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Recent progress in AdS/CFT has provided a good understanding of how the bulk spacetime is encoded in the entanglement structure of the boundary CFT. However, little is known about how spacetime emerges directly from the bulk quantum theory. We address this question in an effective 3d quantum theory of pure gravity, which describes the high temperature regime of a holographic CFT. This theory can be viewed as a $q$-deformation and dimensional uplift of JT gravity. Using this model, we show that the Bekenstein-Hawking entropy of a two-sided black hole equals the bulk entanglement entropy of gravitational edge modes. In the conventional Chern-Simons description, these black holes correspond to Wilson lines in representations of $\PSL(2,\mathbb{R})\otimes \PSL(2,\mathbb{R}) $. We show that the correct calculation of gravitational entropy suggests we should interpret the bulk theory as an extended topological quantum field theory associated to the quantum semi-group $\SL^+_{q}(2,\mathbb{R})\otimes \SL^+_{q}(2,\mathbb{R})$. Our calculation suggests an effective description of bulk microstates in terms of collective, anyonic degrees of freedom whose entanglement leads to the emergence of the bulk spacetime., Revised introduction and summary. Journal version

Human CMV (HCMV) is a ubiquitous pathogen that indelibly shapes the NK cell repertoire. Using transcriptomic, epigenomic, and proteomic approaches to evaluate peripheral blood NK cells from healthy human volunteers, we find that prior HCMV infection promotes NK cells with a T cell–like gene profile, including the canonical markers CD3ε, CD5, and CD8β, as well as the T cell lineage–commitment transcription factor Bcl11b. Although Bcl11b expression is upregulated during NK maturation from CD56bright to CD56dim, we find a Bcl11b-mediated signature at the protein level for FcεRIγ, PLZF, IL-2Rβ, CD3γ, CD3δ, and CD3ε in later-stage, HCMV-induced NK cells. BCL11B is targeted by Notch signaling in T cell development, and culture of NK cells with Notch ligand increases cytoplasmic CD3ε expression. The Bcl11b-mediated gain of CD3ε, physically associated with CD16 signaling molecules Lck and CD247 in NK cells is correlated with increased Ab-dependent effector function, including against HCMV-infected cells, identifying a potential mechanism for their prevalence in HCMV-infected individuals and their prospective clinical use in Ab-based therapies.

Background and aims Immunosuppressed patients are at risk of severe infections with vaccination preventable diseases. We evaluated vaccination rate and immunity of children and adolescents with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). Methods Immunization rate of 329 children with IBD (n = 300) and AIH (n = 29) was assessed in seven German centres using vaccination certificates, history of chicken pox and by determining anti-varicella zoster virus (VZV) and anti-measles IgG antibodies. Results Of the total cohort 86% received long-term immunosuppression. Four doses of a hexavalent vaccine were documented in 89%, at least one dose of measles, mumps, and rubella (MMR) vaccination was documented in 325 (99%), with 300 (92%) receiving two doses. Anti-measles IgG concentrations were insufficient in 11% of the immunized patients. VZV vaccination was officially recommended in Germany since 2004, and implemented in 88% born from 2005 onwards. In patients born earlier VZV catch up vaccination only reached 25% (n = 67). Of 118 patients with documented VZV vaccination 25 (21%) did not display sufficient anti-VZV IgG. Of 198 patients with a history of chicken pox, six had undetectable anti-VZV IgG. Of 29 patients having neither had chicken pox nor VZV vaccination, 20 were found to have sufficient anti-VZV IgG. Conclusions In our cohort vaccination coverage for hexavalent and MMR vaccinations was good, but insufficient for VZV vaccination in patients born before 2005. Neither the vaccination certificate nor the history of chicken pox is reliable to predict VZV immunity indicating a need for serologic investigations and if needed vaccination before initiating immunosuppressive therapy.

After solid-organ transplantation, reactivation of the cytomegalovirus (CMV) is often observed in seronegative patients and associated with a high risk of disease and mortality. CMV-specific T cells can prevent CMV reactivation. In a phase 1 trial, CMV-seronegative patients with end-stage renal disease listed for kidney transplantation were subjected to CMV phosphoprotein 65 (CMVpp65) peptide vaccination and further investigated for T-cell responses. To this end, CMV-specific CD8+ T cells were characterized by bulk T-cell-receptor (TCR) repertoire sequencing and combined single-cell RNA and TCR sequencing. In patients mounting an immune response to the vaccine, a common SYE(N)E TCR motif known to bind CMVpp65 was detected. CMV-peptide-vaccination-responder patients had TCR features distinct from those of non-responders. In a non-responder patient, a monoclonal inflammatory T-cell response was detected upon CMV reactivation. The identification of vaccine-induced CMV-reactive TCRs motifs might facilitate the development of cellular therapies for patients wait-listed for kidney transplantation.

In this work, we revisit the problem of finding entanglement islands in 2d Jackiw-Teitelboim (JT) gravity. We implement the following adjustments to the traditional setup: (1) we do not explicitly couple to a non-gravitating system, instead we implement only pure absorption into a fiducial detector, (2) we utilise the operationally defined renormalised matter entanglement entropy, as defined by the boundary observer's wordline. We show that this leads to a unitary Page curve that we explicitly compute, with an island outside of the event horizon. Next, we extend the analysis to a charged and/or supersymmetric black hole. We find that in a certain regime the charged black hole grows first as it emits superradiation before eventually dissipating. We obtain similar results when embedding the system in a supersymmetric setting., Comment: 40 pages + appendices; v2: added extra discussions and references, matches published version

The chapter puts forward a semantic observation which he claims reflects not only Ripstein’s Kant interpretation, but also his own perspective as a long-term reader of Kant. Mertens observes that Kantian scholarship has become to a large extent an Anglo-Saxon affair, and Kant is read and interpreted against the background of political and legal problems of that world. History has shown that several readings of Kant are possible, and Ripstein presents a new, powerful reading of Kant which is indebted to that Anglo-Saxon background. Mertens discusses several intriguing questions, inter alia, Ripstein’s interpretation of Kant’s view on the law of war is the distinction between the just war tradition and the regular war tradition and Kant’s departure from both traditions.

The epidemiological effect of vaccination is that it primarily reduces the incidence and prevalence of infectious agents and diseases, providing ideal conditions (also from an economic point of view) for prevention. Goal of vaccination is first the individual protection. Other goals may be “herd immunity”, regional repression and global extinction. The STIKO provides recommendations for the implementation of vaccinations and for the implementation of other measures for the specific prevention of communicable diseases and develops criteria for the differentiation of a customary vaccination reaction and damage to health beyond the usual extent of a vaccination reaction. Earlier vaccination recommendations based on “expert opinion” but today are based on the best available evidence. Current STIKO recommendations include vaccination against seasonal influenza, vaccination against HPV, Tdap booster, tetanus PEP, and vaccine management in practice and among migrants. For the success of the vaccination recommendations, it is first and foremost crucial that the medical profession complies with the obligation to inform about vaccination options and needs vis-à-vis patients or guardians.

Although Kant’s final work in moral philosophy, Die Metaphysik der Sitten, currently attracts much scholarly attention, there is still a lot to explore. This article is an attempt to get to grips with a particular, often neglected passage of the Rechtslehre, namely §35. Here Kant defends the view that not only can a person’s good reputation can be tarnished after his death, but also that this constitutes a violation of this dead person’s property. Here I will not be able to fully clarify what Kant means when he holds that persons can be harmed after their death, but I will put Kant’s view in a few perspectives.

Background Vaccination during pregnancy can protect both the expecting mother and the unborn and newborn child from infectious diseases. Methods This review is based on publications retrieved by a selective literature search on the immunological particularities of infectious diseases affecting pregnant women, unborn children, and neonates, with particular attention to the guidelines of the German Standing Committee on Vaccinations (Standige Impfkommission, STIKO) and the pertinent guidelines. Results Vaccination during pregnancy protects the expecting mother from a severe course of a number of different infectious diseases. Vaccination with inactivated vaccines against influenza, tetanus, and pertussis is effective, safe, and well tolerated. Women who are pregnant or of child-bearing age should be immunized against tetanus according to the STIKO recommendations. All pregnant women from the second trimester onward should receive an inactivated quadrivalent influenza vaccine. The immunity acquired after vaccination with an acellular pertussis vaccine is present only for a limited time. In a cohort study involving 72,781 pregnant women, pertussis vaccination during pregnancy was found to yield 91% protection against pertussis for their subsequently born children in the first three months of life. Further types of vaccine can also be given during pregnancy if indicated. Additional reasonable measures to protect the health of mother and child include the vaccination of other persons in close contact as well as the closure of relevant vaccination gaps among young adults, particularly women of child-bearing age. Treating physicians play a crucial role in encouraging vaccine acceptance by their patients. Conclusion Maternal immunization is a safe and effective strategy for giving neo - nates passive immune protection against life-threatening infections by the vertical transmission of maternal antibodies until they are able to build up their own adaptive immunity.

Human CMV (HCMV) is a ubiquitous pathogen that indelibly shapes the NK cell repertoire. Using transcriptomic, epigenomic, and proteomic approaches to evaluate peripheral blood NK cells from healthy human volunteers, we find that prior HCMV infection promotes NK cells with a T cell–like gene profile, including the canonical markers CD3ε, CD5, and CD8β, as well as the T cell lineage–commitment transcription factor Bcl11b. Although Bcl11b expression is upregulated during NK maturation from CD56(bright) to CD56(dim), we find a Bcl11b-mediated signature at the protein level for FcεRIγ, PLZF, IL-2Rβ, CD3γ, CD3δ, and CD3ε in later-stage, HCMV-induced NK cells. BCL11B is targeted by Notch signaling in T cell development, and culture of NK cells with Notch ligand increases cytoplasmic CD3ε expression. The Bcl11b-mediated gain of CD3ε, physically associated with CD16 signaling molecules Lck and CD247 in NK cells is correlated with increased Ab-dependent effector function, including against HCMV-infected cells, identifying a potential mechanism for their prevalence in HCMV-infected individuals and their prospective clinical use in Ab-based therapies.

Background and aims Children with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH) receiving immunosuppressive treatment are at risk for severe varicella zoster virus (VZV)-induced disease. This study evaluated vaccination of susceptible patients with stable disease and documented immunoreactivity without interruption of their current immunosuppression (IS). Methods This prospective multicentre observational study used a prevaccination checklist to select patients with low-intensity and high-intensity IS for VZV vaccination. Tolerability and safety after immunization were assessed by questionnaire. The immune response was measured by the VZV-IgG concentration, relative avidity index (RAI), and specific lymphocyte proliferative response. Results A total of 29 VZV vaccinations were performed in 17 seronegative patients aged 3–16 years (IBD n = 15, AIH n = 2). Eight patients received high-intensity immunosuppression, another six low-intensity immunosuppression, and three patients interrupted IS before VZV vaccination. All 29 vaccinations were well tolerated; only minor side effects such as fever and abdominal pain, were reported in two patients. One patient experienced a flare of Crohn’s disease the day after vaccination. The VZV-IgG-concentration increased significantly (p = 0.018) after vaccination, and a specific lymphocyte response towards VZV in vitro was detected in all tested patients which correlated with the RAI (r = 0.489; p = 0.078). Conclusions VZV vaccination was well tolerated, safe and immunogenic in children receiving ongoing IS due to IBD and AIH. Ensuring immunoreactivity by clinical and laboratory parameters, rather than the type and dosage of IS, is a reasonable approach to decide on live-attenuated virus vaccinations in immunosuppressed children (German clinical trials DRKS00016357).

Apart from classical antigen-presenting cells (APCs) like dendritic cells and macrophages, there are semiprofessional APCs such as endothelial cells (ECs) and Langerhans' cells. Human cytomegalovirus (HCMV) infects a wide range of cell types including the ECs which are involved in the trafficking and homing of T cells. By investigating the interaction of naive T cells obtained from HCMV-seronegative umbilical cord blood with autologous HCMV-infected human umbilical vein ECs (HUVECs), we could show that the activation of naive T cells occurred after 1 day of peripheral blood mononuclear cell (PBMC) exposure to HCMV-infected HUVECs. The percentage of activated T cells increased over time and the activation of naive T cells was not induced by either autologous uninfected HUVECs or by autologous HCMV-infected fibroblasts. The activation of T cells occurred also when purified T cells were co-cultured with HCMV-infected HUVECs. In addition, in most of the donors only CD8+ T cells were activated, when the purified T cells were exposed to HCMV-infected HUVECs. The activation of naive T cells was inhibited when the NKG2D receptor was blocked on the surface of T cells and among the different NKG2D ligands, we identified two ligands (ULBP4 and MICA) on HCMV-infected HUVECs which might be the interaction partners of the NKG2D receptor. Using a functional cell culture assay, we could show that these activated naive T cells specifically inhibited HCMV transmission. Altogether, we identified a novel specific activation mechanism of naive T cells from the umbilical cord by HCMV-infected autologous HUVECs through interaction with NKG2D.

A live attenuated vaccine (Zostavax (R)) against herpes zoster (HZ) and posther-petic neuralgia (PHN) was licensed for persons 50 years of age and older in 2006 and became available in Germany in September 2013. Based on the conclusion, that an effective and sustainable reduction of the HZ disease burden cannot be achieved with this vaccine, the STIKO decided against issuing a recommendation for routine HZ vaccination at this time. This decision is based on a systematic review of available data on the efficacy, duration of protection, and safety of the vaccine, and is supported by the results of health economic modelling. Both, the risk of developing HZ and the severity of the illness increase markedly with age. The efficacy of the vaccine, however, decreases with advancing age, from 70% for persons in their 50s to 41% for persons in their 70s to less than 20% for persons 80 years of age and older. The duration of vaccine related protection is limited to only a few years. The modelling results show only a slight, age-dependent reduction in the total number of HZ cases through vaccination with the live attenuated vaccine. The reduction ranged from 2.6% for persons vaccinated at the age of 50 to 0.6% for those vaccinated at the age of 80, based on assumed vaccine coverage of 35.5%. In addition to the vaccine's poor efficacy and duration of protection, HZ vaccination does not offer any added value in terms of herd immunity, since HZ is a disease of an endogenously reactivated pathogen with low transmission potential. Finally, the live attenuated vaccine is often contraindicated in persons who are at greatest risk of HZ and its complications. Thus, in the overall appraisal, the epidemiological benefit-risk assessment of the HZ vaccination did not lead to a recommendation for routine vaccination with the live attenuated vaccine. An individual benefit-risk assessment may, however, lead to a different decision in individual patients.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

Rationale: Patients receiving an allogeneic stem cell graft from cytomegalovirus (CMV) seronegative donors are particularly prone to CMV reactivation with a high risk of disease and mortality. Therefore we developed and manufactured a novel vaccine and initiated a clinical phase I trial with a CMV phosphoprotein 65 (CMVpp65)-derived peptide. Methods: Ten patients after allogeneic stem cell transplantation received four vaccinations at a biweekly interval. All patients were monitored for CMVpp65 antigenemia. Flow cytometry for CMV-specific CD8+ and γδ T cells as well as neutralizing anti-CMV antibodies were correlated to clinical parameters. Results: The vaccination was well tolerated. Seven of nine patients cleared CMVpp65 antigenemia after four vaccinations and are still free from antigenemia to this day. Two patients with CMV reactivation showed persisting CMV antigenemia. One patient received prophylactic vaccination and did not develop antigenemia. An increase of up to six-fold in frequency of both CMV-specific CD8+ T cells and/or Vδ2negative γδ T cells was detected. Titers of neutralizing antibodies increased up to the tenfold. Humoral and cellular immune responses correlated with clearance of CMV. Conclusion: In summary, CMVpp65 peptide vaccination for patients after allogeneic stem cell transplantation at high risk for CMV reactivation was safe, well tolerated and clinically encouraging. A study in solid-organ transplant patients is ongoing.

The epidemiological effect of vaccination is that it primarily reduces the incidence and prevalence of infectious agents and diseases, providing ideal conditions (also from an economic point of view) for prevention. Goal of vaccination is first the individual protection. Other goals may be "herd immunity", regional repression and global extinction. The STIKO provides recommendations for the implementation of vaccinations and for the implementation of other measures for the specific prevention of communicable diseases and develops criteria for the differentiation of a customary vaccination reaction and damage to health beyond the usual extent of a vaccination reaction. Earlier vaccination recommendations based on "expert opinion" but today are based on the best available evidence. Current STIKO recommendations include vaccination against seasonal influenza, vaccination against HPV, Tdap booster, tetanus PEP, and vaccine management in practice and among migrants. For the success of the vaccination recommendations, it is first and foremost crucial that the medical profession complies with the obligation to inform about vaccination options and needs vis-à-vis patients or guardians.

Bespreking van: M.A. Kramer,Torture and Moral Integrity. A Philosophical Enquiry Oxford:Oxford University Press ,2014 9780198714200

Bespreking van: R. Maliks,Kant’s Politics in Context Oxford:Oxford University Press ,2014 9780199645152 C. Horn,Nichtideale Normativitat. Ein neuer Blick auf Kants politische Philosophie Berlin:Suhrkamp Verlag ,2014 9783518296745

Objective:: Pathogenic microbes may be transmitted directly from the orthodontist to the patient or from the patient to the doctor, and indirectly from patient to patient. The latter may occur via contaminated instruments or surfaces, and is referred to as cross-contamination. The objective of this study was to evaluate the extent of bacterial contamination of orthodontic pliers and the efficacy of the disinfection techniques applied after clinical use. We also sought to examine under standardized conditions the virucidal, bactericidal and fungicidal effects of disinfection techniques used in practice. Materials and Methods:: The efficacy of various disinfection methods was determined after clinical use in-vivo on 10 test subjects and in-vitro with deliberate contamination. The following disinfection methods were tested: 1. Iso-Septol spray 2. Incidur® spray 3. Trough disinfection in combination with 5% Sekusept® Plus solution 4. Ultrasound bath in combination with 5% Sekusept® Plus solution 5. Thermal disinfection For in-vitro contamination we used the test organisms Staphylococcus aureus, Escherichia coli, Candida albicans, Coxsackie virus B4, HSV 1, and Adenovirus type 5. The tests were carried out six to eight times for each organism. The Weingart pliers and distalend cutters were tested. The criteria for effective disinfection were a reduction in infectiosity of five log steps (for bacteria and fungi) or four log steps (viruses). Statistical analysis was carried out using the Wilcoxon and Whitney U-test. Results:: The presence of contamination following clinical use was not adequately eliminated with all disinfection methods. The spray methods exhibited shortcomings in disinfection. For the type of contamination defined, trough disinfection with 5% Sekusept® Plus and the Incidur® and Iso-Septol spray disinfection methods provided insufficient disinfection. Conversely, the ultrasound bath with 5% Sekusept® Plus solution and steam disinfection met the criteria for effective disinfection for all microbes. No statistically significant difference was found between the oiled and unoiled states. In some cases, there were slightly higher rates of contamination with the Weingart pliers as with the distalend cutters. However, these were not statistically significant. Conclusions:: It should be possible to disinfect lipophilic viruses and the usual bacterial infections adequately with all methods, provided that the use of sprays and trough disinfection is preceded by cleaning with brush and water, followed by drying. With hydrophilic viruses, however, the spray and trough disinfection methods are limited in their efficacy and cannot be considered adequate. Exclusively chemical methods are therefore less effective than thermal or physical-chemical methods. Thermal disinfection and the ultrasound bath in combination with 5% Sekusept® Plus are clearly superior to spray disinfection and trough disinfection alone. The ultrasound bath and thermal disinfection can therefore be recommended for the disinfection of orthodontic pliers. We recommend that the pliers be cleaned beforehand due to their uneven surfaces

Background The goal of this study was to apply the varicella zoster virus (VZV) vaccine to patients with pediatric rheumatic diseases (PRD) at risk for severe chickenpox, without interrupting their current immunosuppression, including biological agents, using an immunological-based pre-vaccination checklist to assure safety. A pre-vaccination checklist was implemented to ensure adequate immune competence prior to immunization. Methods This prospective study included seronegative patients (VZV-IgG ≤200 mIU/ml) and patients who had previously received only a single dose of VZV vaccine. All vaccinees demonstrated clinically inactive PRD. Patients were categorized according to their actual treatment in low-intensity IS (LIIS) and high-intensity IS (HIIS) including biological therapy. The pre-vaccination checklist defined thresholds for the following basic laboratory tests: white blood cell count ≥3000/mm3, lymphocytes ≥1200/mm3, serum IgG ≥500 mg/dl, IgM ≥20 mg/dl, tetanus toxoid antibody ≥0.1 IU/ml. In case of HIIS additional specifications included a CD4+ lymphocyte count ≥200/mm3 and a positive T-cell function (via analyzable positive control of a standard tuberculosis interferon-gamma-release-assay (TB-IGRA) indicating mitogen-induced T cell proliferation). Patients who met the criteria of the pre-vaccination checklist received the first and/or second VZV vaccination. Immunologic response and side effects were monitored. Results Twenty-three patients were recruited of whom nine had already received one VZV immunization before initiating IS. All patients met the pre-vaccination checklist criteria despite ongoing IS. There was no overall difference in VZV-IgG levels when comparing the LIIS (n=9) and HIIS (n=14) groups. In total, 21 patients (91%) showed a positive vaccination response, after the first immunization the median VZV-IgG across all patients was 224 (59-1219) mIU/ml (median (range)), after booster immunization it increased to 882 (30-4685) mIU/ml. Two patients in the HIIS group failed to raise positive VZV-IgG, despite booster immunization. All nine patients receiving only the second immunization on IS reached high titers of VZV-IgG >500 mIU/ml (1117 (513-4685) mIU/ml). There were no cases of rash or other vaccine-induced varicella disease symptoms and no evidence of PRD flare. Conclusions VZV vaccination is safe and largely immunogenic in children with ongoing IS fulfilling an immunological based pre-vaccination checklist. This new approach is based on immunologic function rather than on type of medications. Trial registration number ISRCRTN trial registration number 21654693, date of registration February 12, 2018, retrospectively registered. Electronic supplementary material The online version of this article (10.1186/s12969-018-0231-3) contains supplementary material, which is available to authorized users.