Extension Phase Research Articles

Preliminary Geological Mapping, Petrographic, and Structural Studies of Precambrian Basement Complex Rocks in Part of Chulwe-Matale, South Kivu, DR Congo

A geological map is a veritable planning tool for the economic development of any nation. This map contains the distribution of various types of bedrock in the area. A geological map of Congo’s geographic landmass has been produced since 1974 with the recently updated map of Kivu (Eastern part of Congo) in February 2018. This map largely omits some local geology of interest, possibly owing to its large area coverage. Thus, local geologic mapping must be encouraged to bridge this lacuna; the focus of this study. Field traversing and rock sample collections were carried out and thin sections of the different rock types were prepared and mounted on glass slides for microscopic observation. Geological mapping revealed that the study area is made of ferruginous, graphitic sandstone schists and quartzite with interbedded metadoleritic sills. The petrographic studies revealed the mineral assemblages of quartz-feldspars-muscovite and olivine-pyroxene and plagioclase feldspars respectively for the first and the second group geological units. The structural investigations come out of two deformation phases: the strike-slip type would be at the origin of the cleavages and folds. It’s related to the D1 of the Kibarian orogeny. The second is an extensive phase responsible for the NW-SE fracturation mapped in the study area. The Matale discordance crosses all these lithologies, a later phase is possible. This discontinuity would have acted in the region studied by switching the lithology units from NE-SW to ENE-WSW orientation. This research recommends that the Chulwe-Matale formations would be typical of the Lower Kibarian (Bugarama group) but the geochronology and geochemical data are lacking to confirm this hypothesis.

Simulation-Guided Conformational Space Exploration to Assess Reactive Conformations of a Ribozyme.

Self-splicing ribozymes are small ribonucleic acid (RNA) enzymes that catalyze their own cleavage through a transphosphoesterification reaction. While this process is involved in some specific steps of viral RNA replication and splicing, it is also of importance in the context of the (putative) first autocatalytic RNA-based systems that could have preceded the emergence of modern life. The uncatalyzed phosphoester bond formation is thermodynamically very unfavorable, and many experimental studies have focused on understanding the molecular features of catalysis in these ribozymes. However, chemical reaction paths are short-lived and not easily characterized by experimental approaches, so molecular simulation approaches appear as an ideal tool to unveil the molecular details of the reaction. Here, we focus on the model hairpin ribozyme. We show that identifying a relevant initial conformation for reactivity studies, which is frequently overlooked in mixed quantum-classical studies that predominantly concentrate on the chemical reaction itself, can be highly challenging. These challenges stem from limitations in both available experimental structures (which are chemically altered to prevent self-cleavage) and the accuracy of force fields, together with the necessity for comprehensive sampling. We show that molecular dynamics simulations, combined with extensive conformational phase space exploration with Hamiltonian replica-exchange simulations, enable us to characterize the relevant conformational basins of the minimal hairpin ribozyme in the ligated state prior to self-cleavage. We find that what is usually considered a canonical reactive conformation with active site geometries and hydrogen-bond patterns that are optimal for the addition-elimination reaction with general acid/general base catalysis is metastable and only marginally populated. The thermodynamically stable conformation appears to be consistent with the expectations of a mechanism that does not require the direct participation of ribozyme residues in the reaction. While these observations may suffer from forcefield inaccuracies, all investigated forcefields lead to the same conclusions upon proper sampling, contrasting with previous investigations on shorter timescales suggesting that at least one reparametrization of the Amber99 forcefield allowed to stabilize aligned active site conformations. Our study demonstrates that identifying the most pertinent reactant state conformation holds equal importance alongside the accurate determination of the thermodynamics and kinetics of the chemical steps of the reaction.

Effect of Lurasidone on Life Engagement in Schizophrenia: Post-Hoc Analysis of the JEWEL Study.

To evaluate the effect of lurasidone on a new, patient Life Engagement scale in schizophrenia. This post-hoc analysis included participants (ages 18 to 74) diagnosed with schizophrenia who were randomized to lurasidone (40 mg/day) or placebo in a 6-week double-blind efficacy study and those who continued in a subsequent 12-week open-label extension study during which patients received either 40 or 80/mg day lurasidone (flexibly dosed). Change in life engagement was measured using the Positive and Negative Syndrome Scale (PANSS) 11-item Life Engagement subscale score, and individual subscale items, at week 6 during the double-blind phase and extension phase week 12 during the open-label extension phase. Analysis focused on 478 subjects randomized to lurasidone or placebo during the 6-week trial, and 146 who received lurasidone during the extension phase. During the 6-week trial, there was a significantly greater change on the PANSS11 Life Engagement subscale score from baseline to week 6 in the lurasidone group compared to the placebo group (mean changes of -6.4 and -4.8, respectively, p = 0.006; effect size = 0.27). Further improvement was evident during the extension phase for patients who received lurasidone in both phases, with a mean change from double-blind baseline to week 12 of the open-label treatment phase of -10.1 on in PANSS11 Life Engagement subscale. This post-hoc analysis suggests that lurasidone may improve life engagement in patients with schizophrenia, a meaningful outcome from patients' perspective. Further studies are needed to confirm this effect. Trial registration: EudraCT Numbers: 2016-000060-42; 2016-000061-23.

Paleostress inversion of fault-slip in the Ayhan Basin, Kırşehir Block (Turkey) since the Late Cretaceous: Insights into the Neotethys closure

Kırşehir Block, a large triangular continental domain exposed in Central Anatolia, is surrounded by ophiolitic melanges that mark former subduction zones associated with the closure of the northern and southern branches of the Neotethys Ocean. Notably, the Ayhan Basin, located in the inner part of the block, is one of the few locations containing a geological record from the Upper Cretaceous to the Pliocene. It provides a unique opportunity to examine the crustal deformation and the temporal and spatial stress distribution over the Central Anatolian orogen. This study encompasses a comprehensive analysis of the Ayhan Basin’s stratigraphy and structure, combined with the paleostress inversion solutions derived from over 400 fault-slip data. The findings reveal that the Ayhan Basin underwent three distinct tectonic phases: (1) ∼ NE-SW extensional phase from Late Cretaceous to Lutetian, which refers to the main basin-forming stress configuration. Importantly, this extensional phase is crucial to delineate the spatial extent of the concurrent collision in the north. (2) ∼ N-S compressional phase during the Lutetian, mainly governed by the shortening of the Kırşehir Block. This compressional phase caused the inversion of the inherited normal faults in the basin; and (3) ∼ NE-SW extensional phase active since the Late Miocene was accompanied by volcanism and uplift in the region. The Cyprus Slab’s southward retreat might be this extension’s triggering mechanism. Consequently, the temporal and spatial extent of the tectonic phases and their resultant deformations are crucial for understanding the underlying geodynamic processes and establishing their timing.

Two-year Pivotal Study Analysis of the Safety and Efficacy of Implantable Tibial Nerve Stimulation With eCoin for Urgency Urinary Incontinence

ObjectiveTo evaluate the continued effectiveness and safety of the eCoin Implantable Tibial Nerve Stimulator system (ITNS) for urgency urinary incontinence in patients with overactive bladder.The one-year pivotal study was extended through two years. The ITNS is a novel and recently FDA-approved therapy. MethodsA prospective, multicenter, single-arm trial was conducted on 137 subjects with refractory urgency urinary incontinence to evaluate eCoin ITNS therapy. A 3-day voiding diary was collected along with the overactive bladder questionnaire, Patient Global Impression of Improvement, and a custom Likert scale on subject satisfaction. The primary efficacy measure was the proportion of subjects who achieved at least 50% reduction from baseline in number of urgency urinary incontinence episodes. The primary safety measure was device-related adverse events. Results72 subjects completed the 96-week evaluation. 78% (95% CI: 67% - 87%) experienced at least 50% reduction in urgency urinary incontinence episodes; 48% (95% CI, 36%-60%) experienced at least 75% reduction, and 22% (95% CI, 13%-33%) were dry on a 3-day diary. Subjects reported a decrease from baseline in their urgency urinary incontinence episodes/day of 2.61 (SD 2.97) and 2.97 (SD 2.64) at 48 weeks and 96 weeks, respectively. 91.3% did not require additional medications for overactive bladder. No serious or unanticipated adverse events were reported in this extension phase. ConclusionsThe eCoin ITNS demonstrated consistent continuing effectiveness and safety in treating overactive bladder patients with urgency urinary incontinence. The findings support it as an excellent treatment option for refractory patients.

Modeling performance evaluation in badminton sports: a fuzzy logic approach

Spectators and many young students have flocked to badminton matches in recent years. Badminton practice has received a lot of media coverage. The current state of badminton evaluation methods is lacking in reliability. This article's overarching goal is to examine the many applications of fuzzy logic in badminton performance evaluation and improvement. Data on the badminton technique's flexion and extension phases are mapped into the suggested model using a fuzzy inference system (FIS). This study suggests a fuzzy logic-based badminton-specific objective fuzzy inference system (Bmt-FIS) to evaluate team sports. Despite the gravity of the situation, decisions involving performance reviews often use subjective data. These common decision-making problems may be realistically addressed by fuzzy logic models. Fuzzy logic has the potential to be an effective tool in situations where both quantitative and qualitative data interpretation are allowed. To do this, it accounts for the inherent variability in athletic performance by taking into consideration the 'hazy' or 'uncertain' limitations of data. By taking limitations into account, a rule-based approach makes performance evaluation more precise. Here, a fuzzy inference system (FIS) uses the input variables to evaluate the student's performance. While data mining approaches have been studied, the adaptive neural fuzzy method outperforms others because of its exceptional accuracy.This method eloquently and clearly conveys the many levels of integrity and ambiguity. Also, fuzzy logic may be a great tool for evaluating badminton skills. This foundational study connects the dynamic realm of sports with static measures.

The Effect of Kinesio Taping on Lumbar Kinematic After Static Lumbar Flexion in Healthy Subjects

Introduction: The application of Kinesio taping (KT) is a rehabilitation technique used to provide muscle and joint support and stability, without limiting the range of motion (ROM). No study evaluated the effects of KT on lumbar flexion relaxation phenomenon and kinematic details after static flexion. This study aims to find out the results of KT on erector spinae (ES) muscle activity, flexion relaxation pattern, and trunk, lumbar, and hip range of motion in healthy subjects during static flexion Materials and Methods: This study used a two-factor within-group design. Twenty-two healthy female students participated in this study. We used surface electromyography (EMG) to assess ES muscle activity and measured kinematic information with data from the camera. Variables related to muscle activity and angles in forward bending movement before and after creep were investigated. The test was performed in two situations with and without the use of KT. Results: KT reduced the time of muscle activity during bending. Also, KT increased trunk, and hip angles at the end of forward flexion. In the lumbar extension phase, the ES muscles were activated later Conclusion: KT can prevent the increase of lumbar spine flexion angle due to the creep effect. It can be used to protect the strained viscoelastic structures and increase the involvement of cutaneous receptors. KT can act as a protector in the dynamic stabilization system of lumbar joints in flexion positions in healthy people.

Effect of 48 Months of Closed-Loop Insulin Delivery on Residual C-Peptide Secretion and Glycemic Control in Newly Diagnosed Youth With Type 1 Diabetes: A Randomized Trial.

We evaluated the effect of long-term intensive metabolic control with hybrid closed-loop (CL) on residual C-peptide secretion and glucose control compared with standard insulin therapy in youth with type 1 diabetes over 48 months. Following the 24-month primary phase of a multicenter, randomized, parallel trial of 96 newly diagnosed youth aged 10 to 16.9 years, participants were invited to an extension phase using treatment allocated at randomization. They continued with hybrid CL using the Cambridge algorithm or standard insulin therapy (control) until 48 months after diagnosis. Analysis was by intention-to-treat. At 24 months after diagnosis, 81 participants (mean ± SD age 14 ± 2 years) continued in the extension phase (47 CL, 34 control). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 5 ± 9 vs. control: 6 ± 14 pmol/L per mmol/L; mean adjusted difference -2 [95% CI -7, 4; P = 0.54]). Central laboratory HbA1c remained lower in the CL group by 0.9% (10 mmol/mol [95% CI 0.2, 1.5; 3, 17 mmol/mol); P = 0.009). Time in target range of 3.9 to 10.0 mmol/L was 12 percentage points (95% CI 3, 20; P = 0.008) higher in the CL group compared with control. There were 11 severe hypoglycemic events (6 CL, 5 control) and 7 diabetic ketoacidosis events (3 CL, 4 control) during the extension phase. Improved glycemic control was sustained over 48 months after diagnosis with CL insulin delivery compared with standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion.

Remdesivir for Treatment of COVID-19 Requiring Oxygen Support: A Cross-Study Comparison from Two Large, Open-Label Studies.

Remdesivir, an RNA-polymerase prodrug inhibitor approved for treatment of COVID-19, shortens recovery time and improves clinical outcomes. This prespecified analysis compared remdesivir plus standard-of-care (SOC) with SOC alone in adults hospitalized with COVID-19 requiring oxygen support in the early stage of the pandemic. Data for 10-day remdesivir treatment plus SOC from the extension phase of an open-label study (NCT04292899) were compared with real-world, retrospective data on SOC alone (EUPAS34303). Both studies included patients aged ≥18 years hospitalized with SARS-CoV-2 up to 30 May 2020, with oxygen saturation ≤94%, on room air or supplemental oxygen (all forms), and with pulmonary infiltrates. Propensity score weighting was used to balance patient demographics and clinical characteristics across treatment groups. The primary endpoint was time to all-cause mortality or end of study (day 28). Time-to-discharge, with a 10-day landmark to account for duration of remdesivir treatment, was a secondary endpoint. 1974 patients treated with remdesivir plus SOC, and 1426 with SOC alone, were included after weighting. Remdesivir significantly reduced mortality versus SOC (hazard ratio [HR]: 0.46, 95% confidence interval: 0.39-0.54). This association was observed at each oxygen support level, with the lowest HR for patients on low-flow oxygen. Remdesivir significantly increased the likelihood of discharge at day 28 versus SOC in the 10-day landmark analysis (HR: 1.64; 95% confidence interval: 1.43-1.87). Remdesivir plus early-2020 SOC was associated with a 54% lower mortality risk and shorter hospital stays compared with SOC alone in patients hospitalized with COVID-19 requiring oxygen support. ClinicalTrials.gov NCT04292899 and EUPAS34303.

Seismo-stratigraphic and morpho-bathymetric analysis revealing recent fluid-rising phenomena on the Adventure Plateau (northwestern Sicily Channel)

The northwestern region of the Sicily Channel hosts a great number of morphological highs, the widest of which is the Adventure Plateau that is part of the Sicilian Maghrebian Fold and Thrust Belt system, formed since the Neogene. The Adventure Plateau was shaped in the Early Pliocene by an extensional phase that produced high-angle normal faults mostly WNW-ESE to N-S oriented. Through these faults, magmatic fluids ascended and produced widespread volcanic manifestations often associated to fluid flow processes. The interpretation of multibeam echosounder, seismic reflection (sparker, airgun) and well-log data allow us to identify several features related to the presence of fluids in the study area. The morpho-structural analysis showed a NW–SE oriented fault system and a string of pockmarks that follow the same trend. A detailed well-log analysis confirmed the presence of oil traces, at a depth of ~ 250 m, and gas (i.e., CO2) at a depth of ~ 450 m. The seismo-stratigraphic analysis highlighted seismic signals located below the pockmarks, (e.g. seismic chimneys, bright spots) which suggest the presence of fluids that would rise to a few meters’ depth. Based on the observations, two sources and two corresponding rising mechanisms have been identified. Morphometric analysis of pockmarks has been performed to delineate their possible interaction with the bottom currents. A fluids pathway model has been reconstructed, revealing the source of fluids emissions at depth in the Adventure Plateau, and providing new insights into the identification of fluid leakage pathways.

Exploratory Efficacy Evaluation of Apremilast for the Treatment of Japanese Patients with Palmoplantar Pustulosis: 32-Week Results from a Phase2, Randomized, Placebo-Controlled Study.

Palmoplantar pustulosis (PPP) is a pruritic, painful, chronic dermatitis that greatly impacts functioning and quality of life and can be difficult to treat. Approved treatment options for PPP are limited, and many patients do not fully respond to current treatments. This was a randomized, double-blind, placebo-controlled, phase2 study in Japanese patients with moderate to severe PPP and inadequate response to topical treatment. Patients were randomized 1:1 to receive apremilast 30mg twice daily or placebo for 16weeks followed by an extension phase where all patients received apremilast through week32. PPP Area and Severity Index (PPPASI), modified PPPASI (which evaluates pustules and vesicles separately), and Palmoplantar Severity Index (PPSI) total scores and subscores (erythema, pustules/vesicles, and desquamation/scales) were evaluated over 32weeks of apremilast treatment. Achievement of ≥ 50% improvement in PPPASI (PPPASI-50) was evaluated at week16 among baseline demographic and clinical characteristic subgroups. At week16, improvements in total score and subscores for PPPASI, modified PPASI, and PPSI, as well as rates of PPPASI-50 were at least moderately greater with apremilast than placebo. Mean PPPASI total score decreased by - 68.3% from baseline to week32 with continued apremilast treatment. At week32, mean change from baseline in PPPASI/modified PPPASI subscores ranged from - 58.5% to - 77.0% with apremilast. At week32, PPSI total score for physician and patient assessments decreased by - 51.3% and - 40.0%, respectively, with continued apremilast treatment. PPPASI-50 response at week16 was greater with apremilast versus placebo in most demographic and baseline characteristic subgroups. Improvements in all PPPASI and PPSI total scores and subscores observed with apremilast over 16weeks were maintained through 32weeks in patients with moderate to severe PPP and inadequate response to topical treatment. Rates of PPPASI-50 response at week16 were mostly consistent across patient subgroups. GOV: NCT04057937.

Mineralogical characterization and structural control of the Tadaout-Tizi n’Rsas vein field (eastern Anti-Atlas Morocco)

The Tadaout-Tizi n’Rsas (TTR) polymetallic (Pb, Cu, Zn) vein field, located at the southeastern of the Moroccan eastern Anti-Atlas, is hosted in sedimentary sandstone formations of the Ktaoua Group of the upper Ordovician. These deposits are reported to be late Variscan to Post-variscan in age, and are related to the emplacement of late Permian doleritic magma event outcropping in the Tafilalet region. Structural and paragenetic studies of the TTR mineralization deposit were conducted in order to establish a general model of the mineralization. A two-stage model of the formation of the mineralized veins of the TTR vein field is proposed herein. The first episode is attributed to the late Variscan phase. It is a trantensive regime characterized by the presence of lenticular structures related to the normal dextral movement of the major faults. This episode is coeval with the emplacement and brecciation of the polymetallic mineralization of the TTR vein field (galena, chalcopyrite, sphalerite, and pyrite). The second episode is associated with normal faults, during the extensional phase corresponding to the tectonic relaxation of shortening (Upper Permian) and more probably during the Atlantic rifting. It is characterized by the formation of a banded texture of mineralization.

Long-Term Safety and Effectiveness of Rituximab Biosimilar RTXM83: A Retrospective Extension Study in Brazilian Patients with Diffuse Large B-Cell Lymphoma.

RTXM83, a biosimilar of rituximab, was approved after physicochemical, functional, non-clinical,and clinical studies demonstrated their similarity; these studies included RTXM83-AC-01-11, a multicentric double-blind international prospective pivotal study. Long-term data on biosimilars can potentially elucidate their clinical robustness and facilitate their broader adoption. In this retrospective observational study, we analyzed a dataset from a Brazilian cohort previously randomized in the RTXM83-AC-01-11 study followed by the assessment of long-term outcomes in an observational extension phase from randomization in the RTXM83-AC-01-11 study to the last recorded evaluation. Patients with diffuse large B cell lymphoma (DLBCL) received either reference rituximab (R) or RTXM83 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as adjuvant treatment. The median follow-up period was 77.0months. Patients with initial DLBCL stages III and IV comprised 50% of the R-CHOP group and 40% of the biosimilar group. Five (18.5%) patients, including two RTXM83-CHOP-treated and three R-CHOP-treated individuals, experienced late adverse events (AEs) of interest. No new safety signs were established. At the final assessment, the progression-free survival (PFS) rates were 93.3% and 50.0% in the RTXM83-CHOP and R-CHOP groups, respectively. Median PFS was not achieved in the RTXM83-CHOP group, which was 40.5months in the R-CHOP group. The overall survival (OS) rates were 100% and 66.7% in the RTXM83-CHOP and R-CHOP groups, respectively. The median OS was not reached in any group. This study demonstrated the long-term safety and effectiveness of RTXM83 in treating DLBCL; outcomes comparable to those of the reference product and potentially improved access to treatment have been indicated. However, further research with more diverse patient groups can validate these findings and advocate the broader adoption of biosimilars in cancer care. ClinicalTrials.gov Identifier:NCT04928573. June 16, 2021, "retrospectively registered".

VERIFY: A randomized controlled phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera (PV).

TPS6592 Background: PV is a myeloproliferative neoplasm characterized by overproduction of red blood cells and increased risk of thrombosis. Patients may require frequent therapeutic phlebotomies (TP) alone or in combination with cytoreductive therapy to maintain hematocrit (HCT) <45%. Hepcidin regulates iron homeostasis but is downregulated in PV, increasing iron availability for erythropoiesis, which complicates TP optimization. In a phase 2 study (REVIVE, NCT04057040), rusfertide led to rapid, sustained, and durable HCT control with over 90% of patients achieving TP independence in part 2.1 It was well tolerated; majority (77.1%) of treatment-emergent adverse events (TEAEs) had a maximum grade of 2. There were no Grade 4 or 5 TEAEs. The phase 3 study VERIFY (NCT05210790) aims to confirm efficacy and safety of rusfertide in patients with PV. Methods: VERIFY is a multicenter, global, randomized trial comparing efficacy and safety of rusfertide (starting dose: 20 mg subcutaneously once weekly) vs. placebo when added to ongoing therapy for PV. Patients with PV who require frequent TP with or without concurrent cytoreductive therapy to control HCT are included in this 3-part study: Part 1a: 1:1 randomized, double-blind, placebo-controlled, add-on parallel-group period lasting 32 weeks (Week 0-32); Part 1b: open-label treatment phase with cross-over for previous placebo-treated patients. During this phase, all patients who completed Part 1a successfully will receive rusfertide for 20 weeks (Week 32-52); and Part 2: long term extension phase where all patients who complete Part 1b will continue to receive rusfertide for 104 weeks (Week 52-156). Results: Major inclusion criteria prior to randomization include PV diagnosis by 2016 WHO criteria; ≥3 TP in the previous 28 weeks or ≥5 in the previous 12 months due to inadequate HCT control; HCT <45%, white blood cells 4-20 × 109/L and platelets 100-1000 × 109/L at Week 0; stable PV therapy regimen in patients receiving cytoreduction at randomization; and cessation of cytoreductive therapy 2-6 months before screening in patients treated with TP alone. Major exclusion criteria are thrombosis or bleeding (active and/or chronic) within 2 months before randomization and a history of invasive malignancy within the previous 5 years. Primary endpoint is the proportion of patients achieving a response in Part 1a from Week 20-32. A response is defined as absence of TP eligibility. TP eligibility: HCT ≥45% and ≥3% higher than baseline HCT or HCT ≥48%. Secondary endpoints are mean number of TPs from Week 0-32; proportion of patients with HCT <45% from Week 0-32; mean change from baseline to Week 32 in total fatigue score measured by PROMIS Short Form and in total symptom score measured by MFSAF v4.0. Conclusions: VERIFY opened in January 2022 and aims to enroll approximately 250 patients globally. Reference: 1. Ritchie EK, et al. Blood.2023;142(Suppl 1):745. Clinical trial information: NCT05210790 .

Phase separation provides a mechanism to drive phenotype switching.

Phenotypic switching plays a crucial role in cell fate determination across various organisms. Recent experimental findings highlight the significance of protein compartmentalization via liquid-liquid phase separation in influencing such decisions. However, the precise mechanism through which phase separation regulates phenotypic switching remains elusive. To investigate this, we established a mathematical model that couples a phase separation process and a gene expression process with feedback. We used the chemical master equation theory and mean-field approximation to study the effects of phase separation on the gene expression products. We found that phase separation can cause bistability and bimodality. Furthermore, phase separation can control the bistable properties of the system, such as bifurcation points and bistable ranges. On the other hand, in stochastic dynamics, the droplet phase exhibits double peaks within a more extensive phase separation threshold range than the dilute phase, indicating the pivotal role of the droplet phase in cell fate decisions. These findings propose an alternative mechanism that influences cell fate decisions through the phase separation process. As phase separation is increasingly discovered in gene regulatory networks, related modeling research can help build biomolecular systems with desired properties and offer insights into explaining cell fate decisions.

Acute patellar dislocation during isokinetic knee strength testing: A case report

Key Clinical MessageIsokinetic testing is a maximal muscle strength test which requires adequate patient's preparation and observer's care. While the available data suggests that isokinetic devices are safe, their use may rarely cause severe injuries. The screening of predisposing anatomical factors could help preventing injuries before testing.AbstractA 29‐year‐old athletic man presented an acute patellar dislocation on a healthy right knee during isokinetic muscle strength testing, which was conducted in the setting of an intensive physical rehabilitation program, for persistent left knee pain after arthroscopic surgery for meniscal tear. This is the first case to occur in an adult male without clear risk factors such as patellar dysplasia. Predisposing factors may include slightly elevated patellar tilt and lateral shift compared to the contralateral knee (researched from subsequent review of pre‐injury X‐rays), and an elevated quadricipital strength in the context of recreational bodybuilding. The dislocation occurred during eccentric extension phase of testing. Medial patellofemoral ligament reconstruction was conducted 6 months later. Isokinetic muscle strength testing is generally considered as a safe method, despite limited data on the devices' safety. Since severe injuries might rarely occur, adequate patient preparation is needed, as well as the screening of predisposing factors.

Mathematical Models of the Arabidopsis Circadian Oscillator

We review the construction and evolution of mathematical models of the Arabidopsis circadian clock, structuring the discussion into two distinct historical phases of modeling strategies: extension and reduction. The extension phase explores the bottom-up assembly of regulatory networks, introducing as many components and interactions as possible to capture the oscillatory nature of the clock. The reduction phase deals with functional decomposition, distilling complex models to their essential dynamical repertoire. Current challenges in this field, including the integration of spatial considerations and environmental influences like light and temperature, are also discussed. The review emphasizes the ongoing need for models that balance molecular detail with practical simplicity.

Three-Year Outcomes With Fractional Flow Reserve-Guided or Angiography-Guided Multivessel Percutaneous Coronary Intervention for Myocardial Infarction.

In patients with multivessel disease with successful primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction, the FLOWER-MI trial (Flow Evaluation to Guide Revascularization in Multivessel ST-Elevation Myocardial Infarction) showed that a fractional flow reserve (FFR)-guided strategy was not superior to an angiography-guided strategy for treatment of noninfarct-related artery lesions regarding the 1-year risk of death from any cause, myocardial infarction, or unplanned hospitalization leading to urgent revascularization. The extension phase of the trial was planned using the same primary outcome to determine whether a difference in outcomes would be observed with a longer follow-up. In this multicenter trial, we randomly assigned patients with ST-segment-elevation myocardial infarction and multivessel disease with successful percutaneous coronary intervention of the infarct-related artery to receive complete revascularization guided by either FFR (n=586) or angiography (n=577). After 3 years, a primary outcome event occurred in 52 of 498 patients (9.40%) in the FFR-guided group and in 44 of 502 patients (8.17%) in the angiography-guided group (hazard ratio, 1.19 [95% CI, 0.79-1.77]; P=0.4). Death occurred in 22 patients (4.00%) in the FFR-guided group and in 23 (4.32%) in the angiography-guided group (hazard ratio, 0.96 [95% CI, 0.53-1.71]); nonfatal myocardial infarction in 23 (4.13%) and 14 (2.56%), respectively (hazard ratio, 1.63 [95% CI, 0.84-3.16]); and unplanned hospitalization leading to urgent revascularization in 21 (3.83%) and 18 (3.36%; hazard ratio, 1.15 [95% CI, 0.61-2.16]), respectively. Although event rates in the trial were lower than expected, in patients with ST-segment-elevation myocardial infarction undergoing complete revascularization, an FFR-guided strategy did not have a significant benefit over an angiography-guided strategy with respect to the risk of death, myocardial infarction, or urgent revascularization up to 3 years. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02943954.

Structural framework of the Caswell Sub-basin, North West Shelf, Australia

The Caswell Sub-basin, situated within the Browse Basin in the North West Shelf constitutes one of Australia’s primary hydrocarbon producing regions, with notable gas-condensate producing fields including Ichthys and Prelude. Jurassic syn-rift sandstones are extensively distributed across the basin and serve as one of the major reservoirs. However, reservoir sequences are typically intensely faulted and exhibit heterogeneity in thickness and lithofacies, with some areas experiencing localised erosion on uplifted fault blocks (e.g. Northern Caswell Sub-basin). Hence, understanding the nature of the 3D fault patterns and their growth history is crucial for evaluating the reservoir characteristics for field development and additional exploration activities. This study, therefore, aims to evaluate the structural framework and the tectonic evolution of the Caswell Sub-basin. Detailed structural interpretation of Paleozoic and younger sequences was conducted using multiple 3D seismic datasets extending over Ichthys, Prelude, Lasseter, and Crown fields. Our study focuses mainly on Mesozoic faulting patterns and kinematics evaluated from interpreted structural maps, thickness changes of each stratigraphic interval and fault throw profiles of major bounding faults. The extensional phase during the Early–Middle Jurassic triggered the development of NE–SW trending faults and the deepening of the Brewster Graben. While, from the Late Jurassic to the Early Cretaceous, the development of E–W trending faults in the north of the Crown and Lasseter fields indicate a shift in the regional stress regime. We highlight the importance of evaluating the structural linkage from basement to cover sequences to achieve a comprehensive understanding of reservoirs and associated petroleum systems.

A new perspective on regional structural architecture across the offshore Otway Basin

Geoscience Australia has undertaken a regional seismic mapping study of the offshore Otway Basin extending across the explored inner basin to the frontier deep-water region. Seismic interpretation covers over 18,000 line-km of new and reprocessed data acquired in the 2020 Otway Basin seismic program and over 40,000 line-km of legacy 2D seismic data. We present new basin-scale isochore maps that show the distribution of the Cretaceous depocentres. Maps for the Lower Cretaceous Crayfish and Eumeralla supersequences, together with those recently published for the Upper Cretaceous Shipwreck and Sherbrook supersequences, complete the set of isochore maps for the main tectonostratigraphic basin intervals. Mapping of basement-involved faults has revealed structural fabrics that have influenced depocentre development. The tectonostratigraphic development of depocentres and maps of deep crustal units delineate crustal thinning trends related to late Cretaceous extension phases. This work highlights the need to review and update structural elements. For example, the boundary between the Otway and Sorell basins is now geologically constrained. The refinements to the tectonostratigraphic evolution of the Otway Basin presented here have important implications for the distribution and potential maturity of petroleum systems, especially with regard to heat flow associated with crustal extension.