Rapid phagosome isolation enables unbiased multiomic analysis of human microglial phagosomes.

Microglia are the resident macrophages of the central nervous system (CNS). Their phagocytic activity is central during brain development and homeostasis-and in a plethora of brain pathologies. However, little is known about the composition, dynamics, and function of human microglial phagosomes under homeostatic and pathological conditions. Here, we developed a method for rapid isolation of pure and intact phagosomes from human pluripotent stem cell-derived microglia under various in vitro conditions, and from human brain biopsies, for unbiased multiomic analysis. Phagosome profiling revealed that microglial phagosomes were equipped to sense minute changes in their environment and were highly dynamic. We detected proteins involved in synapse homeostasis, or implicated in brain pathologies, and identified the phagosome as the site where quinolinic acid was stored and metabolized for de novo nicotinamide adenine dinucleotide (NAD+) generation in the cytoplasm. Our findings highlight the central role of phagosomes in microglial functioning in the healthy and diseased brain.

A vaccine targeting mutant IDH1 in newly diagnosed glioma.

Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma1-3. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours in syngeneic MHC-humanized mice4,6-8. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)+ astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG+ and CXCL13+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Cardio-renal-metabolic disease in primary care setting.

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well-established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium-glucose co-transporter-2 inhibitors (SGLT2i) and Glucagon-like peptide-receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage.

Towards the standardisation of adult person-reported outcome domains in diabetes research: A Consensus Statement development panel.

Diabetes is unique among chronic diseases because clinical outcomes are intimately tied to how the person living with diabetes reacts to and implements treatment recommendations. It is further characterised by widespread social stigma, judgement and paternalism. This physical, social and psychological burden collectively influences self-management behaviours. It is widely recognised that the individual's perspective about the impact of trying to manage the disease and the burden that self-management confers must be addressed to achieve optimal health outcomes. Standardised, rigorous assessment of mental and behavioural health status, in interaction with physical health outcomes is crucial to aid understanding of person-reported outcomes (PROs). Whilst tempting to conceptualise PROs as an issue of perceived quality of life (QoL), in fact health-related QoL is multi-dimensional and covers indicators of physical or functional health status, psychological and social well-being. This complexity is illuminated by the large number of person reported outcome measures (PROMs) that have been developed across multiple psychosocial domains. Often measures are used inappropriately or because they have been used in the scientific literature rather than based on methodological or outcome assessment rigour. Given the broad nature of psychosocial functioning/mental health, it is important to broadly define PROs that are evaluated in the context of therapeutic interventions, real-life and observational studies. This report summarises the central themes and lessons derived in the assessment and use of PROMs amongst adults with diabetes. Effective assessment of PROMs routinely in clinical research is crucial to understanding the true impact of any intervention. Selecting appropriate measures, relevant to the specific factors of PROs important in the research study will provide valuable data alongside physical health data.

Effects of tumor treating fields (TTFields) on human mesenchymal stromal cells.

PURPOSE: Mesenchymal stromal cells (MSCs) within the glioblastoma microenvironment have been shown to promote tumor progression. Tumor Treating Fields (TTFields) are alternating electric fields with low intensity and intermediate frequency that exhibit anti-tumorigenic effects. While the effects of TTFields on glioblastoma cells have been studied previously, nothing is known about the influence of TTFields on MSCs. METHODS: Single-cell RNA sequencing and immunofluorescence staining were employed to identify glioblastoma-associated MSCs in patient samples. Proliferation and clonogenic survival of human bone marrow-derived MSCs were assessed after TTFields in vitro. MSC' characteristic surface marker expression was determined using flow cytometry, while multi-lineage differentiation potential was examined with immunohistochemistry. Apoptosis was quantified based on caspase-3 and annexin-V/7-AAD levels in flow cytometry, and senescence was assessed with ß-galactosidase staining. MSCs' migratory potential was evaluated with Boyden chamber assays. RESULTS: Single-cell RNA sequencing and immunofluorescence showed the presence of glioblastoma-associated MSCs in patient samples. TTFields significantly reduced proliferation and clonogenic survival of human bone marrow-derived MSCs by up to 60% and 90%, respectively. While the characteristic surface marker expression and differentiation capacity were intact after TTFields, treatment resulted in increased apoptosis and senescence. Furthermore, TTFields significantly reduced MSCs' migratory capacity. CONCLUSION: We could demonstrate the presence of tumor-associated MSCs in glioblastoma patients, providing a rationale to study the impact of TTFields on MSCs. TTFields considerably increase apoptosis and senescence in MSCs, resulting in impaired survival and migration. The results provide a basis for further analyses on the role of MSCs in glioblastoma patients receiving TTFields.

Treatment outcome of IDH1/2 wildtype CNS WHO grade 4 glioma histologically diagnosed as WHO grade II or III astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH)1/2 wildtype (wt) astrocytomas formerly classified as WHO grade II or III have significantly shorter PFS and OS than IDH mutated WHO grade 2 and 3 gliomas leading to a classification as CNS WHO grade 4. It is the aim of this study to evaluate differences in the treatment-related clinical course of these tumors as they are largely unknown. METHODS: Patients undergoing surgery (between 2016-2019 in six neurosurgical departments) for a histologically diagnosed WHO grade 2-3 IDH1/2-wt astrocytoma were retrospectively reviewed to assess progression free survival (PFS), overall survival (OS), and prognostic factors. RESULTS: This multi-center study included 157 patients (mean age 58 years (20-87 years); with 36.9% females). The predominant histology was anaplastic astrocytoma WHO grade 3 (78.3%), followed by diffuse astrocytoma WHO grade 2 (21.7%). Gross total resection (GTR) was achieved in 37.6%, subtotal resection (STR) in 28.7%, and biopsy was performed in 33.8%. The median PFS (12.5 months) and OS (27.0 months) did not differ between WHO grades. Both, GTR and STR significantly increased PFS (P < 0.01) and OS (P < 0.001) compared to biopsy. Treatment according to Stupp protocol was not associated with longer OS or PFS compared to chemotherapy or radiotherapy alone. EGFR amplification (P = 0.014) and TERT-promotor mutation (P = 0.042) were associated with shortened OS. MGMT-promoter methylation had no influence on treatment response. CONCLUSIONS: WHO grade 2 and 3 IDH1/2 wt astrocytomas, treated according to the same treatment protocols, have a similar OS. Age, extent of resection, and strong EGFR expression were the most important treatment related prognostic factors.

Practical strategies to manage obesity in type 2 diabetes.

The rising phenomenon of obesity, a major risk factor for the development and progression of type 2 diabetes, is a complex and multifaceted issue that requires a comprehensive and coordinated approach to be prevented and managed. Although novel pharmacological measures to combat obesity have achieved unprecedented efficacy, a healthy lifestyle remains essential for the long-term success of any therapeutic intervention. However, this requires a high level of intrinsic motivation and continued behavioural changes in the face of multiple metabolic, psychological and environmental factors promoting weight gain, particularly in the context of type 2 diabetes. This review is intended to provide practical recommendations in the context of a holistic, person-centred approach to weight management, including evidence-based and expert recommendations addressing supportive communication, shared decision-making, as well as nutritional and pharmacological therapeutic approaches to achieve sustained weight loss.

The role of incretin receptor agonists in the treatment of obesity.

INTRODRODUCTION: Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon-like peptide-1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co-agonists. METHODS: The objective of this narrative review was to summarize the available data on approved and emerging incretin-based agents for the treatment of obesity. RESULTS: In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction-associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation. CONCLUSIONS: Many dual and triple co-agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin-based therapies; however, data are promising, and further results are eagerly awaited.

Surgical closure of spinal cerebrospinal fluid leaks improves symptoms in patients with superficial siderosis.

BACKGROUND AND PURPOSE: Spinal cerebrospinal fluid (CSF) leaks may cause a myriad of symptoms, most common being orthostatic headache. In addition, ventral spinal CSF leaks are a possible etiology of superficial siderosis (SS), a rare condition characterized by hemosiderin deposits in the central nervous system (CNS). The classical presentation of SS involves ataxia, bilateral hearing loss, and myelopathy. Unfortunately, treatment options are scarce. This study was undertaken to evaluate whether microsurgical closure of CSF leaks can prevent further clinical deterioration or improve symptoms of SS. METHODS: This cohort study was conducted using data from a prospectively maintained database in two large spontaneous intracranial hypotension (SIH) referral centers in Germany and Switzerland of patients who meet the modified International Classification of Headache Disorders, 3rd edition criteria for SIH. Patients with spinal CSF leaks were screened for the presence of idiopathic infratentorial symmetric SS of the CNS. RESULTS: Twelve patients were included. The median latency between the onset of orthostatic headaches and symptoms attributed to SS was 9.5 years. After surgical closure of the underlying spinal CSF leak, symptoms attributed to SS improved in seven patients and remained stable in three. Patients who presented within 1 year after the onset of SS symptoms improved, but those who presented in 8-12 years did not improve. We could show a significant association between patients with spinal longitudinal extrathecal collections and SS. CONCLUSIONS: Long-standing untreated ventral spinal CSF leaks can lead to SS of the CNS, and microsurgical sealing of spinal CSF leaks might stop progression and improve symptoms in patients with SS in a time-dependent manner.

Current Practice of Podiatrists in Testing for Diabetic Polyneuropathy and Implementing Foot Care (PROTECT Study Survey 2).

AIMS: Podiatrists constitute a key member of a multidisciplinary foot care team, but their services remain underutilized. We sought to gain insights into the daily practice of podiatrists focusing on screening for and monitoring of diabetic sensorimotor polyneuropathy (DSPN) as well as foot management. METHODS: This cross-sectional survey included 125 podiatrists from 12 federal states across Germany who responded to an online questionnaire. RESULTS: The majority of patients treated in podiatry practices were referred by general practitioners and diabetologists. Screening for or follow-up of DSPN was performed by 36% of the respondents at least once a year, by 28% only at initial examination, by 21% only at suspicion, and by 10% basically at each treatment visit. Instruments to assess vibration, touch/pressure, and temperature sensation were used by 81% to 94% of the podiatrists. Previously undiagnosed DSPN and foot ulcers were detected frequently/very frequently (≥6 cases/mo) by 24.0 and 18.4% of the podiatrists, respectively. Almost all podiatrists advised daily self-monitoring of feet and appropriate foot care and >50% gave advice on medical treatment. CONCLUSIONS: Podiatrists play an important role in the detection, monitoring, and management of both DSPN and diabetic foot ulcers, suggesting that the utilization of their services should be fostered.

Undetected permanent dental inflammation as a possible trigger for brain abscesses? A retrospective analysis over the last 2 decades.

BACKGROUND: Recently, there is increasing evidence that the proportion of odontogenic brain abscesses is greater than previously known. In this study, we aim to differentiate the oral infections as triggers more precisely and to classify them in the clinical setting. METHODS: For analysis, we conducted a retrospective single center study. We reviewed patients with brain abscesses who have undergone treatment in the University Hospital of Freiburg, Germany in the period between 2000-2021. Inclusion required two main criteria: 1. The brain abscess must not have an other focus than odontogenic. 2. The microbial spectrum identified in the brain abscess must be consistent with an odontogenic origin. RESULTS: Of 217 brain abscess patients, 26 met the inclusion criteria. 42% (11 patients) suffered from immunosuppressive conditions. Odontogenic foci were diagnosed in 18 cases (69%). Neurologic deficits included vigilance reduction and hemiparesis. Pathogens of the Streptococcus anginosus group were the most frequent causative agent (21 cases, 81%). Metronidazole (54%) and ceftriaxone (42%) were part of the targeted antibiotic therapy. All brain abscesses were surgically treated. Teeth were extracted in 14 of 17 cases for focus control. 18 cases (72%) showed complete or partial resolution of neurologic symptoms and 3 cases were fatal. CONCLUSION: Apparently silent or chronic oral infections are sufficient to cause bacterial colonization of the brain, especially in immunocompromised patients. Therefore, special care should be taken to maintain good oral health. An interdisciplinary management should become a standard to prevent and treat the occurrence of brain abscesses.

A framework for standardised tissue sampling and processing during resection of diffuse intracranial glioma: joint recommendations from four RANO groups.

Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, how to define those regions on the basis of preoperative imaging, and the optimal sample volume. Practical recommendations for tissue sampling are given for people with low-grade and high-grade gliomas, as well as for people with newly diagnosed and recurrent disease. Sampling of liquid biopsies is also addressed. A standardised workflow for subsequent handling of the resected tissue is proposed to avoid information loss due to decreasing tissue quality or insufficient clinical information. The recommendations offer a framework for prospective biobanking studies.

Data from network meta-analyses can inform clinical practice guidelines and decision-making in diabetes management: perspectives of the taskforce of the guideline workshop.

In recent years, several novel agents have become available to treat individuals with type 2 diabetes (T2D), such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i), tirzepatide, which is a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP RA)/glucagon-like peptide-1 receptor agonist (GLP-1 RA), and finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA) that confers significant renal and cardiovascular benefits in individuals with (CKD). New medications have the potential to improve the lives of individuals with diabetes. However, clinicians are challenged to understand the benefits and potential risks associated with these new and emerging treatment options. In this article, we discuss how use of network meta-analyses (NMA) can fill this need.

CVOT Summit 2022 Report: new cardiovascular, kidney, and glycemic outcomes.

The 8th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Kidney, and Glycemic Outcomes was held virtually on November 10-12, 2022. Following the tradition of previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed outcomes trials as well as key trials important to the cardiovascular (CV) field. This year's focus was on the results of the DELIVER, EMPA-KIDNEY and SURMOUNT-1 trials and their implications for the treatment of heart failure (HF) and chronic kidney disease (CKD) with sodium-glucose cotransporter-2 (SGLT2) inhibitors and obesity with glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. A broad audience of primary care physicians, diabetologists, endocrinologists, cardiologists, and nephrologists participated online in discussions on new consensus recommendations and guideline updates on type 2 diabetes (T2D) and CKD management, overcoming clinical inertia, glycemic markers, continuous glucose monitoring (CGM), novel insulin preparations, combination therapy, and reclassification of T2D. The impact of cardiovascular outcomes on the design of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) trials, as well as the impact of real-world evidence (RWE) studies on the confirmation of CVOT outcomes and clinical trial design, were also intensively discussed. The 9th Cardiovascular Outcome Trial Summit will be held virtually on November 23-24, 2023 ( http://www.cvot.org ).

Long-term neurocognitive function and quality of life after multimodal therapy in adult glioma patients: a prospective long-term follow-up.

PURPOSE: Multimodal therapies have significantly improved prognosis in glioma. However, in particular radiotherapy may induce long-term neurotoxicity compromising patients' neurocognition and quality of life. The present prospective multicenter study aimed to evaluate associations of multimodal treatment with neurocognition with a particular focus on hippocampal irradiation. METHODS: Seventy-one glioma patients (WHO grade 1-4) were serially evaluated with neurocognitive testing and quality of life questionnaires. Prior to (baseline) and following further treatment (median 7.1 years [range 4.6-11.0] after baseline) a standardized computerized neurocognitive test battery (NeuroCog FX) was applied to gauge psychomotor speed and inhibition, verbal short-term memory, working memory, verbal and non-verbal memory as well as verbal fluency. Mean ipsilateral hippocampal radiation dose was determined in a subgroup of 27 patients who received radiotherapy according to radiotherapy plans to evaluate its association with neurocognition. RESULTS: Between baseline and follow-up mean performance in none of the cognitive domains significantly declined in any treatment modality (radiotherapy, chemotherapy, combined radio-chemotherapy, watchful-waiting), except for selective attention in patients receiving chemotherapy alone. Apart from one subtest (inhibition), mean ipsilateral hippocampal radiation dose > 50 Gy (Dmean) as compared to < 10 Gy showed no associations with long-term cognitive functioning. However, patients with Dmean < 10 Gy showed stable or improved performance in all cognitive domains, while patients with > 50 Gy numerically deteriorated in 4/8 domains. CONCLUSIONS: Multimodal glioma therapy seems to affect neurocognition less than generally assumed. Even patients with unilateral hippocampal irradiation with > 50 Gy showed no profound cognitive decline in this series.

New insights into the treatment of obesity.

Obesity is a chronic, progressive and relapsing disease with a rising global prevalence associated with increased morbidity and mortality and reduced quality of life. Treatment of obesity requires a comprehensive medical approach that includes behavioural interventions, pharmacotherapy and bariatric surgery. The degree of weight loss with all approaches is highly heterogeneous, and long-term weight maintenance remains challenging. For years, antiobesity medications have been limited in number, often delivering meagre efficacy and raising numerous safety concerns. Therefore, there is a need for the development of highly efficacious and safe new agents. Recent insights into the complex pathophysiology of obesity have increased our understanding of intervenable targets for pharmacotherapies to treat obesity and improve weight-related cardiometabolic complications, namely, type 2 diabetes, hyperlipidaemia and hypertension. As a result, novel potent therapies have emerged, such as semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) recently approved for the treatment of obesity. Semaglutide 2.4 mg once weekly significantly reduces body weight by approximately 15%, with simultaneous improvement in cardiometabolic risk factors and physical functioning in people with obesity. Tirzepatide, the first dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA, has recently demonstrated that body weight reduction exceeding 20% in people with obesity and coupled with improved cardiometabolic measures is feasible. Thus, these novel agents promise to narrow the gap between the weight-loss effects of behaviour interventions, previous pharmacotherapies, and bariatric surgery. In this narrative review, we highlight established and emerging therapeutic treatments for long-term obesity management and position them in a framework according to their weight loss effects.

Herniation World Federation of Neurosurgical Societies Scale Improves Prediction of Outcome in Patients With Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Favorable outcomes are seen in up to 50% of patients with World Federation of Neurosurgical Societies (WFNS) grade V aneurysmal subarachnoid hemorrhage. Therefore, the usefulness of the current WFNS grading system for identifying the worst scenarios for clinical studies and for making treatment decisions is limited. We previously modified the WFNS scale by requiring positive signs of brain stem dysfunction to assign grade V. This study aimed to validate the new herniation WFNS grading system in an independent prospective cohort. METHODS: We conducted an international prospective multicentre study in poor-grade aneurysmal subarachnoid hemorrhage patients comparing the WFNS classification with a modified version-the herniation WFNS scale (hWFNS). Here, only patients who showed positive signs of brain stem dysfunction (posturing, anisocoric, or bilateral dilated pupils) were assigned hWFNS grade V. Outcome was assessed by modified Rankin Scale score 6 months after hemorrhage. The primary end point was the difference in specificity of the WFNS and hWFNS grading with respect to poor outcomes (modified Rankin Scale score 4-6). RESULTS: Of the 250 patients included, 237 reached the primary end point. Comparing the WFNS and hWFNS scale after neurological resuscitation, the specificity to predict poor outcome increased from 0.19 (WFNS) to 0.93 (hWFNS) (McNemar, P<0.001) whereas the sensitivity decreased from 0.88 to 0.37 (P<0.001), and the positive predictive value from 61.9 to 88.3 (weighted generalized score statistic, P<0.001). For mortality, the specificity increased from 0.19 to 0.93 (McNemar, P<0.001), and the positive predictive value from 52.5 to 86.7 (weighted generalized score statistic, P<0.001). CONCLUSIONS: The identification of objective positive signs of brain stem dysfunction significantly improves the specificity and positive predictive value with respect to poor outcome in grade V patients. Therefore, a simple modification-presence of brain stem signs is required for grade V-should be added to the WFNS classification. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02304328.

New strategies to improve clinical outcomes for diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. MAIN BODY: This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. CONCLUSION: With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes.

Managing thrombotic risk in patients with diabetes.

It is well known that diabetes is a prominent risk factor for cardiovascular (CV) events. The level of CV risk depends on the type and duration of diabetes, age and additional co-morbidities. Diabetes is an independent risk factor for atrial fibrillation (AF) and is frequently observed in patients with AF, which further increases their risk of stroke associated with this cardiac arrhythmia. Nearly one third of patients with diabetes globally have CV disease (CVD). Additionally, co-morbid AF and coronary artery disease are more frequently observed in patients with diabetes than the general population, further increasing the already high CV risk of these patients. To protect against thromboembolic events in patients with diabetes and AF or established CVD, guidelines recommend optimal CV risk factor control, including oral anticoagulation treatment. However, patients with diabetes exist in a prothrombotic and inflammatory state. Greater clinical benefit may therefore be seen with the use of stronger antithrombotic agents or innovative drug combinations in high-risk patients with diabetes, such as those who have concomitant AF or established CVD. In this review, we discuss CV risk management strategies in patients with diabetes and concomitant vascular disease, stroke prevention regimens in patients with diabetes and AF and how worsening renal function in these patients may complicate these approaches. Accumulating evidence from clinical trials and real-world evidence show a benefit to the administration of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with diabetes and AF.