Macrophage and monocyte subsets as new therapeutic targets in cancer immunotherapy.

The introduction of immune checkpoint inhibitors (ICIs) for the treatment of solid cancers dramatically turned the tables in clinical routine. However, therapy success is still limited with up to 70% of non-responders in patients with ICI treatment. Traditionally, most immunotherapy approaches aim at directly stimulating anti-tumor T cell responses. More recently, tumor-associated macrophages have come into focus due to their predominance in solid tumors. Intensive cross-talk with tumor cells and immune as well as stromal cells within the tumor microenvironment can drive either pro- or anti-tumorigenic macrophage phenotypes. In turn, tumor-associated macrophages strongly shape cytokine and metabolite levels in the tumor microenvironment and thus are central players in anti-tumor immunity. Thus, ambivalent macrophage populations exist which raises therapeutic possibilities to either enhance or diminish their functionality. However, molecular signals controlling tumor-associated macrophage polarization are incompletely understood. Gaining in-depth understanding of monocyte/macrophage properties both in circulation and within distinct tumor microenvironments would (i) allow the development of new therapeutic approaches, and (ii) could additionally aid our understanding of underlying mechanisms limiting current therapy with the option of combinatorial therapies to increase efficacy. In this review, we summarize recent data addressing heterogeneity of tumor-associated macrophage populations and we discuss strategies to target macrophages using known molecular pathways with the potential for straight-forward clinical application.

TICI-RANKIN mismatch: Poor clinical outcome despite complete endovascular reperfusion in the ETIS Registry.

INTRODUCTION: Endovascular treatment (EVT) is a well-established technic for acute ischemic stroke, but despite a high recanalization rate of near 80%, at 3 months roughly 50% of patients have a poor functional outcome with a modified Rankin score (mRS) ≥3. The aim of this study was to determine predictive factors of poor functional outcomes in patients with complete recanalization after EVT, defined as modified thrombolysis in cerebral infarction (mTICI) 3. PATIENTS AND METHODS: This retrospective analysis based on the prospective multicenter ETIS registry (endovascular treatment in ischemic stroke) in France included 795 patients from January 2015 and November 2019 with acute ischemic stroke due to anterior circulation occlusion and prestroke mRS 0-1, treated with EVT and who achieved complete recanalization. Univariate and multivariate logistic regression models were used to identify predictive factors of poor functional outcome. RESULTS: 365 patients (46%) showed a poor functional outcome (mRS>2). In backward-stepwise logistic regression analysis, poor functional outcome was independently associated with older age (OR per 10-year increase, 1.51; 95%CI, 1.30 to 1.75), higher admission NIHSS (OR per 1 point increase, 1.28; 95%CI, 1.21 to 1.34), absence of prior intravenous thrombolysis (OR, 0.59; 95%CI, 0.39 to 0.90), and an unfavorable 24-hour NIHSS change (24h-baseline) (OR, 0.82; 95%CI, 0.79 to 0.87). We calculated that patients whose 24h NIHSS decreased by less than 5 points are more at risk of a poor outcome, with a sensitivity and a specificity of 65.0%. CONCLUSION: Despite complete reperfusion after EVT, half of patients had a poor clinical outcome. These patients, who were mainly older with a high initial NIHSS and an unfavorable post-EVT 24h NIHSS change, could represent a target population for early neurorepair and neurorestorative strategies.

Successful Reperfusion is Associated with Favorable Functional Outcome despite Vessel Perforation during Thrombectomy: A Case Series and Systematic Review.

BACKGROUND: Arterial perforation is a potentially serious complication during endovascular thrombectomy. PURPOSE: Our aim was to describe interventional approaches after arterial perforation during endovascular thrombectomy and to determine whether reperfusion remains associated with favorable outcome despite this complication. DATA SOURCES: Data from consecutive patients with acute stroke undergoing endovascular thrombectomy were retrospectively collected between 2015 to 2020 from a single-center cohort, and a systematic review was performed using PubMed, EMBASE, and Ovid MEDLINE up to June 2020. STUDY SELECTION: Articles reporting functional outcome after arterial perforation during endovascular thrombectomy were selected. DATA ANALYSIS: Functional outcomes of patients achieving successful reperfusion (TICI 2b/3) were compared with outcomes of those with unsuccessful reperfusion in our single-center cohort. We then summarized the literature review to describe interventional approaches and outcomes after arterial perforation during endovascular thrombectomy. DATA SYNTHESIS: In our single-center cohort, 1419 patients underwent endovascular thrombectomy, among whom 32 (2.3%) had vessel perforation and were included in the analysis. The most common hemostatic strategy was watchful waiting (71% of cases). Patients with successful reperfusion had a higher proportion of favorable 90-day mRS scores (60% versus 12.5%; P = .006) and a lower mortality rate (13.3% versus 56.3%, P = .01) than patients without successful reperfusion. Thirteen articles were included in the systematic review. Successful reperfusion also appeared to be associated with better outcomes. LIMITATIONS: Given the low number of published reports, we performed only a descriptive analysis. CONCLUSIONS: Arterial perforation during endovascular thrombectomy is rare but is associated with high mortality rates and poor outcome. However, successful reperfusion remains correlated with favorable outcome in these patients.

Endovascular therapy for acute ischemic stroke: The importance of blood pressure control, sedation modality and anti-thrombotic management to improve functional outcomes.

Since 2015, endovascular therapy (EVT) following intravenous thrombolysis (IVT) is the gold standard treatment for patients suffering from acute ischemic stroke (AIS) due to an anterior large vessel occlusion (LVO). Despite high recanalization rates, nearly half of successfully treated patients remain dependent at three months. This result underlines that other factors may have a prognostic value, such as blood pressure (BP) management, the sedation modality and anti-thrombotic strategy during and after EVT. Extreme BP variations before and after recanalization are associated with worse outcomes. During EVT, BP variability is strongly associated with worse functional outcomes. Indeed, several studies have highlighted the deleterious impact of BP drops and hypotension duration on functional outcomes and final infarct volume. Interestingly, several studies have shed light on the potential value of an individualized BP management based on several baseline clinical or radiological parameters, such as the collateral status or the circle of Willis conformation. Such approaches are being investigated and could lead to a paradigm shift compared to the one-size-fits-all approach. After EVT, recent evidence suggests that an intensive systolic BP reduction (100-129mmHg) does not reduce the occurrence of intracranial hemorrhage compared to the guideline-recommended systolic BP control (130-185mmHg). Anesthetic management also seems to have a major impact on functional outcome. The latest studies suggest that general anesthesia may be associated with better functional outcomes and faster procedures and may have neuroprotective effects. However, further studies are needed in order to clarify the best anesthetic management for EVT. Finally, new anti-thrombotic treatments are increasingly used during EVT and are currently investigated to increase recanalization rates and improve reperfusion. However, the current literature is scarce regarding the association of IVT, EVT and antiplatelet therapy such as anti-GPIIbIIIa or P2Y12 inhibitors. These strategies raise several issues, such as an increase in intracranial hemorrhage rates.

Large vessel stroke in six patients following SARS-CoV-2 infection: a retrospective case study series of acute thrombotic complications on stable underlying atherosclerotic disease.

BACKGROUND AND PURPOSE: Ischaemic stroke has been described in association with COVID-19. Several pathophysiological mechanisms have been suggested, i.e. prothrombotic state, cardiac injury etc. It was sought to assess the potential association between ischaemic stroke associated with SARS-CoV-2 infection and underlying atherosclerotic lesions. METHODS: A retrospective analysis of stroke related to large vessel occlusion was conducted amongst patients with SARS-CoV-2 infection and underlying mild atherosclerotic disease, between 19 March and 19 April 2020 in six different stroke centers in the Île-de France area, France. RESULTS: The median age was 52 years, median body mass index was 29.5 kg/m2 . All patients displayed previous vascular risk factors such as high blood pressure, diabetes, dyslipidemia or body mass index > 25. The delay between the first respiratory symptoms of COVID-19 and stroke was 11.5 days. At baseline, all had tandem occlusions, i.e. intracerebral and extracerebral thrombus assessed with computed tomography or magnetic resonance imaging. Cases displayed a large thrombus in the cervical carotid artery with underlying mild non-stenosing atheroma, after an etiological workup based on angio-computed tomography or magnetic resonance imaging and/or cervical echography. CONCLUSION: Our study should alert clinicians to scrutinize any new onset of ischaemic stroke during COVID-19 infection, mainly in patients with vascular risk factors or underlying atherosclerotic lesions.

Hemorrhagic transformation after stroke: inter- and intrarater agreement.

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) is a complication of stroke that can occur spontaneously or after treatment. We aimed to assess the inter- and intrarater reliability of HT diagnosis. METHODS: Studies assessing the reliability of the European Cooperative Acute Stroke Study (ECASS) classification of HT or of the presence (yes/no) of HT were systematically reviewed. A total of 18 raters independently examined 30 post-thrombectomy computed tomography scans selected from the Aspiration versus STEnt-Retriever (ASTER) trial. They were asked whether there was HT (yes/no), what the ECASS classification of the particular scan (0/HI1/HI2/PH1/PH2) (HI indicates hemorrhagic infarctions and PH indicates parenchymal hematomas) was and whether they would prescribe an antiplatelet agent if it was otherwise indicated. Agreement was measured with Fleiss' and Cohen's κ statistics. RESULTS: The systematic review yielded four studies involving few (≤3) raters with heterogeneous results. In our 18-rater study, agreement for the presence of HT was moderate [κ = 0.55; 95% confidence interval (CI), 0.41-0.68]. Agreement for ECASS classification was only fair for all five categories, but agreement improved to substantial (κ = 0.72; 95% CI, 0.69-0.75) after dichotomizing the ECASS classification into 0/HI1/HI2/PH1 versus PH2. The inter-rater agreement for the decision to reintroduce antiplatelet therapy was moderate for all raters, but substantial among vascular neurologists (κ = 0.70; 95% CI, 0.57-0.84). CONCLUSION: The ECASS classification may involve too many categories and the diagnosis of HT may not be easily replicable, except in the presence of a large parenchymal hematoma.

The effect of an education programme (MEDIAS 2 BSC) of non-intensive insulin treatment regimens for people with Type 2 diabetes: a randomized, multi-centre trial.

AIMS: A self-management oriented education programme (MEDIAS 2 BSC) for people with Type 2 diabetes who are on a non-intensive insulin treatment regimen was developed. In a randomized, multi-centre trial, the effect of MEDIAS 2 BSC was compared with an established education programme that acted as a control group. METHODS: The primary outcome was the impact of MEDIAS 2 BSC on glycaemic control. Secondary outcomes included the incidence of severe hypoglycaemia, hypoglycaemia unawareness, diabetes-related distress, diabetes knowledge, quality of life and self-care behaviour. RESULTS: In total, 182 participants were randomized to the control group or MEDIAS 2 BSC [median age 64.0 (interquartile range 58.0-68.5) vs. 63.5 (57.0-70.0) years; HbA1c 62.8 ± 12.7 mmol/mol vs. 63.7 ± 14.0 mmol/mol; 7.9% ± 1.2% vs. 8.0% ± 1.3%]. After a 6-month follow-up, there was a mean decrease in HbA1c of 3.5 mmol/mol (0.32%) in the control group and 6.7 mmol/mol (0.61%) in MEDIAS 2 BSC. After adjusting for baseline differences and study centre, the mean difference between the groups was -3.3 mmol/mol [95% confidence interval (CI) -0.54 to -5.90 mmol/mol] [-0.30% (95% CI -0.05 to -0.54)] in favour of MEDIAS 2 BSC (P = 0.018). There were no increases in severe hypoglycaemia or hypoglycaemia unawareness. The education programmes had no significant effects on psychosocial outcome variables. CONCLUSION: MEDIAS 2 BSC was more effective in lowering HbA1c than the control condition. MEDIAS 2 BSC is a safe educational tool that improves glycaemic control without increasing the risk for hypoglycaemia. (Clinical Trials Registry No; NCT 02748239).

Can a 15-sec FLAIR replace conventional FLAIR sequence in stroke MR protocols?

BACKGROUND AND PURPOSE: Triage imaging facilitates the timely recognition of acute stroke with prognostic implications. Improvement in MR acquisition speed is needed given the extreme time constraints before treatment. We compared an ultrafast Echo-Planar FLAIR sequence (EPI-FLAIR) and a conventional FLAIR sequence (cFLAIR) for their diagnostic performances and ability to estimate the age of infarction. MATERIAL AND METHODS: Between June and August 2014, 125 consecutive patients (age 69±18 years, 48% men) admitted for a suspicion of acute (≤48-hrs) stroke were explored by both FLAIR sequences at 1.5-Tesla. EPI-FLAIR (15-sec) and cFLAIR (2-min and 15-sec) were compared by two readers, blinded to clinical data. RESULTS: EPI-FLAIR was less prone to kinetic artefacts than cFLAIR (2-3% vs. 23-49% depending on the reader, P<0.001). Diagnostic concordance was excellent for both readers (к>0.9). Amongst 8 hemorrhages, one subarachnoid hemorrhage presenting as a sudden deficit was missed on EPI-FLAIR sequence. Amongst 60 infarctions, cFLAIR and EPI-FLAIR were concordant in 50 (83%), while signal changes were visible on cFLAIR only in the remaining 10 (17%) cases. Amongst the 43 patients with known onset time (n=17 within 4.5hrs), FLAIR-DWI mismatch identified<4.5-hrs infarction with the same sensitivity (65%) using cFLAIR and EPI-FLAIR, but the positive predictive value (PPV) was higher for cFLAIR than for EPI-FLAIR (73% vs. 50%, P=0.008). CONCLUSION: EPI-FLAIR allows a drastic reduction of acquisition time devoted to FLAIR sequence and minimizes motion artifacts. Compared with cFLAIR, it is however associated with increased risk of undiagnosed stroke mimics and lower PPV for identifying<4.5-hrs infarctions.

A Consensus German Reporting Standard for Secondary Data Analyses, Version 2 (STROSA-STandardisierte BerichtsROutine für SekundärdatenAnalysen).

Although secondary data analyses have been established in recent years in health research, explicit recommendations for standardized, transparent and complete reporting of secondary data analyses do not exist as yet. Therefore, between 2009 and 2014, a first proposal for a specific reporting standard for secondary data analysis was developed (STROSA 1). Parallel to this national process in Germany, an international reporting standard for routine data analysis was initiated in 2013 (RECORD). Nevertheless, because of the specific characteristics of the German health care system as well as specific data protection requirements, the need for a specific German reporting standard for secondary data analyses became evident. Therefore, STROSA was revised and tested by a task force of 15 experts from the working group Collection and Use of Secondary Data (AGENS) of the German Society for Social Medicine and Prevention (DGSMP) and the German Society for Epidemiology (DGEpi) as well as from the working group Validation and Linkage of Secondary Data of the German Network for Health Services Research (DNVF). The consensus STROSA-2 checklist includes 27 criteria, which should be met in the reporting of secondary data analysis from Germany. The criteria have been illustrated and clarified with specific explanations and examples of good practice. The STROSA reporting standard aims at stimulating a wider scientific discussion on the practicability and completeness of the checklist. After further discussions and possibly resulting modifications, STROSA shall be implemented as a reporting standard for secondary data analyses from Germany. This will guarantee standardized and complete information on secondary data analyses enabling assessment of their internal and external validity.

A patient with a hyperechoic band-shaped structure in the right hepatic vein.

Cement (polymethylmethacrylat) is frequently and increasingly used in vertebral surgery. Complications can occur by spillage of this material; however the vast majority of the patients remain free of symptoms and do not require any specific therapy.Internists, gastroenterologists and radiologists regularly performing abdominal ultrasound and computed tomography should be aware of this complication.A case of spillage of cement in the right hepatic vein is presented.

Contextual representations of negative images modulate intrusion frequency in an intrusion provocation paradigm.

BACKGROUND AND OBJECTIVES: To understand how memories of negative events become highly accessible in the context of trauma, we tested the hypothesis that contextual information modulates how easily intrusions can be provoked by perceptual stimuli.. METHODS: Healthy participants viewed pictures depicting trauma scenes either with or without accompanying moderate (i.e. survival, recovery) or severe (i.e. fatality, permanent injury) outcome information. All participants viewed the same depictions of trauma scenes. Involuntary memories for the pictures were assessed using self-report diaries and an adapted version of the Impact of Event Scales (IES). A blurred picture perceptual priming paradigm was adapted to be used as an intrusion provocation task. RESULTS: The severe outcome group experienced a significantly higher frequency of intrusions on the intrusion provocation task in comparison to both moderate outcome and control (no-context) conditions. The severe outcome condition did not increase intrusions on the self-report diaries or the adapted IES. There was no effect of condition on ratings for the emotionality, self-relevance, valence, or seriousness of the trauma scenes. LIMITATIONS: The analogue method should not be generalized directly to incidences of real-life trauma. It was unclear why differences in intrusion frequency were found in the provocation task only. The relative amount of individual conceptual and data-driven processing adopted by the participants was not assessed. CONCLUSIONS: Manipulating contextual information that determines the meaning of sensory-perceptual features for a trauma scene can modulate subsequent intrusion frequency in response to visually similar cues.

Point Shear Wave Elastography by Acoustic Radiation Force Impulse Quantification in Comparison to Transient Elastography for the Noninvasive Assessment of Liver Fibrosis in Chronic Hepatitis C: A Prospective International Multicenter Study.

PURPOSE: The aim of the present prospective European multicenter study was to demonstrate the non-inferiority of point shear wave elastography (pSWE) compared to transient elastography (TE) for the assessment of liver fibrosis in patients with chronic hepatitis C. MATERIALS AND METHODS: 241 patients with chronic hepatitis C were prospectively enrolled at 7 European study sites and received pSWE, TE and blood tests. Liver biopsy was performed with histological staging by a central pathologist. In addition, for inclusion of cirrhotic patients, a maximum of 10 % of patients with overt liver cirrhosis confirmed by imaging methods were allowed by protocol (n = 24). RESULTS: Owing to slower than expected recruitment due to a reduction of liver biopsies, the study was closed after 4 years before the target enrollment of 433 patients with 235 patients in the 'intention to diagnose' analysis and 182 patients in the 'per protocol' analysis. Therefore, the non-inferiority margin was enhanced to 0.075 but non-inferiority of pSWE could not be proven. However, Paired comparison of the diagnostic accuracy of pSWE and TE revealed no significant difference between the two methods in the 'intention to diagnose' and 'per protocol' analysis (0.81 vs. 0.85 for F ≥ 2, p = 0.15; 0.88 vs. 0.92 for F ≥ 3, p = 0.11; 0.89 vs. 0.94 for F = 4, p = 0.19). Measurement failure was significantly higher for TE than for pSWE (p = 0.030). CONCLUSION: Non-inferiority of pSWE compared to TE could not be shown. However, the diagnostic accuracy of pSWE and TE was comparable for the noninvasive staging of liver fibrosis in patients with chronic hepatitis C.

[Deterministic record linkage with indirect identifiers: data of the Berlin Myocardial Infarction Registry and the AOK Nordost for patients with myocardial infarction]. / Deterministisches Record Linkage mit indirekten Identifikatoren: Daten des Berliner Herzinfarktregisters und der AOK Nordost zum Herzinfarkt.

AIM OF THE STUDY: How can 2 pseudonymised data sets be linked? Using the example of data from the Berlin Myocardial Infarction Registry and from a German sickness fund (AOK Nordost) we will demonstrate how record linkage can be achieved without personal identifiers. METHODS: In different steps the method of deterministic record linkage with indirect identifiers: age, sex, hospital admission date and time, will be explained. RESULTS: We were able to show that 80.6% of the expected maximum number of patients were matched with our approach. As a result we had no duplicate matches in the linkage process, where one AOK patient was linked to 2 or more BMIR patients or vice versa. The matching variables produced enough uniqueness to be used as indirect patient identifiers. CONCLUSION: Deterministic record linkage with the following indirect indicators: age, sex, hospital admission date and time was possible in our study of patients with myocardial infarction in a circumscribed geographical region, which limited the number of cases and avoided mismatches.

[Good Practice of Secondary Data Analysis (GPS): guidelines and recommendations]. / Gute Praxis Sekundärdatenanalyse (GPS): Leitlinien und Empfehlungen.

In 2005, the Working Group for the Survey and Utilisation of Secondary Data (AGENS) of the German Society for Social Medicine and Prevention (DGSMP) and the German Society for Epidemiology (DGEpi) first published "Good Practice in Secondary Data Analysis (GPS)" formulating a standard for conducting secondary data analyses. GPS is intended as a guide for planning and conducting analyses and can provide a basis for contracts between data owners. The domain of these guidelines does not only include data routinely gathered by statutory health insurance funds and further statutory social insurance funds, but all forms of secondary data. The 11 guidelines range from ethical principles and study planning through quality assurance measures and data preparation to data privacy, contractual conditions and responsible communication of analytical results. They are complemented by explanations and practical assistance in the form of recommendations. GPS targets all persons directing their attention to secondary data, their analysis and interpretation from a scientific point of view and by employing scientific methods. This includes data owners. Furthermore, GPS is suitable to assess scientific publications regarding their quality by authors, referees and readers. In 2008, the first version of GPS was evaluated and revised by members of AGENS and the Epidemiological Methods Working Group of DGEpi, DGSMP and GMDS including other epidemiological experts and had then been accredited as implementation regulations of Good Epidemiological Practice (GEP). Since 2012, this third version of GPS is on hand and available for downloading from the DGEpi website at no charge. Especially linguistic specifications have been integrated into the current revision; its internal consistency was increased. With regards to contents, further recommendations concerning the guideline on data privacy have been added. On the basis of future developments in science and data privacy, further revisions will follow.

[Indicators of patient care in Psychiatric and Psychosomatic Facilities (VIPP project)--a database project]. / Versorgungsindikatoren in der Psychiatrie und Psychosomatik (VIPP)--Ein Datenbank-Projekt.

INTRODUCTION: In Germany a new and unique remuneration system for psychiatric and psychosomatic stationary treatments (PEPP system) was introduced in 2013 on an optional basis. From 2015 it will be mandatory for psychiatric and psychosomatic facilities. The introduction of the PEPP system brings up different questions regarding the possible incentives of the new remuneration system and its effects on the supply of psychiatric and psychosomatic treatments. To conduct these necessary analyses a reliable database is needed. MATERIAL AND METHODS: The goal of the project "Indicators of patient care in Psychiatric and Psychosomatic Facilities" (VIPP project) is to gather a representative database which reflects the situation of day-to-day patient care performed by German psychiatric and psychosomatic facilities. The §â€Š21 data set represents the basis of this database which will be complemented by other data sources (i. e., financial statements and other economic data). A number of more than 100 ,000 cases per year has already been exceeded. These case data were provided by a wide range of psychiatric hospitals, departments and universities that participate in this project. The dataset is anonymised and by pooling the data it is not possible to identify the cases of a specific clinic. Participants receive a web-based access and have the possibility to analyse the data independently. RESULTS: Using the examples of coding accuracy and rehospitalisation rates the variety as well as the enormous potential of this database can be demonstrated. DISCUSSION: On the base of the VIPP database valid patient care indicators can be identified and cross-sectional analyses can be conducted. From such results key data on health economic strategies can be derived and the incentives, strengths and limitations of this constantly changing system can be identified.

Electric-field-induced local structural phenomena in relaxor ferroelectric PbSc(0.5)Nb(0.5)O3 near the intermediate temperature T* studied by Raman spectroscopy.

Raman spectroscopy at different temperatures and under an external electric field E was applied to PbSc0.5Nb0.5O3 single crystals in order to gain further insights into the mesoscopic-scale coupling processes in perovskite-type (ABO3) relaxor ferroelectrics. Parallel and cross-polarized Raman spectra were collected between 800-80 K with E applied along the cubic [1 0 0], [1 1 0] or [1 1 1] crystallographic directions. The analysis was focused on the field-induced changes in the temperature evolution of three low-energy phonon modes: the Pb-localized mode near 50 cm(-1), the Pb-BO3 translation mode near 150 cm(-1), and the B-cation-localized mode near 250 cm(-1). The results show that competitive ferroelectric (FE) and antiferroelectric (AFE) coupling exists within the system of off-centred Pb(2+) cations, within the system of off-centred B-site cations as well as between off-centred Pb(2+) and B-site cations. The strong AFE-type coupling between Pb(2+) cations along the cubic body diagonal significantly influences the coupling between the B-site cations via the Pb-BO3 mode and results in AFE-type behaviour of the 'microscopic' T* determined from the B-cation-localized mode near 250 cm(-1), which explains the previously reported non-trivial field dependence of the 'macroscopic' characteristic temperatures: the temperature of the dielectric-permittivity maximum Tm, T*, and the Burns temperature TB. The comparative analysis between PbSc0.5Nb0.5O3 and PbSc0.5Ta0.5O3 indicates that two major displacive order parameters couple to form a relaxor state in B-site complex perovskites: the FE order associated with polar shifts of B-site cations and the AFE order associated with polar shifts of A-site cations. The latter penetrates through both polar and non-polar regions, but it is highly frustrated due to the high density of translation-symmetry faults in the chemical NaCl-type B-site order. The frustrated AFE order of off-centred A-site cations might be the key factor for the existence of a relaxor state.