Correction to: Late Presentation of HIV Infection in the Netherlands: Reasons for Late Diagnoses and Impact on Vocational Functioning.

The original version of this article was published open access. Unfortunately, due to a technical issue, the copyright holder name in the online version (HTML and XML) is incorrectly published as "Springer Science + Business Media, LLC, part of Springer Nature 2018". Instead, it should be "The Author(s) 2018".

Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig.

Donor-specific antibodies (DSAs) are a barrier to improved long-term outcomes after kidney transplantation. Costimulation blockade with CTLA4-Ig has shown promise as a potential therapeutic strategy to control DSAs. T follicular helper (Tfh) cells, a subset of CD4+ T cells required for optimal antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8+ T cells relative to CTLA4-Ig, but the impact of CD28-specific blockade on CD4+ Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model and then used this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh cell-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5+ PD-1high Tfh cells, CD95+ GL7+ germinal center B cells and DSA formation compared with CTLA4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA4 expression, suggesting an important role for CTLA4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.

Late Presentation of HIV Infection in the Netherlands: Reasons for Late Diagnoses and Impact on Vocational Functioning.

Late diagnosis of HIV remains a major challenge in the HIV epidemic. In Europe, about 50% of all people living with HIV are diagnosed late after infection has occurred. Insight into the reasons for late diagnoses is necessary to increase the number of early diagnoses and optimize treatment options. This qualitative study explored the experiences of 34 late-presenters through in-depth semi-structured interviews. A variety of reasons for late diagnoses emerged from our data and led to a division into four groups, characterized by two dimensions. Regarding vocational functioning, the consequences of late diagnoses were health-related problems prior to and since diagnosis, and problems concealing the HIV status. Healthcare providers should offer HIV tests to groups at risk, and be alert for clinical HIV indicator conditions. It is recommended to increase awareness of HIV transmission routes, symptoms and tests, and the benefits of early testing and early entry to HIV care.

Rapamycin ameliorates the CTLA4-Ig-mediated defect in CD8(+) T cell immunity during gammaherpesvirus infection.

Latent viral infections are a major concern among immunosuppressed transplant patients. During clinical trials with belatacept, a CTLA4-Ig fusion protein, patients showed an increased risk of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder, thought to be due to a deficient primary CD8(+) T cell response to the virus. Using a murine model of latent viral infection, we observed that rapamycin treatment alone led to a significant increase in virus-specific CD8(+) T cells, as well as increased functionality of these cells, including the ability to make multiple cytokines, while CTLA4-Ig treatment alone significantly dampened the response and inhibited the generation of polyfunctional antigen-specific CD8(+) T cells. However, the addition of rapamycin to the CTLA4-Ig regimen was able to quantitatively and qualitatively restore the antigen-specific CD8(+) T cell response to the virus. This improvement was physiologically relevant, in that CTLA4-Ig treated animals exhibited a greater viral burden following infection that was reduced to levels observed in untreated immunocompetent animals by the addition of rapamycin. These results reveal that modulation of T cell differentiation though inhibition of mTOR signaling can restore virus-specific immune competence even in the absence of CD28 costimulation, and have implications for improving protective immunity in transplant recipients.

Pathogen Stimulation History Impacts Donor-Specific CD8(+) T Cell Susceptibility to Costimulation/Integrin Blockade-Based Therapy.

Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8(+) memory T cell-mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi-cytokine producers. These data, therefore, demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation.

Cardiac biomarkers for infarct diagnosis and early exclusion of acute coronary syndrome.

The acute coronary syndrome (ACS) represents a diagnostic challenge: on the one hand patients need to be quickly identified to initiate treatment and on the other hand early exclusion of patients without ACS is important to relieve patient stress as well as overcrowded emergency departments. A growing number of biomarkers are becoming available to aid physicians with this task. This review gives an overview of the current research concerning early exclusion with an emphasis on the clinically most important biomarker: cardiac troponin.

Employment-related concerns of HIV-positive people in the Netherlands: input for a multidisciplinary guideline.

PURPOSE: Finding and keeping employment is difficult for people with HIV. To improve supportive care for people with HIV and employment-related problems, a multidisciplinary guideline was developed in the Netherlands in 2010/2011. To identify the employment-related concerns of people with HIV and to formulate the key questions for the guideline, we conducted a qualitative study. The results of this study are described in this article. METHODS: This study was performed in three HIV-treatment centers in the Netherlands. In total 18 participants participated in three focus-group interviews and nine participants were interviewed individually. The data were transcribed ad verbatim and were analyzed according to the principle of constant comparison. RESULTS: Our findings indicate that people with HIV in the Netherlands face many work-related concerns. The themes which emerged from this study were disclosure, stigma and discrimination, knowledge about HIV, physical and psychological factors, working conditions, absenteeism, reintegration, and dismissal and counselling. CONCLUSIONS: This study provides insight into employment-related concerns for people with HIV living in a Western country. It formed the basis for the key questions which were addressed in a multidisciplinary, evidence-based guideline "HIV and work". Finally, it gives leads for further scientific research and opportunities for improving the vocational guidance of people with HIV.

Copper Intoxication in South American Camelids-Review of the Literature and First Report of a Case in a Vicuña (Vicugna vicugna).

Copper (Cu), an essential trace element in the metabolism of mammals, plays a central role in various metabolic processes. However, overdosing can lead to severe symptoms and even fatalities. Chronic Cu intoxication continues to be a problem in grazing and domestic animals, with sheep being particularly sensitive. There are few comparative studies on its impact on South American camelids (SACs). Therefore, this work presents the results of literature research combined with a case report on a 3-year-old female vicuña (Vicugna vicugna) presented to the clinic from a zoological garden in northern Germany. The animal showed reduced food intake, recumbency, bruxism, icteric mucous membranes and sclera. Auscultation revealed atony of the third compartment and the digestive tract. Similar to cases described in the literature, the animal showed rapid deterioration of its condition with unspecific symptoms of liver failure and rapid death. However, in contrast to descriptions in sheep, clinical icterus has not been previously reported in cases of other SACs. Laboratory findings from EDTA and serum samples revealed neutrophilia with a left shift, hypoproteinaemia, lymphopaenia, azotaemia, elevated levels of creatine kinase (CK), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) in the serum. Hyperbilirubinaemia and significantly elevated serum and liver Cu levels were observed. Subsequent blood samples from the remaining vicuñas and alpacas in the same enclosure showed no remarkable abnormalities. To the best of the authors' knowledge, this case report represents the first documented case of Cu intoxication specifically in vicuñas.

An anti-CD154 domain antibody prolongs graft survival and induces Foxp3(+) iTreg in the absence and presence of CTLA-4 Ig.

The use of monoclonal antibodies targeting the CD154 molecule remains one of the most effective means of promoting graft tolerance in animal models, but thromboembolic complications during early clinical trials have precluded their use in humans. Furthermore, the role of Fc-mediated deletion of CD154-expressing cells in the observed efficacy of these reagents remains controversial. Therefore, determining the requirements for anti-CD154-induced tolerance will instruct the development of safer but equally efficacious treatments. To investigate the mechanisms of action of anti-CD154 therapy, two alternative means of targeting the CD40-CD154 pathway were used: a nonagonistic anti-CD40 antibody and an Fc-silent anti-CD154 domain antibody. We compared these therapies to an Fc-intact anti-CD154 antibody in both a fully allogeneic model and a surrogate minor antigen model in which the fate of alloreactive cells could be tracked. Results indicated that anti-CD40 mAbs as well as Fc-silent anti-CD154 domain antibodies were equivalent to Fc-intact anti-CD154 mAbs in their ability to inhibit alloreactive T cell expansion, attenuate cytokine production of antigen-specific T cells and promote the conversion of Foxp3(+) iTreg. Importantly, iTreg conversion observed with Fc-silent anti-CD154 domain antibodies was preserved in the presence of CTLA4-Ig, suggesting that this therapy is a promising candidate for translation to clinical use.

Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+) memory T cells.

The success of belatacept in late-stage clinical trials inaugurates the arrival of a new class of immunosuppressants based on costimulatory blockade, an immunosuppression strategy that disrupts essential signals required for alloreactive T-cell activation. Despite having improved renal function, kidney transplant recipients treated with belatacept experienced increased rates of acute rejection. This finding has renewed focus on costimulatory blockade-resistant rejection and specifically the role of alloreactive memory T cells in mediating this resistance. To study the mechanisms of costimulatory blockade-resistant rejection and enhance the clinical efficacy of costimulatory blockade, we developed an experimental transplant system that models a donor-specific memory CD8(+) T-cell response. After confirming that graft-specific memory T cells mediate costimulatory blockade-resistant rejection, we characterized the role of integrins in this rejection. The resistance of memory T cells to costimulatory blockade was abrogated when costimulatory blockade was coupled with either anti-VLA-4 or anti-LFA-1. Mechanistic studies revealed that in the presence of costimulatory blockade, anti-VLA-4 impaired T-cell trafficking to the graft but not memory T-cell recall effector function, whereas anti-LFA-1 attenuated both trafficking and memory recall effector function. As antagonists against these integrins are clinically approved, these findings may have significant translational potential for future clinical transplant trials.

COVID-19 related stigma and health-protective behaviours among adolescents in the Netherlands: An explorative study.

The COVID-19 pandemic has forced many governments to impose social distancing measures upon its citizens, including in the Netherlands. Motivating adolescents to adhere to measures such as social distancing can be challenging, since adolescents are relatively more affected by them, while experiencing virtually no personal health benefit. In addition, the COVID-19 pandemic seems to impact the social environment of adolescents in schools, as some media sources have reported bullying and stigmatisation of students with an Asian appearance. This study aims to explore the experiences of adolescents regarding their Health-Protective Behaviour (HPB), as well as the prevalence and expression of stigma towards ethnic minorities within the context of the first wave of COVID-19 pandemic. We performed a cross-sectional mixed-methods study, including two independent online questionnaires. An adapted version of the "HPB" questionnaire (n = 528) and the "Measure of Disease-Related Stigma (MDRS)" questionnaire (n = 380), were administered to Dutch adolescents of 10-16 years old, attending primary or secondary school. Furthermore, 15 interviews were held with eight male and seven female adolescents. All data collection took place between March 17 and April 20, 2020. Results show that adolescents perceive COVID-19 as a threat to other peoples' health, rather than their own, and report adherence to public health measures in the interest of older and more vulnerable members of their community. We found no convincing evidence for widespread misinformation or stigmatising of certain ethnic groups among adolescents related to COVID-19 during this study. Participants acknowledged such behaviour happened in the early stages of the pandemic, before this study was initiated. Adolescents are a vital group for public health researchers to engage with during a pandemic, even when reaching them can be challenging.

Dutch healthcare professionals' opinion on vaccination and education to prevent infections in immunocompromised patients: A mixed-method study with recommendations for daily practice.

BACKGROUND: The fast-growing population of immunocompromised patients (ICP) is more vulnerable to infectious diseases, demanding strategies to protect them. These strategies seem inconsistent in available guidelines and in practices. We aim to evaluate healthcare professionals' (HCP) opinions on vaccination to reduce the number and severity of infections in ICP. METHODS: A mixed-method study, with an exploratory sequential design, was performed. Medical specialists from various departments in a tertiary care center in the Netherlands were invited for semi-structured interviews to explore their perspective on preventive care of ICP. Topics that play a substantial role in daily practice for ICP were translated into a survey to gain insight into what extent opinions were generalizable to Erasmus Medical Center. RESULTS: Surveys were completed by 689 HCP (43% of the invitees), 269 of them treated at least two ICP weekly on average and were considered eligible for further analysis. Quantitative data showed that according to 80 percent of HCP, preventive care for ICP can be improved. Education was chosen by 40 percent as the most important intervention to reduce the number and severity of infections. Vaccinations were valued as important by seventeen percent of HCP. Except for influenza, vaccinations were not regularly discussed during routine consultations. Difficulties to administer vaccinations were experienced by 75 percent of HCP. CONCLUSION: According to our respondents, education is the most promising intervention to reduce the number and severity of infections in ICP. To reach a higher vaccine uptake, we recommend HCP to address vaccinations more frequently during consultations and to search for solutions to alleviate barriers to vaccinate.

Prevalence of eosinophilic esophagitis: A multicenter study on a pediatric population evaluated at thirty-six Latin American gastroenterology centers. / Prevalencia de esofagitis eosinofílica: estudio multicéntrico en población pediátrica evaluada en 36 centros de gastroenterología de América Latina.

INTRODUCTION AND OBJECTIVE: Eosinophilic esophagitis is a chronic, immune-mediated disease described in case series and publications worldwide. Over the past twenty years, the authors of different studies have attempted to evaluate its incidence and prevalence. The objetive of the present study was to estimate the prevalence of eosinophilic esophagitis in a group of children seen at 36 pediatric gastroenterology centers in ten Latin American countries. MATERIALS AND METHODS: A multicenter, observational, and cross-sectional study was conducted that estimated the period prevalence of eosinophilic esophagitis in children seen at outpatient consultation and that underwent diagnostic upper gastrointestinal endoscopy for any indication at 36 centers in 10 Latin American countries, within a 3-month time frame. RESULTS: Between April and June 2016, 108 cases of eosinophilic esophagitis were evaluated. Likewise, an average of 29,253 outpatient consultations and 4,152 diagnostic upper gastrointestinal endoscopies were carried out at the 36 participating centers. The period prevalence of eosinophilic esophagitis in the population studied (n=29,253) was 3.69 cases×1,000 (95% CI: 3.04 to 4.44), and among the children that underwent routine upper gastrointestinal endoscopy (n=4,152), it was 26x1,000 (95% CI: 22.6 to 29.4). CONCLUSIONS: The general period prevalence of eosinophilic esophagitis in a group of children evaluated at 36 Latin American pediatric gastroenterology centers was 3.69×1,000, and in the children that underwent endoscopy, it was 26×1,000. There was important prevalence variability between the participating countries and centers. The present analysis is the first study conducted on the prevalence of pediatric eosinophilic esophagitis in Latin America.

Antifungal management practices in liver transplant recipients.

We sought to determine the approach to antifungal prophylaxis, and diagnostic and therapeutic practices for the management of invasive aspergillosis in liver transplant recipients. Data were collected by an electronic survey questionnaire sent to all active liver transplant programs in North America; 63% (67/106) of the sites completed the survey. Overall, 91% of the sites employed antifungal prophylaxis; 28% used universal prophylaxis and 72% targeted it toward high-risk patients. Fluconazole was the most commonly used agent for universal and targeted prophylaxis. The leading choice for mold-active agents for antifungal prophylaxis was the echinocandins. Combination therapy was used as primary therapy for invasive aspergillosis in 47%, and as salvage in 80%. Thus, a vast majority of the surveyed programs employ antifungal prophylaxis and most use targeted prophylaxis. Consideration of these practices could guide clinical trial design to optimize antifungal prophylaxis in these patients. Our findings also merit investigations to better define the role of diagnostic assays and combination therapeutic strategies for invasive aspergillosis in liver transplant recipients.

Prevention of posttransplant cytomegalovirus disease and related outcomes with valganciclovir: a systematic review.

The precise impact of valganciclovir as preventive therapy for cytomegalovirus (CMV) in solid organ transplant (SOT) recipients is not fully defined. Data from studies using valganciclovir as preemptive therapy or prophylaxis for CMV in SOT recipients were synthesized for descriptive analysis. CMV disease occurred in 2.6% and 9.9% of the patients receiving valganciclovir as preemptive therapy and prophylaxis, respectively. Although the incidence of early-onset (90 days posttransplant) CMV disease rose up to 8.9% and 17.7% in the prophylactic group, respectively. On the contrary, no patients developed late-onset CMV disease in preemptive group. Both approaches with valganciclovir have successfully decreased CMV disease in SOT recipients. Late-onset CMV disease is a complication observed uniquely with valganciclovir prophylaxis, particularly in R-/D+ patients, but not with preemptive therapy.

A survey of CMV prevention strategies after liver transplantation.

The degree of variability in the use of CMV prevention strategies and choice of antiviral regimens among LT centers has not been previously investigated. An electronic survey on current CMV prevention strategies was sent to all US and Canadian LT centers. A total of 58 (53%) centers completed the survey. Most use CMV PCR for screening or diagnosis. Prophylaxis was the most common prevention strategy for all donor/recipient subtypes except D-/R- who often receive no prophylaxis. Prophylaxis was usually given for 3 months after LT with valganciclovir the most frequently used agent. In the small percentage of centers utilizing the preemptive approach, monitoring for CMV was typically performed with PCR for 3 months and valganciclovir was most frequently used for treatment of detectable CMV viremia. In conclusion, the majority of LT centers utilize CMV prophylaxis over other strategies. Valganciclovir is the most commonly used agent for both antiviral prophylaxis and treatment of CMV viremia in the preemptive approach.

CD117- and vimentin-positive telocytes in the bovine teat sphincter.

Mastitis is a common economically relevant problem in dairy farming. As the major entry for pathogens is the papillary duct, one of the first defence mechanisms is the teat sphincter. This sphincter shows a rhythmic contractility of yet unknown origin. Searching for possible modulatory pacemaker cells, teat sphincters of eight cows were stained immunohistochemically with antibodies against CD117 and vimentin and evaluated microscopically for the presence of telocytes. CD117- and vimentin-positive telocytes with telopodes were found in close contact with smooth muscle cells. Our findings present a first evidence of telocytes in the teat of bovines.

Wound infection secondary to snakebite.

BACKGROUND: Snakebites can produce severe local and systemic septic complications as well as being associated with significant overall morbidity and even mortality. OBJECTIVE: A prospective audit was undertaken to determine the bacterial causation of wound infection secondary to snakebite, and attempt to quantify the burden of disease. METHODS: The audit was undertaken at Ngwelezane Hospital, which provides both regional and tertiary services for north-eastern KwaZulu-Natal Province, South Africa, over a 4-month period. Records of patients who required surgical debridement for extensive skin and soft-tissue necrosis were analysed. At the time of debridement, tissue samples of necrotic or infected tissue were sent for bacteriological analysis as standard of care. Microbiology results were analysed. RESULTS: A total of 164 patients were admitted to hospital for management of snakebite, of whom 57 required surgical debridement and 42 were included in the final microbiological analysis. Children were found to be the most frequent victims of snakebite; 57.8% of patients in this study were aged ≤10 years and 73.7% ≤15 years. Culture showed a single organism in 32/42 cases, two organisms in 8 and no growth in 2. Eight different types of organisms were cultured, five of them more than once. Thirty-five specimens (83.3%) grew Gram-negative Enterobacteriaceae, the most frequent being Morganella morganii and Proteus species. Thirteen specimens (31.0%) grew Enterococcus faecalis. Gram-negative Enterobacteriaceae showed 31.4% sensitivity to ampicillin, 40.0% sensitivity to amoxicillin plus clavulanic acid, 34.3% sensitivity to cefuroxime, 97.1% sensitivity to ceftriaxone, and 100% sensitivity to ciprofloxacin, gentamicin and amikacin. E. faecalis was 92.3% sensitive to amoxicillin, 92.3% sensitive to amoxicillin plus clavulanic acid, 100% sensitive to ciprofloxacin, 92.3% resistant to erythromycin and 100% resistant to ceftriaxone. CONCLUSION: Children are particularly vulnerable to snakebite, and the consequences can be devastating. While the majority of patients in this study were shown to have secondary bacterial infection, debridement and subsequent wound management is considered the mainstay of treatment. Common organisms are Enterobacteriaceae and enterococci. There appears to be a role for antibiotics in the management of these patients. A good antibiotic policy is strongly advocated.

Work-related stigma and disclosure: A daily challenge for people living with HIV.

BACKGROUND: Stigma and disclosure are important work-related issues for people living with HIV (PLWH). To gain better understanding and improve the position of PLWH in the labor market, further insight in these issues is needed. OBJECTIVE: This study reviews the scientific evidence related to work-related stigma and disclosure. METHODS: A sensitive literature search was performed in the databases of Medline, Embase, Cochrane Library, Cinahl and Psychinfo for articles published between 1996 and 2016. All studies on PLWH in western countries and investigating disclosure or stigma in relation to work were included. RESULTS: Of the 866 identified studies, 19 met the inclusion criteria: 4 addressed both disclosure and stigma (2 quantitative), 9 addressed only disclosure (4 quantitative) and 7 studies addressed only stigma (4 quantitative). CONCLUSION: This review provides a unique overview of the research on work-related disclosure and stigma, which will enable health care providers to support PWLH to make well-considered decisions. However, the available literature was heterogeneous and in most studies the topics of our interest were secondary outcomes and provided only basic insight.