Diversity of intratumoral regulatory T cells in B-cell non-Hodgkin lymphoma.

Tumor-infiltrating regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. Despite extensive studies, the prognostic impact of tumor-infiltrating Tregs in B-cell non-Hodgkin lymphomas (B-NHLs) remains unclear. Emerging studies suggest substantial heterogeneity in the phenotypes and suppressive capacities of Tregs, emphasizing the importance of understanding Treg diversity and the need for additional markers to identify highly suppressive Tregs. Here, we applied single-cell RNA sequencing and T-cell receptor sequencing combined with high-dimensional cytometry to decipher the heterogeneity of intratumoral Tregs in diffuse large B-cell lymphoma and follicular lymphoma (FL), compared with that in nonmalignant tonsillar tissue. We identified 3 distinct transcriptional states of Tregs: resting, activated, and unconventional LAG3+FOXP3- Tregs. Activated Tregs were enriched in B-NHL tumors, coexpressed several checkpoint receptors, and had stronger immunosuppressive activity compared with resting Tregs. In FL, activated Tregs were found in closer proximity to CD4+ and CD8+ T cells than other cell types. Furthermore, we used a computational approach to develop unique gene signature matrices, which were used to enumerate each Treg subset in cohorts with bulk gene expression data. In 2 independent FL cohorts, activated Tregs was the major subset, and high abundance was associated with adverse outcome. This study demonstrates that Tregs infiltrating B-NHL tumors are transcriptionally and functionally diverse. Highly immunosuppressive activated Tregs were enriched in tumor tissue but absent in the peripheral blood. Our data suggest that a deeper understanding of Treg heterogeneity in B-NHL could open new paths for rational drug design, facilitating selective targeting to improve antitumor immunity.

Prevalent and immunodominant CD8 T cell epitopes are conserved in SARS-CoV-2 variants.

The emergence of SARS-CoV-2 variants of concern (VOC) is driven by mutations that mediate escape from neutralizing antibodies. There is also evidence that mutations can cause loss of T cell epitopes. However, studies on viral escape from T cell immunity have been hampered by uncertain estimates of epitope prevalence. Here, we map and quantify CD8 T cell responses to SARS-CoV-2-specific minimal epitopes in blood drawn from April to June 2020 from 83 COVID-19 convalescents. Among 37 HLA ligands eluted from five prevalent alleles and an additional 86 predicted binders, we identify 29 epitopes with an immunoprevalence ranging from 3% to 100% among individuals expressing the relevant HLA allele. Mutations in VOC are reported in 10.3% of the epitopes, while 20.6% of the non-immunogenic peptides are mutated in VOC. The nine most prevalent epitopes are conserved in VOC. Thus, comprehensive mapping of epitope prevalence does not provide evidence that mutations in VOC are driven by escape of T cell immunity.

Rituximab-treated patients with lymphoma develop strong CD8 T-cell responses following COVID-19 vaccination.

B-cell depletion induced by anti-cluster of differentiation 20 (CD20) monoclonal antibody (mAb) therapy of patients with lymphoma is expected to impair humoral responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination, but effects on CD8 T-cell responses are unknown. Here, we investigated humoral and CD8 T-cell responses following two vaccinations in patients with lymphoma undergoing anti-CD20-mAb therapy as single agent or in combination with chemotherapy or other anti-neoplastic agents during the last 9 months prior to inclusion, and in healthy age-matched blood donors. Antibody measurements showed that seven of 110 patients had antibodies to the receptor-binding domain of the SARS-CoV-2 Spike protein 3-6 weeks after the second dose of vaccination. Peripheral blood CD8 T-cell responses against prevalent human leucocyte antigen (HLA) class I SARS-CoV-2 epitopes were determined by peptide-HLA multimer analysis. Strong CD8 T-cell responses were observed in samples from 20/29 patients (69%) and 12/16 (75%) controls, with similar median response magnitudes in the groups and some of the strongest responses observed in patients. We conclude that despite the absence of humoral immune responses in fully SARS-CoV-2-vaccinated, anti-CD20-treated patients with lymphoma, their CD8 T-cell responses reach similar frequencies and magnitudes as for controls. Patients with lymphoma on B-cell depleting therapies are thus likely to benefit from current coronavirus disease 2019 (COVID-19) vaccines, and development of vaccines aimed at eliciting T-cell responses to non-Spike epitopes might provide improved protection.

Faster speed of onset of the depressive episode is associated with lower cytokine serum levels (IL-2, -4, -6, -10, TNF-α and IFN-γ) in patients with major depression.

INTRODUCTION: Cytokines might play a key role in the pathophysiology of major depressive disorder (MDD). The speed of onset of depressive episodes has been discussed as an important clinical parameter in MDD. The aim of this study was to investigate a potential influence of the speed of onset of the depressive episode on cytokine serum levels. METHOD: Serum level of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ) granulocyte and monocyte colony stimulating factor (GM-CSF) were measured in a total of 92 patients with MDD that did not respond to at least one previous antidepressant treatment. Patients were retrospectively divided in two groups: Faster (≤4 weeks) and slower (>4 weeks) onset of the depressive episode defined as the time passing from the first depressive symptoms to a full-blown depressive episode by using information from a clinical interview. RESULTS: We found significantly lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with a faster onset compared to patients with a slower onset of the depressive episodes. Furthermore, lower cytokine serum levels of IL-2, IL-8, IL-10 and IFN-γ were found in patients with a shorter duration (less than 6 months) compared to a longer duration (6-24 months) of the current depressive episode. This effect on cytokines was independent from the effect of the speed of onset of the depressive episode. CONCLUSIONS: Patients with faster onset of the depressive episode might represent a biological subtype of MDD with lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ.

Extended plasma half-life of albumin-binding domain fused human IgA upon pH-dependent albumin engagement of human FcRn in vitro and in vivo.

Albumin has a serum half-life of 3 weeks in humans. This feature can be used to improve the pharmacokinetics of shorter-lived biologics. For instance, an albumin-binding domain (ABD) can be used to recruit albumin. A prerequisite for such design is that the ABD-albumin interaction does not interfere with pH-dependent binding of albumin to the human neonatal Fc receptor (FcRn), as FcRn acts as the principal regulator of the half-life of albumin. Thus, there is a need to know how ABDs act in the context of fusion partners and human FcRn. Here, we studied the binding and transport properties of human immunoglobulin A1 (IgA1), fused to a Streptococcus protein G-derived engineered ABD, in in vitro and in vivo systems harboring human FcRn. IgA has great potential as a therapeutic protein, but its short half-life is a major drawback. We demonstrate that ABD-fused IgA1 binds human FcRn pH-dependently and is rescued from cellular degradation in a receptor-specific manner in the presence of albumin. This occurs when ABD is fused to either the light or the heavy chain. In human FcRn transgenic mice, IgA1-ABD in complex with human albumin, gave 4-6-fold extended half-life compared to unmodified IgA1, where the light chain fusion showed the longest half-life. When the heavy chain-fused protein was pre-incubated with an engineered human albumin with improved FcRn binding, cellular rescue and half-life was further enhanced. Our study reveals how an ABD, which does not interfere with albumin binding to human FcRn, may be used to extend the half-life of IgA.Abbreviations: ABD - Albumin binding domain, ADA - anti-drug-antibodies, ADCC - Antibody-dependent cellular cytotoxicity, ELISA - Enzyme-linked Immunosorbent assay, FcαRI - Fcα receptor, FcγR - Fcγ receptor, FcRn - The neonatal Fc receptor, GST - Glutathione S-transferase, HC - Heavy chain, HERA - Human endothelial cell-based recycling assay, Her2 - Human epidermal growth factor 2, HMEC - Human microvascular endothelial cells, IgG - Immunoglobulin G, IgA - Immunoglobulin A, LC - Light chain, QMP - E505Q/T527M/K573P, WT - Wild type.

Novel chimerized IgA CD20 antibodies: Improving neutrophil activation against CD20-positive malignancies.

Current combination therapies elicit high response rates in B cell malignancies, often using CD20 antibodies as the backbone of therapy. However, many patients eventually relapse or develop progressive disease. Therefore, novel CD20 antibodies combining multiple effector mechanisms were generated. To study whether neutrophil-mediated destruction of B cell malignancies can be added to the arsenal of effector mechanisms, we chimerized a panel of five previously described murine CD20 antibodies to the human IgG1, IgA1 and IgA2 isotype. Of this panel, we assessed in vitro antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and direct cell death induction capacity and studied the efficacy in two different in vivo mouse models. IgA antibodies outperformed IgG1 antibodies in neutrophil-mediated killing in vitro, both against CD20-expressing cell lines and primary patient material. In these assays, we observed loss of CD19 with both IgA and IgG antibodies. Therefore, we established a novel method to improve the assessment of B-cell depletion by CD20 antibodies by including CD24 as a stable cell marker. Subsequently, we demonstrated that only IgA antibodies were able to reduce B cell numbers in this context. Additionally, IgA antibodies showed efficacy in both an intraperitoneal tumor model with EL4 cells expressing huCD20 and in an adoptive transfer model with huCD20-expressing B cells. Taken together, we show that IgA, like IgG, can induce ADCC and CDC, but additionally triggers neutrophils to kill (malignant) B cells. We conclude that antibodies of the IgA isotype offer an attractive repertoire of effector mechanisms for the treatment of CD20-expressing malignancies.

New insights in Type I and II CD20 antibody mechanisms-of-action with a panel of novel CD20 antibodies.

Based on their mechanisms-of-action, CD20 monoclonal antibodies (mAbs) are grouped into Type I [complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)] and Type II [programmed cell death (PCD) and ADCC] mAbs. We generated 17 new hybridomas producing CD20 mAbs of different isotypes and determined unique heavy and light chain sequence pairs for 13 of them. We studied their epitope binding, binding kinetics and structural properties and investigated their predictive value for effector functions, i.e. PCD, CDC and ADCC. Peptide mapping and CD20 mutant screens revealed that 10 out of these 11 new mAbs have an overlapping epitope with the prototypic Type I mAb rituximab, albeit that distinct amino acids of the CD20 molecule contributed differently. Binding kinetics did not correlate with the striking differences in CDC activity among the mIgG2c mAbs. Interestingly, chimerization of mAb m1 resulted in a mAb displaying both Type I and II characteristics. PCD induction was lost upon introduction of a mutation in the framework of the heavy chain affecting the elbow angle, supporting that structural changes within this region can affect functional activities of CD20 mAbs. Together, these new CD20 mAbs provide further insights in the properties dictating the functional efficacy of CD20 mAbs.

[Users of regional dementia care networks in Germany : First results of the evaluation study DemNet-D]. / Nutzer und Nutzerinnen regionaler Demenznetzwerke in Deutschland : Erste Ergebnisse der Evaluationsstudie DemNet-D.

BACKGROUND: In Germany a growing number of community-based support services for people with dementia (PwD) and their caregivers are organized in dementia care networks (DCN), which provide a single point of entry to social facilities and offer personal care and support. OBJECTIVE: The aim of this study was to describe the health, functional and social characteristics of PwDs enrolled in DCNs throughout Germany because no data are currently available on this aspect. MATERIAL AND METHODS: As part of the multi-center, multi-professional 12-month follow-up study DemNet-D, data on functional and psychological health, sociodemographic and dementia-specific factors and social inclusion were collected in standardized interviews with PwDs living at home. RESULTS: A total of 560 PwDs with an average age of 80 years were enrolled in the study. Of the participants approximately 50 % had Alzheimer's dementia and more than 75 % demonstrated at least a challenging form of behavior. More than half of the participants lived together with a partner or relative. Instrumental activities of daily living (IADLs) were very limited; nevertheless, one in five PwDs showed no long-term care-dependency level. The participants reported having a relatively low feeling of loneliness and a high feeling of social inclusion, depending on the severity of dementia. CONCLUSION: This is one of the very first studies generating data on PwDs who receive domiciliary care within DCNs in Germany. The results suggest that the regional DCNs make a successful contribution to overcoming the interface problem and can, therefore, contribute to a more stable care situation and better social integration of PwDs.

[Regional Dementia Care Networks in Germany--results from the DemNet-D-Study regarding the quality of life of their users]. / Regionale Demenznetzwerke in Deutschland. Ergebnisse der DemNet-D-Studie zur Lebensqualität der Nutzer(innen).

BACKGROUND: Regional dementia care networks become more and more important in the care for community-dwelling persons with dementia (PwD). However, the quality of life of PwD, served by dementia care networks, has not been investigated yet. It also remains unclear if there are differences between urban and rural dementia care networks. This study therefore aims at investigating the quality of life of PwD using this care model, also regarding possible regional differences. METHODS: Within the DemNet-D-Study, PwD and their primary caregivers were interviewed using typical outcome parameters (quality of life: QoL-AD, depression: GDS, challenging behaviour: CMAI, capacities of daily living: IADL, caregiver burden: BIZA-D). In addition to these parameters, regional differences were analysed using multi-level-analysis. RESULTS: In total, 560 PwD (79.7 years; 57.0 % female) and their caregivers participated in the study. Both self- and proxy-rated quality of life is on a moderate level. The analysis shows a sufficient explanation of the quality of life. (self: p<0.001, R2=0.493; proxy: p<0.001, R2=0.406). Higher quality of life was found for PwD living together with their care givers and for those PwD with higher capacities of daily living. Regional (urban vs. rural) differences could not be found. CONCLUSION: The quality of life of community-dwelling PwD using regional dementia care networks is comparable to those in other studies of outpatient dementia care. Further investigation should be carried out regarding different types of dementia care networks.

A comparison of anti-HER2 IgA and IgG1 in vivo efficacy is facilitated by high N-glycan sialylation of the IgA.

Monomeric IgA has been proposed as an alternative antibody format for cancer therapy. Here, we present our studies on the production, purification and functional evaluation of anti-HER2 IgA antibodies as anti-cancer agents in comparison to the anti-HER2 IgG1 trastuzumab. MALDI-TOF MS analysis showed profound differences in glycosylation traits across the IgA isotypes and cell lines used for production, including sialylation and linkage thereof, fucosylation (both core and antennary) and the abundance of high-mannose type species. Increases in sialylation proved to positively correlate with in vivo plasma half-lives. The polymerization propensity of anti-HER2 IgA2m2 could be suppressed by an 18-aa deletion of the heavy chain tailpiece - coinciding with the loss of high-mannose type N-glycan species - as well as by 2 cysteine to serine mutations at positions 320 and 480. The HER2 F(ab')2-mediated anti-proliferative effect of the IgA2m1 and IgA2m2 subtypes was similar to IgG1, whereas the IgA1 isotype displayed considerably lower potency and efficacy. The Fc-mediated induction of antibody-dependent cell-mediated cytotoxicity (ADCC) using human whole blood ADCC assays did not demonstrate such clear differences between the IgA isotypes. However, the potency of the anti-HER2 IgA antibodies in these ADCC assays was found to be significantly lower than that of trastuzumab. In vivo anti-tumor activity of the anti-HER2 IgA antibodies was compared to that of trastuzumab in a BT-474 breast cancer xenograft model. Multiple dosing and sialylation of the IgA antibodies compensated for the short in vivo half-life of native IgA antibodies in mice compared to a single dose of IgG1. In the case of the IgA2m2 antibody, the resulting high plasma exposure levels were sufficient to cause clear tumor stasis comparable to that observed for trastuzumab at much lower plasma exposure levels.

An Anti-EGFR IgA That Displays Improved Pharmacokinetics and Myeloid Effector Cell Engagement In Vivo.

Antibodies of IgA isotype effectively engage myeloid effector cells for cancer immunotherapy. Here, we describe preclinical studies with an Fc engineered IgA2m(1) antibody containing the variable regions of the EGFR antibody cetuximab. Compared with wild-type IgA2m(1), the engineered molecule lacked two N-glycosylation sites (N166 and N337), two free cysteines (C311 and C472), and contained a stabilized heavy and light chain linkage (P221R mutation). This novel molecule displayed improved production rates and biochemical properties compared with wild-type IgA. In vitro, Fab- and Fc-mediated effector functions, such as inhibition of ligand binding, receptor modulation, and engagement of myeloid effector cells for antibody-dependent cell-mediated cytotoxicity, were similar between wild-type and engineered IgA2. The engineered antibody displayed lower levels of terminal galactosylation leading to reduced asialoglycoprotein-receptor binding and to improved pharmacokinetic properties. In a long-term in vivo model against EGFR-positive cancer cells, improved serum half-life translated into higher efficacy of the engineered molecule, which required myeloid cells expressing human FcαRI for its full efficacy. However, Fab-mediated effector functions contributed to the in vivo efficacy because the novel IgA antibody demonstrated therapeutic activity also in non-FcαRI transgenic mice. Together, these results demonstrate that engineering of an IgA antibody can significantly improve its pharmacokinetics and its therapeutic efficacy to inhibit tumor growth in vivo.

Improved in vivo anti-tumor effects of IgA-Her2 antibodies through half-life extension and serum exposure enhancement by FcRn targeting.

Antibody therapy is a validated treatment approach for several malignancies. All currently clinically applied therapeutic antibodies (Abs) are of the IgG isotype. However, not all patients respond to this therapy and relapses can occur. IgA represents an alternative isotype for antibody therapy that engages FcαRI expressing myeloid effector cells, such as neutrophils and monocytes. IgA Abs have been shown to effectively kill tumor cells both in vitro and in vivo. However, due to the short half-life of IgA Abs in mice, daily injections are required to reach an effect comparable to IgG Abs. The relatively long half-life of IgG Abs and serum albumin arises from their capability of interacting with the neonatal Fc receptor (FcRn). As IgA Abs lack a binding site for FcRn, we generated IgA Abs with the variable regions of the Her2-specific Ab trastuzumab and attached an albumin-binding domain (ABD) to the heavy or light chain (HCABD/LCABD) to extend their serum half-life. These modified Abs were able to bind albumin from different species in vitro. Furthermore, tumor cell lysis of IgA-Her2-LCABD Abs in vitro was similar to unmodified IgA-Her2 Abs. Pharmacokinetic studies in mice revealed that the serum exposure and half-life of the modified IgA-Her2 Abs was extended. In a xenograft mouse model, the modified IgA1 Abs exhibited a slightly, but significantly, improved anti-tumor response compared to the unmodified Ab. In conclusion, empowering IgA Abs with albumin-binding capacity results in in vitro and in vivo functional Abs with an enhanced exposure and prolonged half-life.

Fc receptor inside-out signaling and possible impact on antibody therapy.

Fc receptors (FcR) are expressed on immune cells and bind to the Fc tail of antibodies. This interaction is essential for FcR-mediated signaling and triggering of cellular effector functions. FcR activation is tightly regulated to prevent immune responses by non-antigen bound antibodies or in the absence of 'danger signals'. FcR activity may be modulated at the plasma membrane via cross-talk with integrins. In addition, cytokines at the site of infection/inflammation can increase FcR avidity, a process referred to as inside-out signaling. This regulatory mechanism has been described for FcγRI (CD64), FcγRIIa (CD32a), and FcαRI (CD89) and is also well-known for integrins. Key cellular events during inside-out signaling are (de)phosphorylation, clustering, cytoskeleton rearrangements, and conformational changes. The latter can be studied with antibodies that specifically recognize epitopes exposed by the active (high affinity) or inactive (low affinity) state of the FcR. These antibodies are important tools to investigate the role of FcR activation in disease settings. Research on FcR has gained momentum with the rise of monoclonal antibodies (mAb) entering the clinic for the treatment of cancer and other diseases. The clinical outcome of mAb therapy may be improved by increasing FcR avidity by cytokine stimulation.

Simultaneous Targeting of FcγRs and FcαRI Enhances Tumor Cell Killing.

Efficacy of anticancer monoclonal antibodies (mAb) is limited by the exhaustion of effector mechanisms. IgG mAbs mediate cellular effector functions through FcγRs expressed on effector cells. IgA mAbs can also induce efficient tumor killing both in vitro and in vivo. IgA mAbs recruit FcαRI-expressing effector cells and therefore initiate different effector mechanisms in vivo compared with IgG. Here, we studied killing of tumor cells coexpressing EGFR and HER2 by the IgG mAbs cetuximab and trastuzumab and their IgA variants. In the presence of a heterogeneous population of effector cells (leukocytes), the combination of IgG and IgA mAbs to two different tumor targets (EGFR and HER2) led to enhanced cytotoxicity compared with each isotype alone. Combination of two IgGs or two IgAs or IgG and IgA against the same target did not enhance cytotoxicity. Increased cytotoxicity relied on the presence of both the peripheral blood mononuclear cell and the polymorphonuclear (PMN) fraction. Purified natural killer cells were only cytotoxic with IgG, whereas cytotoxicity induced by PMNs was strong with IgA and poor with IgG. Monocytes, which coexpress FcγRs and FcαRI, also displayed increased cytotoxicity by the combination of IgG and IgA in an overnight killing assay. Coinjection of cetuximab and IgA2-HER2 resulted in increased antitumor effects compared with either mAb alone in a xenograft model with A431-luc2-HER2 cells. Thus, the combination of IgG and IgA isotypes optimally mobilizes cellular effectors for cytotoxicity, representing a promising novel strategy to improve mAb therapy.

Antidementia drug treatment in dementia networks in Germany: use rates and factors associated with treatment use.

BACKGROUND: Dementia networks in Germany constitute a specialised setting for integrated dementia care and have shown benefits on relevant outcomes, including those of drug treatment. National guidelines recommend treatment with acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) or the N-Methyl-D-Aspartate antagonist (memantine) to reduce cognitive symptoms. However, prescription rates are lower than 30 % in general practises. This study aims to describe antidementia drug treatment and the factors that are associated with the treatment in different dementia networks across Germany. METHODS: We have analysed the socio-demographic, clinical and utilisation data from 560 patients with dementia (PWD), as well as data from their caregivers, in 13 selected dementia networks in Germany. The patients and caregivers were interviewed in their homes or in the network facilities. Multiple logistic regression models were fitted to evaluate the socio-demographic and clinical factors associated with the utilisation of antidementia drug treatment in the various networks. RESULTS: In all of the networks in the study, 52 % of the participants received an antidementia drug treatment. Factors associated with the utilisation of the antidementia drug treatment were: formal diagnosis (OR = 16.81, p < 0.001), association with a physician in the network (OR = 3.69, p < 0.001), higher number of comorbidities (OR = 0.88, p = 0.039), living alone (OR = 0.51, p = 0.032) and higher age (OR = 2.97, p = 0.002). CONCLUSION: Medical treatment of PWD with antidementia drugs in dementia networks in Germany is more frequent than in primary and nursing home care settings. Our findings also suggest that participants with a formal diagnosis and a physician in the network have increased rates of receiving antidementia drug treatments. These findings suggest that dementia networks focusing on medical treatment should support diagnostic procedures and incorporate physician specialists.

Family visits in shared-housing arrangements for residents with dementia--a cross-sectional study on the impact on residents' quality of life.

BACKGROUND: Shared-housing arrangements (SHA) are a German type of small-scale living arrangements for people with dementia (PwD). The involvement of family members is one core domain of SHA. But it has not been investigated yet, what are factors associated with family visits and if family involvement within SHA contributes to better residents' quality of life (QoL). METHOD: A cross-sectional study including all SHA in Berlin/Germany was performed. Main parameters of interest were residents' QoL (QUALIDEM) and frequencies of family visits within the SHA. Besides descriptive analyses we used logistic regression and ANCOVA to analyze the data. RESULTS: 58 SHA with 396 residents (78.4 years, 69.4% female) participated in the study. Older (OR: 1.034; 95% CI: 1.005; 1.064) and female residents (OR: 2.006; 95% CI: 1.018; 3.950) got more often visited by family members. An active participation of family members in SHA contributes on average to a better QoL in terms of social relationship and social isolation (all ANCOVA p < 0.005). A decreased QoL was found for people without family visits compared to those without family members. CONCLUSIONS: The involvement of family members in SHA is common but on a similar level compared to other care arrangements. Staff should convince available family members to visit PwD, in order to improve residents QoL. However, the response rate in the present study was about 13%, which may limit the results.

Nutritional status of care-dependent people with dementia in shared-housing arrangements--a one-year follow-up.

BACKGROUND: Malnutrition in the elderly is an important nursing challenge. Persons with dementia disease are often affected by malnutrition. During recent years, shared-housing arrangements (SHA) for older care-dependent people, frequently with dementia disease, have evolved in Germany. SHA can be an alternative to traditional residential care in nursing homes. The prevalence of malnutrition in SHA is compared to the prevalence in community dwellings and lower than the prevalence of malnutrition in nursing homes. There are no scientific data about the development of the nutritional status of older care-dependent people in SHA over one year. The aim of this study is to describe the nutritional status of care-dependent people with dementia disease living in SHA and to investigate changes over a period of one year. METHOD: A longitudinal study with a one-year follow-up was performed. Standardised interviews with nurses were conducted concerning nutritional status (Mini Nutritional Assessment--MNA), cognitive capacities (Mini Mental State Examination--MMSE), activities of daily living (Extended Barthel-Index--EBI) and socio-demographic characteristics. Nutritional data were available for 45 residents at baseline and 36 residents at follow-up. RESULTS: At baseline, 45 residents with an average age of 78.4 years living in SHA in the state of Berlin, Germany, were included in the study. Predominantly, residents were female (73.3%) and diagnosed with dementia (88.9%), with a moderate to severe cognitive impairment (MMSE: 10.8) and low daily living abilities (EBI: 33.7). Most residents (80.6%) have a risk of malnutrition regarding the MNA. The average MNA score did decline slightly within one year (t0 = 20.8 vs. t1 = 19.7). CONCLUSION: Regular screenings for malnutrition using validated standardised assessments, which are easy to apply, should be implemented in SHA to avoid nutritional and health-related problems arising from malnutrition. Flexible structures for care, as in SHA, can facilitate coping with nutritional problems.

Quality of life ratings in dementia care--a cross-sectional study to identify factors associated with proxy-ratings.

OBJECTIVE: Quality of life (QoL) is one major outcome parameter in the care for people with dementia (PwD); however, their assessment is lacking a gold standard. The purpose of this study was to evaluate potential factors associated with nurse-rated quality of life of PwD in nursing homes in Berlin, Germany. METHOD: An explorative cross-sectional study was performed in five nursing homes to evaluate QoL. Nurses rated the QoL for all residents with dementia by completing two different standardised assessments (ADRQL, QUALIDEM). Potential associated factors were evaluated concerning resident and nurse related factors. A fixed-effects models of analysis of co-variance (ANCOVA) was used to analyse effects of assumed associated factors of the major outcome parameters ADRQL and QUALIDEM. Associated factors were severity of dementia (GDS), challenging behaviour (CMAI), and other characteristics. Regarding the nurses, burnout (MBI), satisfaction with life (SWLS), attitude (ADQ) and empathy toward residents (JSPE), as well as circumstances of the ratings and days worked in advance of the ratings were assessed. RESULTS: In total, 133 PwD and 88 nurses were included. Overall, the ratings show moderate to high QoL in every subscale independent of the instrument used. Assumed confounders relevantly influenced 14 out of 17 ratings. Predominantly, residents' challenging behaviour, nurses' burnout and satisfaction with life as well as the circumstances of the ratings are significant and clinically relevant associated factors. CONCLUSION: Assessing QoL of PwD is acknowledged as a central component of health care and health care research. In later stages of dementia, proxy-reported information obtained from quality of life questionnaires is and will continue to be essential in this research. However, methodological issues that underline this research - matters of measurement and instrument validity - must receive more attention. Associated factors in proxy-ratings have to be routinely assessed in order to get more valid and comparable estimates.

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer.

The complement system is a powerful tool of the innate immune system to eradicate pathogens. Both in vitro and in vivo evidence indicates that therapeutic anti-tumor monoclonal antibodies (mAbs) can activate the complement system by the classical pathway. However, the contribution of complement to the efficacy of mAbs is still debated, mainly due to the lack of convincing data in patients. A beneficial role for complement during mAb therapy is supported by the fact that cancer cells often upregulate complement-regulatory proteins (CRPs). Polymorphisms in various CRPs were previously associated with complement-mediated disorders. In this review the role of complement in anti-tumor mAb therapy will be discussed with special emphasis on strategies aiming at modifying complement activity. In the future, clinical efficacy of mAbs with enhanced effector functions together with comprehensive analysis of polymorphisms in CRPs in mAb-treated patients will further clarify the role of complement in mAb therapy.