Signaling through the Inhibitory Fc Receptor FcγRIIB Induces CD8+ T Cell Apoptosis to Limit T Cell Immunity.

Effector CD8+ T cells are important mediators of adaptive immunity, and receptor-ligand interactions that regulate their survival may have therapeutic potential. Here, we identified a subset of effector CD8+ T cells that expressed the inhibitory fragment crystallizable (Fc) receptor FcγRIIB following activation and multiple rounds of division. CD8+ T cell-intrinsic genetic deletion of Fcgr2b increased CD8+ effector T cell accumulation, resulting in accelerated graft rejection and decreased tumor volume in mouse models. Immunoglobulin G (IgG) antibody was not required for FcγRIIB-mediated control of CD8+ T cell immunity, and instead, the immunosuppressive cytokine fibrinogen-like 2 (Fgl2) was a functional ligand for FcγRIIB on CD8+ T cells. Fgl2 induced caspase-3/7-mediated apoptosis in Fcgr2b+, but not Fcgr2b-/-, CD8+ T cells. Increased expression of FcγRIIB correlated with freedom from rejection following withdrawal from immunosuppression in a clinical trial of kidney transplant recipients. Together, these findings demonstrate a cell-intrinsic coinhibitory function of FcγRIIB in regulating CD8+ T cell immunity.

MHC and Peptide Specificity Underpin CD8+ T cell Direct Alloresponse.

The direct alloresponse, pivotal in transplant rejection, occurs when recipient T cells recognize intact allogeneic peptide-MHC complexes. Despite extensive research, our understanding of alloreactive CD8+ T cells against an individual MHC allele in humans remains limited, especially their precursor frequency, MHC specificity, and peptide specificity. By utilizing K562 cell-based artificial antigen-presenting cells (aAPCs) expressing HLA-A*01:01, HLA-A*02:01, or HLA-A*03:01, we determined that the precursor frequency of alloreactive CD8+ T cells against a single MHC allele ranges from 0.1% to 0.5%. Further, these cells exhibited MHC-specificity regarding proliferation, activation, IFN-γ secretion, and cytolytic ability, with limited cross-reactivity towards non-targeted MHC alleles. Focusing on anti-A2 alloreactive CD8+ T cells, we developed a peptide-exchangeable aAPC that displays selected peptides on HLA-A*02:01. From a set of 95 computationally curated A2-restricted peptides most abundant in renal tubular cells, we identified two immunogenic kidney peptides across multiple donors. Overall, our findings significantly enhance the understanding of direct alloresponse and provide a toolkit for future mechanistic studies and reproducible patient monitoring.

The top 10 priorities in adults living with type 1 diabetes in Ireland and the United Kingdom - A James Lind Alliance priority setting partnership.

AIMS: To undertake a Priority Setting Partnership (PSP), identifying the most important unanswered questions in type 1 diabetes in Ireland and the United Kingdom and to compare these to priorities identified in a 2011 PSP. METHODS: A steering committee (including eight individuals with lived experience/charity representatives and six clinicians) designed a survey which asked stakeholders to list three questions about type 1 diabetes. This was disseminated through social media, direct email contact, and printed posters. Following analysis, a second survey asked participants to rank these priorities in order of importance. The top questions were then carried forward to an online, 2 days final workshop where the final top 10 were ranked. RESULTS: There were 1050 responses (64% female, 78% adults living with type 1 diabetes, 9% healthcare professionals, 9% family members) to the first survey and 2937 individual questions were submitted. Sixty-five summary questions were submitted into a second survey, completed by 497 individuals (76% adults living with type 1 diabetes, 9% healthcare professionals, and 11% family members). Nineteen questions from the interim survey progressed to a final workshop, which identified the top 10 priorities through group discussion. As in 2011, there was emphasis on psychological health, diabetes-related complications, and hypoglycaemia. New themes prioritised included artificial intelligence and women's health. CONCLUSIONS: The research priorities, which have been identified using a robust and proven methodology, highlight the key concerns of those living with type 1 diabetes, their families and representatives, as well as clinicians in Ireland and the UK.

Mitigating the Prozone-Like Effect in HLA Antibody Testing: A Case Report of Therapeutic Plasma Exchange for Antibody-Mediated Rejection Post-Heart Transplantation.

Therapeutic plasma exchange (TPE) is a cornerstone treatment for antibody-mediated rejection (AMR) post-organ transplantation, aiming to eliminate pathogenic donor-specific HLA antibodies (DSA). However, limitations in HLA antibody interpretation due to the prozone-like effect (PLE) can lead to inaccurate assessment of treatment efficacy. We present a case of a heart transplant recipient with suspected AMR, where an unexpected increase in DSA levels post-TPE prompted investigation into PLE. Solid-phase Luminex assays were employed to detect HLA antibodies. Serum was run neat as well as after treatment with ethylenediaminetetraacetic acid (EDTA). Nephelometry was used to detect complement levels. Laboratory analysis of pre-TPE serum revealed higher DSA levels with EDTA treatment, characteristic of PLE. Complement measurements supported complement-mediated interference in the pre-TPE sample. This case underscores the importance of being aware that PLE can occur in HLA testing and can impact the interpretation of TPE efficacy for AMR.

Clinical recommendations for posttransplant assessment of anti-HLA (Human Leukocyte Antigen) donor-specific antibodies: A Sensitization in Transplantation: Assessment of Risk consensus document.

Although anti-HLA (Human Leukocyte Antigen) donor-specific antibodies (DSAs) are commonly measured in clinical practice and their relationship with transplant outcome is well established, clinical recommendations for anti-HLA antibody assessment are sparse. Supported by a careful and critical review of the current literature performed by the Sensitization in Transplantation: Assessment of Risk 2022 working group, this consensus report provides clinical practice recommendations in kidney, heart, lung, and liver transplantation based on expert assessment of quality and strength of evidence. The recommendations address 3 major clinical problems in transplantation and include guidance regarding posttransplant DSA assessment and application to diagnostics, prognostics, and therapeutics: (1) the clinical implications of positive posttransplant DSA detection according to DSA status (ie, preformed or de novo), (2) the relevance of posttransplant DSA assessment for precision diagnosis of antibody-mediated rejection and for treatment management, and (3) the relevance of posttransplant DSA for allograft prognosis and risk stratification. This consensus report also highlights gaps in current knowledge and provides directions for clinical investigations and trials in the future that will further refine the clinical utility of posttransplant DSA assessment, leading to improved transplant management and patient care.

Sensitization in transplantation: Assessment of Risk 2022 Working Group Meeting Report.

The Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and Immunogenetics that aims at providing recommendations for clinical testing, highlights gaps in current knowledge, and proposes areas for further research to enhance histocompatibility testing in support of solid organ transplantation. This report provides updates on topics discussed by the previous Sensitization in Transplantation: Assessment of Risk working groups and introduces 2 areas of exploration: non-human leukocyte antigen antibodies and utilization of human leukocyte antigen antibody testing measurement to evaluate the efficacy of antibody-removal therapies.

Recommendations from Diabetes UK's 2022 diabetes and physical activity workshop.

AIMS: To describe the process and outputs of a workshop convened to identify key priorities for future research in the area of diabetes and physical activity and provide recommendations to researchers and research funders on how best to address them. METHODS: A 1-day research workshop was conducted, bringing together researchers, people living with diabetes, healthcare professionals, and members of staff from Diabetes UK to identify and prioritise recommendations for future research into physical activity and diabetes. RESULTS: Workshop attendees prioritised four key themes for further research: (i) better understanding of the physiology of exercise in all groups of people: in particular, what patient metabolic characteristics influence or predict the physiological response to physical activity, and the potential role of physical activity in beta cell preservation; (ii) designing physical activity interventions for maximum impact; (iii) promoting sustained physical activity across the life course; (iv) designing physical activity studies for groups with multiple long-term conditions. CONCLUSIONS: This paper outlines recommendations to address the current gaps in knowledge related to diabetes and physical activity and calls on the research community to develop applications in these areas and funders to consider how to stimulate research in these areas.

Assessing the feasibility of a web-based outcome measurement system in child and adolescent mental health services - myHealthE a randomised controlled feasibility pilot study.

BACKGROUND: Interest in internet-based patient reported outcome measure (PROM) collection is increasing. The NHS myHealthE (MHE) web-based monitoring system was developed to address the limitations of paper-based PROM completion. MHE provides a simple and secure way for families accessing Child and Adolescent Mental Health Services to report clinical information and track their child's progress. This study aimed to assess whether MHE improves the completion of the Strengths and Difficulties Questionnaire (SDQ) compared with paper collection. Secondary objectives were to explore caregiver satisfaction and application acceptability. METHODS: A 12-week single-blinded randomised controlled feasibility pilot trial of MHE was conducted with 196 families accessing neurodevelopmental services in south London to examine whether electronic questionnaires are completed more readily than paper-based questionnaires over a 3-month period. Follow up process evaluation phone calls with a subset (n = 8) of caregivers explored system satisfaction and usability. RESULTS: MHE group assignment was significantly associated with an increased probability of completing an SDQ-P in the study period (adjusted hazard ratio (HR) 12.1, 95% CI 4.7-31.0; p = <.001). Of those caregivers' who received the MHE invitation (n = 68) 69.1% completed an SDQ using the platform compared to 8.8% in the control group (n = 68). The system was well received by caregivers, who cited numerous benefits of using MHE, for example, real-time feedback and ease of completion. CONCLUSIONS: MHE holds promise for improving PROM completion rates. Research is needed to refine MHE, evaluate large-scale MHE implementation, cost effectiveness and explore factors associated with differences in electronic questionnaire uptake.

Ageing well with diabetes: A workshop to co-design research recommendations for improving the diabetes care of older people.

AIMS: To identify key research questions where answers could improve care for older people living with diabetes (PLWD), and provide detailed recommendations for researchers and research funders on how best to address them. METHODS: A series of online research workshops were conducted, bringing together a range of PLWD and an acknowledged group of academic and clinical experts in their diabetes care to identify areas for future research. Throughout the pre-workshop phase, during each workshop, and in manuscript preparation and editing, PLWD played an active and dynamic role in discussions as part of both an iterative and narrative process. RESULTS: The following key questions in this field were identified, and research recommendations for each were developed: How can we improve our understanding of the characteristics of older people living with diabetes (PLWD) and their outcomes, and can this deliver better person-centred care? How are services to care for older PLWD currently delivered, both for their diabetes and other conditions? How can we optimise and streamline the process and ensure everyone gets the best care, tailored to their individual needs? What tools might be used to evaluate the level of understanding of diabetes in the older population amongst non-specialist Healthcare Professionals (HCPs)? How can virtual experts or centres most effectively provide access to specialist multi-disciplinary team (MDT) expertise for older PLWD and the HCPs caring for them? Is a combination of exercise and a nutrition-dense, high protein diet effective in the prevention of the adverse effects of type 2 diabetes and deterioration in frailty, and how might this be delivered in a way which is acceptable to people with type 2 diabetes? How might we best use continuous glucose monitoring (CGM) in older people and, for those who require support, how should the data be shared? How can older PLWD be better empowered to manage their diabetes in their own home, particularly when living with additional long-term conditions? What are the benefits of models of peer support for older PLWD, both when living independently and when in care? CONCLUSIONS: This paper outlines recommendations supported by PLWD through which new research could improve their diabetes care and calls on the research community and funders to address them in future research programmes and strategies.

Atypical action updating in a dynamic environment associated with adolescent obsessive-compulsive disorder.

BACKGROUND: Computational research had determined that adults with obsessive-compulsive disorder (OCD) display heightened action updating in response to noise in the environment and neglect metacognitive information (such as confidence) when making decisions. These features are proposed to underlie patients' compulsions despite the knowledge they are irrational. Nonetheless, it is unclear whether this extends to adolescents with OCD as research in this population is lacking. Thus, this study aimed to investigate the interplay between action and confidence in adolescents with OCD. METHODS: Twenty-seven adolescents with OCD and 46 controls completed a predictive-inference task, designed to probe how subjects' actions and confidence ratings fluctuate in response to unexpected outcomes. We investigated how subjects update actions in response to prediction errors (indexing mismatches between expectations and outcomes) and used parameters from a Bayesian model to predict how confidence and action evolve over time. Confidence-action association strength was assessed using a regression model. We also investigated the effects of serotonergic medication. RESULTS: Adolescents with OCD showed significantly increased learning rates, particularly following small prediction errors. Results were driven primarily by unmedicated patients. Confidence ratings appeared equivalent between groups, although model-based analysis revealed that patients' confidence was less affected by prediction errors compared to controls. Patients and controls did not differ in the extent to which they updated actions and confidence in tandem. CONCLUSIONS: Adolescents with OCD showed enhanced action adjustments, especially in the face of small prediction errors, consistent with previous research establishing 'just-right' compulsions, enhanced error-related negativity, and greater decision uncertainty in paediatric-OCD. These tendencies were ameliorated in patients receiving serotonergic medication, emphasising the importance of early intervention in preventing disorder-related cognitive deficits. Confidence ratings were equivalent between young patients and controls, mirroring findings in adult OCD research.

Intravenous vitamin C administration to patients with septic shock: a pilot randomised controlled trial.

BACKGROUND: Intravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C's enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock. METHODS: This was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations. RESULTS: Median plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35-62) hours and in the placebo group was 54 (95% CI 41-62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05). CONCLUSIONS: Our pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence. TRIAL REGISTRATION: ACTRN12617001184369 (11/8/2017).

Systematic review of tendon transfers in the foot and ankle using interference screw fixation: Outcomes and safety of early versus standard postoperative rehabilitation.

AIMS: To compare the outcomes of early and standard rehabilitation protocols following tendon transfers in the foot and ankle using interference screw fixation (ISF). METHODS: A systematic review was performed for relevant articles (1998 to 2020) reporting foot tendon transfer using ISF in adults. The primary outcome was early tendon failure. Secondary outcomes included function and complications. RESULTS: In total, 21 studies met the inclusion criteria, totalling 494 patients. Seven studies reported early rehabilitation protocols. The rate of early tendon failure was zero for each protocol and studies consistently reported a significant improvement in function. No differences were found comparing different rehabilitation protocols for tendon transfer for Achilles tendon pathology and foot drop. CONCLUSION: Both early and standard rehabilitation protocols are associated with high patient satisfaction and low complication rates, but currently there is a lack of evidence to support early loaded activities or motion. LEVEL OF EVIDENCE: IV Systematic review including case series.

The top 10 research priorities in diabetes and pregnancy according to women, support networks and healthcare professionals.

AIMS: To undertake a Priority Setting Partnership (PSP) to establish priorities for future research in diabetes and pregnancy, according to women with experience of pregnancy, and planning pregnancy, with any type of diabetes, their support networks and healthcare professionals. METHODS: The PSP used established James Lind Alliance (JLA) methodology working with women and their support networks and healthcare professionals UK-wide. Unanswered questions about the time before, during or after pregnancy with any type of diabetes were identified using an online survey and broad-level literature search. A second survey identified a shortlist of questions for final prioritisation at an online consensus development workshop. RESULTS: There were 466 responses (32% healthcare professionals) to the initial survey, with 1161 questions, which were aggregated into 60 unanswered questions. There were 614 responses (20% healthcare professionals) to the second survey and 18 questions shortlisted for ranking at the workshop. The top 10 questions were: diabetes technology, the best test for diabetes during pregnancy, diet and lifestyle interventions for diabetes management during pregnancy, emotional and well-being needs of women with diabetes pre- to post-pregnancy, safe full-term birth, post-natal care and support needs of women, diagnosis and management late in pregnancy, prevention of other types of diabetes in women with gestational diabetes, women's labour and birth experiences and choices and improving planning pregnancy. CONCLUSIONS: These research priorities provide guidance for research funders and researchers to target research in diabetes and pregnancy that will achieve greatest value and impact.

The Effects of Unilateral Versus Bilateral Motor Training on Upper Limb Function in Adults with Chronic Stroke: A Systematic Review.

OBJECTIVES: Rehabilitation goals for chronic stroke patients are largely focused around regaining functional ability and independence, with particular focus on upper limb motor function. Unilateral and Bilateral motor training may help achieve this. Our objective was to evaluate and compare the effects of unilateral and bilateral motor training on upper limb motor function in chronic stroke patients. MATERIALS AND METHODS: A comprehensive literature search was conducted until June 2020 through several electronic databases (CENTRAL, Medline, CINAHL, EBSCO, AMED and PEDro) to identify relevant studies. Studies that used the Fugl Meyer Assessment (FMA) as a minimum, to assess upper limb motor function following unilateral versus bilateral training in chronic stroke patients, qualified for inclusion within the review. Randomised controlled trial (RCT), cohort study and cross-sectional study designs were considered. The Cochrane risk of bias tool was used to assess Randomised Controlled Trials (RCTs). The findings were qualitatively synthesised. RESULTS: From a total of 838 studies identified, 7 RCTs were included in this review. All except one of the studies included reported an unclear risk of bias, with one low risk of bias reported. Overall, the studies reported that unilateral and bilateral training improved upper limb function in chronic stroke patients. Improvements between interventions were equivocal. Bilateral upper limb training however may be more efficacious for increasing upper limb strength and quality of movement, with unilateral training more beneficial for recovering functional ability for activities of daily living. CONCLUSION: While the findings of the included studies support the use of unilateral and bilateral motor training post chronic stroke, the seven studies that were included methodologically all presented with limitations, hence strong conclusions cannot be drawn and further research is warranted.

Sociodemographic factors associated with routine outcome monitoring: a historical cohort study of 28,382 young people accessing child and adolescent mental health services.

BACKGROUND: Patient-reported outcome measures (PROMs) are important tools to inform patients, clinicians and policy-makers about clinical need and the effectiveness of any given treatment. Consistent PROM use can promote early symptom detection, help identify unexpected treatment responses and improve therapeutic engagement. Very few studies have examined associations between patient characteristics and PROM data collection. METHODS: We used the electronic mental health records for 28,382 children and young people (aged 4-17 years) accessing Child and Adolescent Mental Health Services (CAMHS) across four South London boroughs between the 1st of January 2008 to the 1st of October 2017. We examined the completion rates of the caregiver Strengths and Difficulties Questionnaire (SDQ), a ubiquitous PROM for CAMHS at baseline and 6-month follow-up. RESULTS AND CONCLUSIONS: SDQs were present for approximately 40% (n = 11,212) of the sample at baseline, and from these, only 8% (n = 928) had a follow-up SDQ. Patterns of unequal PROM collection by sociodemographic factors were identified: males were more likely (aOR 1.07, 95% CI 1.01-1.13), whilst older age (aOR 0.87, 95% CI 0.87-0.88), Black (aOR 0.79 95% CI 0.74-0.84) and Asian ethnicity (aOR 0.75 95% CI 0.66-0.86) relative to White ethnicity, and residence within the most deprived neighbourhood (aOR 0.87 95% CI 0.80-0.94) were less likely to have a record of baseline SDQ. Similar results were found in the sub-group (n = 11,212) with follow-up SDQ collection. Our findings indicate systematic differences in the currently available PROMS data and highlights which groups require increased focus if we are to gain equitable PROM collection. We need to ensure representative PROM collection for all individuals accessing treatment, regardless of ethnic or socioeconomic background; biased data have adverse ramifications for policy and service level decision-making.

Memory T cell-mediated rejection is mitigated by FcγRIIB expression on CD8+ T cells.

Donor-reactive memory T cells generated via heterologous immunity represent a potent barrier to long-term graft survival following transplantation because of their increased precursor frequency, rapid effector function, altered trafficking patterns, and reduced reliance on costimulation signals for activation. Thus, the identification of pathways that control memory T cell survival and secondary recall potential may provide new opportunities for therapeutic intervention. Here, we discovered that donor-specific effector/memory CD8+ T cell populations generated via exposure to acute vs latent vs chronic infections contain differential frequencies of CD8+ T cells expressing the inhibitory Fc receptor FcγRIIB. Results indicated that frequencies of FcγRIIB-expressing CD8+ donor-reactive memory T cells inversely correlated with allograft rejection. Furthermore, adoptive T cell transfer of Fcgr2b-/- CD8+ T cells resulted in an accumulation of donor-specific CD8+ memory T cells and enhanced recall responses, indicating that FcγRIIB functions intrinsically to limit T cell CD8+ survival in vivo. Lastly, we show that deletion of FcγRIIB on donor-specific CD8+ memory T cells precipitated costimulation blockade-resistant rejection. These data therefore identify a novel cell-intrinsic inhibitory pathway that functions to limit the risk of memory T cell-mediated rejection following transplantation and suggest that therapeutic manipulation of this pathway could improve outcomes in sensitized patients.

Biological effects of inhaled hydraulic fracturing sand dust. III. Cytotoxicity and pro-inflammatory responses in cultured murine macrophage cells.

Cultured murine macrophages (RAW 264.7) were used to investigate the effects of fracking sand dust (FSD) for its pro-inflammatory activity, in order to gain insight into the potential toxicity to workers associated with inhalation of FSD during hydraulic fracturing. While the role of respirable crystalline silica in the development of silicosis is well documented, nothing is known about the toxicity of inhaled FSD. The FSD (FSD 8) used in these studies was from an unconventional gas well drilling site. FSD 8was prepared as a 10 mg/ml stock solution in sterile PBS, vortexed for 15 s, and allowed to sit at room temperature for 30 min before applying the suspension to RAW 264.7cells. Compared to PBS controls, cellular viability was significantly decreased after a 24 h exposure to FSD. Intracellular reactive oxygen species (ROS) production and the production of IL-6, TNFα, and endothelin-1 (ET-1) were up-regulated as a result of the exposure, whereas the hydroxyl radical (.OH) was only detected in an acellular system. Immunofluorescent staining of cells against TNFα revealed that FSD 8 caused cellular blebbing, and engulfment of FSD 8 by macrophages was observed with enhanced dark-field microscopy. The observed changes in cellular viability, cellular morphology, free radical generation and cytokine production all confirm that FSD 8 is cytotoxic to RAW 264.7 cells and warrants future studies into the specific pathways and mechanisms by which these toxicities occur.

Monitoring severe acute maternal morbidity across Europe: A feasibility study.

BACKGROUND: Monitoring severe acute maternal morbidity (SAMM) appears essential for optimising care and informing health care policies, especially given changes in obstetric practices and mother profiles. International comparisons can identify areas where improvement is needed, but the comparability of indicators must be evaluated. OBJECTIVE: To assess the feasibility of monitoring SAMM using common definitions from hospital discharge databases across Europe. METHODS: We used hospital discharge data in eight countries (2 826 868 deliveries) to identify women with SAMM among all hospitalisations of women of reproductive age admitted for antenatal or delivery care. Five SAMM indicators were investigated: eclampsia, septicaemia, hysterectomy, hysterectomy associated with a diagnosis of obstetric haemorrhage, and red blood cell (RBC) transfusion associated with a diagnosis of obstetric haemorrhage. Between-country variation was described, by the ratio of the highest to lowest rates, while external validation was assessed by comparing with population-based studies on maternal morbidity. RESULTS: Ratios for hysterectomy and red blood cell (RBC) transfusion in the context of obstetric haemorrhage were 1:2.1 and 1:3.5, respectively. High values of hysterectomy and low values of transfusion were both consistent with high maternal mortality from haemorrhage (France, Italy, Portugal). Ratios across countries were relatively low for eclampsia (1:3.4) but very high for septicaemia (1:22.5). Compared to population-based morbidity estimates, eclampsia was over-reported in hospital databases whereas the two indicators of severe haemorrhage had good external validity. CONCLUSIONS: In association with diagnosis codes indicating obstetric haemorrhage, hysterectomy and RBC transfusion appear to be good candidates for surveillance of maternal morbidity in Europe.

Citalopram overdose and severe serotonin syndrome in an intermediate metabolizing patient.

INTRODUCTION: Citalopram is a selective serotonin reuptake inhibitor used for treatment of depression. Metabolism is primarily through CYP3A4 and CYP2C19; activity of the latter can vary depending on genetics. Although rare after single agent exposure, large citalopram ingestions can lead to serotonin syndrome. We report a case of citalopram overdose in an intermediate CYP2C19 metabolizer complicated by severe serotonin syndrome. CASE DETAILS: A 25-year-old female presented after intentional citalopram overdose with seizures, tachycardia, persistent neuromuscular findings, and severe hyperthermia requiring aggressive sedation and cooling. Protracted symptoms required critical care services throughout a 14 day hospital stay despite traditional treatment of serotonin syndrome. Pharmacogenomic studies revealed intermediate CYP2C19 metabolism which reduces citalopram inactivation and may cause increased levels and toxicity. DISCUSSION: In the majority of serotonin syndrome cases, symptoms resolve rapidly after treatment initiation and discontinuation of the offending agents. Severe cases are typically associated with ingestion of multiple serotonergic agents. Our patient had severe toxicity after single agent ingestion. Pharmacogenetic testing identified abnormal CYP2C19 activity and previous cases have associated enzyme dysfunction and citalopram toxicity. CONCLUSION: Citalopram overdose may be associated with severe serotonin syndrome and further investigation is warranted to understand the impact of enzyme genotype on toxicity.

When rubber meets the road: how innate features of adaptive immune cells play critical roles in transplant alloimmunity.

PURPOSE OF REVIEW: Studies on adaptive cells have largely focused on features that are specific to adaptive immunity. However, adaptive cells utilize innate cell features to modulate their responses, and this area of T and B-cell biology is understudied. This review will highlight recent work done to understand how innate features of adaptive immune cells modulate alloimmunity. RECENT FINDINGS: Over the past year, research has shown that T-cell-expressed danger-associated molecular patterns, Toll-like receptors, complement receptors, and Fc receptors regulate T-cell alloimmunity in a cell-intrinsic manner. Further, IL-17 and p40 of IL-12 have been implicated in the migration of T cells into allografts. Lastly, innate B cells, specifically B1 cells, have been shown to produce clinically relevant autoantibody associated with poor graft outcome. SUMMARY: These data provide evidence that innate features are utilized by adaptive immune cells to control adaptive alloimmunity.