Psychological support for individuals historically infected with HIV and/or hepatitis C as a result of NHS-supplied blood transfusions and blood products, and for affected families

BACKGROUND: Between 1970 and 1991, between 30,000 and 33,000 people in the UK were infected with HIV and/or hepatitis C as a result of treatment with NHS blood and blood products; 2,900 deaths during 1970-2019 are estimated to be attributable to these infections, and people are still dying. The statutory Infected Blood Inquiry, launched in July 2018, has been investigating the circumstances that led to individuals becoming infected and the impacts this has had on them and their families. Among the many issues raised, the Inquiry emphasised the psychosocial impacts and the lack of access to dedicated psychological support for those infected and affected. The England Infected Blood Support Scheme (EIBSS) provides access to a discretionary payment of up to £900 for privately arranged psychological support per year (with the option of ‘further treatment’ funding), which can be accessed upon application. However, uptake of the payment among EIBSS beneficiaries and their family members has been very low, and the reasons for this are unclear. There is lack of robust evidence on the needs for psychological support among those infected and affected by infected blood and blood products. The need for this evidence has become more urgent with the Inquiry concluding in autumn 2023. This study was commissioned to help fill this evidence gap and to inform and consider options for improving the existing offer of psychological support services for infected and affected people. APPROACH We conducted in-depth interviews with 52 infected and affected people and 14 mental health practitioners and experts to understand these needs and explore possible service improvements. Interview participants came from a fairly broad age range and across regions in England, although there were a larger number of women and people identifying as White British than would reflect the UK population. Interviews were conducted between January and May 2023. PRINCIPAL FINDINGS: The infected blood scandal had, and continues to have, a profound impact on the mental health and wellbeing of infected and affected people. Study participants shared multiple accounts of grief and loss, anger, fear and anxiety, guilt, and facing stigma, isolation and discrimination because of infection. About half of the people who participated in the study explicitly said they had experienced trauma, and most described incidents that have caused them significant distress. Additionally, many participants described further long-term ill health linked to the side-effects of their infection(s) and their treatments, which many described as having life-changing impacts on their wellbeing. Affected people also reported very significant impacts of their loved one’s infection on their own wellbeing, including profound emotional and financial consequences of bereavement. Only some of those interviewed for this study had been able to access and use psychological support services for their mental health over the years, and only just over half of the study participants were aware of EIBSS payments for psychological support. Some participants only learnt about the availability of the EIBSS discretionary payment during the research interview. Identified barriers that prevented people from accessing counselling and psychological support included social and personal issues, such as feeling unable to open up, stigma 2 of NHS-supplied blood transfusions and blood products, and for affected families – Final report through encounters with the wider health system; study participants reported instances of discrimination in healthcare settings, which made it even more difficult for people to seek professional help. Only a very small number of people found the EIBSS payment scheme for psychological support easy to work through. Most described this route as requiring substantial effort, and being physically and mentally unwell further exacerbated these experiences. Study participants described feeling burdened by the application process and reported that finding a competent and suitable practitioner was often difficult. There is a substantial need for psychological support in the infected and affected communities, and this need is likely to increase once the Inquiry concludes. Practitioners working with infected and affected people cited instances where the Inquiry had already impeded the progress of clients working towards improving their mental health outcomes. Conclusions Existing psychological support services in England – whether accessed through the NHS or privately – do not currently meet the needs of infected and affected communities. Access to psychological support that is effective and experienced as tailored to an individual’s needs is not common and finding the right match between client and therapist is often down to chance. Accordingly, a future improved psychological support service should: • involve infected and affected people with a range of experiences in the development and design of the psychological support service; • address the substantial distrust in and legacy of EIBSS and the wider health system to provide an effective service; • be offered as standard to all individuals known to be infected or affected, and not just upon application; • be proactive, reaching out to and encouraging individuals to take up support; • be accessible through various routes with self-referral important to empower people and reduce access barriers; • be inclusive and broadened to a wider group of affected people than is currently the case; • be flexible and agile, allowing infected and affected people to access the service when they need it and re-enter it without additional administrative burdens for them; • be compassionate, respectful of its clients and non-judgemental. • be set in a specialist setting, include assessment, and offer individual therapy as well as peer support; • offer a range of therapeutic modalities and delivery modes (in-person, online, telephone); • work with adequately qualified, accredited and registered practitioners who have experience of working with trauma-affected populations, understand long-term health conditions that impact mental health and vice versa, and, importantly, have sensitivity to, and knowledge about the infected blood scandal, and related conditions including but not limited to HIV and hepatitis C. The service should be of high quality, with appropriate mechanisms for oversight and accountability. It should be embedded in a wider support system that is proactive, so that those who face the highest barriers or who are most vulnerable are still able to engage and benefit from this support service. This includes the creation of a single contact point or person (a navigator) who assists individuals to navigate the health and social care system more effectively. A service that ‘does the work’ by proactively reaching out to infected and affected people was seen as an important way in which the government could begin to address the harm it caused

Stage-Specific Germ-Cell Marker Genes Are Expressed in All Mouse Pluripotent Cell Types and Emerge Early during Induced Pluripotency

Embryonic stem cells (ESCs) generated from the in-vitro culture of blastocyst stage embryos are known as equivalent to blastocyst inner cell mass (ICM) in-vivo. Though several reports have shown the expression of germ cell/pre-meiotic (GC/PrM) markers in ESCs, their functional relevance for the pluripotency and germ line commitment are largely unknown. In the present study, we used mouse as a model system and systematically analyzed the RNA and protein expression of GC/PrM markers in ESCs and found them to be comparable to the expression of cultured pluripotent cells originated from the germ line. Further, siRNA knockdown experiments have demonstrated the parallel maintenance and independence of pluripotent and GC/PrM networks in ESCs. Through chromatin immunoprecipitation experiments, we observed that pluripotent cells exhibit active chromatin states at GC marker genes and a bivalent chromatin structure at PrM marker genes. Moreover, gene expression analysis during the time course of iPS cells generation revealed that the expression of GC markers precedes pluripotency markers. Collectively, through our observations we hypothesize that the chromatin state and the expression of GC/PrM markers might indicate molecular parallels between in-vivo germ cell specification and pluripotent stem cell generation

Multipotent adult germ-line stem cells, like other pluripotent stem cells, can be killed by cytotoxic T lymphocytes despite low expression of major histocompatibility complex class I molecules

BACKGROUND: Multipotent adult germ-line stem cells (maGSCs) represent a new pluripotent cell type that can be derived without genetic manipulation from spermatogonial stem cells (SSCs) present in adult testis. Similarly to induced pluripotent stem cells (iPSCs), they could provide a source of cellular grafts for new transplantation therapies of a broad variety of diseases. To test whether these stem cells can be rejected by the recipients, we have analyzed whether maGSCs and iPSCs can become targets for cytotoxic T lymphocytes (CTL) or whether they are protected, as previously proposed for embryonic stem cells (ESCs). RESULTS: We have observed that maGSCs can be maintained in prolonged culture with or without leukemia inhibitory factor and/or feeder cells and still retain the capacity to form teratomas in immunodeficient recipients. They were, however, rejected in immunocompetent allogeneic recipients, and the immune response controlled teratoma growth. We analyzed the susceptibility of three maGSC lines to CTL in comparison to ESCs, iPSCs, and F9 teratocarcinoma cells. Major histocompatibility complex (MHC) class I molecules were not detectable by flow cytometry on these stem cell lines, apart from low levels on one maGSC line (maGSC Stra8 SSC5). However, using a quantitative real time PCR analysis H2K and B2m transcripts were detected in all pluripotent stem cell lines. All pluripotent stem cell lines were killed in a peptide-dependent manner by activated CTLs derived from T cell receptor transgenic OT-I mice after pulsing of the targets with the SIINFEKL peptide. CONCLUSION: Pluripotent stem cells, including maGSCs, ESCs, and iPSCs can become targets for CTLs, even if the expression level of MHC class I molecules is below the detection limit of flow cytometry. Thus they are not protected against CTL-mediated cytotoxicity. Therefore, pluripotent cells might be rejected after transplantation by this mechanism if specific antigens are presented and if specific activated CTLs are present. Our results show that the adaptive immune system has in principle the capacity to kill pluripotent and teratoma forming stem cells. This finding might help to develop new strategies to increase the safety of future transplantations of in vitro differentiated cells by exploiting a selective immune response against contaminating undifferentiated cells. REVIEWERS: This article was reviewed by Bhagirath Singh, Etienne Joly and Lutz Walter

Impact of measured versus estimated glomerular filtration rate-based screening on living kidney donor characteristics:A study of multiple cohorts

Background Most transplant centers in the Netherlands use estimated glomerular filtration rate (eGFR) for evaluation of potential living kidney donors. Whereas eGFR often underestimates GFR, especially in healthy donors, measured GFR (mGFR) allows more precise kidney function assessment, and therefore holds potential to increase the living donor pool. We hypothesized that mGFR-based donor screening leads to acceptance of donors with lower predonation eGFR than eGFR-based screening. Methods In this longitudinal cohort study, we compared eGFR (CKD-EPI) before donation in one center using mGFR-based screening (mGFR-cohort, n = 250) with two centers using eGFR-based screening (eGFR-cohort1, n = 466 and eGFR-cohort2, n = 160). We also compared differences in eGFR at five years after donation. Results Donor age was similar among the cohorts (mean±standard deviation (SD) mGFR-cohort 53 ±10 years, eGFR-cohort1 52±13 years, P = 0.16 vs. mGFR-cohort, and eGFR-cohort2 53±9 years, P = 0.61 vs. mGFR-cohort). Estimated GFR underestimated mGFR by 10±12 mL/ min/1.73m2 (mean±SD), with more underestimation in younger donors. In the overall cohorts, mean±SD pre-donation eGFR was lower in the mGFR-cohort (91±13 mL/min/ 1.73m2) than in eGFR-cohort1 (93±15 mL/min/1.73m2, P<0.05) and eGFR-cohort2 (94±12 mL/min/1.73m2, P<0.05). However, these differences disappeared when focusing on more recent years, which can be explained by acceptance of more older donors with lower predonation eGFR over time in both eGFR-cohorts. Five years post-donation, mean±SD eGFR was similar among the centers (mGFR-cohort 62±12 mL/min/1.73m2, eGFR-cohort1 61±14 mL/min/1.73m2, eGFR-cohort2 62±11 mL/min/1.73m2, P = 0.76 and 0.95 vs. mGFR-cohort respectively). In the mGFR-cohort, 38 (22%) donors were excluded from donation due to insufficient mGFR with mean±SD mGFR of 71±9 mL/min/1.73m2. Conclusions Despite the known underestimation of mGFR by eGFR, we did not show that the routine use of mGFR in donor screening leads to inclusion of donors with a lower pre-donation eGFR. Therefore eGFR-based screening will be sufficient for the majority of the donors. Future studies should investigate whether there is a group (e.g. young donors with insufficient eGFR) that might benefit from confirmatory mGFR testing

Early increase in single-kidney glomerular filtration rate after living kidney donation predicts long-term kidney function

Single-kidney glomerular filtration rate (GFR) increases after living kidney donation due to compensatory hyperfiltration and structural changes. The implications of inter-individual variability in this increase in single-kidney GFR are unknown. Here, we aimed to identify determinants of the increase in single-kidney GFR at three-month postdonation, and to investigate its relationship with long-term kidney function. In a cohort study in 1024 donors, we found considerable inter-individual variability of the early increase in remaining single-kidney estimated GFR (eGFR) (median [25th-75th percentile]) 12 [8-18] mL/min/1.73m(2). Predonation eGFR, age, and cortical kidney volume measured by CT were the main determinants of the early postdonation increase in single-kidney eGFR. Individuals with a stronger early increase in single-kidney eGFR had a significantly higher five-year postdonation eGFR, independent of predonation eGFR and age. Addition of the postdonation increase in single-kidney eGFR to a model including predonation eGFR and age significantly improved prediction of a five-year postdonation eGFR under 50 mL/min/1.73m(2). Results at ten-year follow-up were comparable, while accounting for left-right differences in kidney volume did not materially change the results. Internal validation using 1251-iothalamate-based measured GFR in 529 donors and external validation using eGFR data in 647 donors yielded highly similar results. Thus, individuals with a more pronounced increase in single-kidney GFR had better long-term kidney function, independent of predonation GFR and age. Hence, the early postdonation increase in single-kidney GFR, considered indicative for kidney reserve capacity, may have additional value to eGFR and age to personalize follow-up intensity after living kidney donation

Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice

Background—Exaggerated and prolonged inflammation after myocardial infarction (MI) accelerates left ventricular remodeling. Inflammatory pathways may present a therapeutic target to prevent post-MI heart failure. However, the appropriate magnitude and timing of interventions are largely unknown, in part because noninvasive monitoring tools are lacking. Here, we used nanoparticle-facilitated silencing of CCR2, the chemokine receptor that governs inflammatory Ly-6Chigh monocyte subset traffic, to reduce infarct inflammation in apolipoprotein E–deficient (apoE−/−) mice after MI. We used dual-target positron emission tomography/magnetic resonance imaging of transglutaminase factor XIII (FXIII) and myeloperoxidase (MPO) activity to monitor how monocyte subset–targeted RNAi altered infarct inflammation and healing. Methods and Results—Flow cytometry, gene expression analysis, and histology revealed reduced monocyte numbers and enhanced resolution of inflammation in infarcted hearts of apoE−/− mice that were treated with nanoparticle-encapsulated siRNA. To follow extracellular matrix cross-linking noninvasively, we developed a fluorine-18–labeled positron emission tomography agent (18F-FXIII). Recruitment of MPO-rich inflammatory leukocytes was imaged with a molecular magnetic resonance imaging sensor of MPO activity (MPO-Gd). Positron emission tomography/magnetic resonance imaging detected anti-inflammatory effects of intravenous nanoparticle-facilitated siRNA therapy (75% decrease of MPO-Gd signal; P<0.05), whereas 18F-FXIII positron emission tomography reflected unimpeded matrix cross-linking in the infarct. Silencing of CCR2 during the first week after MI improved ejection fraction on day 21 after MI from 29% to 35% (P<0.05). Conclusion—CCR2-targeted RNAi reduced recruitment of Ly-6Chigh monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling.National Heart, Lung, and Blood InstituteUnited States. Dept. of Health and Human Services (contract No. HHSN268201000044C)National Institutes of Health (U.S.) (grant R01-HL096576)National Institutes of Health (U.S.) (grant R01-HL095629)National Institutes of Health (U.S.) (grant T32-HL094301)Deutsche Forschungsgemeinschaft (HE-6382/1-1

Efficient Killing of Murine Pluripotent Stem Cells by Natural Killer (NK) Cells Requires Activation by Cytokines and Partly Depends on the Activating NK Receptor NKG2D

Natural killer (NK) cells play an important role as cytotoxic effector cells, which scan the organism for infected or tumorigenic cells. Conflicting data have been published whether NK cells can also kill allogeneic or even autologous pluripotent stem cells (PSCs) and which receptors are involved. A clarification of this question is relevant since an activity of NK cells against PSCs could reduce the risk of teratoma growth after transplantation of PSC-derived grafts. Therefore, the hypothesis has been tested that the activity of NK cells against PSCs depends on cytokine activation and specifically on the activating NK receptor NKG2D. It is shown that a subcutaneous injection of autologous iPSCs failed to activate NK cells against these iPSCs and can give rise to teratomas. In agreement with this result, several PSC lines, including two iPSC, two embryonic stem cell (ESC), and two so-called multipotent adult germline stem cell (maGSC) lines, were largely resistant against resting NK cells although differences in killing were found at low level. All PSC lines were killed by interleukin (IL)-2-activated NK cells, and maGSCs were better killed than the other PSC types. The PSCs expressed ligands of the activating NK receptor NKG2D and NKG2D-deficient NK cells from Klrk1−/− mice were impaired in their cytotoxic activity against PSCs. The low-cytotoxic activity of resting NK cells was almost completely dependent on NKG2D. The cytotoxic activity of IL-2-activated NKG2D-deficient NK cells against PSCs was reduced, indicating that also other activating receptors on cytokine-activated NK cells must be engaged by ligands on PSCs. Thus, NKG2D is an important activating receptor involved in killing of murine PSCs. However, NK cells need to be activated by cytokines before they efficiently target PSCs and then also other NK receptors become relevant. These features of NK cells might be relevant for transplantation of PSC-derived grafts since NK cells have the capability to kill undifferentiated cells, which might be present in grafts in trace amount

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels