Cytokine adsorption in patients with acute-on-chronic liver failure (CYTOHEP)-A single center, open-label, three-arm, randomized, controlled intervention pilot trial.

BACKGROUND: To investigate the efficacy of bilirubin reduction by hemoadsorption with CytoSorb® in patients with acute-on-chronic liver failure (ACLF) receiving continuous renal replacement therapy (CRRT). METHODS: A prospective, randomized, single-center, open-label, controlled pilot trial. Patients with ACLF, acute kidney injury, and serum bilirubin ≥5 mg/dL were assigned 1:1:1 to one of three study groups (CRRT with or without hemoadsorption, no CRRT). In the hemoadsorption group, the CytoSorb adsorber was incorporated into the CRRT system, replaced after 12, 24, and 48 h, and removed after 72 h. The primary endpoint was the serum bilirubin level after 72 h. RESULTS: CYTOHEP was terminated early due to difficulties in recruiting patients and ethical concerns. Three of 9 patients (33%) were treated in each group. Comparing the three groups, mean bilirubin levels after 72 h were lower by -8.0 mg/dL in the "CRRT with hemoadsorption" group compared to "CRRT without hemoadsorption" (95% CI, -21.3 to 5.3 mg/dL; p = 0.17). The corresponding mean difference between "CRRT without hemoadsorption" and "no CRRT" was -1.4 mg/dL (95% CI, -14.2 to 11.5 mg/dL; p = 0.78). Comparing "CRRT with hemoadsorption" and "no CRRT," it was -9.4 mg/dL (95% CI, -20.8 to 2.1 mg/dL; p = 0.0854). Only 1/9 patients (11%, "no CRRT" group) survived day 30 after study inclusion but died on day 89. IL-6, liver function parameters, and clinical scores were similar between the study groups. CONCLUSIONS: CYTOHEP failed to demonstrate that extracorporeal hemoadsorption combined with CRRT can reduce serum bilirubin in ACLF patients with acute kidney failure.

Clinical phenotype and outcome of persistent SARS-CoV-2 replication in immunocompromised hosts: a retrospective observational study in the Omicron era.

PURPOSE: This study aims to describe clinical, virological and radiological characteristics as well as treatment strategies and outcomes of immunocompromised patients with persistent SARS-CoV-2 replication. METHODS: We performed a retrospective cohort study of immunocompromised patients at the University Medical Center Freiburg between 01/2022 and 05/2023. Patients with substantial immunosuppression and persistent SARS-CoV-2 detection (Ct-value < 30 after 14 days) were included. RESULTS: 36 patients in our cohort reported mainly fever, dyspnoea or continuous cough. Viral load was significantly higher in concurrent samples taken from the lower respiratory tract (Ct-value = 26) than from the upper respiratory tract (Ct-value = 34). Time of detectable viral RNA after start of antiviral treatment was shorter in patients receiving two antivirals (median 15 days vs. 31 days with one antiviral agent). Short-course antiviral therapy (≤ 5 days) was less efficient in reduction of symptoms and viral load than prolonged therapy > 10 days. In 30% (8/27) of patients with repeated CT scans, we found the emergence of chronic pulmonary changes, which were more frequently in patients with B cell depletion (37%, 7/19) compared to patients with organ transplantation (12%, 2/17). CONCLUSION: Ongoing SARS-CoV-2 replication in the lower respiratory tract is a relevant differential diagnosis in patients with severe immunosuppression and continuous cough, fever or dyspnoea even if nasopharyngeal swabs test negative for SARS-CoV-2. Especially in B cell-depleted patients, this may lead to inflammatory or fibrotic-like pulmonary changes, which are partially reversible after inhibition of viral replication. Antiviral therapy seems to be most effective in combination and over a prolonged period of time of > 10 days. TRIAL REGISTRATION NUMBER: DRKS 00027299.

Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior.

Deletion of the obsessive-compulsive disorder (OCD)-associated gene SAP90/PSD-95-associated protein 3 (Sapap3), which encodes a postsynaptic anchoring protein at corticostriatal synapses, causes OCD-like motor behaviors in mice. While corticostriatal synaptic dysfunction is central to this phenotype, the striatum efficiently adapts to pathological changes, often in ways that expand upon the original circuit impairment. Here, we show that SAPAP3 deletion causes non-synaptic and pathway-specific alterations in dorsolateral striatum circuit function. While somatic excitability was elevated in striatal projection neurons (SPNs), dendritic excitability was exclusively enhanced in direct pathway SPNs. Layered on top of this, cholinergic modulation was altered in opposing ways: striatal cholinergic interneuron density and evoked acetylcholine release were elevated, while basal muscarinic modulation of SPNs was reduced. These data describe how SAPAP3 deletion alters the striatal landscape upon which impaired corticostriatal inputs will act, offering a basis for how pathological synaptic integration and unbalanced striatal output underlying OCD-like behaviors may be shaped.

The impact of transcatheter aortic valve implantation planning and procedure on acute and chronic renal failure.

BACKGROUND: Severe aortic valve stenosis inhibits renal perfusion, thereby potentially worsening renal function, in particular in elderly patients most often assigned to transcatheter aortic valve implantation (TAVI). Pre-TAVI diagnostics and the procedure itself may adversely impact renal function, however renal perfusion and function may also improve post-procedure. This study aimed to clarify the impact of TAVI planning and procedure on kidney function METHODS: In this retrospective study, kidney function of patients who underwent transfemoral TAVI at a tertiary university hospital between 2016 and 2019 was analyzed. The present study investigated kidney function at baseline, after computed tomography (CT) was performed for evaluation of TAVI, after TAVI, at discharge and at follow-up. RESULTS: Among 366 patients, the prevalence of acute kidney injury (AKI) was 14.5% after TAVI. Independent predictors of AKI were arterial hypertension, baseline creatinine, AKI post CT and coronary intervention during pre-procedural diagnostics. At discharge and follow-up, 2.1% and 3.4%, respectively had sustained relevant impairment of kidney function (defined as creatinine/baseline creatinine > 1.5 or renal replacement therapy). Patients with known chronic kidney disease showed no higher rates of short- and long-term impairment, but higher rates of improvement of renal function after TAVI. CONCLUSIONS: In most cases TAVI does not worsen renal function. A sustained impairment after TAVI was found in only a few cases. This was independent of reduced baseline kidney function. Transfemoral TAVI can thus be planned and performed even in patients with higher stages of chronic kidney disease.

Is the future of peer review automated?

The rising rate of preprints and publications, combined with persistent inadequate reporting practices and problems with study design and execution, have strained the traditional peer review system. Automated screening tools could potentially enhance peer review by helping authors, journal editors, and reviewers to identify beneficial practices and common problems in preprints or submitted manuscripts. Tools can screen many papers quickly, and may be particularly helpful in assessing compliance with journal policies and with straightforward items in reporting guidelines. However, existing tools cannot understand or interpret the paper in the context of the scientific literature. Tools cannot yet determine whether the methods used are suitable to answer the research question, or whether the data support the authors' conclusions. Editors and peer reviewers are essential for assessing journal fit and the overall quality of a paper, including the experimental design, the soundness of the study's conclusions, potential impact and innovation. Automated screening tools cannot replace peer review, but may aid authors, reviewers, and editors in improving scientific papers. Strategies for responsible use of automated tools in peer review may include setting performance criteria for tools, transparently reporting tool performance and use, and training users to interpret reports.

Cytokine adsorption in patients with acute-on-chronic liver failure (CYTOHEP)-a single center, open-label, three-arm, randomized, controlled intervention trial.

BACKGROUND: Liver cirrhosis is a major healthcare problem and the mortality rate is high. During recent years, systemic inflammation has been recognized as a major driver of hepatic decompensation and progression of liver cirrhosis to acute-on-chronic liver failure (ACLF). The aim of the CYTOHEP study is to assess the impact of extracorporeal hemoadsorption with the CytoSorb adsorber on serum bilirubin concentrations, humoral inflammation parameters, liver function parameters, and patient survival in patients with ACLF and acute kidney injury (AKI). METHODS: The CYTOHEP study is a prospective, single-center, open-label, three-arm, randomized, controlled intervention trial. Patients with ACLF and AKI stage 3 according to Kidney Disease: Improving Global Outcome (KDIGO) criteria will be randomized into three groups to be treated with (1) continuous renal replacement therapy (CRRT) and CytoSorb, (2) CRRT without CytoSorb, and (3) without both, CRRT and CytoSorb. In the hemoadsorption group, CytoSorb will be used for 72 h. The other groups receive standard of care with early or late initiation of CRRT, respectively. Primary endpoint of the study is serum bilirubin concentration after 72 h, important secondary endpoints are 30-day survival and a panel of inflammatory parameters. DISCUSSION: The CYTOHEP study is designed to evaluate the benefit of extracorporeal hemoadsorption in patients with ACLF. The results of this study will help to better understand the potential role of hemoadsorption for the treatment of ACLF and its impact on bilirubin levels, inflammatory parameters, and survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT05019352. Registered on August 24, 2021. Deutsches Register Klinischer Studien (DRKS) DRKS00026082.

A Framework to Advance Biomarker Development in the Diagnosis, Outcome Prediction, and Treatment of Traumatic Brain Injury.

Multi-modal biomarkers (e.g., imaging, blood-based, physiological) of unique traumatic brain injury (TBI) endophenotypes are necessary to guide the development of personalized and targeted therapies for TBI. Optimal biomarkers will be specific, sensitive, rapidly and easily accessed, minimally invasive, cost effective, and bidirectionally translatable for clinical and research use. For both uses, understanding how TBI biomarkers change over time is critical to reliably identify appropriate time windows for an intervention as the injury evolves. Biomarkers that enable researchers and clinicians to identify cellular injury and monitor clinical improvement, inflection, arrest, or deterioration in a patient's clinical trajectory are needed for precision healthcare. Prognostic biomarkers that reliably predict outcomes and recovery windows to assess neurodegenerative change and guide decisions for return to play or duty are also important. TBI biomarkers that fill these needs will transform clinical practice and could reduce the patient's risk for long-term symptoms and lasting deficits. This article summarizes biomarkers currently under investigation and outlines necessary steps to achieve short- and long-term goals, including how biomarkers can advance TBI treatment and improve care for patients with TBI.

A Review of Implementation Concepts and Strategies Surrounding Traumatic Brain Injury Clinical Care Guidelines.

Despite considerable efforts to advance the science surrounding traumatic brain injury (TBI), formal efforts supporting the current and future implementation of scientific findings within clinical practice and healthcare policy are limited. While many and varied guidelines inform the clinical management of TBI across the spectrum, clinicians and healthcare systems are not broadly adopting, implementing, and/or adhering to them. As part of the Brain Trauma Blueprint TBI State of the Science, an expert workgroup was assembled to guide this review article, which describes: (1) possible etiologies of inadequate adoption and implementation; (2) enablers to successful implementation strategies; and (3) strategies to mitigate the barriers to adoption and implementation of future research.

Roadmap for Advancing Pre-Clinical Science in Traumatic Brain Injury.

Pre-clinical models of disease have long played important roles in the advancement of new treatments. However, in traumatic brain injury (TBI), despite the availability of numerous model systems, translation from bench to bedside remains elusive. Integrating clinical relevance into pre-clinical model development is a critical step toward advancing therapies for TBI patients across the spectrum of injury severity. Pre-clinical models include in vivo and ex vivo animal work-both small and large-and in vitro modeling. The wide range of pre-clinical models reflect substantial attempts to replicate multiple aspects of TBI sequelae in humans. Although these models reveal multiple putative mechanisms underlying TBI pathophysiology, failures to translate these findings into successful clinical trials call into question the clinical relevance and applicability of the models. Here, we address the promises and pitfalls of pre-clinical models with the goal of evolving frameworks that will advance translational TBI research across models, injury types, and the heterogenous etiology of pathology.

Epidemiology of Chronic Effects of Traumatic Brain Injury.

Although many patients diagnosed with traumatic brain injury (TBI), particularly mild TBI, recover from their symptoms within a few weeks, a small but meaningful subset experience symptoms that persist for months or years after injury and significantly impact quality of life for the person and their family. Factors associated with an increased likelihood of negative TBI outcomes include not only characteristics of the injury and injury mechanism, but also the person's age, pre-injury status, comorbid conditions, environment, and propensity for resilience. In this article, as part of the Brain Trauma Blueprint: TBI State of the Science framework, we examine the epidemiology of long-term outcomes of TBI, including incidence, prevalence, and risk factors. We identify the need for increased longitudinal, global, standardized, and validated assessments on incidence, recovery, and treatments, as well as standardized assessments of the influence of genetics, race, ethnicity, sex, and environment on TBI outcomes. By identifying how epidemiological factors contribute to TBI outcomes in different groups of persons and potentially impact differential disease progression, we can guide investigators and clinicians toward more-precise patient diagnosis, along with tailored management, and improve clinical trial designs, data evaluation, and patient selection criteria.

Phenotyping the Spectrum of Traumatic Brain Injury: A Review and Pathway to Standardization.

It is widely appreciated that the spectrum of traumatic brain injury (TBI), mild through severe, contains distinct clinical presentations, variably referred to as subtypes, phenotypes, and/or clinical profiles. As part of the Brain Trauma Blueprint TBI State of the Science, we review the current literature on TBI phenotyping with an emphasis on unsupervised methodological approaches, and describe five phenotypes that appear similar across reports. However, we also find the literature contains divergent analysis strategies, inclusion criteria, findings, and use of terms. Further, whereas some studies delineate phenotypes within a specific severity of TBI, others derive phenotypes across the full spectrum of severity. Together, these facts confound direct synthesis of the findings. To overcome this, we introduce PhenoBench, a freely available code repository for the standardization and evaluation of raw phenotyping data. With this review and toolset, we provide a pathway toward robust, data-driven phenotypes that can capture the heterogeneity of TBI, enabling reproducible insights and targeted care.

Long-term Follow-up of ABO-Incompatible Kidney Transplantation in Freiburg, Germany: A Single-Center Outcome Report.

BACKGROUND: ABO-incompatible kidney transplantation (ABOi-KT) is an established way to enlarge the donor pool around the world. Comparability of long-term success and complications to ABO-compatible kidney transplantation (ABOc-KT) are still under debate. METHODS: We evaluated all patients with a living donor kidney transplantation performed between April 1, 2004, and March 31, 2019. RESULTS: A total of 137 ABOi-KT and 346 ABOc-KT were analyzed. We excluded 4 ABOi-KT recipients and 178 ABOc-KT recipients with cyclosporine A-based immunosuppression or without basiliximab induction. Three patients of the ABOi-KT cohort and 6 patients of the ABOc-KT cohort were lost to follow-up and therefore excluded. The patient characteristics were comparable except for the higher age of transplant recipients in the ABOc-KT cohort and longer follow-up of the ABOi-KT cohort. The mean estimated 15-year recipient survival was 89% in the ABOi-KT cohort and 91% in the ABOc-KT cohort (P = .39). Mean estimated graft survival was 71% in the ABOi-KT cohort and 87% in the ABOc-KT cohort (P = .68). The estimated glomerular filtration rate (Modification of Diet in Renal Disease) measured in the last follow-up was 51 mL/min/1.73 m2 in the ABOi-KT cohort and 50 mL/min/1.73 m2 in the ABOc-KT cohort (P = .36). The incidence for antibody-mediated rejection, T cell-mediated rejections, and infectious complications requiring hospitalization was not different between the cohorts. In the ABOi-KT cohort, we found significantly more lymphoceles and consequent surgical revision procedures. CONCLUSIONS: At our center, ABOi-KT has as good long-term results as ABOc-KT in terms of patient survival, graft survival, and complications, with the exception of increased lymphocele formation.

Dopamine Oppositely Modulates State Transitions in Striosome and Matrix Direct Pathway Striatal Spiny Neurons.

Corticostriatal synaptic integration is partitioned among striosome (patch) and matrix compartments of the dorsal striatum, allowing compartmentalized control of discrete aspects of behavior. Despite the significance of such organization, it's unclear how compartment-specific striatal output is dynamically achieved, particularly considering new evidence that overlap of afferents is substantial. We show that dopamine oppositely shapes responses to convergent excitatory inputs in mouse striosome and matrix striatal spiny projection neurons (SPNs). Activation of postsynaptic D1 dopamine receptors promoted the generation of long-lasting synaptically evoked "up-states" in matrix SPNs but opposed it in striosomes, which were more excitable under basal conditions. Differences in dopaminergic modulation were mediated, in part, by dendritic voltage-gated calcium channels (VGCCs): pharmacological manipulation of L-type VGCCs reversed compartment-specific responses to D1 receptor activation. These results support a novel mechanism for the selection of striatal circuit components, where fluctuating levels of dopamine shift the balance of compartment-specific striatal output.

Evidence of Interleukin-2-Receptor-Antibody Induction in Low-Risk Living Donor Kidney Transplantation: A Single-Center Pilot Study.

BACKGROUND: The recommended standard immunosuppressive therapy for renal transplant recipients comprises an initial induction therapy mainly with an interleukin-2-receptor antibody (IL2-RA) and a triple maintenance therapy. With tacrolimus and mycophenolate acid it is unknown whether IL2-RA application affects the short- and long-term results. This question is addressed in the present analysis. METHODS: From July 2007 to June 2019 a total of 127 living donor kidney transplant recipients meeting the center-specific definition of immunologic low risk situation (first transplantation, HLA-mismatch ≤3, panel reactive antibody ≤10%) were identified. In 83 recipients with a first-degree relationship to the donor we omitted the IL2-RA induction (IL2-RA-). The remaining 44 recipients, mostly not first-degree relatives, served as controls (IL2-RA+). Biopsy-proven acute rejection and long-term patient and graft survival rates were compared. RESULTS: Biopsy-proven acute rejection rates after 3 months were similar in both groups with 4.8% (IL2-RA-) vs 13.7% (IL2-RA+; P = .0937), including borderline rejection rates of 18.0% (IL2-RA-) vs 18.3% (IL2-RA+; P = 1.000), respectively. Ten-year long-term survival rates were comparable between the IL2-RA- and the IL2-RA+ group with 95.6% vs 93.5% (patient survival; P = .5465) and 92.1% vs 90.6% (death-censored graft survival; P = .8893). CONCLUSION: For low-risk living donor kidney transplant recipients with first-degree relationship to the donor, it is safe to omit induction therapy with IL2-RA.

Compartmental function and modulation of the striatum.

The striatum plays a central role in guiding numerous complex behaviors, ranging from motor control to action selection and reward learning. The diverse responsibilities of the striatum are reflected by the complexity of its organization. In this review, we will summarize what is currently known about the compartmental layout of the striatum, an organizational principle that is crucial for allowing the striatum to guide such a diverse array of behaviors. We will focus on the anatomical and functional properties of striosome (patch) and matrix compartments of the striatum, and how the engagement of these compartments is uniquely controlled by their afferents, intrinsic properties, and neuromodulation. We will give examples of how advances in technology have opened the door to functionally dissecting the striatum's compartmental design, and close by offering thoughts on the future and relevance for human disease.

Improving transparency and scientific rigor in academic publishing.

Progress in basic and clinical research is slowed when researchers fail to provide a complete and accurate report of how a study was designed, executed, and the results analyzed. Publishing rigorous scientific research involves a full description of the methods, materials, procedures, and outcomes. Investigators may fail to provide a complete description of how their study was designed and executed because they may not know how to accurately report the information or the mechanisms are not in place to facilitate transparent reporting. Here, we provide an overview of how authors can write manuscripts in a transparent and thorough manner. We introduce a set of reporting criteria that can be used for publishing, including recommendations on reporting the experimental design and statistical approaches. We also discuss how to accurately visualize the results and provide recommendations for peer reviewers to enhance rigor and transparency. Incorporating transparency practices into research manuscripts will significantly improve the reproducibility of the results by independent laboratories. SIGNIFICANCE: Failure to replicate research findings often arises from errors in the experimental design and statistical approaches. By providing a full account of the experimental design, procedures, and statistical approaches, researchers can address the reproducibility crisis and improve the sustainability of research outcomes. In this piece, we discuss the key issues leading to irreproducibility and provide general approaches to improving transparency and rigor in reporting, which could assist in making research more reproducible.