Clinical Endpoints Research Articles

Individualization of piperacillin dosage based on therapeutic drug monitoring with or without model-informed precision dosing: a scenario analysis.

Model-informed precision dosing (MIPD) combines population pharmacokinetic knowledge with therapeutic drug monitoring (TDM) to optimize dosage adjustment. It could improve target concentration attainment over empirical TDM, still widely practised for broad-spectrum antibiotics. To evaluate the respective performance of TDM and MIPD in achieving target piperacillin exposure. Measurements from 80 courses of intermittent piperacillin infusions, each with two TDM samples, were retrospectively submitted to our MIPD software TUCUXI. We considered six dosage adjustment strategies: identical dosage for all (4000 mg q8h), actual initial dosage (chart-based), actual empirical adjustment following first TDM, a priori MIPD-based dosage, a posteriori MIPD-based adjustment after first TDM and MIPD including both TDM measurements. Dosing strategies were compared regarding daily dosage, trough levels distribution and PTA (with target trough 8-32 mg/L). Median trough concentration fell within 8-32 mg/L for all strategies except a priori MIPD-based dosage (42 mg/L). Distributions of trough concentrations predicted with the six dosage adjustment strategies showed significant differences, with both a posteriori MIPD-based strategies best reducing their standard deviation (P < 0.001). PTA of 32%, 32%, 55%, 29%, 83% and 94% were estimated, respectively for the six strategies (P < 0.001). Poor performance of a priori MIPD-based dosage did not hinder a posteriori MIPD-based strategies from significantly improving target attainment. Whilst empirical TDM improves exposure standardization and target attainment compared with no TDM, MIPD can still bring further improvement. Prospective trials remain warranted to confirm MIPD benefits not only on target attainment but also on clinical endpoints.

Diffuseness of coronary artery disease impacts on immediate hemodynamic and predicted clinical outcomes

Diffuse coronary artery disease (CAD) impacts the immediate hemodynamic and clinical outcomes of percutaneous coronary intervention (PCI). We evaluated whether the diffuse pattern of CAD derived from angiographic Quantitative flow ratio (QFR) impacts the immediate hemodynamic outcome post-PCI and the medium term predicted vessel-oriented composite endpoint (VOCE). Paired pre-procedure QFRs were assessed in 503 patients and 1022 vessels in the Multivessel TALENT (MVT) trial. The pathophysiological pattern of CAD was defined as “predominantly diffuse” or “focal” according to a virtual QFR pullback pressure gradient (PPG) index < 0.78 and ≥ 0.78, respectively. Physiological “focal severity” was assessed using the QFR gradient per mm (dQFR/ds), with a value ≥ 0.025/mm the threshold for a “major gradient”. A post-PCI QFR ≥ 0.91 was considered optimal. Median pre-PCI PPG index was 0.70 (IQR 0.59–0.80). The prevalence of “predominantly diffuse” CAD and “major gradient” were 68.6% and 85.8%, respectively. A “Predominantly diffuse” pattern with a major gradient had a higher risk of a post-PCI QFR < 0.91 (OR 1.52,95%CI 1.47–1.58). In multivariable analysis, low QFR PPG index (diffuse disease) was an independent determinant of a post-PCI QFR < 0.91 (per 0.1 decrease of QFR PPG index, OR:9.8, 95% CI 3.0–32.2, p < 0.001). Based on post-PCI QFR the predicted 2-year VOCE, a powered endpoint in the MVT trial, was 6.1% and 4.2% in diffuse and focal lesions, respectively. A pre-procedure physiological pattern of diffuse CAD is an independent determinant of an unfavourable immediate hemodynamic outcome post-PCI, and detrimentally affects the predicted 2-year VOCE.Clinical Trial Registration URL: https://www.clinicaltrials.gov/ct2/show/NCT04390672Unique Identifier: NCT04390672 (registration date 15/05/2020)

Biomarkers of disease progression in progressive supranuclear palsy for use in clinical trials

Abstract Progressive supranuclear palsy is a rare neurodegenerative disease with no current disease-modifying treatments approved. Longitudinal research and clinical trials for progressive supranuclear palsy are ongoing and require reliable measures which are sensitive to disease progression. Despite susceptibility to subjective limitations clinical and cognitive assessments are the most used instruments in therapeutic trials in progressive supranuclear palsy. The objective of this review is to identify measures which have been studied longitudinally as measures of progression and which are suitable for use as clinical trial endpoints. We reviewed the measures currently used as trial endpoints, identifying the clinical, cognitive, fluid and imaging measures which have previously been studied longitudinally, and discussing current diagnostic and emerging measures which are yet to be studied longitudinally but which may be sensitive to disease progression. We found that many fluid and imaging measures require further research to validate their use as longitudinal measures of change, including emerging measures which have not yet been studied specifically in progressive supranuclear palsy. We also summarise the sample size estimates required to detect changes in a 2-arm, 52-week therapeutic trial and found that specific MRI volumes require the smallest sample sizes to detect change.

The Clinical Significance of PCI-Related Myocardial Infarctions in Stable Ischemic Heart Disease Patients in the Era of hs-Troponin

The definition and clinical relevance of percutaneous coronary intervention (PCI)-related myocardial infarction (MI) has been a topic of significant debate and controversy. It has particularly garnered widespread attention recently due to a contemporary trend of including it as a component of primary end points in major trials. The study aimed to assess the clinical relevance of PCI-related MI (PMI) according to the Fourth Universal Definition of MIusing a high-sensitivity troponin (hs-Tn) assay in a real-world setting. This was a single centre, retrospective registry analysis of consecutive patients who underwent elective PCI for stable ischaemic heart disease between January 2014 to December 2018. The primary end point was major adverse cardiovascular events (MACEs)-the composite of death, spontaneous MI, stent thrombosis and the need for repeat revascularisation within 12 months from the index procedure. We treated 858 patients with a mean age of 67.6 years and 78.3% were men. The incidence of PMI in our cohort was 12.8%. On univariable analysis, contrast volume >150 mL, prior coronary artery bypass graft, final thrombolysis in MI flow 0-2, total stent length and stent length >20 mm were significantly associated with increased risk of PMI. There were 46 (5.4%) MACE in total with seven (6.4%) in the PMI group and 39 (5.2%) in the non-PMI group (p=0.6). Kaplan-Meier survival curves were used to estimate 1-year MACE-free survival for the patients with PMI versus non-PMI and there was no significant difference. On multivariable Cox proportional hazards analysis, contrast volume >150 mL, prior coronary artery bypass graft and estimated glomerular filtration rate <60 (mL/min/1.73 m2) were independent predictors of MACE during 1-year follow-up, whereas PMI was not an independent predictor. PMI defined according to the Fourth Universal Definition of MI and using hs-Tn was common, occurring in 12.8% of patients, but not independently predictive of MACE in 1 year. As PMIs are increasingly used as a component of composite primary end points in major, practice-changing trials, establishing a clinically relevant definition of PMI is of utmost importance.

A physiologically-based quantitative systems pharmacology model for mechanistic understanding of the response to alogliptin and its application in patients with renal impairment.

Alogliptin is a highly selective inhibitor of dipeptidyl peptidase-4 and primarily excreted as unchanged drug in the urine, and differences in clinical outcomes in renal impairment patients increase the risk of serious adverse reactions. In this study, we developed a comprehensive physiologically-based quantitative systematic pharmacology model of the alogliptin-glucose control system to predict plasma exposure and use glucose as a clinical endpoint to prospectively understand its therapeutic outcomes with varying renal function. Our model incorporates a PBPK model for alogliptin, DPP-4 activity described by receptor occupancy theory, and the crosstalk and feedback loops for GLP-1-GIP-glucagon, insulin, and glucose. Based on the optimization of renal function-dependent parameters, the model was extrapolated to different stages renal impairment patients. Ultimately our model adequately describes the pharmacokinetics of alogliptin, the progression of DPP-4 inhibition over time and the dynamics of the glucose control system components. The extrapolation results endorse the dose adjustment regimen of 12.5mg once daily for moderate patients and 6.25mg once daily for severe and ESRD patients, while providing additional reflections and insights. In clinical practice, our model could provide additional information on the in vivo fate of DPP4 inhibitors and key regulators of the glucose control system.

Radial Artery Used as Conduit for Coronary Artery Bypass Grafting

It was in 1989 that we first reported on the use of the radial artery (RA) as a secondary arterial graft for coronary artery bypass grafting (CABG). Nevertheless, discrepancies in clinical endpoints between the RA and alternative conduits have been reported in consecutive randomised trials. With over fifty years of accumulated practice in RA bypass grafting, we sought to identify the second-best option for CABG by reviewing the literature. A consistently successful second-best conduit for CABG has been demonstrated using the radial artery. Compared to saphenous vein grafts, the findings indicate improved outcomes and better patency results. Furthermore, it has been demonstrated to be a safe and effective conduit in the territory of the right coronary artery. The lack of available literature and the scarcity of similar case series restrict the application of the gastroepiploic artery. After five decades of utilisation, it can be unequivocally stated that the radial artery is the optimal conduit for coronary bypass surgery following the left internal thoracic artery to the left anterior descending artery.

Assessing patient-reported outcomes in primary sclerosing cholangitis: an update.

Patient-reported outcome (PRO) measures validated in primary sclerosing cholangitis (PSC) are needed for clinical trials. This review describes the recent US Food & Drug Administration (FDA) Patient-Focused Drug Development (PFDD) guidelines, existing PRO measures used in PSC studies, and the design of PSC-specific symptom measures adherent with the guidelines. FDA released updated guidance reflecting best practices for the design and evaluation of clinical outcome assessments (including PROs) and the design of trial endpoints. Two recent systematic reviews (2018, 2020) identified multiple PRO measures used in PSC studies, with two additional measures published since. Of these, four were developed in samples inclusive of PSC patients and six have been psychometrically evaluated in PSC. Published evidence to sufficiently support alignment with the recent guidance is sparse. We review the design of three symptom measures for PSC to illustrate alignment with FDA guidance, including qualitative and quantitative studies to provide evidence for their validity for use in adult PSC trials. Investigators planning to use PRO measures as study endpoints for PSC need to be adherent with the recent FDA guidelines and build the evidence base to support the measure as fit-for-purpose as an endpoint for clinical trials.

Proposed biological definitions of Parkinson's disease confuse understanding without delivering meaningful advances

This article reflects on two proposals to classify and stage Parkinson's disease (PD) and related conditions based on the presence of aggregated alpha-synuclein (ASN) detected by alpha-synuclein aggregation assay (SAA). The authors highlight the significant shortcomings of the proposals: detection of ASN by SAA is not specific of PD or other well-established clinical conditions; they do not allow prediction of clinical course and prognosis; and they are not suitable as an endpoint for clinical trials. To move forward with proposals reflecting so many uncertainties and unknowns will just sow confusion and misunderstanding within the PD community.

Cerebral Hemodynamic Responses to Disease-Modifying and Curative Sickle Cell Disease Therapies.

Sickle cell disease (SCD) is a hemoglobinopathy resulting in hemoglobin-S production, hemolytic anemia, and elevated stroke risk. Treatments include oral hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation (HSCT). Our objective was to evaluate the neurologic relevance of these therapies by characterizing how treatment-induced changes in hemoglobin (Hb) affect brain health biomarkers. In this interventional study, adults with and without SCD underwent a 3T-MRI at Vanderbilt University Medical Center at 2 time points before and after clinically indicated transfusion or HSCT or at 2 time points without the introduction of a new Hb-altering therapy (adult controls and patients with SCD on hydroxyurea). Cerebral blood flow (CBF; mL/100 g/min) and cerebral venous blood relaxation rate (s-1; a marker of Hb and blood oxygen content) responses were assessed to understand how these markers of brain health vary with Hb modulation. CBF was assessed with arterial spin labeling MRI, and blood relaxation rate was assessed using T2 relaxation under spin tagging MRI. Measures were pairwise compared within each cohort using a 2-tailed Wilcoxon signed-rank test, and regression was applied to evaluate the parameter and Hb change relationships. The significance criterion was 2-sided p < 0.05. Adults with (n = 43; age 28.7 ± 7.7 years; 42% male) and without (n = 13; age 33.5 ± 12.2 years; 46% male) SCD were evaluated. In adults receiving hydroxyurea (n = 10), neither Hb, CBF, nor venous relaxation rate changed between time 1 (Hb = 8.6 ± 1.2 g/dL) and time 2 (Hb = 9.0 ± 1.8 g/dL) (all p > 0.05). In transfusion patients (n = 19), Hb increased from 8.2 ± 1.4 g/dL to 9.3 ± 1.3 g/dL before vs after transfusion (p < 0.001), paralleling a CBF decrease of 14.2 mL/100 g/min (p < 0.001) toward control levels. The venous relaxation rate did not change after transfusion (p = 0.71). In HSCT patients (n = 14), Hb increased from 8.9 ± 1.9 g/dL to 12.9 ± 2.7 g/dL (p < 0.001) before vs after transplant, paralleling CBF decreases from 68.16 ± 20.24 to 47.43 ± 12.59 mL/100 g/min (p < 0.001) and increase in venous relaxation rate (p = 0.004). Across the Hb spectrum, a CBF decrease of 5.02 mL/100 g/min per g/dL increase in Hb was observed. Findings demonstrate improvement in cerebral hemodynamics after transfusion and transplant therapies compared with hydroxyurea therapy; quantitative relationships should provide a framework for using these measures as trial end points to assess how new SCD therapies affect brain health.

Insights from 3D echocardiography: unveiling the prognostic value of RV function in pulmonary hypertension: a systematic review and meta-analysis.

The role of right ventricular (RV) dysfunction in pulmonary hypertension (PH) has garnered increasing interest in terms of outcomes. This systematic review and meta-analysis evaluated the prognostic utility of three-dimensional echocardiography (3DE) derived right ventricular ejection fraction (RVEF) in PH. A systematic review and meta-analysis were performed using MEDLINE, Embase, and Scopus databases for publications reporting the hazard ratio (HR) of 3DE-derived RVEF in PH patients for the clinical end-points of composite outcome or all-cause mortality. Nine articles totaling 885 subjects were included, among which 67.23% had pulmonary arterial hypertension (PAH), with the remainder having a range of PH etiologies. The mean value of 3DE-derived RVEF was 35.5 ± 9.07% reflecting impaired RV function. The primary endpoint was all-cause mortality in three studies, while the rest of the studies reported composite outcomes. Follow-up duration ranges from 6 to 44months. From seven publications, the pooled HR by 3DE-derived RVEF was 0.91 (95% CI: 0.85 to 0.97, p = 0.001; heterogeneity: I2 = 62%, p = 0.004). In subgroup analysis, 3DE-derived RVEF was a significant prognostic factor for group 1 PH (HR: 0.90, CI: 0.86-0.94; heterogeneity I2 = 43%, p < 0.0001). From meta-regression analysis, only follow-up duration was found statistically significant with the HR of RVEF in the population (estimate: 0.028, p = 0.026). 3DE-derived RVEF provides important prognostic value in a large population of PH patients, especially for group 1 PH. Further accumulation of evidence is needed to perform a detailed subgroup analysis in each type of PH.

Impact of co-mutations and transcriptional signatures in non-small cell lung cancer patients treated with adagrasib in the KRYSTAL-1 trial.

KRAS inhibitors are revolutionizing the treatment of NSCLC, but clinico-genomic determinants of treatment efficacy warrant continued exploration. Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib (KRYSTAL-1-NCT03785249) were included in the analysis. Pre-treatment NGS data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free and overall survival. KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens. KEAP1MUT and STK11MUT were associated with shorter survival to adagrasib (KEAP1: PFS 4.1m vs 9.9m, HR 2.7, p<0.01; OS 5.4m vs 19.0m, HR 3.6, p<0.01; STK11: PFS 4.2m vs 11.0m, HR 2.2, p<0.01; OS 9.8m vs NR, HR 2.6, p<0.01). KEAP1WT/STK11WT status identified adagrasib-treated patients with significantly longer PFS (16.9m) and OS (NR). Pre-clinical analyses further validate the association between KEAP1 loss-of-function and adagrasib resistance. Adagrasib and mTOR inhibitor combinations produced higher treatment efficacy in NSCLC models harboring STK11 and KEAP1 co-mutations. NRF2HIGH signaling was associated with shorter survival to adagrasib (PFS: 4.2m vs 8.4m, HR 2.0, p=0.02; OS: 6.5m vs 19.0m, HR 2.8, p<0.01) even in KEAP1WTNSCLC patients. KEAP1WT/STK11WT/NRF2LOW status identified patients - 32% - with longer survival to adagrasib (PFS 12.0m vs 4.2m, HR 0.2, p<0.01; OS NR vs 8.0m, HR 0.1, p<0.01). KEAP1, STK11 and NRF2 status define KRASG12C-mutant NSCLC patients with markedly distinct outcomes to adagrasib. These results further support the use of genomic features - mutational and non-mutational - for treatment selection of KRASG12C-mutant NSCLC patients.

Identifying novel response markers for spinal muscular atrophy revealed by targeted proteomics following gene therapy.

Spinal muscular atrophy (SMA) is a progressive disease that affects motor neurons, with symptoms usually starting in infancy or early childhood. Recent breakthroughs in treatments targeting SMA have improved both lifespan and quality of life for infants and children with the disease. Given the impact of these treatments, it is essential to develop methods for managing treatment-induced changes in disease characteristics. Zolgensma® is the first effective and approved gene therapy for SMA caused by biallelic mutation in the SMN1 gene. In three children with SMA treated with Zolgensma®, neuronal, glial, inflammation, and vascular markers in the plasma exhibited a quicker response, emphasizing their potential as valuable biomarkers of treatment efficacy in clinical trials. We chose the novel Nucleic acid Linked Immuno-Sandwich Assay, to investigate a predefined panel of neuroinflammatory markers in plasma samples collected from SMA patients at baseline and six months after Zolgensma® treatment. We identified a set of novel targets whose levels differed between pre and post Zolgensma® treatment group and that were responsive to treatment. Even though our results warrant validation in larger SMA cohorts and longer follow-up time, they may pave the way for a panel of responsive proteins solidifying biomarker endpoints in SMA clinical trials.

The Screening Tomosynthesis Trial with Advanced Reader Methods (STREAM): design and rationale of a population-based breast cancer screening trial.

It is uncertain what the effects of introducing digital breast tomosynthesis (DBT) in the Dutch breast cancer screening programme would be on detection, recall, and interval cancers (ICs), while reading times are expected to increase. Therefore, an investigation into the efficiency and cost-effectiveness of DBT screening while optimising reading is required. The Screening Tomosynthesis trial with advanced REAding Methods (STREAM) aims to include 17,275 women (age 50-72 years) eligible for breast cancer screening in the Netherlands for two biennial DBT screening rounds to determine the short-, medium-, and long-term effects and acceptability of DBT screening and identify an optimised strategy for reading DBT. The control group will consist of 86,400 women selected from the database of the Dutch breast cancer screening programme screened with digital mammography. The intervention group will undergo DBT examinations only. Four different reading strategies will be evaluated on a subset of first-round screening exams. These four strategies will also be evaluated combined with replacing one of the two readers with AI predictions. The Microsimulation Screening Analysis (MISCAN)-Breast model will be used to estimate the long-term outcomes of DBT screening assuming the best-performing reading method. The primary outcome measure is the IC and advanced cancer rate at the second round (combined endpoint) in the DBT group compared to the control group. Secondary outcome measures are participation, recall and detection rates, positive predictive value, acceptability, reading method with the best case-based area under the curve and reading time, predicted breast cancer mortality, number of cancers overdiagnosed, and cost-effectiveness. Question The short-, medium-, and long-term effects of digital breast tomosynthesis (DBT)imaging in the Dutch breast cancer screening programme are unknown, but essential to decide about implementation. Findings This protocol paper describes the primary endpoint of the STREAM trial: the combined interval and advanced cancer detection rate at the second DBT round. Clinical relevance The STREAM trial is a prospective, non-randomised, population-based study in the Dutch breast cancer screening programme, that aims to evaluate the effects and acceptability of two rounds of DBT screening to determine if DBT can enhance the programme's outcomes.

Evaluation of clinical risk stratification to determine benefit from long-term versus short-term androgen deprivation in high-risk localized prostate cancer.

Patients treated with RT and long-term androgen deprivation therapy (ltADT) for high-risk localized prostate cancer (HRLPC) with 1 high-risk factor (any of Gleason ≥8, PSA > 20 ng/mL, ≥cT3; "high-risk") have better outcomes than those with 2-3 factors and/or cN1 disease ("very high risk"). We evaluated whether this risk stratification could determine benefit from ltADT versus short-term (stADT). The Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) repository of randomized trials was queried to identify eligible patients and trials. The key outcomes of interest were metastasis-free survival (MFS), overall survival (OS), time to metastasis (TTM) and prostate cancer-specific mortality (PCSM). Stratified Cox and Gray's regression were used to obtain the overall treatment effect for outcomes and risk groups, and the Wald interaction test to estimate whether treatment benefit differed by risk group or trial. Heterogeneity of studies was assessed by Cochran's Q and I2. 2780 patients from 3 trials were included. Patients with very-high risk disease had greater benefit with ltADT compared to high-risk disease (MFS HR 0.77 [0.68-0.88] vs. 0.89 [0.76-1.03]; TTM 0.61 [0.51-0.74] vs. 0.77 [0.59-0.99]; PCSM 0.71 [0.56-0.90] vs. 0.82 [0.59-1.14]; OS 0.87 [0.76-1.00] vs. 0.93 [0.79-1.08]), but there was no statistically significant difference in treatment effect by risk group (p-interaction >0.1). Heterogeneity for treatment effect across trials was low in the very high-risk group and moderate in the high-risk group. Clinical risk stratification merits further evaluation in clinical trials to identify which patients with HRLPC may benefit from ltADT versus stADT.

Contemporary Use of Post-Dilatation for Stent Optimization During Percutaneous Coronary Intervention; Results From the Netherlands Heart Registration.

Post-dilatation after stenting with a non-compliant (NC) balloon can be used to improve overall percutaneous coronary intervention (PCI) result. Due to lack of evidence on the effect of post-dilatation on adverse clinical endpoints there is no consensus whether post-dilatation should be used routinely. The aim of the current study was to determine the contemporary practice of post-dilatation. This study included patients from the Netherlands Heart Registration who underwent PCI between the 4th quarter of 2020 and the 3rd quarter of 2021. The primary endpoint was the rate of post-dilatation with a NC balloon. Secondary endpoints included differences in baseline and procedural characteristics of patients that received post-dilatation and patients that did not receive post-dilatation. Out of 12,960 patients from 11 hospitals, 49.9% underwent post-dilatation. There was a variety in post-dilatation between hospitals ranging from 29.3% to 82.7% and among operators ranging from 15.9% to 90.5%. Post-dilatation was used less frequent in patients presenting with ST-elevation myocardial infarction or out of hospital cardiac arrest. Multivessel and left main PCI, long stent length and use of intracoronary imaging and calcium modification were associated with increased use of post-dilatation. When imaging was used, the percentage of post-dilatation was 79.4%. In the Netherlands, stent optimization with post-dilatation using NC balloon is performed in only half of the patients undergoing PCI, with variations in frequency across centres and operators. Post-dilatation is more often used in cases of complex PCI and when intracoronary imaging or calcium modification techniques are used.

Pharmacogenetics of opioid medications for relief of labor pain and post-cesarean pain: a systematic review and meta-analysis.

Several studies have attempted to identify genetic determinants of clinical response to opioids administered during labor or after cesarean section. However, their results were often contrasting. A systematic review and meta-analysis was conducted to quantitatively assess the association between gene polymorphisms and clinical outcomes of opioid administration in the treatment of labor pain and post-cesarean pain. A comprehensive search was performed up to December 2023 using PubMed, Web of Knowledge, Cochrane Library, and OpenGrey databases. The clinical endpoints of interest were pain score after opioid treatment, total opioid consumption, patient's analgesic satisfaction, and incidence of opioid side effects. Random-effects meta-analyses were conducted when data were available in at least three studies. Twenty-six studies enrolling 7765 patients were included in the systematic review. Overall, a total of 12 candidate polymorphic genes (OPRM1, COMT, CYP2D6, CYP3A4, ABCB1, ABCC3, UGT2B7, CGRP, OPRK1, OPRD1, KCNJ6, KCNJ9) were considered by the included studies, among which the most investigated variant was OPRM1 rs1799971. Overall pooled results indicated that individuals carrying the G allele of OPRM1 rs1799971 required higher opioid doses for pain management in comparison to rs1799971 AA subjects (standardized mean difference: 0.26; 95% CI: 0.09-0.44; P = 0.003). Such an association was confirmed in the subgroups of patients with labor pain and post-cesarean pain. The present meta-analysis provides strong evidence of an association between OPRM1 rs1799971 and opioid dose requirement for relief of labor pain or post-cesarean pain. However, given the insufficient evidence for other polymorphic gene variants, large studies are still needed to investigate the impact of genetic variability on the efficacy and safety of opioid medications for relief of labor pain and post-cesarean pain (INPLASY Registration No. 202410040).

Resistant and Apparently Resistant Hypertension in Peritoneally Dialyzed Patients.

Hypertension in chronic kidney disease patients is very common. The definition of resistant hypertension in the general population is as follows: uncontrolled blood pressure (BP) on three or more hypotensive agents in adequate doses, or when patients are on four or more hypotensive agent categories irrespective of the BP control, with diuretics included in the therapy. However, these resistant hypertension definitions do not apply to the setting of end-stage kidney disease. True resistant hypertension is diagnosed when adherence to treatment and uncontrolled values of BP by ambulatory blood pressure measurement or home blood pressure measurement are confirmed. Due to these limitations, apparent treatment-resistant hypertension (ATRH) is now defined as an uncontrolled blood pressure on three or more antihypertensive medication classes or the introduction and use of four or more medications regardless of blood pressure level. Concerning dialysis patients, data are very limited on hypertension, its epidemiology, and the prevalence of apparent treatment-resistant hypertension in peritoneal dialysis. In this review, therefore, we discuss the hypertension definitions, targets of the therapy in patients on peritoneal dialyses, and their biases and limitations. We present the pathophysiology, diagnosis, and management of high blood pressure in the peritoneally dialyzed population together with published data on the apparent treatment-resistant hypertension prevalence in this population. Peritoneally dialyzed patients represent a unique population of dialyzed subjects; therefore, studies should be conducted on a larger population with a higher quality of drug adherence and target blood pressure values. The definition of resistant hypertension and apparent resistant hypertension in this group should be redefined, which should also consider residual kidney function in relation to both subclinical and clinical endpoints.

Systemic Sodium Iodate Injection as a Model for Expanding Geographic Atrophy.

Geographic atrophy (GA), an advanced form of dry age-related macular degeneration (AMD), has limited treatment options. This study introduces a novel mouse model featuring an expanding GA patch that can be used to test mechanisms and therapeutics. C57Bl/6J male mice (n = 96) aged 9-10 weeks received an intraperitoneal (IP) injection of 20mg/kg sodium iodate (NaIO3). In vivo confocal scanning laser ophthalmoscope (cSLO) and optical coherence tomography imaging were done at one, four, eight, and 16 weeks after injection, with GA area measurements taken at weeks 8 and 16. Mice were euthanized on weeks 8 and 16 for histological analysis. Administration of 20mg/kg intraperitoneal NaIO3 caused variable damage levels. Approximately 22% of cases showed damage (speckled autofluorescence) covering 35% to 90% of the 102° field of view cSLO image at one week after injection. These mice developed an expanding patch of GA by week 8, with a mean 1.45-fold increase in area by week 16. This region showed complete photoreceptor and retinal pigment epithelium loss and complement activation at the atrophy edge, whereas the inner retina remained undamaged. Mice with less damage (48% of cases) only developed incomplete outer retinal degeneration, and mice with more damage (30% of cases) had too much GA for measurable expansion. Although expanding GA formed in only 22% of mice, the model's simplicity and predictability for GA development via one-week post-injection imaging make it suitable for GA therapeutic experimentation. This murine model provides a valuable tool for testing GA therapies, mirroring clinical endpoints relevant to human trials.

Ravulizumab and Efgartigimod in Myasthenia Gravis: A Real-World Study.

Biologics that target pathogenic antibodies (Abs) and their effector functions such as the complement inhibitor ravulizumab and the neonatal Fc receptor agonist efgartigimod have recently been approved for the treatment of acetylcholine receptor (AChR)-Ab-positive myasthenia gravis (MG), but comparative studies are lacking. In a prospective, exploratory real-world study, we assessed clinical efficacy, safety, and biological effects of ravulizumab and efgartigimod treatment initiation. Myasthenia Gravis-Activities of Daily Living and Quantitative Myasthenia Gravis scores were used as clinical endpoints. Ab effector functions were determined by AChR-Ab-dependent complement activation and phagocytosis assays and systemic complement activation profiling. We observed similar moderate short-term efficacy of ravulizumab and efgartigimod in achieving clinical improvement. Ravulizumab reduced systemic terminal complement activation, but neither treatment showed significant effects on complement pathways proximal to C5 or functional capacities of AChR-Abs. Both treatment modalities were well tolerated with no serious adverse events reported. Clinical benefits obtained with ravulizumab and efgartigimod can be remarkably heterogeneous in daily clinical practice. Neither treatment relevantly changed effector functions of pathogenic AChR-Abs, supporting the concept that durable disease control in MG requires continuous administration of both fast-acting agents. This study provides Class III evidence that in AChR-Ab-positive patients with generalized MG, ravulizumab and efgartigimod provide comparable modest improvement in MG functional scales.

Complete Revascularization Techniques for Acute Myocardial Infarction: A Systematic Review and Meta‐Analysis Comparing Angiography‐ and Coronary Physiology‐Guided PCI

Background: It is generally accepted that for patients with multivessel disease and myocardial infarction, complete revascularization is preferable than culprit‐only revascularization. However, existing studies comparing coronary physiology‐guided versus angiography‐guided complete revascularization percutaneous coronary intervention (PCI) present conflicting conclusions.Methods: The investigation involved a comprehensive search of PubMed/Medline, Embase, and the Cochrane library for studies comparing coronary physiology‐guided with angiography‐guided PCI in patients with MI‐MVD. Clinical endpoints, including major adverse cardiovascular events, all‐cause mortality, recurrent MI, major adverse cardiac and cerebral event, planned revascularization, repeated revascularization, average stent number per patient, heart failure, and contrast nephropathy during any follow‐up period post PCI, were considered for analysis. Odds ratios (ORs) and mean differences with 95% confidence intervals (CIs) were calculated for binary and continuous variables, respectively. The analyses were conducted using Review Manager 5.1.Results: Our analysis included a total of 2493 patients from 5 studies. The physiology‐guided PCI group exhibited a lower rate of planned revascularization (OR: 0.10, 95% CIs: 0.07–0.14, p ≤ 0.001, and I2 = 96.6%) and average stent number per patient (mean difference: −0.47, 95% CIs: −0.56–−0.38, p ≤ 0.001, and I2 = 58.6%). However, there were no significant differences between the two groups regarding major adverse cardiac event (MACE) (OR: 0.89, 95% CIs: 0.63–1.26, p = 0.520, and I2 = 67.8%), all‐cause mortality (OR: 0.65, 95% CIs: 0.38–1.12, p = 0.120, and I2 = 50.5%), recurrent MI (OR: 0.74, 95% CIs: 0.28–2.00, p = 0.558, and I2 = 77.2%), major adverse cardiac and cerebral event (MACCE) (OR = 0.77, 95% CIs: 0.43–1.37, p = 0.378, and I2 = 0%), repeated revascularization (OR = 1.47, 95% CIs: 0.54–3.99, p = 0.452, and I2 = 76.5%), heart failure (OR: 1.04, 95% CIs: 0.43–2.56, p = 0.924, and I2 = 0%), and contrast nephropathy (OR: 1.26, 95% CIs: 0.27–5.81, p = 0.766, and I2 = 0%).Conclusions: Among patients with MI‐MVD, physiology‐guided PCI appeared to reduce the need for planned revascularization without triggering repeated revascularization, leading to fewer stents compared with angiography‐guided PCI. Other prespecified clinical outcomes including MACE, all‐cause mortality, recurrent MI, MACCE, heart failure, and contrast nephropathy were not significantly different between these two approaches.