahan dari penelitian ini adalah: (1) Bagaimana efektivitas penerapan e-Court dalam proses beracara di Pengadilan Agama Kelas I A Kota Ternate dan (2) Apa saja kendala yang mempengaruhi penerapan e-Court di Pengadilan Agama Kelas I A Kota Ternate. Metode: Penelitian ini merupakan penelitian empiris yang menggunakan pendekatan perundang-undangan dan pendekatan kasus. Dalam penelitian ini, peneliti menggunakan pendekatan studi kasus langsung yang diterapkan pada suatu fenomena hukum dengan proses yang sedang berlangsung. Hasil: menunjukkan bahwa penerapan e-Court sudah efektif. Penerapannya sudah sesuai dengan tujuan Pasal 2 ayat (4) UU No. 48 Tahun 2009 tentang Kekuasaan Kehakiman. E-Court memberikan bentuk penyelesaian perkara perdata yang lebih sederhana, cepat, dan murah. Hambatan dalam e-Court antara lain kurangnya sumber daya manusia, fasilitas internet yang belum memadai, dan budaya masyarakat. Perlu adanya peningkatan jaringan dan sosialisasi mengenai penerapan e-Court di wilayah hukum Pengadilan Agama Ternate Kelas I A. Fungsi: Penelitian ini memberikan informasi tentang efektivitas penerapan e-Court. Kebaruan: Tulisan ini memberikan kebaruan karena belum ada penelitian sebelumnya yang mengkaji tentang efektivitas penerapan e-Court dalam proses beracara di Pengadilan Agama Kelas I A Kota Ternate.

Genome-Wide Survey of the Potential Function of CrLBDs in Catharanthus roseus MIA Biosynthesis.

Catharanthus roseus (C. roseus) can produce over 150 types of monoterpenoid indole alkaloids (MIAs), including vinblastine and vincristine, which are currently the primary sources of these alkaloids. Exploring the complex regulatory mechanisms of C. roseus is significant for resolving MIA biosynthesis. The Lateral Organ Boundaries Domain (LBD) is a plant-specific transcription factor family that plays crucial roles in the physiological processes of plant growth, stress tolerance, and specialized metabolism. However, the LBD gene family has not been extensively characterized in C. roseus, and whether its members are involved in MIA biosynthesis is still being determined. A total of 34 C. roseus LBD (CrLBD) genes were identified. RNA-Seq data were investigated to examine the expression patterns of CrLBD genes in various tissues and methyl jasmonate (MeJA) treatments. The results revealed that the Class Ia member CrLBD4 is positively correlated with iridoid biosynthetic genes (p < 0.05, r ≥ 0.8); the Class IIb member CrLBD11 is negatively correlated with iridoid biosynthetic genes (p < 0.05, r ≤ -0.8). Further validation in leaves at different growth stages of C. roseus showed that CrLBD4 and CrLBD11 exhibited different potential expression trends with iridoid biosynthetic genes and the accumulation of vindoline and catharanthine. Yeast one-hybrid (Y1H) and subcellular localization assays demonstrated that CrLBD4 and CrLBD11 could bind to the "aattatTCCGGccgc" cis-element and localize to the nucleus. These findings suggest that CrLBD4 and CrLBD11 may be potential candidates for regulating MIA biosynthesis in C. roseus. In this study, we systematically analyzed the CrLBD gene family and provided insights into the roles of certain CrLBDs in the MIA biosynthesis of C. roseus.