Impact of newborn screening for SCID on the management of congenital athymia.

BACKGROUND: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). OBJECTIVE: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. METHODS: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. RESULTS: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. CONCLUSION: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.

Expanding the clinical and immunological phenotypes of PAX1-deficient SCID and CID patients.

Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34+ cells into mature T cells demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment.

Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API).

BACKGR OUND: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. METHODS: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. RESULTS: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. CONCLUSION: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.

OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.

Isolated limb perfusion for locally advanced melanoma in the immunotherapy era.

BACKGROUND: Prior to the advent of effective systemic therapy for melanoma, isolated limb perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma (ITM). However, many patients who are now treated by ILP will have received prior immunotherapy. We sought to compare response rates to ILP in patients who had previously received immunotherapy compared to immunotherapy naive patients. MATERIALS AND METHODS: All patients who underwent ILP for ITM between January 2015 and July 2020 for melanoma were identified retrospectively from two tertiary institutions. Surgical morbidity and oncologic outcomes were compared between immunotherapy naive and immunotherapy pre-treated patients. RESULTS: 97 perfusions were performed for melanoma. Of those, 18 patients had undergone prior immunotherapy. There were no differences in clinicopathological characteristics or perioperative outcomes between cohorts. Surgical morbidity and local toxicity were similar between both cohorts. Patients who underwent immunotherapy prior to ILP had significantly decreased complete response (CR) rates compared with immunotherapy-naïve (6% vs 47%, p = 0.0018) and a significantly decreased overall survival (OS) and distant progression free survival (DPFS) (p = 0.0031 and p = 0.0006 respectively). There was no difference in overall response (OR), partial response (PR), stable disease (SD), progressive disease (PD) and local progression free survival (LPFS) between cohorts. CONCLUSION: Oncological outcomes and complete response rates are worse in patients who have received immunotherapy prior to ILP compared with immunotherapy naïve patients. Despite this, ILP is still a valuable second line treatment for local control in patients who have multiple, bulky and/or recurrent ITM post immunotherapy.

Deletion of glyceraldehyde-3-phosphate dehydrogenase (gapN) in Clostridium saccharoperbutylacetonicum N1-4(HMT) using CLEAVE™ increases the ATP pool and accelerates solvent production.

The development and advent of mutagenesis tools for solventogenic clostridial species in recent years has allowed for the increased refinement of industrially relevant strains. In this study we have utilised CLEAVE™, a CRISPR/Cas genome editing system developed by Green Biologics Ltd., to engineer a strain of Clostridium saccharoperbutylacetonicum N1-4(HMT) with potentially useful solvents titres and energy metabolism. As one of two enzymes responsible for the conversion of glyceraldehyde-3-phosphate (GAP) to 3-phosphoglyceric acid in glycolysis, it was hypothesised that deletion of gapN would increase ATP and NADH production that could in turn improve solvent production. Herein, whole genome sequencing has been used to evaluate CLEAVE™ and the successful knockout of gapN, demonstrating a clean knockout with no other detectable variations from the wild type sequence. Elevated solvent levels were detected during the first 24 h of batch fermentation, indicating an earlier shift to solventogenesis. A 2.4-fold increase in ATP concentration was observed, and quantitation of NAD(P)H derivatives revealed a more reducing cytoplasm for the gapN strain. These findings expand our understanding of clostridium carbon metabolism and report a new approach to optimising biofuel production.

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia.

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).

Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects.

Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue.

Expanding the Nude SCID/CID Phenotype Associated with FOXN1 Homozygous, Compound Heterozygous, or Heterozygous Mutations.

Human nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with FOXN1 homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions.

T cell phenotype in paediatric heart transplant recipients.

Paediatric heart transplantation recipients suffer an increased incidence of infectious, autoimmune and allergic problems. The relative roles of thymus excision and immunosuppressive treatments in contributing to these sequelae are not clear. We compared the immunological phenotypes of 25 heart transplant recipients (Tx), 10 children who underwent thymus excision during non-transplantation cardiac surgery (TE) and 25 age range-matched controls, in two age bands: 1-9 and 10-16 years. Significant differences from controls were seen mainly in the younger age band with Tx showing lower CD3 and CD4 cell counts whilst TE showed lower CD8 cell counts. Naïve T cell and recent thymic emigrant proportions and counts were significantly lower than controls in both groups in the lower age band. T cell recombination excision circle (TREC) levels were lower than controls in both groups in both age bands. There were no differences in regulatory T cells, but in those undergoing thymus excision in infancy, their proportions were higher in TE than Tx, a possible direct effect of immunosuppression. T cell receptor V beta spectratyping showed fewer peaks in both groups than in controls (predominantly in the older age band). Thymus excision in infancy was associated with lower CD8 cell counts and higher proportions of Tregs in TE compared to Tx. These data are consistent with thymus excision, particularly in infancy, being the most important influence on immunological phenotype after heart transplantation.

Replacing defective thymus function.

PURPOSE OF REVIEW: Transplantation of cultured postnatal allogeneic thymus has been successful for treating athymia, mostly associated with complete DiGeorge syndrome, for more than 20 years. Advances in molecular genetics provide opportunities for widening the range of athymic conditions that can be treated while advances in cell culture and organ/tissue regeneration may offer the prospect of alternative preparations of thymic tissue. There are potential broader applications of this treatment outside congenital athymia. RECENT FINDINGS: At the same time as further characterization of the cultured thymus product in terms of thymic epithelial cells and lymphoid composition, preclinical studies have looked at de-novo generation of thymic epithelial cells from stem cells and explored scaffolds for delivering these as three-dimensional structures. In the era of newborn screening for T-cell lymphopaenia, a broadening range of defects leading to athymia is being recognized and new assays should allow differentiation of these from haematopoietic cell defects, pending their genetic/molecular characterization. Evidence suggests that the tolerogenic effect of transplanted thymus could be exploited to improve outcomes after solid organ transplantation. SUMMARY: Thymus transplantation, the accepted standard treatment for complete DiGeorge syndrome is also appropriate for other genetic defects leading to athymia. Improved strategies for generating thymus may lead to better outcomes and broader application of this treatment.

Diagnosis and management of severe combined immunodeficiency in Australia and New Zealand.

This consensus document outlines the recommendations from the Australasian Society of Clinical Immunology and Allergy Transplantation and Primary Immunodeficiency group for the diagnosis and management of patients with severe combined immunodeficiency. It also provides a proposed framework for the early investigation, management and supportive care prior to haematopoietic stem cell transplantation.

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

ADA2 deficiency complicated by EBV-driven lymphoproliferative disease.

A 29-year old male with recurrent respiratory and skin infections, anaemia and neutropaenia during childhood required immunoglobulin replacement for antibody deficiency from age 16. He remained relatively well until age 28 when he presented with a two-week history of fatigue, sore throat, fever and productive cough. He was found to have EBV viraemia and splenomegaly and a diagnosis of EBV-driven lymphoproliferative disease was made following bone marrow trephine. Family history was notable with three siblings: a healthy sister and two brothers with anaemia and neutropaenia; one who succumbed to septicaemia secondary to neutropaenic enterocolitis age 5 and another who developed intestinal vasculitis and antibody deficiency and had a successful haemopoetic stem cell transplant. The proband's DNA underwent targeted sequencing of 279 genes associated with immunodeficiency (GRID panel). The best candidates were two ADA2 variants, p.Arg169Gln (R169Q) and p.Asn370Lys (N370K). Sanger sequencing and co-segregation of variants in the parents, unaffected sister and all three affected brothers was fully consistent with compound heterozygous inheritance. Subsequent whole genome sequencing of the proband identified no other potential causal variants. ADA2 activity was consistent with a diagnosis of ADA2 deficiency in affected family members. This is the first description of EBV-driven lymphoproliferative disease in ADA2 deficiency. ADA2 deficiency may cause susceptibility to severe EBV-induced disease and we would recommend that EBV status and viral load is monitored in patients with this diagnosis and allogeneic SCT is considered at an early stage for patients whose ADA2 deficiency is associated with significant complications.

Anti-Müllerian hormone and Inhibin B after stem cell transplant in childhood: a comparison of myeloablative, reduced intensity and treosulfan-based chemotherapy regimens.

Serum concentrations of Anti-Müllerian hormone (AMH) and Inhibin B were used to assess potential fertility in survivors of childhood haematopoietic stem cell transplantation (HSCT) after three chemotherapy-conditioning regimens of differing intensity. Of 428 patients transplanted between 1990-2012 for leukaemia and immunodeficiency 121 surviving >1 year after a single HSCT were recruited. Group A had a treosulfan-based regimen (low-toxicity); Group B had fludarabine/melphalan (Flu-Mel) (reduced-intensity) and Group C had busulphan/cyclophosphamide (Bu-Cy) (myelo-ablative). Mean age at HSCT and follow-up and length of follow-up were 3.6, 11.8 and 9.9 years. Mean AMH standard deviation scores (SDS) were significantly higher in Group A (-1.047) and Group B (-1.255) than Group C (-1.543), suggesting less ovarian reserve impairment after treosulfan and Flu-Mel than after Bu-Cy. Mean serum AMH concentration was significantly better with treosulfan (>1.0 µg/l) than with Flu-Mel or Bu-Cy. In males, mean Inhibin B SDS was significantly higher in Group A (-0.506) than in Group B (-2.53) and Group C (-1.23) with the Flu-Mel group suffering greatest impairment. In conclusion, a treosulfan-based regimen confers a more favourable outlook for gonadal reserve than Flu-Mel or Bu-Cy in both sexes. Higher values of Inhibin B after Bu-Cy than after Flu-Mel may reflect recovery over time.

What's new in atopic eczema? An analysis of systematic reviews published in 2017. Part 2: epidemiology, aetiology and risk factors.

This article forms part of a series of annual updates that summarizes the evidence base for atopic eczema (AE). It provides a summary of key findings from 28 systematic reviews that were published or indexed during 2017, and focuses on the epidemiology, aetiology and risk factors of AE. AE is the largest single contributor to morbidity associated with skin disease worldwide, once mortality has been excluded. There is a high prevalence of sleep disturbance in individuals with AE and they take more sick leave than controls. While there is a lack of skin bacterial diversity in patients with AE, there is a relative abundance of Staphylococcus aureus and Staphylococcus epidermidis. Compared with controls, affected individuals more often show an IgE response to S. aureus antigens and have higher serum interleukin-31 levels. Early antibiotic exposure, environmental pollutants, maternal atopy and food allergy are associated with an increased risk of AE, and very preterm birth is associated with decreased risk. Patients with AE have a reduced risk of meningioma, but are more likely to develop attention-deficit hyperactivity disorder compared with controls. Patients with eosinophilic oesophagitis are significantly more likely than unaffected individuals to have AE. There is no significant overall association between AE and allergic contact dermatitis (ACD), and in children referred for patch testing, ACD was more common in those without AE. Hand eczema is more prevalent in patients with AE. There is no association between AE and Type 2 diabetes, hypertension, stroke or myocardial infarction.

Chronic Cholangiopathy Associated with Primary Immune Deficiencies Can Be Resolved by Effective Hematopoietic Stem Cell Transplantation.

OBJECTIVES: To investigate effects and outcome of hematopoietic stem cell transplantation (HSCT) on sclerosing cholangitis, in pediatric patients with different primary immunodeficiencies (PIDs). STUDY DESIGN: From databases in 2 tertiary centers for immunodeficiencies and liver disease, we have identified children with PIDs and sclerosing cholangitis, who have paired clinical, radiologic, and histologic information before and after HSCT and studied their clinical progress and outcome. RESULTS: Seven of 13 children (53.8%) died at a median interval of 4 months (range, 3 months-5 years) after HSCT. However, 6 surviving children (46.2%) with different PIDs and less severe cholangiopathies showed an improvement in markers of liver injury within months of successful unrelated reduced intensity conditioning HSCT. The repeated native liver biopsy, performed in 4 patients at a median of 96 (range, 4-144) months post-HSCT, showed a considerable improvement. Biochemical markers of liver function in the survivors completely normalized after a median of 13 months (range, 2-48). All patients continue to have a mildly dilated extrahepatic biliary system on ultrasonography with no intrahepatic ductal changes on magnetic resonance cholangiography after a follow-up of median 18 years (range, 2-20). CONCLUSIONS: Effective HSCT has the potential to improve biochemical and histologic features of cholangiopathy in children with PIDs, presumably by clearance of chronic infection following establishment of immune competence. However, careful patient selection is critical as advanced liver injury is often associated with serious complications and mortality.

Selective reduction and homologation of carbon monoxide by organometallic iron complexes.

Carbon monoxide is a key C1 feedstock for the industrial production of hydrocarbons, where it is used to make millions of tonnes of chemicals, fuels, and solvents per annum. Many transition metal complexes can coordinate CO, but the formation of new C-C bonds in well-defined compounds from the scission and subsequent coupling of two or more CO moieties at a transition metal centre remains a challenge. Herein, we report the use of low-coordinate iron(II) complexes for the selective scission and homologation of CO affording unusual squaraines and iron carboxylates at ambient temperature and pressure. A modification of the ligand framework allows for the isolation and structural characterisation of a proposed metallacyclic Fe(II) carbene intermediate. These results indicate that, with the appropriate choice of supporting ligands, it is possible to cleave and homologate carbon monoxide under mild conditions using an abundant and environmentally benign low-coordinate, first row transition metal.

Mycobacterium chimaera infection following cardiac surgery in the United Kingdom: clinical features and outcome of the first 30 cases.

OBJECTIVES: Mycobacterium chimaera infection following cardiac surgery, due to contaminated cardiopulmonary bypass heater-cooler units, has been reported worldwide. However, the spectrum of clinical disease remains poorly understood. To address this, we report the clinical and laboratory features, treatment and outcome of the first 30 UK cases. METHODS: Case note review was performed for cases identified retrospectively through outbreak investigations and prospectively through ongoing surveillance. Case definition was Mycobacterium chimaera detected in any clinical specimen, history of cardiothoracic surgery with cardiopulmonary bypass, and compatible clinical presentation. RESULTS: Thirty patients were identified (28 with prosthetic material) exhibiting a spectrum of disease including prosthetic valve endocarditis (14/30), sternal wound infection (2/30), aortic graft infection (4/30) and disseminated (non-cardiac) disease (10/30). Patients presented a median of 14 months post surgery (maximum 5 years) most commonly complaining of fever and weight loss. Investigations frequently revealed lymphopenia, thrombocytopenia, liver cholestasis and non-necrotizing granulomatous inflammation. Diagnostic sensitivity for a single mycobacterial blood culture was 68% but increased if multiple samples were sent. In all, 27 patients started macrolide-based combination treatment and 14 had further surgery. To date, 18 patients have died (60%) a median of 30 months (interquartile range 20-39 months) after initial surgery. Survival analysis identified younger age, mitral valve surgery, mechanical valve replacement, higher serum sodium concentration and lower C-reactive protein as factors associated with better survival. CONCLUSIONS: Mycobacterium chimaera infection following cardiac surgery is associated with a wide spectrum of disease. The diagnosis should be considered in all patients who develop an unexplained illness following cardiac surgery.