Background People living with diabetes have an increased risk of developing active tuberculosis and are more likely to have poor tuberculosis-treatment outcomes, which may impact on control of tuberculosis as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in active tuberculosis patients relative to healthy individuals. The effects of diabetes and intermediate hyperglycaemia on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-tuberculosis comorbidity. Methods Whole blood samples were collected from active tuberculosis patients with diabetes (HbA1c ≥6.5%) or intermediate hyperglycaemia (HbA1c 5.7-6.5%), tuberculosis-only patients and healthy controls in four countries: South Africa, Romania, Indonesia and Peru. Differential blood gene expression was determined by RNA-seq (n=249). Results Diabetes increased the magnitude of gene expression change in the host transcriptome in tuberculosis, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with intermediate hyperglycaemia and tuberculosis exhibited blood transcriptomes much more similar to diabetes-tuberculosis patients than to patients with only tuberculosis. Both diabetes-tuberculosis and intermediate hyperglycaemia-tuberculosis patients had a decreased type I interferon response relative to tuberculosis-only patients. Conclusions Co-morbidity in individuals with both tuberculosis and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type 1 interferon responses in co-morbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with intermediate hyperglycaemia, showing that altered immunity to tuberculosis may also be present in this group. The TB disease outcomes in individuals with intermediate hyperglycaemia diagnosed with TB should be investigated further.

Pathogenic variants in BRCA1 gene in heterozygous state are known to be associated with breast-ovarian cancer susceptibility; however, biallelic variants cause a phenotype recognised as Fanconi anaemia complementation group S. Due to its rarity, medical management and preventive screening measures are insufficiently understood. Here, we present nine individuals (one new and eight previously presented) with biallelic variants in BRCA1 gene, to delineate clinical features in comparison with other chromosome instability syndromes and understand the patients’ health risk. Features seen in these 9 individuals (7 females/2 males) include prenatal and postnatal growth failure (9/9), microcephaly (9/9), hypo/hyperpigmented lesions (9/9), facial dysmorphism (9/9), mild developmental delay (8/9) and early-onset solid tumours (5/9). None presented bone marrow failure or immunodeficiency. Individuals with biallelic variants in BRCA1 also showed chromosomal instability by mitomycin and diepoxybutane test. The phenotype caused by biallelic BRCA1 variants is best framed between Fanconi anaemia and Nijmegen syndrome, yet distinct due to lack of bone marrow failure and immunodeficiency. We hypothesise that disease class should be reframed and medical management in people with biallelic variants in BRCA1 should emphasise on detection of solid tumour development and avoiding exposure to ionising radiation.

on behalf of the TANDEM consortium (members listed in full in submitted excel 9 spreadsheet) 10 11 1. Population Summary 48Background 49 Diabetes (DM) is common among tuberculosis (TB) patients and often undiagnosed or poorly 50 controlled. We compared point of care (POC) with laboratory glycated haemoglobin (HbA1c) tests 51 among newly diagnosed TB patients to assess POC test accuracy, safety, and acceptability in settings 52where immediate access to DM services may be difficult. 53 Methods 54We measured POC and accredited laboratory HbA1c (HPLC method) in 1942 TB patients aged over 18, 55 recruited from Peru, Romania, Indonesia, and South Africa. We calculated overall agreement and 56 individual variation (mean ± 2 standard deviations); stratified by country, age, sex, body mass index 57 (BMI), HbA1c level and comorbidities (anaemia, human immunodeficiency virus (HIV)). We used an 58 error grid approach to identify disagreement that could raise significant concerns. 59 Results 60Overall mean POC HbA1c values were modestly greater than laboratory HbA1c by 0.14% units (95% 61 confidence intervals 0.11 to 0.18), but there was a substantial discrepancy for those with severe 62 anaemia (1.07% HbA1c, 95%CI 0.67 to 1.46). For 89.6% of 1942 patients, both values indicated the 63 same DM status (no DM; HbA1c <6.5%) or had acceptable deviation (relative difference <6%). 64 Individual agreement was variable, with POC values up to 1.84% units higher or 1.56% lower. For a 65 minority, use of POC HbA1c alone could result in error leading to potential over-treatment (n=40, 2.1%) 66 or under treatment (n=1, 0.05%). The remainder had moderate disagreement, less likely to influence 67 clinical decisions. 68 Conclusion 69 POC HbA1c is pragmatic and sufficiently accurate to screen for hyperglycaemia and DM risk among TB 70 patients. 71 72 73 74 POC HbA1c (analysed using Hemocue® HbA1c 501 Analyser)[34] was collected during the participants' 131 clinic visits, and within 72 hours after TB diagnosis. In Romania, HemoCue® was not available so the 132 QuoTest[35] HbA1c Analyser QTD (by EKF Diagnostics) was substituted for Hemocue®. Laboratory 133 HbA1c was estimated from venous blood sample collection taken at the same time as the POC test. 134 All laboratory HbA1c samples were analysed using the HPLC method as per WHO guidelines and were 135 carried out in an accredited laboratory with NGSP certification[36]. 136 Consent and ethical approval 137