Macroprolactin over time: Is there any point in rechecking it in people with a persistently elevated serum prolactin?

OBJECTIVE AND DESIGN: Macroprolactinemia may influence the interpretation of serum prolactin levels-a recognised phenomenon since 1981. The degree of macroprolactinaemia over time is less well described. We determined how macroprolactin status (based on polyethylene glycol (PEG) precipitation) varied by analysing serial measurements in hyperprolactinaemic individuals over a period of 9 years. PATIENTS AND MEASUREMENTS: Results from 1810 individuals were included. All serum total prolactin results (measured using Roche Cobas 8000 analyser) were extracted from the laboratory information system for the period 1 January 2012 to 1 April 2021, along with relevant patient demographic/test data. Samples with a macroprolactin screening test performed (on samples with prolactin > 700 miu/L) were included in the main analysis. RESULTS: During the study period, 2782 macroprolactin checks were performed (12.5% of all prolactin tests) in 1810 individuals (599 males/2183 females, median-age: 35, interquartile range: 25-47, range: 16-93 years). Multiple macroprolactin checks were carried out on 465 patients (1437 measurements) with 94 patients (141 measurements) screening positive (<60% recovery). Only 19 patients (18 female) had at least one result above and one below the 60% screening cut-off, with 10 of these patients having results close to the 60% cut-off; in 9 patients, results were clearly different between repeat samples. In seven cases, the adjusted monomeric prolactin showed a potentially clinically significant difference. CONCLUSIONS: In this study, only 19/465 patients appeared to change macroprolactin status based on a 60% PEG recovery cut-off. The majority of these 19 patients were on antipsychotic/antidepressant medication(s) or had a prolactinoma; in only 7 did monomeric prolactin change significantly. This suggests that once macroprolactin status has been determined, clinical decision making is rarely affected by repeating it.

Number of CAG repeats and mortality in middle aged and older men.

DESIGN: The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon-1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all-cause mortality in men and the influence of testosterone level on the association. PATIENTS AND MEASUREMENTS: Follow-up data to 27 January 2018 were available for men aged 40-79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI). RESULTS: One thousand nine hundred and seventy-seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow-up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22-23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95% CI for mortality were, <22 CAG repeats 1.17 (0.93-1.49) and >23 CAG repeats 1.14 (0.88-1.47). In a post-hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97-2.27) and 1.68 (1.06-2.67) versus 22-23 repeats. CONCLUSIONS: Our European-wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation.

Failure to control conventional cardiovascular risk factors in women with type 2 diabetes might explain worse mortality.

INTRODUCTION: The standardised mortality rate (SMR) for people with diabetes in England is 1.5-1.7, with differences in outcomes between sexes. There has been little work examining the factors that could have an impact on this or on what may determine sex differences in outcome. METHODS: Data were extracted for patients with type 2 diabetes (T2D) in Salford (England) in 2010 for the years up to 2020, including any deaths recorded. Expected deaths were calculated from annual Office of National Statistics mortality rate and life expectancy by age and gender, adjusted for the local Index of Multiple Deprivation (IMD). This provided the SMR deprivation (SMRd), and life expectancy years lost per death (LEYLD). The effects of treatment type, and clinical features on SMRd relative to sex were examined by univariable and multivariable analysis. RESULTS: Data from n = 11,806 (F = 5184; M = 6622) patients were included. Of these, n = 5540 were newly diagnosed and n = 3921 died (F = 1841; M = 2080). In total, n = 78,930 patient years. The expected deaths numbered n = 2596 (adjusted for age, sex, and IMD). Excess deaths were n = 1325 (F = 689; M = 636). Life expectancy years lost (LEYL) 18,989 (F = 9714; M = 9275). SMRd 1.51 (F = 1.60; M = 1.44) and LEYLD 4.84 years (F = 5.28; M = 4.46). The impact of risk factors was not different by sex. However, women had higher prevalence of % diagnosed >65 years of age; % last eGFR <60 mLs/min/1.73 m2 , and lower prevalence of % prescribed ACE-inhibitor/ARB, DPP4-inhibitor and SGLT2-inhibitor. Applying the male prevalence rate to the female population and expected mortality suggested n = 437 (55%) of excess T2D female deaths were attributed to sex difference in the prevalence of these risk and protective factors. CONCLUSIONS: Outcomes in women with T2DM are worse than in men, contributed to by greater prevalence of adverse factors and less prescribing of cardioprotective medication.

Adapting Rapid Diagnostic Tests to Detect Historical Dengue Virus Infections.

The only licensed dengue vaccine, Dengvaxia®, increases risk of severe dengue when given to individuals without prior dengue virus (DENV) infection but is protective against future disease in those with prior DENV immunity. The World Health Organization has recommended using rapid diagnostic tests (RDT) to determine history of prior DENV infection and suitability for vaccination. Dengue experts recommend that these assays be highly specific (≥98%) to avoid erroneously vaccinating individuals without prior DENV infection, as well as be sensitive enough (≥95%) to detect individuals with a single prior DENV infection. We evaluated one existing and two newly developed anti-flavivirus RDTs using samples collected >6 months post-infection from individuals in non-endemic and DENV and ZIKV endemic areas. We first evaluated the IgG component of the SD BIOLINE Dengue IgG/IgM RDT, which was developed to assist in confirming acute/recent DENV infections (n=93 samples). When evaluated following the manufacturer's instructions, the SD BIOLINE Dengue RDT had 100% specificity for both non-endemic and endemic samples but low sensitivity for detecting DENV seropositivity (0% non-endemic, 41% endemic). Sensitivity increased (53% non-endemic, 98% endemic) when tests were allowed to run beyond manufacturer recommendations (0.5 up to 3 hours), but specificity decreased in endemic samples (36%). When tests were evaluated using a quantitative reader, optimal specificity could be achieved (≥98%) while still retaining sensitivity at earlier timepoints in non-endemic (44-88%) and endemic samples (31-55%). We next evaluated novel dengue and Zika RDTs developed by Excivion to detect prior DENV or ZIKV infections and reduce cross-flavivirus reactivity (n=207 samples). When evaluated visually, the Excivion Dengue RDT had sensitivity and specificity values of 79%, but when evaluated with a quantitative reader, optimal specificity could be achieved (≥98%) while still maintaining moderate sensitivity (48-75%). The Excivion Zika RDT had high specificity (>98%) and sensitivity (>93%) when evaluated quantitatively, suggesting it may be used alongside dengue RDTs to minimize misclassification due to cross-reactivity. Our findings demonstrate the potential of RDTs to be used for dengue pre-vaccination screening to reduce vaccine-induced priming for severe dengue and show how assay design adaptations as well quantitative evaluation can further improve RDTs for this purpose.

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.

Real-world practice level data analysis confirms link between variability within Blood Glucose Monitoring Strip (BGMS) and glycosylated haemoglobin (HbA1c) in Type 1 Diabetes.

AIMS/HYPOTHESIS: Our aim was to quantify the impact of Blood Glucose Monitoring Strips variability (BGMSV) at GP practice level on the variability of reported glycated haemoglobin (HbA1cV) levels. METHODS: Overall GP Practice BGMSV and HbA1cV were calculated from the quantity of main types of BGMS being prescribed combined with the published accuracy, as % results within ±% bands from reference value for the selected strip type. The regression coefficient between the BGMSV and HbA1cV was calculated. To allow for the aggregation of estimated three tests/day over 13 weeks (ie, 300 samples) of actual Blood Glucose (BG) values up to the HbA1c, we multiplied HbA1cV coefficient by √300 to estimate an empirical value for impact of BGMSV on BGV. RESULTS: Four thousand five hundred and twenty-four practice years with 159 700 T1DM patient years where accuracy data were available for more than 80% of strips prescribed were included, with overall BGMSV 6.5% and HbA1c mean of 66.9 mmol/mol (8.3%) with variability of 13 mmol/mol equal to 19% of the mean. At a GP practice level, BGMSV and HbA1cV as % of mean HbA1c (in other words, the spread of HbA1c) were closely related with a regression coefficient of 0.176, P < 0.001. Thus, greater variability in the BGMS at a GP practice level resulted in a greater spread of HbA1C readings in T1DM patients. Applying this factor for BGMS to the national ISO accepted standard where 95% results must be ≤±15% from reference, revealed that for BG, 95% results would be ≤±45% from the reference value. Thus, the variation in BG is three times that of the BGMS. For a patient with BG target @10 mmol/L using the worst performing ISO standard strips, on 1/20 occasions (average 1/week) actual blood glucose value could be >±4.5 mmol/L from target, compared with the best performing BGMS with BG >±2.2 mmol/L from reference on 1/20 occasions. CONCLUSION: Use of more variable/less accurate BGMS is associated both theoretically and in practice with a larger variability in measured BG and HbA1c, with implications for patient confidence in their day-to-day monitoring experience.

The pattern of prescribing of glucose modulating agents for type 2 diabetes in general practices in England 2016/17.

BACKGROUND: In the financial year 2016/17 there were 52.0 million items prescribed for diabetes at a total net ingredient cost of £983.7 million - up from 28.9 million prescription items and £572.4 million in 2006/07. Anti-diabetes drugs (British National Formulary section 6.1.2) make up 45.1 per cent of the total £983.7 million net ingredient cost of drugs used in diabetes and account for 72.0 per cent of prescription items for all diabetes prescribing. METHODS: We examined the way that agents licensed to treat type 2 diabetes were used across GP practices in England in the year 2016/2017. Analysis was at a GP practice level not at the level of patient data. RESULTS: Annual prescribing costs / patient / medication type for monotherapy varied considerable from £11/year for gliclazide and glimepiride to £885/year for Liraglutide. The use of SGLT-2i agents grew strongly at 70% per annum to around 100,000 DDD with prescriptions seen in 95% of GP practices. Liraglutide expenditure (11% of total) was high for a relatively small number of patients (1.3% of Defined Daily Doses), with still significant spend on exenatide. Liraglutide use significantly exceeded that of other glucagon-like peptide-1 (GLP-1) agonists. CONCLUSIONS: Our work demonstrates the significant cost of medication to modulate tissue glucose levels in type 2 diabetes and the dominance of some non-generic preparations in terms of number of prescriptions and overall spend. There are some older sulphonylureas in use, which should not generally be prescribed. Regular audit of patient treatment at a general practice level will ensure appropriate targeted use of licensed medications and of their cost effectiveness.

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.

Insulin-like growth factor-II and insulin-like growth factor binding protein-2 prospectively predict longitudinal elevation of HDL-cholesterol in type 2 diabetes.

INTRODUCTION: Associations of insulin-like growth factor-II (IGF-II) and insulin-like growth factor binding protein-2 (IGFBP-2) with cardiovascular risk have been inadequately studied. We hypothesized that IGF-II and IGFBP-2 associate with longitudinal trends in lipid profiles in type 2 diabetes patients. SUBJECTS AND METHODS: Four hundred and eighty nine subjects with type 2 diabetes (age 27-87 years) from the Salford Diabetes Cohort were studied. Longitudinal clinical information was extracted for an eight-year period (2002-2009) from an integrated electronic dataset of primary care and hospital data. RESULTS: There were 294 male subjects and mean age was 62.9 years. At baseline, IGF-II concentration was 602 ng/mL. HDL cholesterol at baseline was associated with log-IGF-II concentration in a model adjusted for age, gender, baseline body-mass index (BMI), estimated glomerular filtration rate (eGFR) and lipid-lowering therapy. IGFBP-1 and IGFBP-2 were associated with high HDL-cholesterol. A higher circulating IGF-II concentration at baseline was also associated with longitudinal increase in HDL-cholesterol in mixed-effects regression analyses independent of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, age, gender, eGFR, BMI and lipid-lowering therapy. Log-transformed baseline concentrations of IGFBP-1 and IGFBP-2 were also associated with longitudinal elevation in HDL-cholesterol. No association was observed for IGF-II or IGFBP-2 with longitudinal LDL cholesterol trends. CONCLUSION: Our analyses based on 'real world' data demonstrate that higher baseline IGF-II and IGFBP-2 predict increased HDL concentration over time, implicating IGF-II in modulation of circulating HDL-cholesterol concentrations.

Conflict resolution in end-of-life decisions in the neonatal unit.

End-of-life decisions are always stressful for families and professionals. As the decades pass, ethics and the law both change, even in one society, and cannot always provide perfect choices for each individual patient. Conflict should rarely arise in the neonatal unit. High-quality communication and compassion should allow professionals and families to build a team approach to the care of their child, even when the infant is imperilled. Each unit should have structures in place to deal with conflict, and every senior professional must be trained in conflict resolution so that the care of the family is outstanding.

Interventions to improve rates of post-mortem examination after stillbirth.

OBJECTIVE: Despite recognition of the value of post-mortem examination following stillbirth, worldwide rates have declined since the early 1990s. There is a paucity of published evidence relating to factors that can improve post-mortem uptake. The aim of this study was to assess post-mortem rates following stillbirth and identify trends in the past 18 years that may have affected acceptance of the investigation. STUDY DESIGN: Retrospective cohort study. RESULTS: Sharp declines in post-mortems coincided with publicity surrounding unlawful organ retention. Although nationally post-mortem rates have continued to fall, in our unit there was recovery in post-mortem rates. This increase was associated with implementation of policies to promote the uptake of perinatal post-mortem, including availability of specialist perinatal pathologists, education in the value of post-mortem, and senior staff involvement in counselling regarding the procedure. CONCLUSION: The need to improve uptake of post-mortem examination following stillbirth is internationally recognized. The results of this study suggest that increased local availability of specialist perinatal pathologists, who can support education in the value of post-mortem, along with senior staff obtaining consent, may help achieve this goal.

Normative values of substance P and neurokinin A in neonates.

BACKGROUND: Substance P (SP) and neurokinin A (NKA) are neuropeptides that have been researched as pain markers in adults, as they are involved in transmission and modulation of pain signals. There is a potential role for them as neurochemical markers of pain in neonates, but this has never previously been investigated. AIM: To establish normative values of SP and NKA in neonates. METHODS: Longitudinal once-daily morning blood samples were collected over two weeks from 142 neonates, gestation 23-40 weeks. Peptides were extracted, and then quantified using an in-house radioimmunoassay. Infants with presumed painful conditions were excluded. RESULTS: SP concentrations ranged from <0.98 to 11.2 pmol/L (median 1.7 pmol/L) and NKA concentrations from <1.95 to 74.6 pmol/L (median 6.0 pmol/L). Gestation and birth weight had no significant correlation with peptide concentrations. Postnatally, there was a gradual rise in median SP during the first three days, which decreased again by day 14. Median NKA showed a similar rise, but was not statistically significant. This postnatal rise and fall were more apparent in preterm infants < or = 32 weeks gestation. CONCLUSIONS: This is the first description of normative values of SP and NKA in neonates. SP and NKA show changes with postnatal age, which are more marked in preterm infants.

The use of anti-Müllerian hormone and antral follicle count to predict the potential of oocytes and embryos.

OBJECTIVE: To investigate whether anti-Müllerian hormone (AMH) is better than antral follicle count (AFC) in predicting oocyte yield and embryo quality after controlled ovarian hyperstimulation for in vitro fertilization (IVF). STUDY DESIGN: This is a prospective observational study involving 162 women (<40 years old) undergoing their first IVF cycle at an IVF unit within a university hospital. AMH and AFC measurements were made on day 3 of the cycle within 3 months of starting ovarian stimulation. A standard long down-regulation protocol using gonadotrophin releasing hormone agonist and recombinant follicle stimulating hormone was used. A maximum of two embryos were transferred on day 2 or 3 following oocyte retrieval. The primary outcome was the number of good quality embryos available for transfer and freezing. Embryos were graded according to the number of blastomeres, the difference in blastomere size and the degree of fragmentation, into grades 1-4. Secondary outcomes included the number of oocytes retrieved and fertilized and the live birth rate. Correlation between different parameters was calculated using Spearman's correlation coefficient. Receiver operating characteristic (ROC) curves were generated for AMH and AFC to compare ability of parameters to predict top quality or frozen embryos and the occurrence of a live birth. RESULTS: Of the 137 women who had fresh embryo transfer, 52 became pregnant (32.1% pregnancy rate per cycle started) and 38 had a live birth (23.5% live birth rate per cycle started). Both AMH and AFC had highly significant correlations with the number of oocytes retrieved and the number of oocytes fertilized (P<0.001). The two markers were also significantly associated with the number of top quality embryos available for transfer and the number of embryos frozen (P<0.01). With regard to live birth, AMH performed better than AFC (P<0.01 and P<0.05, respectively), but both markers were more valuable in predicting the absence rather than the occurrence of live birth (negative predictive value 84%). CONCLUSIONS: AMH and AFC are comparable predictors of oocytes retrieved and of the number of good quality embryos available for transfer and freezing. Prediction of live birth may help clinicians selecting patients suitable for single embryo transfer.

The relationships between AMH, androgens, insulin resistance and basal ovarian follicular status in non-obese subfertile women with and without polycystic ovary syndrome.

BACKGROUND: Hyperandrogenaemia and insulin resistance are prominent features of polycystic ovary syndrome (PCOS) and influence the process of folliculogenesis in women with the endocrinopathy. Anti-Müllerian hormone (AMH) levels are elevated in women with PCOS and studies including IVF subjects have shown that this is a reliable marker of ovarian performance. The aims of this prospective study were to assess the relationship between insulin resistance, androgens and AMH, and whether AMH contributes to altered folliculogenesis in non-obese women with PCOS. METHODS: A total of 232 IVF candidates, 49 of whom had PCOS according to the Rotterdam 2003 consensus criteria, were recruited. AMH levels and ovarian morphology were assessed. The relationships between AMH and insulin resistance and androgenaemia in patients with and without PCOS were studied. RESULTS: PCOS patients were slightly older than controls (median ages 34 and 30 years, respectively). AMH generally increased with antral follicle count (AFC), insulin, homeostatic model assessment of tissue insulin sensitivity (HOMA-IR), testosterone, free androgen index and luteinising hormone, and decreased with chronological age, homeostatic model assessment of steady state beta cell function (HOMA-B) and serum sex hormone binding globulin (SHBG). For these relationships there were no significant differences in the slopes between PCOS and non-PCOS patients. The ratio of AMH per antral follicle (AMH/AF) was higher in PCOS patients. Both PCOS and non-PCOS groups showed a very similar increase in AMH with increases in AFC, but the PCOS patients had consistently higher AMH across all AFC levels. CONCLUSIONS: These observations indicate that AMH is similarly related to insulin resistance and androgens in women with and without PCOS. This effect appears to be independent of age although an indirect causal effect due to ageing or some other mechanism cannot be ruled out. Excessive granulosa cell activity may be implicated in the abnormal follicular dynamic of the syndrome.