Peripartaler Stoffwechsel-und Gesundheitsstatus sowie Fruchtbarkeit bei unterschiedlichen Milchleistungen von Schwarzbunten Kühen

Ziel der Untersuchungen war es, im Rahmen einer umfangreichen Bestandsanalyse, mögliche Haupteinflüsse auf die Stoffwechselsituation der Kühe zu ermitteln. Die Frage, ob hochleistende Tiere stärker belastet sind, sollte näher beleuchtet werden. Dazu wurden bei 758 Tieren aus einem Bestand Gesundheitsstatus, Parität und Milchleistung in Beziehung zu Stoffwechsel-, Fruchtbarkeits-, Milchleistungsparametern und Körperkondition gesetzt. Die Parameter des Energiestoffwechsels und die Körperkondition decken eine Energiemangelsituation im untersuchten Bestand auf, deren Folge eine hohe Morbidität und unbefriedigende Fruchtbarkeit ist. Kühe hoher und niedriger Milchleistung haben die höchste Morbidität und die stärksten Abweichungen der Energiestoffwechselparameter (Freie Fettsäuren, Betahydroxybutyrat, Bilirubin). Unterschiede zwischen Kühen und Färsen bestehen häufig und bedürfen besonderer Beachtung im Herdenmanagement. Bei höheren Milchleistungen besteht ein stärkerer und längerer Körpermasseverlust, dementsprechend verschlechtern sich mit höherer Milchleistung die Fruchtbarkeitsparameter

Peripartaler Stoffwechsel-und Gesundheitsstatus sowie Fruchtbarkeit bei unterschiedlichen Milchleistungen von Schwarzbunten Kühen

Ziel der Untersuchungen war es, im Rahmen einer umfangreichen Bestandsanalyse, mögliche Haupteinflüsse auf die Stoffwechselsituation der Kühe zu ermitteln. Die Frage, ob hochleistende Tiere stärker belastet sind, sollte näher beleuchtet werden. Dazu wurden bei 758 Tieren aus einem Bestand Gesundheitsstatus, Parität und Milchleistung in Beziehung zu Stoffwechsel-, Fruchtbarkeits-, Milchleistungsparametern und Körperkondition gesetzt. Die Parameter des Energiestoffwechsels und die Körperkondition decken eine Energiemangelsituation im untersuchten Bestand auf, deren Folge eine hohe Morbidität und unbefriedigende Fruchtbarkeit ist. Kühe hoher und niedriger Milchleistung haben die höchste Morbidität und die stärksten Abweichungen der Energiestoffwechselparameter (Freie Fettsäuren, Betahydroxybutyrat, Bilirubin). Unterschiede zwischen Kühen und Färsen bestehen häufig und bedürfen besonderer Beachtung im Herdenmanagement. Bei höheren Milchleistungen besteht ein stärkerer und längerer Körpermasseverlust, dementsprechend verschlechtern sich mit höherer Milchleistung die Fruchtbarkeitsparameter

Peripartaler Stoffwechsel-und Gesundheitsstatus sowie Fruchtbarkeit bei unterschiedlichen Milchleistungen von Schwarzbunten Kühen

Ziel der Untersuchungen war es, im Rahmen einer umfangreichen Bestandsanalyse, mögliche Haupteinflüsse auf die Stoffwechselsituation der Kühe zu ermitteln. Die Frage, ob hochleistende Tiere stärker belastet sind, sollte näher beleuchtet werden. Dazu wurden bei 758 Tieren aus einem Bestand Gesundheitsstatus, Parität und Milchleistung in Beziehung zu Stoffwechsel-, Fruchtbarkeits-, Milchleistungsparametern und Körperkondition gesetzt. Die Parameter des Energiestoffwechsels und die Körperkondition decken eine Energiemangelsituation im untersuchten Bestand auf, deren Folge eine hohe Morbidität und unbefriedigende Fruchtbarkeit ist. Kühe hoher und niedriger Milchleistung haben die höchste Morbidität und die stärksten Abweichungen der Energiestoffwechselparameter (Freie Fettsäuren, Betahydroxybutyrat, Bilirubin). Unterschiede zwischen Kühen und Färsen bestehen häufig und bedürfen besonderer Beachtung im Herdenmanagement. Bei höheren Milchleistungen besteht ein stärkerer und längerer Körpermasseverlust, dementsprechend verschlechtern sich mit höherer Milchleistung die Fruchtbarkeitsparameter

Characterisation of novel human CD27-specific monoclonal antibodies for cancer therapy

Monoclonal antibodies (mAbs) are employed in the frontline treatment of cancer. These mAbs are known to work through a variety of mechanisms, for example by directly targeting tumour cells to mediate their clearance, or to augment immune responses against cancers. The majority of agonistic mAbs target members of the tumour necrosis factor receptor superfamily (TNFRSF), which provide T-cell costimulatory signalling. Cluster of differentiation (CD) 27 is a member of the TNFRSF and pre-clinical studies investigating mAbs targeting CD27 have demonstrated substantial anti-tumour activity in murine tumour models. In particular, durable cures were observed when anti-CD27 mAb was combined with a direct tumour targeting anti-CD20 mAb. The stimulation of CD27 on T cells promoted myeloid cell activation, leading to enhanced antibody-dependent cellular phagocytosis (ADCP), mediated by the anti-CD20 mAb, which contributed to tumour clearance. Similarly, anti-human CD27 (hCD27) mAb, varlilumab, induced in vitro activation of peripheral blood monocytes, indicated by CD14 downregulation. Despite these promising data, the therapeutic efficacy of anti-hCD27 mAbs in the clinic has been less impressive, potentially due to a lack of understanding of the ideal mAb format. Identifying the key determinants that govern hCD27 agonism might help to achieve better therapeutic outcomes.Four novel and two clinically relevant anti-hCD27 mAbs were characterised with regards to epitope specificity, and the influence of both epitope and isotype on agonism. A range of affinities and avidities via cell-surface binding and surface plasmon resonance (SPR) were identified. Alanine scanning mutagenesis showed that the mAbs bound across the three cysteine-rich domains (CRDs) of the receptor with membrane-distally binding mAbs being more agonistic than membrane-proximal binding ones in an in vitro reporter cell assay. Further, mAbs binding to the external surface of a hCD27 homodimer were stronger agonists than mAbs binding internally-facing residues. When the agonistic activity of anti-hCD27 mAbs of different isotypes was compared, human immunoglobulin 2 (hIgG2, h2) mAb outperformed hIgG1 (h1) counterparts by inducing stronger transcriptional activation and increased CD8+ T-cell proliferation. Increased agonism was also observed by inhibitory Fcγ receptor (FcγR) IIb-mediated hCD27 cross-linking, through co-culture with FcγRIIb-expressing cells or the use of Fc-engineered h1 mAbs with enhanced affinity to FcγRIIb.The therapeutic efficacy of hCD27.15 (the best agonist in vitro) in combination with the clinically relevant direct targeting mAb (daratumumab, anti-hCD38) was investigated in vivo. However, no survival benefit was observed in hCD27 transgenic hCD38 A20-tumour-bearing mice. Treatment of Daudi lymphoma bearing, human PBMC-injected mice with hCD27.15 monotherapy resulted in some slowing of tumour growth.Finally, the bystander effects of anti-hCD27 mAbs in PBMCs were explored. Only stimulation of PBMCs with varlilumab (but no other anti-hCD27 mAb) resulted in indirect effects on monocytes, causing downregulation of CD14 and upregulation of CD16 and CD86, suggesting differentiation of monocytes. The CD14 downregulation might partially be mediated by hCD27- or T-cell receptor signalling. Further work into the underlying mechanism is required.Together this work highlights the importance of mAb-engineering and the selection of the optimal mAb format in order to generate more clinically efficacious anti-CD27 mAb agonists with better therapeutic outcomes

Dataset to support the Southampton Doctoral thesis "Characterisation of novel human CD27-specific antibodies for cancer therapy"

The dataset supports a thesis &quot;Characterisation of novel human CD27-specific antibodies for cancer therapy&quot;. The dataset includes four excel spreadsheets containing raw data for each result chapter of the thesis, subdivided by figure numbers. Parts of this data have been published in: Heckel, F., Turaj, A.H., Fisher, H. et al. Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering. Commun Biol 5, 229 (2022). https://doi.org/10.1038/s42003-022-03182-6</span

Nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) at a palliative care unit: A prospective single service analysis

Background The emergence of multidrug-resistant bacterial microorganisms is a particular challenge for the health care systems. Little is known about the occurrence of methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Gram-negative bacteria (MDRGNB) in patients of palliative care units (PCU). Aim The primary aim of this study was to determine the carriage of MRSA among patients of a PCU at a German University Hospital and to assess whether the positive cases would have been detected by a risk-factor-based screening-approach. Design Between February 2014 and January 2015 patients from our PCU were tested for MRSA carriage within 48 hours following admission irrespective of pre-existing risk factors. In addition, risk factors for MRSA colonization were assessed. Samples from the nostrils and, if applicable, from pre-existing wounds were analysed by standardized culture-based laboratory techniques for the presence of MRSA and of other bacteria and fungi. Results from swabs taken prior to admission were also recorded if available. Results 297 out of 317 patients (93.7%) fulfilled one or more MRSA screening criteria. Swabs from 299 patients were tested. The detection rate was 2.1% for MRSA. All MRSA cases would have been detected by a risk-factor-based screening-approach. Considering the detected cases and the results from swabs taken prior to admission, 4.1% of the patients (n = 13) were diagnosed with MRSA and 4.1% with MDRGNB (n = 13), including two patients with MRSA and MDRGNB (0.6%). The rate of MRSA carriage in PCU patients (4.1%) was elevated compared to the rate seen in the general cohort of patients admitted to our University Hospital (2.7%). Conclusions PCU patients have an increased risk to carry MRSA compared to other hospitalized patients. Although a risk factor-based screening is likely to detect all MRSA carriers amongst PCU patients, we rather recommend a universal screening to avoid the extra effort to identify the few risk factor-negative patients (<7%). As we did not perform a systematic MDRGNB screening, further studies are needed to determine the true prevalence of MDRGNB amongst PCU patients

Understanding institutional stakeholders’ perspectives on multidrug-resistant bacterial organism at the end of life: a qualitative study

Background: Information lacks about institutional stakeholders’ perspectives on management approaches of multidrug-resistant bacterial organism in end-of-life situations. The term “institutional stakeholder” includes persons in leading positions with responsibility in hospitals’ multidrug-resistant bacterial organism management. They have great influence on how strategies on multidrug-resistant bacterial organism management approaches in institutions of the public health system are designed. This study targeted institutional stakeholders’ individual perspectives on multidrug-resistant bacterial organism colonization or infection and isolation measures at the end of life. Methods: Between March and December 2014, institutional stakeholders of two study centers, a German palliative care unit and a geriatric ward, were queried in semistructured interviews. Interviews were audiotaped, transcribed verbatim, and analyzed qualitatively with the aid of the software MAXQDA for qualitative data analysis using principles of Grounded Theory. In addition, two external stakeholders were interviewed to enrich data. Results: Key issues addressed by institutional stakeholders (N=18) were the relevance of multidrug-resistant bacterial organism in palliative and geriatric care, contradictions between hygiene principles and patients’ and family caregivers’ needs and divergence from standards, frame conditions, and reflections on standardization of multidrug-resistant bacterial organism end-of-life care procedures. Results show that institutional stakeholders face a dilemma between their responsibility in protecting third persons and ensuring patients’ quality of life. Until further empirical evidence establishes a clear multidrug-resistant bacterial organism management approach in end-of-life care, stakeholders suggest a case-based approach. Conclusion: The institutional stakeholders’ perspectives and their suggestion of a case-based approach advance the development process of a patient-, family-, staff-, and institutional-centered approach of how to deal with multidrug-resistant bacterial organism-positive patients in end-of-life care. Institutional stakeholders play an important role in the implementation of recommendations following this approach

Recorded MRSA-screening criteria and MRSA risk factors (n = 317 patients).

<p>Recorded MRSA-screening criteria and MRSA risk factors (n = 317 patients).</p