Detectable respiratory SARS-CoV-2 RNA is associated with low vitamin D levels and high social deprivation.

BACKGROUND: Accumulating evidence links COVID-19 incidence and outcomes with vitamin D status. We investigated if an interaction existed between vitamin D levels and social deprivation in those with and without COVID-19 infection. METHODS: Upper or lower respiratory tract samples from 104 patients were tested for SARS-CoV-2 RNA in accordance with Public Health England criteria (January-May 2020) using RT-PCR. The latest serum total 25-hydroxyvitamin D(25-OHD) levels, quantified by LC-MS/MS, was obtained for each patient (September 2019-April 2020). Index of Multiple Deprivation (IMD) was generated for each patient. Univariate and logistic regression analyses examined associations between age, gender, 25-OHD, IMD score and SARS-CoV-2 result in the total cohort and subgroups. RESULTS: In the total cohort, a positive SARS-CoV-2 test was significantly associated with lower 25-OHD levels and higher IMD. A positive test was associated with higher IMD in the male subgroup and with lower 25-OHD levels in those aged >72 years. Low 25-OHD and IMD quintile 5 were separately associated with positive COVID-19 outcome in the cohort. Patients in IMD quintile 5 with vitamin D levels ≤ 34.4 nmol/L were most likely to have a positive COVID-19 outcome, even more so if aged >72 years (OR: 19.07, 95%CI: 1.71-212.25; P = .016). CONCLUSIONS: In this cohort, combined low vitamin D levels and higher social deprivation were most associated with COVID-19 infection. In older age, this combination was even more significant. Our data support the recommendations for normalising vitamin D levels in those with deficient / insufficient levels and in groups at high risk for deficiency.

CD6 monoclonal antibodies differ in epitope, kinetics and mechanism of action.

CD6 is a type I T-cell surface receptor that modulates antigen receptor signalling. Its activity is regulated by binding of its membrane proximal domain (domain 3) to a cell surface ligand, CD166. CD6 monoclonal antibodies (mAbs) specific for the membrane distal domain (domain 1) perturb CD6 function including itolizumab (Alzumab™), which has reached the clinic for treatment of autoimmune disease. We characterized molecular and functional properties of several CD6 mAbs including itolizumab to define potential mechanisms of action. Epitope mapping using the crystal structure of CD6 to design mutants identified two distinct binding sites on different faces of domain 1, one containing residue R77, crucial for MT605 and T12.1 binding and the other, E63, which is crucial for itolizumab and MEM98. Analysis of binding kinetics revealed that itolizumab has a lower affinity compared with other CD6 domain 1 mAbs. We compared potential agonistic (triggering) and antagonistic (blocking) properties of CD6 mAbs in assays where the mechanism of action was well defined. CD6 domain 1 and 3 mAbs were equally effective in triggering interleukin-2 production by a cell line expressing a chimeric antigen receptor containing the extracellular region of CD6. CD6 domain 1 mAbs hindered binding of multivalent immobilized CD166 but were inferior compared with blocking by soluble CD166 or a CD6 domain 3 mAb. Characterization of CD6 mAbs provides an insight into how their functional effects in vivo may be interpreted and their therapeutic use optimized.

Serum testosterone levels in male hypogonadism: Why and when to check-A review.

AIM: Although "late onset hypogonadism", a condition that includes low testosterone and symptoms, is common in men over the age of 40 years, diagnosis is not clear cut amongst non-specialists. It is the aim of this review to provide an up to date picture of how this state should be diagnosed and managed. METHODS: We aim to describe how primary and secondary hypogonadism should be excluded before the diagnosis of late onset hypogonadism is reached. As laboratory testosterone measurements are essential the current pitfalls such as inappropriate sample collection and the use of population derived reference ranges are expanded. We review current evidence to determine associations between late onset hypogonadism and morbidity/mortality and benefits following testosterone replacement therapy. RESULTS: A review of the current evidence shows that late onset hypogonadism is associated with a worse metabolic state and increased mortality. Longitudinal studies have suggested that significant reductions in both symptoms and mortality are seen, especially in patients with type 2 diabetes. DISCUSSION: This review highlights the importance of diagnosing late onset hypogonadism due to its association with morbidity/mortality and benefits following testosterone replacement. Thus, after making recommendations to ensure correct diagnosis we speculate whether the time has come to move away from population derived testosterone levels towards evidence based action limits.

Socioeconomic Deprivation as Measured by the Index of Multiple Deprivation and Its Association with Low Sex Hormone Binding Globulin in Women.

OBJECTIVE: Sex hormone binding globulin (SHBG) is a marker of insulin resistance. Given established links between BMI and socioeconomic disadvantage, we investigated how SHBG varies by index of multiple deprivation (IMD). RESEARCH DESIGN AND METHODS: Using laboratory data from a Midlands UK population of mixed ethnicity, we examined the relation between blood concentrations of SHBG and IMD in 1160 women aged between 17 and 71 years. Women with a serum SHBG >250 nmol/L were excluded. RESULTS: Mean age was 28.7 (95% confidence interval (CI) 28.2-29.1) years. 48.2% of women were of Caucasian origin, 15.5% of Southern Asian ethnicity and 2.6% were of African or other origin (33.7% were of unknown origin). SHBG increased with age (Spearman's ρ=0.195; p<0.001). A higher proportion of women of South Asian origin versus other ethnic groups had an SHBG <30 nmol/L (OR 1.93 (95% CI 1.37-2.71)). SHBG level was lower in individuals with greater socioeconomic disadvantage as measured by IMD (Spearman's ρ= -0.09; p=0.004 for SHBG versus IMD). In multivariate logistic regression, IMD women in the quartiles 2-5 (higher socioeconomic disadvantage) were more likely to have an SHBG <30 nmol/L (compatible with significant insulin resistance) versus quartile 1 (odds ratio (OR) 1.71 (95% confidence interval (CI) 1.17-2.53), adjusted for age (OR=0.97 (95% CI 0.95-0.98)) and ethnicity (for South Asian ethnicity OR=2.00 (95% CI 1.42-2.81) versus the rest). CONCLUSION: Lower SHBG levels in women are associated with a higher level of socioeconomic disadvantage. Given the known association between lower SHBG and higher plasma glucose, our findings suggest a link between socioeconomic disadvantage and future risk of type 2 diabetes.

Urine microalbumin excretion in relation to exercise-induced electrocardiographic myocardial ischaemia.

BACKGROUND: Microalbuminuria, a marker of endothelial cell dysfunction, is associated with atherosclerosis and is a predictor of coronary heart disease. It has been suggested that patients with coronary heart disease have exaggerated exercise-induced urinary microalbumin excretion but this is controversial. We, therefore, measured urine microalbumin excretion in men before and after an exercise electrocardiogram. MATERIAL/METHODS: Urine microalbumin excretion expressed as the albumin-creatinine ratio (ACR) was measured before and after an exercise electrocardiogram in 10 subjects with exercise-induced myocardial ischaemia and 14 subjects without exercise-induced myocardial ischaemia. RESULTS: In subjects with a positive exercise electrocardiogram, the pre-exercise electrocardiogram ACR 3.3 +/- 5.50; (mean+/-SD) significantly increased (p=0.0371) following exercise (6.30 +/-10.25). In subjects with a negative exercise electrocardiogram, the pre-exercise electrocardiogram ACR (0.73 +/-0.52) also significantly increased (p=0.0295) following exercise (2.04 +/-1.81). Pre-exercise ACR was higher (p=0.0164) in subjects with a positive exercise electrocardiogram (3.3 +/-5.50) than in those subjects with a negative exercise electrocardiogram (0.73 +/-0.52). Incremental and post-exercise ACR were not significantly different in those with normal and abnormal exercise electrocardiograms. CONCLUSIONS: Patients with exercise-induced myocardial ischaemia have pre-exercise urine microalbumin excretion. Exaggerated urine microalbumin excretion in response to exercise is not associated with exercise-induced myocardial ischaemia.