Valuing biomarker diagnostics for dementia care: enhancing the reflection of patients, their care-givers and members of the wider public

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Non-compressible truncal and junctional hemorrhage:A retrospective analysis quantifying potential indications for advanced bleeding control in Dutch trauma centers

Background: Truncal and junctional hemorrhage is the leading cause of potentially preventable deaths in trauma patients. To reduce this mortality, the application of advanced bleeding control techniques, such as resuscitative endovascular balloon occlusion of the aorta (REBOA), junctional tourniquets, Foley catheters, or hemostatic agents should be optimized. This study aimed to identify trauma patients with non-compressible truncal and junctional hemorrhage (NCTJH) who might benefit from advanced bleeding control techniques during initial trauma care. We hypothesized that there is a substantial cohort of Dutch trauma patients that can possibly benefit from advanced bleeding control techniques.Methods: Adult trauma patients with an Abbreviated Injury Scale ≥3 in the torso, neck, axilla, or groin region, who were presented between January 1st, 2014 and December 31st, 2018 to two Dutch level-1 trauma centers, were identified from the Dutch Trauma Registry. Potential indications for advanced bleeding control in patients with NCTJH were assessed by an expert panel of three trauma surgeons based on injury characteristics, vital signs, response to resuscitation, and received treatment. Results: In total, 1719 patients were identified of whom 249 (14.5 %) suffered from NCTJH. In 153 patients (60.6 %), hemorrhagic shock could have been mitigated or prevented with advanced bleeding control techniques. This group was younger and more heavily injured: median age of 40 versus 48 years and median ISS 33 versus 22 as compared to the entire cohort. The mortality rate in these patients was 31.8 %. On average, each of the included level-1 trauma centers treated an NCTJH patient every 24 days in whom a form of advanced bleeding control could have been beneficial. Conclusions: More than half of included Dutch trauma patients with NCTJH may benefit from in-hospital application of advanced bleeding control techniques, such as REBOA, during initial trauma care. Widespread implementation of these techniques in the Dutch trauma system may contribute to reduction of mortality and morbidity from non-compressible truncal and junctional hemorrhage.</p

Normal numbers of stem cell memory T cells despite strongly reduced naive T cells support intact memory T cell compartment in Ataxia Telangiectasia

Ataxia Telangiectasia (AT) is a rare inherited disorder characterized by progressive cerebellar ataxia, chromosomal instability, cancer susceptibility and immunodeficiency. AT is caused by mutations in the ATM gene, which is involved in multiple processes linked to DNA double strand break repair. Immunologically, ATM mutations lead to hampered V(D)J recombination and consequently reduced numbers of naive B and T cells. In addition, class switch recombination is disturbed resulting in antibody deficiency causing common, mostly sinopulmonary, bacterial infections. Yet, AT patients in general have no clinical T cell associated infections and numbers of memory T cells are usually normal. In this study we investigated the naive and memory T cell compartment in five patients with classical AT and compared them with five healthy controls using a 24-color antibody panel and spectral flow cytometry. Multidimensional analysis of CD4 and CD8 TCR alpha beta(+) cells revealed that early naive T cell populations, i.e. CD4(+)CD31(+) recent thymic emigrants and CD8(+)CCR7(++)CD45RA(++) T cells, were strongly reduced in AT patients. However, we identified normal numbers of stem cell memory T cells expressing CD95, which are antigen-experienced T cells that can persist for decades because of their self-renewal capacity. We hypothesize that the presence of stem cell memory T cells explains why AT patients have an intact memory T cell compartment. In line with this novel finding, memory T cells of AT patients were normal in number and expressed chemokine receptors, activating and inhibitory receptors in comparable percentages as controls. Comparing memory T cell phenotypes by Boolean gating revealed similar diversity indices in AT compared to controls. We conclude that AT patients have a fully developed memory T cell compartment despite strongly reduced naive T cells. This could be explained by the presence of normal numbers of stem cell memory T cells in the naive T cell compartment, which support the maintenance of the memory T cells. The identification of stem cell memory T cells via our spectral flow cytometric approach is highly relevant for better understanding of T cell immunity in AT. Moreover, it provides possibilities for further research on this recently identified T cell population in other inborn errors of immunity.Transplantation and immunomodulatio

Immediate and long-term effects of the COVID-19 pandemic and lockdown on physical activity in patients with implanted cardiac devices

Background: Physical activity (PA) is an important determinant of cardiovascular health that may be affected the COVID-19 pandemic. Therefore, we examined the immediate and long-term effects of the pandemic and lockdown on PA in patients with established cardiovascular risk. Methods: Objectively-measured daily PA data was obtained from cardiovascular implantable electronic devices (CIEDs) from 3453 U.S patients (mean and standard deviations [SD] age, 72.65 [13.24] years; 42% women). Adjusted mixed-effects models stratified by device type were used to compare daily PA from periods in 2020: pre-lockdown (March 1–14), lockdown (March 15 to May 8), and the reopening phase of the pandemic (May 9 to December 31) versus 2019. Patient characteristics and events associated with inactivity during lockdown and the proportion of patients who returned to their 2019 PA-level by the end of reopening phase (December 31, 2020) were examined. Results: Daily PA was significantly lower during the lockdown compared to the same period in 2019 (−15%; p <.0001), especially for pacemaker patients, adults aged <65, and patients more active prior to lockdown. Non-COVID hospitalization and ICD shock were similarly associated with low PA during lockdown (p =.0001). In the reopening phase of the pandemic, PA remained 14.4% lower in the overall sample and only 23% of patients returned to their 2019 PA level by the end of follow-up. Conclusions: In this large cohort of patients with CIEDs, PA was markedly lower during the lockdown and remained lower for months after restrictions were lifted. Strategies to maintain PA during a national emergency are urgently needed

GATA3 haploinsufficiency causes a rapid deterioration of distortion product otoacoustic emissions (DPOAEs) in mice

Human HDR (hypoparathyroidism, deafness and renal dysplasia)-syndrome is caused by haploinsufficiency of zinc-finger transcription factor GATA3. The hearing loss due to GATA3 haploinsufficiency has been shown to be peripheral in origin, but it is unclear to what extent potential aberrations in the outer hair cells (OHCs) contribute to this disorder. To further elucidate the pathophysiological mechanism underlying the hearing defect in HDR-syndrome, we investigated the OHCs in heterozygous Gata3-knockout mice at both the functional and morphological level. While the signal-to-noise ratios of distortion product otoacoustic emissions (DPOAE) in wild type mice did not change significantly during the first half-year of live, those in the heterozygous Gata3 mice decreased dramatically. In addition, both light microscopic and transmission electron microscopic analyses showed that the number of OHCs containing vacuoles was increased in the mutants. Together, these findings indicate that outer hair cell malfunctioning plays a major role in the hearing loss in HDR-syndrome

Differential expression of CD49a and CD49b determines localization and function of tumor-infiltrating CD8(+) T cells

CD8(+) T-cell infiltration and effector activity in tumors are correlated with better overall survival of patients, suggesting that the ability of T cells to enter and remain in contact with tumor cells supports tumor control. CD8(+) T cells express the collagen-binding integrins CD49a and CD49b, but little is known about their function or how their expression is regulated in the tumor microenvironment (TME). Here, we found that tumor-infiltrating CD8(+) T cells initially expressed CD49b, gained CD49a, and then lost CD49b over the course of tumor outgrowth. This differentiation sequence was driven by antigen-independent elements in the TME, although T-cell receptor (TCR) stimulation further increased CD49a expression. Expression of exhaustion markers and CD49a associated temporally but not mechanistically. Intratumoral CD49a-expressing CD8(+) T cells failed to upregulate TCR-dependent Nur77 expression, whereas CD69 was constitutively expressed, consistent with both a lack of productive antigen engagement and a tissue-resident memory-like phenotype. Imaging T cells in live tumor slices revealed that CD49a increased their motility, especially of those in close proximity to tumor cells, suggesting that it may interfere with T-cell recognition of tumor cells by distracting them from productive engagement, although we were not able to augment productive engagement by short-term CD49a blockade. CD49b also promoted relocalization of T cells at a greater distance from tumor cells. Thus, our results demonstrate that expression of these integrins affects T-cell trafficking and localization in tumors via distinct mechanisms, and suggests a new way in which the TME, and likely collagen, could promote tumor-infiltrating CD8(+) T-cell dysfunction.Experimental cancer immunology and therap

Case report:: severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation

DNA ligase I deficiency is an extremely rare primary immunodeficiency with only 6 patients reported in the literature. Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy. Two-month-old girl with delayed development, T-B-NK+ SCID, and macrocytic anemia presented features of Omenn syndrome. Whole exome sequencing revealed two novel, heterozygous variants (c.2312 G>A, p.Arg771Gly and c.776+5G>T, p.Pro260*) in the LIG1 gene (NM_000234.1). Hematopoietic stem cell transplantation from a fully matched unrelated donor was performed at the age of 4 months using GEFA03 protocol. Mixed donor-recipient chimerism was observed, with 60-70% chimerism in the mononucleated cell compartment and over 90% in T-lymphocyte compartment, but autologous myeloid recovery. Stable CD4+ and CD8+ T-cell counts above 200/mu L were achieved after 2 months, but the patient remained transfusion-dependent. Despite satisfactory immunological reconstitution, the second transplantation due to constitutional hemolytic defect has been considered. In light of possible re-transplantation, an issue of optimal conditioning protocol with sufficient myeloid engraftment is important. For the first time Omenn syndrome is described in a compound heterozygote carrying two the novel variants p.Arg771Gly and p.Pro260* in the LIG1 gene. Patients diagnosed with SCID and Omenn syndrome showing macrocytic anemia, should be screened for DNA ligase I deficiency.Transplantation and immunomodulatio

Combining offshore wind energy and large-scale mussel farming: background & technical, ecological and economic considerations

This Blauwdruk project report presents background and technical, ecological and economic considerations of the potential combination of offshore wind energy production and large-scale mussel farming in offshore areas in the North Sea. The main objective of the Blauwdruk project was to study the feasibility of such a combination on the Dutch Continental Shelf

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome

The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome

B-cell targeting with anti-CD38 daratumumab:implications for differentiation and memory responses

B cell–targeted therapies, such as CD20-targeting mAbs, deplete B cells but do not target the autoantibody-producing plasma cells (PCs). PC-targeting therapies such as daratumumab (anti-CD38) form an attractive approach to treat PC-mediated diseases. CD38 possesses enzymatic and receptor capabilities, which may impact a range of cellular processes including proliferation and differentiation. However, very little is known whether and how CD38 targeting affects B-cell differentiation, in particular for humans beyond cancer settings. Using in-depth in vitro B-cell differentiation assays and signaling pathway analysis, we show that CD38 targeting with daratumumab demonstrated a significant decrease in proliferation, differentiation, and IgG production upon T cell–dependent B-cell stimulation. We found no effect on T-cell activation or proliferation. Furthermore, we demonstrate that daratumumab attenuated the activation of NF-κB in B cells and the transcription of NF-κB–targeted genes. When culturing sorted B-cell subsets with daratumumab, the switched memory B-cell subset was primarily affected. Overall, these in vitro data elucidate novel non-depleting mechanisms by which daratumumab can disturb humoral immune responses. Affecting memory B cells, daratumumab may be used as a therapeutic approach in B cell–mediated diseases other than the currently targeted malignancies.</p