A Causal Mediation Approach to Account for Interaction of Treatment and Intercurrent Events: Using Hypothetical Strategy.

Hypothetical strategy is a common strategy for handling intercurrent events (IEs). No current guideline or study considers treatment-IE interaction to target the estimand in any one IE-handling strategy. Based on the hypothetical strategy, we aimed to (1) assess the performance of three estimators with different considerations for the treatment-IE interaction in a simulation and (2) compare the estimation of these estimators in a real trial. Simulation data were generalized based on realistic clinical trials of Alzheimer's disease. The estimand of interest was the effect of treatment with no IE occurring under the hypothetical strategy. Three estimators, namely, G-estimation with and without interaction and IE-ignored estimation, were compared in scenarios where the treatment-IE interaction effect was set as -50% to 50% of the main effect. Bias was the key performance measure. The real case was derived from a randomized trial of methadone maintenance treatment. Only G-estimation with interaction exhibited unbiased estimations regardless of the existence, direction or magnitude of the treatment-IE interaction in those scenarios. Neglecting the interaction and ignoring the IE would introduce a bias as large as 0.093 and 0.241 (true value, -1.561) if the interaction effect existed. In the real case, compared with G-estimation with interaction, G-estimation without interaction and IE-ignored estimation increased the estimand of interest by 33.55% and 34.36%, respectively. This study highlights the importance of considering treatment-IE interaction in the estimand framework. In practice, it would be better to include the interaction in the estimator by default.

Current Approaches to Design Space Development and Regulatory Applications for Drug Products: Findings from the IQ Utilization of Design Space for Filings Working Group Survey.

PURPOSE: The concept of a Design Space (DSp) was introduced in ICH Q8 as a tool within the quality-by-design (QbD) approach to pharmaceutical development with the intent of being globally applicable. However, there appears to be variance in the regulatory agency expectations in pharmaceutical product filing and implementation of DSp. This paper presents some of the current industry perspective on design space. METHODS: The Utilization of Design Space for Filings (UDSpF) Working Group in the Innovation and Quality (IQ) Consortium conducted a survey to establish a baseline for the current understanding of DSp among IQ member companies and assess the similarities and/or differences in strategies when filing a DSp. The survey focused on how IQ member companies approach DSp development, the primary drivers for the DSp, the presentation of the DSp in the filing, DSp verification and the benefits and flexibility anticipated and/or realized. RESULTS: A total of 14 responses were received and analyzed representing a small sample size but a large proportion of the innovator industry/large pharmaceutical companies. The survey results revealed that DSp is not yet a commonplace for small molecule drug products and may not even be utilized as much in large molecule drug products. The benefits of DSp, with respect to enhanced process understanding, are well understood by the sponsors; however, the benefits of filed DSp with respect to manufacturing flexibility are not fully realized in the commercial lifecycle of the product. There are also challenges in gaining consistent buy-in/value proposition for DSp among cross-functional teams within organizations. CONCLUSIONS: There are still gaps in design space implementation for its full benefit in the pharmaceutical industry. The WG has presented a unified view from member companies on the approach to DSp considering when/where the DSp experiments are conducted and on the extent of the DSp development proposed in a dossier.

Neurologic complications in patients receiving aortic versus subclavian versus femoral arterial cannulation for post-cardiotomy extracorporeal life support: results of the PELS observational multicenter study.

BACKGROUND: Cerebral perfusion may change depending on arterial cannulation site and may affect the incidence of neurologic adverse events in post-cardiotomy extracorporeal life support (ECLS). The current study compares patients' neurologic outcomes with three commonly used arterial cannulation strategies (aortic vs. subclavian/axillary vs. femoral artery) to evaluate if each ECLS configuration is associated with different rates of neurologic complications. METHODS: This retrospective, multicenter (34 centers), observational study included adults requiring post-cardiotomy ECLS between January 2000 and December 2020 present in the Post-Cardiotomy Extracorporeal Life Support (PELS) Study database. Patients with Aortic, Subclavian/Axillary and Femoral cannulation were compared on the incidence of a composite neurological end-point (ischemic stroke, cerebral hemorrhage, brain edema). Secondary outcomes were overall in-hospital mortality, neurologic complications as cause of in-hospital death, and post-operative minor neurologic complications (seizures). Association between cannulation and neurological outcomes were investigated through linear mixed-effects models. RESULTS: This study included 1897 patients comprising 26.5% Aortic (n = 503), 20.9% Subclavian/Axillary (n = 397) and 52.6% Femoral (n = 997) cannulations. The Subclavian/Axillary group featured a more frequent history of hypertension, smoking, diabetes, previous myocardial infarction, dialysis, peripheral artery disease and previous stroke. Neuro-monitoring was used infrequently in all groups. Major neurologic complications were more frequent in Subclavian/Axillary (Aortic: n = 79, 15.8%; Subclavian/Axillary: n = 78, 19.6%; Femoral: n = 118, 11.9%; p < 0.001) also after mixed-effects model adjustment (OR 1.53 [95% CI 1.02-2.31], p = 0.041). Seizures were more common in Subclavian/Axillary (n = 13, 3.4%) than Aortic (n = 9, 1.8%) and Femoral cannulation (n = 12, 1.3%, p = 0.036). In-hospital mortality was higher after Aortic cannulation (Aortic: n = 344, 68.4%, Subclavian/Axillary: n = 223, 56.2%, Femoral: n = 587, 58.9%, p < 0.001), as shown by Kaplan-Meier curves. Anyhow, neurologic cause of death (Aortic: n = 12, 3.9%, Subclavian/Axillary: n = 14, 6.6%, Femoral: n = 28, 5.0%, p = 0.433) was similar. CONCLUSIONS: In this analysis of the PELS Study, Subclavian/Axillary cannulation was associated with higher rates of major neurologic complications and seizures. In-hospital mortality was higher after Aortic cannulation, despite no significant differences in incidence of neurological cause of death in these patients. These results encourage vigilance for neurologic complications and neuromonitoring use in patients on ECLS, especially with Subclavian/Axillary cannulation.

Enhancement of per- and Polyfluoroalkyl Substances (PFAS) quantification on surface waters from marinas in the douro river, Portugal.

PFAS, known as "forever" compounds, are prevalent in various environments, including soils and aquatic systems, due to extensive usage. Surface waters in several European countries, especially marinas and ports with high boat traffic, require further study as potential contamination sources. Reliable methods for the extraction and quantification of these emergent compounds are essential. This study aimed to improve an existent solid phase extraction method to analyse marinas and ports' surface waters with variable salinities (2, 9 and 17 PSU). The objectives were to: 1) optimise the solid phase extraction method, considering matrix salinity effects and cross-contaminations, 2) validate the extraction and quantification method of 18 EPA 537.1 PFAS in estuarine surface waters, using the Ultra-High Performance Liquid Chromatography - Quadrupole Time - Of - Flight - Tandem Mass spectrometry, and 3) apply the optimised method for PFAS quantification in three Portuguese marinas. All ICH criteria were successfully validated considering 9 PSU. Limits of quantification ranged from 117.80 ng/L to 385 ng/L, except for PFHpA (645.85 ng/L). PFAS levels (PFOA, HFPO-DA, PFBS, PFHxS and PFOS) were relatively low, reaching a maximum of 0.32 ng/L only for the PFOA. In Freixo marina, total average concentrations were slightly higher (∑PFAS = 1.02 ng/L) when compared to the ones found in Cais da Ribeira Port (∑PFAS = 0.94 ng/L) and Afurada marina (∑PFAS = 0.81 ng/L). PFOS concentrations are below the limit values set by the Environmental Quality Standards (36000 ng/L of PFOS for inland surface water, respectively), similar to other Portuguese river studies. This study enabled the development of a precise and reliable extraction and quantification method to quantify PFAS in estuarine surface waters, particularly from marinas. This method can be readily applied to analyse PFAS in other estuarine samples.

Incidence and pattern of neurological emergencies in Ramadan.

BACKGROUND: The impact of Ramadan fasting on various neurological emergencies remains relatively unexplored. This study aimed to clarify the incidence and pattern of the different neurological emergencies in Ramadan compared to Shaaban. METHODS: In this cross-sectional study, all adult patients attending the emergency room at two Egyptian centers with neurological emergencies during Shaaban and Ramadan were evaluated. Clinical, laboratory, and radiological assessments were made on an individual basis upon which the diagnosis of neurological disorder was made. IBM SPSS Version 25 was used to analyze the data. RESULTS: Seventy-twenty patients were included, 382 during Shaaban and 338 during Ramadan. Among causes of delirium, the frequency of dehydration was significantly higher, and the frequency of illicit drug abuse was significantly lower during Ramadan compared to Shaaban (P = 0.004, 0.030, respectively). The incidence of ICH was significantly reduced during Ramadan compared to Shaaban (10.8% vs 19.7%, P = 0.031). The incidence of cardioembolic strokes significantly increased during Ramadan than Shaaban (40.5% vs 26.4%, P = 0.014), whereas the incidence of small vessel disease (SVD) significantly decreased during Ramadan than Shaaban (21.6% vs. 42.1%, P < 0.001). The incidence of a single seizure was significantly higher in Ramadan than in Shaaban (69.4% vs. 34.6%, P = 0.007). The incidence of functional neurological disorders was significantly reduced in Ramadan than in Shaaban (P < 0.001). CONCLUSION: The incidence of delirium caused by illicit drug abuse, ICH, SVD, and functional neurological disorders declined during Ramadan, while the incidence of delirium triggered by dehydration, cardioembolic strokes, and a single seizure increased during Ramadan.

The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

Medical versus neurosurgical treatment in ICH patients: a single center experience.

BACKGROUND AND AIMS: The effect of surgical treatment for spontaneous intracerebral hemorrhage (ICH) remains uncertain. We conducted an observational retrospective cohort study on supra-centimeter spontaneous ICH treated with either neurosurgical or conservative management. The baseline demographics and risk factors were correlated with in-hospital mortality and 3 and 6-month survival rates stratified by management. METHODS: We included all patients with evidence of spontaneous ICH > 1 cm detected by CT and admitted between august 2020 and march 2021 to the "SMM" Hospital in Perugia. RESULTS: Onehundredandtwentytwo patients were included in the study, and 45% (n.55) were surgically treated. The mean age was 71.9 ± 15.3, and 61% (n.75) were males. Intra-hospital mortality ended up being 31% (n.38), 3 months-survival was 63% (n.77) and 6 months-survival was 60% (n.73). From the multivariate analysis of the surgical patients versus medical patient, we observed that the surgical patients were younger (67.5 ± 14.9 vs 75.5 ± 14.7 y; OR 0.87; Cl 95% 0.85-0.94; p 0.001), with greater ICH volume at the onset (61 ± 39.4 cc vs 51 ± 64 cc; OR 1.03; Cl 95% 1.005-1.07; p 0.05), more midline shift (7.61 ± 5.54 mm vs 4.09 ± 5.88 mm; OR 1.37; Cl 95% 1.045-1.79; p 0.023), and a higher ICH score (3 vs 2 mean ICH score; OR 21.12; Cl 95% 2.6-170.6; p 0.004). Intra-hospital mortality in the surgical group and in the conservative treatment group was respectively 33% vs 30%, 3 month-survival was 64% vs 63% and 6 month- survival were 60% in both groups. CONCLUSIONS: Our patient cohort shows no overall benefit from surgery over conservative treatment, but surgical patients were younger and had larger ICH volume.

Evaluation of next-generation sequencing performance for in vitro detection of viruses in biological products.

Next-Generation Sequencing (NGS) can detect nucleic acid sequences in a massively parallel sequencing. This technology is expected to be widely applied for the detection of viral contamination in biologics. The recently published ICH-Q5A (R2) draft indicates that NGS could be an alternative or supplement to in vitro viral tests. To examine the performance of NGS for the in vitro detection of viruses, adenovirus type 5 (Ad5), a model virus, was inoculated into Vero cells, which are the most popular indicator cells for the detection of adventitious viruses in the in vitro test. Total RNA extracted from the Vero cells infected with Ad5 was serially diluted with that from non-infected Vero cells, and each sample was analyzed using short- or long-read NGSs. The limits of detection of both NGS methods were almost the same and both methods were sensitive enough to detect viral sequences as long as there was at least one copy in one assay. Although the multiplexing in NGS carries the risk of cross-contamination among the samples, which could lead to false positives, this technology has the potential to become a rapid and sensitive method for detecting adventitious agents in biologics.

Non-mutagenic impurities - Recent industry experience of using dose durational limits in drug development.

Absence of clear guidance on the qualification threshold for non-mutagenic impurities during clinical development is a source of inconsistency in both sponsor qualification approaches and health authority requests. A survey was conducted in March 2020 with 6 member companies of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Thirteen examples were gathered of where non-International Council for Harmonisation (ICH) limits have been used in regulatory submissions for various indications and stages of development, together with the regulatory outcomes. As expected, few challenges were faced in early clinical development, with health authorities generally commenting that sponsors should work towards ICH Q3A and Q3B guideline specification limits as development progresses. However, inconsistent health authority requests were noted even for early phase clinical trials in late-stage oncology patients. For an optimised use of resources, consistent approaches would have the benefit of supporting faster access of safe medicines to patients while including Replacement, Reduction and Refinement (the 3Rs) considerations with respect to animal testing.

Analysis of non-mutagenic substances in the context of drug impurity assessment - Few are potent toxicants.

ICH Q3A/B guidelines provide qualification thresholds for impurities or degradation products in new drug substances and products. However, the guidelines note that certain impurities/degradation products may warrant further safety evaluation for being unusually potent or toxic. The purpose of this study was to confirm that especially toxic non-mutagenic compounds are rare and to identify classes of compounds that could warrant lower qualification thresholds. A total of 2815 compounds were evaluated, of which 2213 were assessed as non-mutagenic. For the purpose of this analysis, compounds were considered potent when the point of departure was ≤0.2 mg/kg/day based on the qualification threshold (1 mg/day or 0.02 mg/kg/day for a 50 kg human) in a new drug substance, with an additional 10-fold margin. Only 54 of the entire set (2.4%) would be considered potent based on this conservative potency analysis, confirming that the existing ICH Q3A/B qualification thresholds are appropriate for the majority of impurities. If the Q3A/B threshold, without the additional 10-fold margin is used, 14 compounds (0.6%) are considered "highly potent". Very few non-mutagenic structural classes were identified, including organothiophosphates and derivatives, polychlorinated benzenes and polychlorinated polycyclic aliphatics, that correlate with potential high potency, consistent with prior publications.

Deriving acceptable limits for non-mutagenic impurities in medicinal products - Durational adjustments.

ICH Q3A/B guidelines are not intended for application during the clinical research phase of development and durationally adjusted qualification thresholds are not included. A central tenet of ICH Q3A is that lifetime exposure to 1 mg/day of an unqualified non-mutagenic impurity (NMI) is not a safety concern. An analysis of in vivo toxicology data from 4878 unique chemicals with established NO(A)ELs was conducted to determine whether durationally adjusted qualification limits can be supported. Although not recommended in ICH Q3A/B, a conservative approach was taken by using allometric scaling in the analysis. Following allometric scaling of the 5th percentile of the distribution of NO(A)ELs from available chronic toxicology studies, it was reconfirmed that there is a safety basis for the 1 mg/day qualification threshold in ICH Q3A. Additionally, allometric scaling of the 5th percentile of the distribution of NO(A)ELs from sub-acute and sub-chronic toxicology studies could support acceptable limits of 20 and 5 mg/day for an unqualified NMI for dosing durations of less than or greater than one month, respectively. This analysis supports durationally adjusted NMI qualification thresholds for pharmaceuticals that protect patient safety and contribute to 3Rs efforts for qualifying impurities using new approach methods.

New limits proposed for the management of non-mutagenic impurities.

Multiple international guidelines exist that describe both quality and safety considerations for the control of the broad spectrum of impurities inherent to drug substance and product manufacturing processes. However, regarding non-mutagenic impurities (NMI) the most relevant ICH Q3A/B guidelines are not applicable during early phases of drug development leading to confusion about acceptable limits at this stage. Thus, there is need for more flexible approaches that ensure that patient safety remains paramount, while taking into consideration the limited duration of exposure. An EFPIA survey, which collected quantitative data from different types of studies applied to qualify impurities in accordance with ICH Q3A, shows that no toxicities could be attributed to any of the 467 impurities at any tested level in vivo. This data combined with earlier published toxicological datasets encompassing drug substances and intermediates, food related substances and chemicals provide convincing evidence that for NMIs, the application of a generic 5 mg/day limit for an exposure duration <6 months, and a 1 mg/day generic limit for life-long exposure, provides sufficient margins to ensure patient safety. Hence, application of these absolute limits to trigger qualification studies (instead of the relative limits described in Q3A/B), is considered warranted. This approach will prevent conduct of unnecessary dedicated impurity qualification studies and the resulting use of animals.

Endeavours made by trade associations, pharmaceutical companies and regulators in the replacement, reduction and refinement of animal experimentation in safety testing of pharmaceuticals.

Following the European Commission decision to develop a roadmap to phase out animal testing and the signing of the US Modernisation Act, there is additional pressure on regulators and the pharmaceutical industry to abandon animal experimentation in safety testing. Often, endeavours already made by governments, regulators, trade associations, and industry to replace, reduce and refine animal experimentation (3Rs) are unnoticed. Herein, we review such endeavours to promote wider application and acceptance of 3Rs. ICH guidelines have stated 3Rs objectives and have enjoyed many successes driven by global consensus. Initiatives driven by US and European regulators such as the removal of the Abnormal Toxicity Test are neutralised by reticent regional regulators. Stream-lined testing requirements have been proposed for new modalities, oncology, impurity management and animal pharmacokinetics/metabolism. Use of virtual controls, value of the second toxicity species, information sharing and expectations for life-threatening diseases, human specific or well-characterised targets are currently being scrutinised. Despite much effort, progress falls short of the ambitious intent of decisionmakers. From a clinical safety and litigation perspective pharmaceutical companies and regulators are reluctant to step away from current paradigms unless replacement approaches are validated and globally accepted. Such consensus has historically been best achieved through ICH initiatives.

Retrospective application of ICH M7 to anti-hypertensive drugs in Brazil: Risk assessment of potentially mutagenic impurities.

Potentially mutagenic impurities are likely to be formed in any drug substance, since their synthesis requires reactive intermediates which may also react with DNA. The ICH M7 guideline, which defines how to risk assess and control mutagenic impurities, was first published in 2014 and is not to be applied retrospectively; however, some impurities have been found above the permitted limits in drug products which were already on the market. This study assessed the implications of applying ICH M7 retrospectively to anti-hypertensive drugs marketed in Brazil by performing a risk assessment and establishing control strategies. The manufacturing processes of 15 drug substances were evaluated and 262 impurities were identified, from which 21% were classified as potentially mutagenic. Most of the impurities were identified below ICH M7 acceptable limits, except for impurities described in a pharmacopoeial monograph. Compendial specifications are defined based on scientific evidence and play an important role in setting quality and safety standards for pharmaceuticals, however there are opportunities for further alignment with ICH guidelines, aiming for a holistic assessment of the impurities profile to ensure the safety of medicines.

A comprehensive comparison of machine learning models for ICH prognostication: Retrospective review of 1501 intra-cerebral hemorrhage patients from the Qatar stroke database.

Multiple prognostic scores have been developed to predict morbidity and mortality in patients with spontaneous intracerebral hemorrhage(sICH). Since the advent of machine learning(ML), different ML models have also been developed for sICH prognostication. There is however a need to verify the validity of these ML models in diverse patient populations. We aim to create machine learning models for prognostication purposes in the Qatari population. By incorporating inpatient variables into model development, we aim to leverage more information. 1501 consecutive patients with acute sICH admitted to Hamad General Hospital(HGH) between 2013 and 2023 were included. We trained, evaluated, and compared several ML models to predict 90-day mortality and functional outcomes. For our dataset, we randomly selected 80% patients for model training and 20% for validation and used k-fold cross validation to train our models. The ML workflow included imbalanced class correction and dimensionality reduction in order to evaluate the effect of each. Evaluation metrics such as sensitivity, specificity, F-1 score were calculated for each prognostic model. Mean age was 50.8(SD 13.1) years and 1257(83.7%) were male. Median ICH volume was 7.5 ml(IQR 12.6). 222(14.8%) died while 897(59.7%) achieved good functional outcome at 90 days. For 90-day mortality, random forest(RF) achieved highest AUC(0.906) whereas for 90-day functional outcomes, logistic regression(LR) achieved highest AUC(0.888). Ensembling provided similar results to the best performing models, namely RF and LR, obtaining an AUC of 0.904 for mortality and 0.883 for functional outcomes. Random Forest achieved the highest AUC for 90-day mortality, and LR achieved the highest AUC for 90-day functional outcomes. Comparing ML models, there is minimal difference between their performance. By creating an ensemble of our best performing individual models we maintained maximum accuracy and decreased variance of functional outcome and mortality prediction when compared with individual models.

Stability indicating RP-HPLC method development and validation for quantification of impurities in gonadotropin-releasing hormone (Elagolix): Robustness study by quality by design.

The purpose of this research was to establish and validate a reverse phase HPLC method for the determination of Elagolix impurities in pharmaceutical dosage form. Mobile phase A, consisting of 10 mM sodium dihydrogen phosphate (pH 6.0) and acetonitrile in a 95:5 v/v ratio, and mobile phase B, containing 85:10:5 v/v/v of acetonitrile, Milli-Q water, and methanol, were used to achieve the method's specificity in the analytical column Kromasil 100-C18 (250 mm × 4.6 mm, 5 µm). The gradient program includes (%B/Time [min]: 36/0, 36/10, 38/15, 85/55, 85/65, 36/67, and 36/75). The flow rate is 0.8 mL/min. The overall run duration is 75.0 min, the injection volume is 10.0 µL, and the detection is at 210 nm in UV. The samples were subjected to hydrolysis, oxidation, and heat conditions in order to facilitate their forced degradation. The procedure was validated and determined with the standards of ICH guidelines. From the LOQ to a concentration level of 200%, the linearity of the technique was ascertained. An accuracy range of LOQ to 150% was established for the method, and the average recovery was acceptable. Design of experiments, part of the quality by design idea, was used to prove the method's reliability.

Effects of preinjury oral anticoagulants on the outcomes of traumatic brain injury in elderly patients: a systematic review and meta-analysis.

BACKGROUND: With the increasing cases of TBI cases in the elderly population taking anticoagulants for comorbidities, there is a need to better understand the safety of new anticoagulants and how to manage anticoagulated TBI patients. METHODS: A meta-analysis using a random-effect model was conducted to compare the effect of preinjury use of DOACs and VKAs on the outcomes following TBI. RESULTS: From 1951 studies, 49 studies with a total sample size of 15,180 met our inclusion criteria. Our meta-analysis showed no difference between preinjury use of DOACs or VKAs on ICH progression, in-hospital delayed ICH, delayed ICH at follow-up, and in-hospital mortality, but using DOACs was associated with a lower risk of immediate ICH (OR = 0.58; 95% CI = [0.42; 0.79]; p < 0.01) and neurosurgical interventions (OR = 0.59; 95% CI = [0.42; 0.82]; p < 0.01) compared to VKAs. Moreover, patients on DOACs experienced shorter length of stay in the hospital than those on VKAs (OR = -0.42; 95% CI = [-0.78; -0.07]; p = 0.02). CONCLUSION: We found a lower risk of immediate ICH and surgical interventions as well as a shorter hospital stay in patients receiving DOACs compared to VKA users before the head injury.

Mesenchymal Stem Cell Therapy in Acute Intracerebral Hemorrhage: A Dose-Escalation Safety and Tolerability Trial.

BACKGROUND: We conducted a preliminary phase I, dose-escalating, safety, and tolerability trial in the population of patients with acute intracerebral hemorrhage (ICH) by using human allogeneic bone marrow-derived mesenchymal stem/stromal cells. METHODS: Eligibility criteria included nontraumatic supratentorial hematoma less than 60 mL and Glasgow Coma Scale score greater than 5. All patients were monitored in the neurosciences intensive care unit for safety and tolerability of mesenchymal stem/stromal cell infusion and adverse events. We also explored the use of cytokines as biomarkers to assess responsiveness to the cell therapy. We screened 140 patients, enrolling 9 who met eligibility criteria into three dose groups: 0.5 million cells/kg, 1 million cells/kg, and 2 million cells/kg. RESULTS: Intravenous administration of allogeneic bone marrow-derived mesenchymal stem/stromal cells to treat patients with acute ICH is feasible and safe. CONCLUSIONS: Future larger randomized, placebo-controlled ICH studies are necessary to validate this study and establish the effectiveness of this therapeutic approach in the treatment of patients with ICH.

Application of Robotic Stereotactic Assistance (ROSA) for spontaneous intracerebral hematoma aspiration and thrombolytic catheter placement.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) accounts for up to 20% of all strokes and results in 40% mortality at 30 days. Although conservative medical management is still the standard treatment for ICH patients with small hematoma, patients with residual hematoma ≤15 mL after surgery are associated with better functional outcomes and survival rates. This study reported our clinical experience with using Robotic Stereotactic Assistance (ROSA) as a safe and effective approach for stereotactic ICH aspiration and intra-clot catheter placement. METHODS: A retrospective analysis was conducted of patients with spontaneous ICH who underwent ROSA-guided ICH aspiration surgery. ROSA-guided ICH surgical techniques, an aspiration and intra-clot catheter placement protocol, and a specific operative workflow (pre-operative protocol, intraoperative procedure and postoperative management) were employed to aspirate ICH using the ROSA One Brain, and appropriate follow-up care was provided. RESULTS: From September 14, 2021 to May 4, 2022, a total of 7 patients were included in the study. Based on our workflow design, ROSA-guided stereotactic ICH aspiration effectively aspirated more than 50% of hematoma volume (or more than 30 mL for massive hematomas), thereby reducing the residual hematoma to less than 15 mL. The mean operative time of entire surgical procedure was 1.3 ± 0.3 h, with very little perioperative blood loss and no perioperative complications. No patients required catheter replacement and all patients' functional status improved. CONCLUSIONS: Within our clinical practice ROSA-guided ICH aspiration, using our established protocol and workflow, was safe and effective for reducing hematoma volume, with positive functional outcomes.

Current developments of the estimand concept.

Since the introduction of the estimand in therapeutical studies, several adaptions have been developed. This short article highlights the important aspects of the estimand concept. A literature research was conducted to identify different extensions to this framework. Different modified strategies for intercurrent events are presented, as well as examples of methods to implement the estimand in clinical studies. The article reflects that the estimand is an ongoing research field with further exploration.