FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia.

Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.

Patient and health provider costs of integrated HIV, diabetes and hypertension ambulatory health services in low-income settings - an empirical socio-economic cohort study in Tanzania and Uganda.

BACKGROUND: Integration of health services might be an efficient strategy for managing multiple chronic conditions in sub-Saharan Africa, considering the scope of treatments and synergies in service delivery. Proven to promote compliance, integration may lead to increased economies-of-scale. However, evidence on the socio-economic consequences of integration for providers and patients is lacking. We assessed the clinical resource use, staff time, relative service efficiency and overall societal costs associated with integrating HIV, diabetes and hypertension services in single one-stop clinics where persons with one or more of these conditions were managed. METHODS: 2273 participants living with HIV infection, diabetes, or hypertension or combinations of these conditions were enrolled in 10 primary health facilities in Tanzania and Uganda and followed-up for up to 12 months. We collected data on resources used from all participants and on out-of-pocket costs in a sub-sample of 1531 participants, while a facility-level costing study was conducted at each facility. Health worker time per participant was assessed in a time-motion morbidity-stratified study among 228 participants. The mean health service cost per month and out-of-pocket costs per participant visit were calculated in 2020 US$ prices. Nested bootstrapping from these samples accounted for uncertainties. A data envelopment approach was used to benchmark the efficiency of the integrated services. Last, we estimated the budgetary consequences of integration, based on prevalence-based projections until 2025, for both country populations. RESULTS: Their average retention after 1 year service follow-up was 1911/2273 (84.1%). Five hundred and eighty-two of 2273 (25.6%) participants had two or all three chronic conditions and 1691/2273 (74.4%) had a single condition. During the study, 84/2239 (3.8%) participants acquired a second or third condition. The mean service costs per month of managing two conditions in a single participant were $39.11 (95% CI 33.99, 44.33), $32.18 (95% CI 30.35, 34.07) and $22.65 (95% CI 21.86, 23.43) for the combinations of HIV and diabetes and of HIV and hypertension, diabetes and hypertension, respectively. These costs were 34.4% (95% CI 17.9%, 41.9%) lower as compared to managing any two conditions separately in two different participants. The cost of managing an individual with all three conditions was 48.8% (95% CI 42.1%, 55.3%) lower as compared to managing these conditions separately. Out-of-pocket healthcare expenditure per participant per visit was $7.33 (95% CI 3.70, 15.86). This constituted 23.4% (95% CI 9.9, 54.3) of the total monthly service expenditure per patient and 11.7% (95% CI 7.3, 22.1) of their individual total household income. The integrated clinics' mean efficiency benchmark score was 0.86 (range 0.30-1.00) suggesting undercapacity that could serve more participants without compromising quality of care. The estimated budgetary consequences of managing multi-morbidity in these types of integrated clinics is likely to increase by 21.5% (range 19.2-23.4%) in the next 5 years, including substantial savings of 21.6% on the provision of integrated care for vulnerable patients with multi-morbidities. CONCLUSION: Integration of HIV services with diabetes and hypertension control reduces both health service and household costs, substantially. It is likely an efficient and equitable way to address the increasing burden of financially vulnerable households among Africa's ageing populations. Additional economic evidence is needed from longer-term larger-scale implementation studies to compare extended integrated care packages directly simultaneously with evidence on sustained clinical outcomes.

[Weaning in a Pandemic Situation - A Position Paper]. / Weaning in der Situation einer Pandemie ­ Ein Positionspapier.

The logistical and infectious peculiarities and requirements challenge the intensive care treatment teams aiming at a successful liberation of patients from long-term mechanical ventilation. Especially in the pandemic, it is therefore important to use all potentials for weaning and decannulation, respectively, in patients with prolonged weaning.Weaning centers represent units of intensive medical care with a particular specialization in prolonged weaning. They are an integral part of a continuous care concept for these patients. A systematic weaning concept in the pandemic includes structural, personnel, equipment, infectiological and hygienic issues. In addition to the S2k guideline "Prolonged weaning" this position paper hightlights a new classification in prolonged weaning and organizational structures required in the future for the challenging pandemic situation. Category A patients with high weaning potential require a structured respiratory weaning in specialized weaning units, so as to get the greatest possible chance to realize successful weaning. Patients in category B with low or currently nonexistent weaning potential should receive a weaning attempt after an intermediate phase of further stabilization in an out-of-hospital ventilator unit. Category C patients with no weaning potential require a permanent out-of-hospital care, alternatively finishing mechanical ventilation with palliative support.Finally, under perspective in the position paper the following conceivable networks and registers in the future are presented: 1. locally organized regional networks of certified weaning centers, 2. a central, nationwide register of weaning capacities accordingly the already existing DIVI register and 3. registration of patients in difficult or prolonged weaning.

Predictors of receiving a diagnosis, referral and treatment of depression in people on antiretroviral therapy in South African primary care: a secondary analysis of data from a randomised trial.

OBJECTIVE: To describe the receipt of a diagnosis, referral and treatment for depression in people receiving antiretroviral therapy (ART), with depressive symptoms and attending primary care clinics in South Africa, and investigate factors associated with receiving these components of care. METHODS: This is a secondary analysis of data from a randomised controlled trial of an intervention intended to improve detection and treatment of depression in primary care patients receiving ART. In this analysis, we combined cross-sectional and longitudinal data from the intervention and control arms. Using regression models and adjusting for intra-cluster correlation of outcomes, we investigated associations between socioeconomic characteristics, depressive symptoms, stress, disability and stigma, and receipt of a diagnosis, referral and treatment for depression. RESULTS: Of 2002 participants enrolled, 18% reported a previous diagnosis of depression by a healthcare worker and 10% reported having received counselling from a specialist mental health worker. Diagnosis, referral and counselling during the follow-up period were appropriately targeted, being independently more frequent in participants with higher enrolment scores for depressive symptoms, stress or disability. Participants with higher stigma scores at enrolment were independently less likely to receive counselling. Severe socio-economic deprivation was common but was not associated with treatment. CONCLUSION: While the receipt of a diagnosis, referral and treatment for depression were uncommon, they seemed to be appropriately targeted. Socio-economic deprivation was not associated with treatment.

OBJECTIF: Décrire la réception d'un diagnostic, de l'orientation et du traitement pour la dépression chez les personnes recevant un traitement antirétroviral (ART), présentant des symptômes dépressifs et fréquentant des cliniques de soins primaires en Afrique du Sud, et étudier les facteurs associés à la réception de ces éléments de soins. MÉTHODES: Il s'agit ici d'une analyse secondaire des données d'un essai contrôlé randomisé d'une intervention destinée à améliorer la détection et le traitement de la dépression chez les patients sous ART dans les soins primaires. Dans cette analyse, nous avons combiné les données transversales et longitudinales des bras d'intervention et témoin. En utilisant des modèles de régression et en ajustant la corrélation intra-grappes des résultats, nous avons étudié les associations entre les caractéristiques sociodémographiques, les symptômes dépressifs, le stress, l'invalidité et la stigmatisation, et la réception d'un diagnostic, d'une orientation et d'un traitement pour la dépression. RÉSULTATS: Sur 2.002 participants inscrits, 18% ont déclaré un diagnostic antérieur de dépression par un agent de santé et 10% ont déclaré avoir reçu des conseils d'un agent spécialisé pour la santé mentale. Le diagnostic, l'orientation et le conseil pendant la période de suivi ont été ciblés de manière appropriée, étant indépendamment plus fréquents chez les participants ayant des scores d'inscription plus élevés pour les symptômes dépressifs, le stress ou l'invalidité. Les participants ayant des scores de stigmatisation plus élevés à l'inscription étaient indépendamment moins susceptibles de recevoir des conseils. La privation socioéconomique sévère était courante mais n'était pas associée au traitement. CONCLUSION: Bien que la réception d'un diagnostic, l'orientation et le traitement de la dépression soient rares, ils semblaient bien ciblés. La privation socioéconomique n'était pas associée au traitement.

[Responsibilities of Weaning Centers during the COVID-19 Pandemic Outbreak - Recommendations for the Assignment of ICU Capacities in COVID-19 Patients as shown by the Berlin-Brandenburg POST-SAVE-Model]. / Aufgaben der Weaning-Zentren im Pandemiefall COVID-19.

The enormous increase in patients with severe respiratory distress due to the COVID-19 pandemic outbreak requires a systematic approach to optimize ventilated patient at risk flow. A standardised algorithm called "SAVE" was developed to distribute patients with COVID-19 respiratory distress syndrome requiring invasive ventilation. This program is established by now in Berlin. An instrumental bottleneck of this approach is the vacant slot assignment in the intensive care unit to guarantee constant patient flow. The transfer of the patients after acute care treatment is needed urgently to facilitate the weaning process. In a next step we developed a triage algorithm to identify patients at SAVE intensive care units with potential to wean and transfer to weaning institutions - we called POST SAVE. This manuscript highlights the algorithms including the use of a standardised digital evaluation tool, the use of trained navigators to facilitate the communication between SAVE intensive care units and weaning institutions and the establishment of a prospective data registry for patient assignment and reevaluation of the weaning potential in the future.

[Nocardiosis as a Differential Diagnosis of Pulmonary Epitheloid Cell Granulomas]. / Nokardiose als Differenzialdiagnose pulmonaler epitheloidzelliger Granulome.

A 47-year-old man presented with fever, weight loss and pulmonary consolidations and cavitation in the x-ray of the thorax. The comprehensive diagnostics resulted pulmonary epitholoid cell granulomas, therefore an immunosuppressive therapy was applied on suspicion of sarcoidosis. Progressivly the pulmonary infiltration increased and cerebral and abdominal abscesses were determined with microbiological detection of Nocardia farcinica. Despite antibiotic therapy, the patient died in a septic shock with multiple organ failure.Nocardiosis is a rare granulomatous bacterial infectious disease. Risk factors include immunosuppression and structural lung diseases. Characteristic is an abscess formation that can occur in any organ, while pulmonary onset is common.The case demonstrates the importance of considering rare differential diagnoses in the detection of pulmonary epithelioid granulomas.

Modification of the equine gastrointestinal microbiota by Jerusalem artichoke meal supplementation.

The objective of this study was to investigate the impact of natural prebiotic active compounds on the microbial composition in different regions of the equine gastrointestinal tract. Twelve adult horses (body weight [bwt] 534 ± 64.5 kg; age 14 ± 7.5 years) were randomly divided into two feeding groups. Six horses received a basal diet consisting of 1.5 kg hay/100 kg bwt x d-1 and oat grains equal to 1.19 g starch/kg bwt x d-1, supplemented with Jerusalem artichoke meal providing prebiotic fructooligosaccharides + inulin in a quantity of 0.15 g/kg bwt x d-1. The remaining horses received a placebo added to the basal diet. The horses were fed for 21 d and euthanized at the end of the feeding period. Digesta samples from different parts of the gastrointestinal tract were taken, DNA extracted and the V1-V2 region of the 16S rRNA gene amplified. Supplementation with the prebiotic increased the relative abundance of Lactobacillus (P < 0.05), with a concurrent reduction of the relative abundance of Streptococcus mainly in the stomach (P < 0.05). In the hindgut, the supplemental prebiotic also increased the relative abundance of Lactobacillus but further reduced the relative abundance of fibrolytic bacteria, specifically the unclassified members of the families Lachnospiraceae (P < 0.05) and Ruminococcaceae. The relative abundance of the genus Ruminococcus increased solely in the caecum and colon transversum. Overall, the addition of the prebiotic significantly increased the diversity in nearly all parts of the gastrointestinal tract (P < 0.05). The feeding of this natural prebiotic compound to horses had an impact on the microbial community in the entire gastrointestinal tract. Furthermore, the effect on the bacterial community in the foregut (especially the stomach) was more pronounced in comparison to the effect in the hindgut. Therefore, the impact on stomach health should be carefully considered.

Determinants of diagnostic discordance for non-diabetic hyperglycaemia and Type 2 diabetes using paired glycated haemoglobin measurements in a large English primary care population: cross-sectional study.

AIM: To investigate factors influencing diagnostic discordance for non-diabetic hyperglycaemia and Type 2 diabetes. METHODS: Some 10 000 adults at increased risk of diabetes were screened with HbA1c and fasting plasma glucose (FPG). The 2208 participants with initial HbA1c ≥ 42 mmol/mol (≥ 6.0%) or FPG ≥ 6.1 mmol/l were retested after a median 40 days. We compared the first and second HbA1c results, and consequent diagnoses of non-diabetic hyperglycaemia and Type 2 diabetes, and investigated predictors of discordant diagnoses. RESULTS: Of 1463 participants with non-diabetic hyperglycaemia and 394 with Type 2 diabetes on first testing, 28.4% and 21.1% respectively had discordant diagnoses on repeated testing. Initial diagnosis of non-diabetic hyperglycaemia and/or impaired fasting glucose according to both HbA1c and FPG criteria, or to FPG only, made reclassification as Type 2 diabetes more likely than initial classification according to HbA1c alone. Initial diagnosis of Type 2 diabetes according to both HbA1c and FPG criteria made reclassification much less likely than initial classification according to HbA1c alone. Age, and anthropometric and biological measurements independently but inconsistently predicted discordant diagnoses and changes in HbA1c . CONCLUSIONS: Diagnosis of non-diabetic hyperglycaemia or Type 2 diabetes with a single measurement of HbA1c in a screening programme for entry to diabetes prevention trials is unreliable. Diagnosis of non-diabetic hyperglycaemia and Type 2 diabetes should be confirmed by repeat testing. FPG results could help prioritise retesting. These findings do not apply to people classified as normal on a single test, who were not retested.

Socioeconomic position and depression in South African adults with long-term health conditions: a longitudinal study of causal pathways.

AIMS: There is convincing evidence that lower socioeconomic position is associated with increased risk of mental disorders. However, the mechanisms involved are not well understood. This study aims to elucidate the causal pathways between socioeconomic position and depression symptoms in South African adults. Two possible causal theories are examined: social causation, which suggests that poor socioeconomic conditions cause mental ill health; and social drift, which suggests that those with poor mental health are more likely to drift into poor socioeconomic circumstances. METHODS: The study used longitudinal and cross-sectional observational data on 3904 adults, from a randomised trial carried out in 38 primary health care clinics between 2011 and 2012. Structural equation models and counterfactual mediation analyses were used to examine causal pathways in two directions. First, we examined social causation pathways, with language (a proxy for racial or ethnic category) being treated as an exposure, while education, unemployment, income and depression were treated as sequential mediators and outcomes. Second, social drift was explored with depression treated as a potential influence on health-related quality of life, job loss and, finally, income. RESULTS: The results suggest that the effects of language on depression at baseline, and on changes in depression during follow-up, were mediated through education and income but not through unemployment. Adverse effects of unemployment and job loss on depression appeared to be mostly mediated through income. The effect of depression on decreasing income appeared to be mediated by job loss. CONCLUSIONS: These results suggest that both social causation and social selection processes operate concurrently. This raises the possibility that people could get trapped in a vicious cycle in which poor socioeconomic conditions lead to depression, which, in turn, can cause further damage to their economic prospects. This study also suggests that modifiable factors such as income, employment and treatable depression are suitable targets for intervention in the short to medium term, while in the longer term reducing inequalities in education will be necessary to address the deeply entrenched inequalities in South Africa.

Electrical impedance tomography in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a clinical entity that acutely affects the lung parenchyma, and is characterized by diffuse alveolar damage and increased pulmonary vascular permeability. Currently, computed tomography (CT) is commonly used for classifying and prognosticating ARDS. However, performing this examination in critically ill patients is complex, due to the need to transfer these patients to the CT room. Fortunately, new technologies have been developed that allow the monitoring of patients at the bedside. Electrical impedance tomography (EIT) is a monitoring tool that allows one to evaluate at the bedside the distribution of pulmonary ventilation continuously, in real time, and which has proven to be useful in optimizing mechanical ventilation parameters in critically ill patients. Several clinical applications of EIT have been developed during the last years and the technique has been generating increasing interest among researchers. However, among clinicians, there is still a lack of knowledge regarding the technical principles of EIT and potential applications in ARDS patients. The aim of this review is to present the characteristics, technical concepts, and clinical applications of EIT, which may allow better monitoring of lung function during ARDS.

Adsorption of flexible polymer chains on a surface: Effects of different solvent conditions.

Polymer chains undergoing a continuous adsorption-desorption transition are studied through extensive computer simulations. A three-dimensional self-avoiding walk lattice model of a polymer chain grafted onto a surface has been treated for different solvent conditions. We have used an advanced contact-density chain-growth algorithm, in which the density of contacts can be directly obtained. From this quantity, the order parameter and its fourth-order Binder cumulant are computed, as well as the corresponding critical exponents and the adsorption-desorption transition temperature. As the number of configurations with a given number of surface contacts and monomer-monomer contacts is independent of the temperature and solvent conditions, it can be easily applied to get results for different solvent parameter values without the need of any extra simulations. In analogy to continuous magnetic phase transitions, finite-size-scaling methods have been employed. Quite good results for the critical properties and phase diagram of very long single polymer chains have been obtained by properly taking into account the effects of corrections to scaling. The study covers all solvent effects, going from the limit of super-self-avoiding walks, characterized by effective monomer-monomer repulsion, to poor solvent conditions that enable the formation of compact polymer structures.

Allergens displayed on virus-like particles are highly immunogenic but fail to activate human mast cells.

BACKGROUND: The goal of allergen-specific immunotherapy is the induction of protective immune responses in the absence of anaphylactic reactions. We have previously shown that Fel d 1, the major cat allergen, displayed in a repetitive fashion on virus-like particles (VLPs) may fulfill these criteria. Specifically, Fel d 1 on VLPs induced strongly increased protective IgG responses compared to free allergen in mice while anaphylactic reactions were essentially abolished. Here we extend these findings to human mast cells and offer a mechanistic explanation for the reduced anaphylactic activity. METHODS: We differentiated human mast cells in vitro from blood-derived stem cell progenitors and sensitized the cells with a monoclonal Fel d 1-specific IgE. We compared the capability of Fel d 1 to induce mast cell activation in its free form versus displayed on VLPs and we performed allergen binding studies by surface plasmon resonance as well as flow cytometry. RESULTS: We show that free Fel d 1 induces degranulation of IgE-sensitized mast cells whereas Fel d 1 displayed on VLPs fails to induce mast cell activation. We demonstrate that this inability to activate mast cells is based on a biophysical as well as a biochemical mechanism. Firstly, Fel d 1 on VLPs showed a strongly impaired ability to bind to surface-bound IgE. Secondly, despite residual binding, repetitively displayed allergen on VLPs failed to cause mast cell activation. CONCLUSION: These findings indicate that repetitively displaying allergens on VLPs increases their immunogenicity while reducing their potential to cause anaphylactic reactions by essentially eliminating IgE-mediated activation of mast cells.

Electronic in-plane symmetry breaking at field-tuned quantum criticality in CeRhIn5.

Electronic nematic materials are characterized by a lowered symmetry of the electronic system compared to the underlying lattice, in analogy to the directional alignment without translational order in nematic liquid crystals. Such nematic phases appear in the copper- and iron-based high-temperature superconductors, and their role in establishing superconductivity remains an open question. Nematicity may take an active part, cooperating or competing with superconductivity, or may appear accidentally in such systems. Here we present experimental evidence for a phase of fluctuating nematic character in a heavy-fermion superconductor, CeRhIn5 (ref. 5). We observe a magnetic-field-induced state in the vicinity of a field-tuned antiferromagnetic quantum critical point at Hc ≈ 50 tesla. This phase appears above an out-of-plane critical field H* ≈ 28 tesla and is characterized by a substantial in-plane resistivity anisotropy in the presence of a small in-plane field component. The in-plane symmetry breaking has little apparent connection to the underlying lattice, as evidenced by the small magnitude of the magnetostriction anomaly at H*. Furthermore, no anomalies appear in the magnetic torque, suggesting the absence of metamagnetism in this field range. The appearance of nematic behaviour in a prototypical heavy-fermion superconductor highlights the interrelation of nematicity and unconventional superconductivity, suggesting nematicity to be common among correlated materials.

Allergen-specific immunotherapy: is it vaccination against toxins after all?

IgE-mediated allergies, in particular allergic rhinoconjunctivitis and asthma, have reached epidemic proportions, affecting about one-third of the population in developed countries. The most effective treatment for allergies is specific immunotherapy (SIT), which involves the injection of increasing doses of an allergen extract to allergic individuals. The current form of SIT was first introduced in 1911 and recently celebrated its 100th birthday for the treatment of hay fever. The concept of this therapy at the time was straightforward, as it was believed that pollen contained toxins against which the patient could be vaccinated. However, the understanding became blurred with the discovery that IgE antibodies were the effector molecules of the allergic response. Subsequent research focused on the idea that SIT should induce tolerance keeping the IgE antibodies at bay. In this review, we will discuss the various hypotheses for the mechanism of SIT and we will put forward the concept that allergens may be viewed as 'protoxins' which need to be activated by IgE antibodies. Within this framework, protoxin-neutralizing antibodies are the key effector molecules while a shift to Th1 or Treg cells mainly contributes to the efficacy of SIT by helping B cells to produce neutralizing IgG antibodies.