An Assessment of the Imaging Performance of Hand-Held Ultrasound Scanners Using the Edinburgh Pipe Phantom.

OBJECTIVE: Although hand-held ultrasound devices (HHUSDs) are currently used for a diverse range of diagnostic and interventional applications the imaging performance of such scanners is rarely considered. The aim of this study was to assess the imaging performance of a wide-range of HHUSDs and compare their imaging performance to cart-based systems utilized for the same clinical applications. METHODS: The grayscale imaging performances of 19 HHUSDs from eight different manufacturers, manufactured between 2016 and 2021, were measured using a figure-of-merit known as the resolution integral. The imaging performance of the HHUSDs were compared to 142 cart-based ultrasound scanners. RESULTS: The HHUSD with the overall highest resolution integral (66) was a Butterfly (Burlington, MA, USA) wired phased array for small parts applications, followed by a Philips (Bothell, WA, USA) Lumify wired curvilinear transducer (57) for abdominal applications, a Butterfly wired phased array (56) for abdominal applications, a GE (Freiburg, Baden-Wurttemberg, Germany) VScan Air wireless linear array (56) for small parts applications, and a Healcerion (Seoul, Korea) Sonon 300L wireless linear array (56) for small parts applications. A GE VScan Extend wired phased array had the highest resolution integral (44) for cardiac applications. CONCLUSIONS: The Butterfly phased array had the highest resolution integral of all the 19 HHUSDs, although this value is still less than the majority of cart-based cardiac and abdominal ultrasound scanners manufactured from 2010 to 2017. Clinical users of HHUSDs should be mindful of the limitations in imaging performance of hand-held ultrasound devices.

Erectile dysfunction predicts mortality in middle-aged and older men independent of their sex steroid status.

BACKGROUND: erectile dysfunction is associated with mortality, whereas the association between low testosterone (T) and higher mortality remains controversial. Sexual dysfunction and low T often coexist, but the relative importance of sexual symptoms versus low T in predicting mortality is not known. We studied the interrelationships between sex steroids and sexual symptoms with all-cause mortality in a large prospective cohort of European men. DESIGN: survival status was assessed in 1,788 community-dwelling men, aged 40-79, who participated in the European Male Ageing Study (EMAS). Sexual symptoms were evaluated via a validated questionnaire (EMAS-SFQ). Sex steroids were measured by mass spectrometry. Cox proportional hazard models were used to study the association between hormones, sexual symptoms and mortality. RESULTS: about 420 (25.3%) men died during a mean follow-up of 12.6 ± 3.1 years. Total T levels were similar in both groups, but free T was lower in those who died. Men with three sexual symptoms (erectile dysfunction, reduced morning erections and lower libido) had a higher mortality risk compared with men with none of these symptoms (adjusted hazard ratio (HR) and 95% confidence intervals: 1.75 (1.28-2.40, P = 0.001)). Particularly, erectile dysfunction and poor morning erections, but not lower libido, were associated with increased mortality (HR 1.40 (1.13-1.74, P = 0.002), 1.28 (1.04-1.59, P = 0.023) and 1.12 (0.90-1.39, P = 0.312), respectively). Further adjusting for total T, free T or oestradiol did not influence the observed risk. CONCLUSIONS: sexual symptoms, in particular erectile dysfunction, predict all-cause mortality independently of sex steroids and can be an early warning sign of a poor health status.

The Imaging Performance of Diagnostic Ultrasound Scanners Using the Edinburgh Pipe Phantom to Measure the Resolution Integral - 15 Years of Experience.

The grayscale imaging performance of a total of 368 different scanner/transducer combinations from 39 scanner manufacturers measured over a period of 15 years is presented. Performance was measured using the resolution integral, a single figure-of-merit to quantify ultrasound imaging performance. The resolution integral was measured using the Edinburgh Pipe Phantom. Transducers included single element, linear, phased, curvilinear and multi-row arrays. Our results demonstrate that the resolution integral clearly differentiates between transducers with varying levels of performance. Two further parameters were also derived from the resolution integral: characteristic resolution and depth of field. We demonstrate that these two parameters can successfully characterize individual transducer performance and differentiate between transducers designed for different clinical and preclinical applications. In conclusion, the resolution integral is an effective metric to quantify and monitor grayscale imaging performance in clinical practice.

Incidence of Paget's disease of bone in the UK: evidence of a continuing decline.

OBJECTIVES: To characterize the incidence of clinically diagnosed Paget's disease of bone in the UK during 1999-2015 and to determine variations in the incidence of disease by age, sex, geography and level of deprivation. METHODS: Incident cases of Paget's disease occurring between 1999 and 2015 were identified from primary care records. Overall crude incidence and incidence stratified by age and sex was calculated each year from 1999 to 2015. Direct age- and sex-standardized incidence was also calculated. We used Poisson regression to look at variations in incidence by deprivation and UK region. RESULTS: A total of 3592 incident cases of Paget's disease were identified between 1999 and 2015. Incidence increased with age and at all ages was greater in men than women. In women and men, respectively, crude incidence increased from 0.037 and 0.074/10 000 population per year among those 45-49 years of age to 3.7 and 6.3/10 000 population per year among those ≥85 years. The overall standardized incidence decreased from 0.75/10 000 person-years in 1999 to 0.20/10 000 person-years in 2015. After adjustment for age and sex, incidence was >30% higher in the most- compared with least-deprived quintile of deprivation. There was evidence of geographic variation, with the highest incidence in the North West of England, which persisted after adjustment for age, sex and level of deprivation. CONCLUSION: The incidence of clinically diagnosed Paget's disease has continued to decrease since 1999. The reason for the decline in incidence remains unknown, although the rapidity of change points to an alteration in one or more environmental determinants.

Evaluation of Intravascular Ultrasound Catheter-Based Transducers Using the Resolution Integral.

Intravascular ultrasound (IVUS) catheters are a specialist imaging modality used in the assessment of cardiovascular disease. The ultrasound transducer may either be of single-element mechanical or phased-array design. Because of their design and operating frequencies (10-45 MHz), evaluation of the imaging performance is not possible with commercially available ultrasound test objects. An existing test object, the Edinburgh Pipe Phantom, was modified to allow measurement of resolution integral (R), depth of field (Lr) and characteristic resolution (Dr) of IVUS catheters. In total, seven IVUS catheters, from two manufacturers and of both single-element mechanical and phased-array design, were tested to provide a measure of performance over different frequencies and technologies. Measurements of R for the tested IVUS catheters ranged from 11.9 to 18.8. The modified Edinburgh Pipe Phantom therefore allows catheter-based ultrasound probes to be evaluated scientifically and their performance to be seen in relation to other similar ultrasound technologies such as pre-clinical ultrasound and endoscopic ultrasound.

Assumptions made when preparing drug exposure data for analysis have an impact on results: An unreported step in pharmacoepidemiology studies.

PURPOSE: Real-world data for observational research commonly require formatting and cleaning prior to analysis. Data preparation steps are rarely reported adequately and are likely to vary between research groups. Variation in methodology could potentially affect study outcomes. This study aimed to develop a framework to define and document drug data preparation and to examine the impact of different assumptions on results. METHODS: An algorithm for processing prescription data was developed and tested using data from the Clinical Practice Research Datalink (CPRD). The impact of varying assumptions was examined by estimating the association between 2 exemplar medications (oral hypoglycaemic drugs and glucocorticoids) and cardiovascular events after preparing multiple datasets derived from the same source prescription data. Each dataset was analysed using Cox proportional hazards modelling. RESULTS: The algorithm included 10 decision nodes and 54 possible unique assumptions. Over 11 000 possible pathways through the algorithm were identified. In both exemplar studies, similar hazard ratios and standard errors were found for the majority of pathways; however, certain assumptions had a greater influence on results. For example, in the hypoglycaemic analysis, choosing a different variable to define prescription end date altered the hazard ratios (95% confidence intervals) from 1.77 (1.56-2.00) to 2.83 (1.59-5.04). CONCLUSIONS: The framework offers a transparent and efficient way to perform and report drug data preparation steps. Assumptions made during data preparation can impact the results of analyses. Improving transparency regarding drug data preparation would increase the repeatability, reproducibility, and comparability of published results.

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. Objective: To investigate the genetic regulation of serum E2 and E1 in men. Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. Main Outcome Measures: Genetic determinants of serum E2 and E1 levels. Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance. Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.

Acoustic Properties of Small Animal Soft Tissue in the Frequency Range 12-32 MHz.

Quality assurance phantoms are made of tissue-mimicking materials (TMMs) the acoustic properties of which mimic those of soft tissue. However, the acoustic properties of many soft tissue types have not been measured at ultrasonic frequencies >9 MHz. With the increasing use of high-frequency ultrasound for both clinical and pre-clinical applications, it is of increasing interest to ensure that TMMs accurately reflect the acoustic properties of soft tissue at these higher frequencies. In this study, the acoustic properties of ex vivo brain, liver and kidney samples from 50 mice were assessed in the frequency range 12-32 MHz. Measurements were performed within 6 min of euthanasia in a phosphate-buffered saline solution maintained at 37.2 ± 0.2 °C. The measured mean values for the speed of sound for all organs were found to be higher than the International Electrotechnical Commission guideline recommended value for TMMs. The attenuation coefficients measured for brain, liver and kidney samples were compared with the results of previous studies at lower frequencies. Only the measured kidney attenuation coefficient was found to be in good agreement with the International Electrotechnical Commission guideline. The information provided in this study can be used as a baseline on which to manufacture a TMM suitable for high-frequency applications.

Elevated luteinizing hormone despite normal testosterone levels in older men-natural history, risk factors and clinical features.

OBJECTIVE: Elevated luteinizing hormone (LH) with normal testosterone (T) suggests compensated dysregulation of the gonadal axis. We describe the natural history, risk factors and clinical parameters associated with the development of high LH (HLH, LH >9.4 U/L) in ageing men with normal T (T ≥ 10.5 nmol/L). DESIGN, PATIENTS AND MEASUREMENTS: We conducted a 4.3-year prospective observational study of 3369 community-dwelling European men aged 40-79 years. Participants were classified as follows: incident (i) HLH (n = 101, 5.2%); persistent (p) HLH (n = 128, 6.6%); reverted (r) HLH (n = 46, 2.4%); or persistent normal LH (pNLH, n = 1667, 85.8%). Potential predictors and changes in clinical features associated with iHLH and rHLH were analysed using regression models. RESULTS: Age >70 years (OR = 4.12 [2.07-8.20]), diabetes (OR = 2.86 [1.42-5.77]), chronic pain (OR = 2.53 [1.34-4.77]), predegree education (OR = 1.79 [1.01-3.20]) and low physical activity (PASE ≤ 78, OR = 2.37 [1.24-4.50]) predicted development of HLH. Younger age (40-49 years, OR = 8.14 [1.35-49.13]) and nonsmoking (OR = 5.39 [1.48-19.65]) predicted recovery from HLH. Men with iHLH developed erectile dysfunction, poor health, cardiovascular disease (CVD) and cancer more frequently than pNLH men. In pHLH men, comorbidities, including CVD, developed more frequently, and cognitive and physical function deteriorated more, than in pNLH men. Men with HLH developed primary hypogonadism more frequently (OR = 15.97 [5.85-43.60]) than NLH men. Men with rHLH experienced a small rise in BMI. CONCLUSIONS: Elevation of LH with normal T is predicted by multiple factors, reverts frequently and is not associated with unequivocal evidence of androgen deficiency. High LH is a biomarker for deteriorating health in aged men who tend to develop primary hypogonadism.

Associations of muscle force, power, cross-sectional muscle area and bone geometry in older UK men.

BACKGROUND: Ageing is associated with sarcopenia, osteoporosis, and increased fall risk, all of which contribute to increased fracture risk. Mechanically, bone strength adapts in response to forces created by muscle contractions. Adaptations can be through changes in bone size, geometry, and bending strength. Muscle mass is often used as a surrogate for muscle force; however, force can be increased without changes in muscle mass. Increased fall risk with ageing has been associated with a decline in muscle power-which is a measure of mobility. The aims of this study were as follows: (i) to investigate the relationship between muscle parameters in the upper and lower limbs with age in UK men and the influence of ethnicity on these relationships; (ii) to examine the relationships between jump force/grip strength/cross-sectional muscle area (CSMA) with bone outcomes at the radius and tibia. METHODS: White European, Black Afro-Caribbean, and South Asian men aged 40-79 years were recruited from Manchester, UK. Cortical bone mineral content, cross-sectional area, cortical area, cross-sectional moment of inertia, and CSMA were measured at the diaphysis of the radius and tibia using peripheral quantitative computed tomography. Lower limb jump force and power were measured from a single two-legged jump performed on a ground-reaction force platform. Grip strength was measured using a dynamometer. Associations between muscle and bone outcomes was determined using linear regression with adjustments for age, height, weight, and ethnicity. RESULTS: Three hundred and one men were recruited. Jump force was negatively associated with age; for every 10 year increase in age, there was a 4% reduction in jump force (P < 0.0001). There was a significant age-ethnicity interaction for jump power (P = 0.039); after adjustments, this was attenuated (P = 0.088). For every 10 year increase in age, grip strength decreased by 11%. Jump force was positively associated with tibial bone outcomes: a 1 standard deviation greater jump force was associated with significantly higher cortical bone mineral content 3.1%, cross-sectional area 4.2%, cortical area 3.4%, and cross-sectional moment of inertia 6.8% (all P < 0.001). Cross-sectional muscle area of the lower leg was not associated with tibial bone outcomes. Both grip strength and CSMA of the arm were positively associated, to a similar extent, with radius diaphyseal bone outcomes. CONCLUSIONS: Jump force and power are negatively associated with age in UK men. In the lower limb, the measurement of jump force is more strongly related to bone outcomes than CSMA. It is important to consider jump force and power when understanding the aetiology of bone loss and mobility in ageing men.

Broadband Acoustic Measurement of an Agar-Based Tissue-Mimicking-Material: A Longitudinal Study.

Commercially available ultrasound quality assurance test phantoms rely on the long-term acoustic stability of the tissue-mimicking-material (TMM). Measurement of the acoustic properties of the TMM can be technically challenging, and it is important to ensure its stability. The standard technique is to film-wrap samples of TMM and to measure the acoustic properties in a water bath. In this study, a modified technique was proposed whereby the samples of TMM are measured in a preserving fluid that is intended to maintain their characteristics. The acoustic properties were evaluated using a broadband pulse-echo substitution technique over the frequency range 4.5-50 MHz at 0, 6 and 12 months using both techniques. For both techniques, the measured mean values for the speed of sound and attenuation were very similar and within the International Electrotechnical Commission-recommended value. However, the results obtained using the proposed modified technique exhibited greater stability over the 1-y period compared with the results acquired using the standard technique.

Ethnic differences in male reproductive hormones and relationships with adiposity and insulin resistance in older men.

OBJECTIVES: To assess ethnic differences in male reproductive hormone levels and to determine whether any differences are explained by adiposity, insulin resistance (IR) or comorbidities in older men. DESIGN: Multi-ethnic cross-sectional observational study. PARTICIPANTS: Community dwelling middle-aged and elderly men residing in the UK aged 40-84 years of South Asian (SA; n = 180), White European (WE; n = 328) or African Caribbean (AC; n = 166) origin. OBSERVATIONS: Measured testosterone (T), calculated free T (cFT), sex hormone-binding globulin and LH in SA, WE and AC men along with an assessment of body composition, IR, lifestyle factors and medical conditions. RESULTS: Age-adjusted mean T and cFT levels were lower in SA men when compared to WE and AC men (mean (SEM) T: SA: 14·0 ± 0·4; WE: 17·1 ± 0·3; AC: 17·2 ± 0·5 nmol/l, P < 0·001; cFT: SA: 283 ± 7; WE: 313 ± 5; AC: 314 ± 8 pmol/l, P < 0·006). Compared to WE and AC men, SA men had higher levels of body fat, IR, comorbidities and diabetes. After adjusting for body fat, IR and other confounders, T levels in SA men remained lower than in WE men (P = 0·04) but ethnic differences in cFT became nonsignificant. LH levels were higher in SA than WE men in age-adjusted and fully adjusted models. CONCLUSIONS: T and cFT are lower in SA men than in WE and AC men. Whether ethnic-specific reference ranges for T and cFT might be appropriate in clinical practice requires further investigation. Ethnic differences in cFT, but not T, appear to be, more readily, explained by ethnic differences in adiposity, thus providing insights into potential pathophysiological mechanisms.

Frailty and bone health in European men.

Background: frailty is associated with an increased risk of fragility fractures. Less is known, however, about the association between frailty and bone health. Methods: men aged 40-79 years were recruited from population registers in eight European centres for participation in the European Male Aging Study. Subjects completed a comprehensive assessment which included quantitative ultrasound (QUS) scan of the heel (Hologic-SAHARA) and in two centres, dual-energy bone densitometry (dual-energy x-ray absorptiometry, DXA). Frailty was defined based on an adaptation of Fried's phenotype criteria and a frailty index (FI) was constructed. The association between frailty and the QUS and DXA parameters was determined using linear regression, with adjustments for age, body mass index and centre. Results: in total, 3,231 subjects contributed data to the analysis. Using the Fried categorisation of frailty, pre-frail and frail men had significantly lower speed of sound (SOS), broadband ultrasound attenuation (BUA) and quantitative ultrasound index (QUI) compared to robust men (P< 0.05). Similar results were seen using the FI after categorisation into 'high', 'medium' and 'low' levels of frailty. Using the Fried categorisation, frail men had lower femoral neck bone mineral density (BMD) compared to robust men (P < 0.05), but not lower lumbar spine BMD. Using the FI categorisation, a 'high' level of frailty (FI > 0.35) was associated with lower lumbar spine BMD (P < 0.05) when compared to those with low (FI < 0.2), but not lower femoral neck BMD. When analysed as a continuous variable, higher FI was linked with lower SOS, BUA and QUI (P < 0.05). Conclusions: optimisation of bone health as well as prevention of falls should be considered as strategies to reduce fractures in frail older people.

Pipe Phantoms With Applications in Molecular Imaging and System Characterization.

Pipe (vessel) phantoms mimicking human tissue and blood flow are widely used for cardiovascular related research in medical ultrasound. Pipe phantom studies require the development of materials and liquids that match the acoustic properties of soft tissue, blood vessel wall, and blood. Over recent years, pipe phantoms have been developed to mimic the molecular properties of the simulated blood vessels. In this paper, the design, construction, and functionalization of pipe phantoms are introduced and validated for applications in molecular imaging and ultrasound imaging system characterization. There are three major types of pipe phantoms introduced: 1) a gelatin-based pipe phantom; 2) a polydimethylsiloxane-based pipe phantom; and 3) the "Edinburgh pipe phantom." These phantoms may be used in the validation and assessment of the dynamics of microbubble-based contrast agents and, in the case of a small diameter tube phantom, for assessing imaging system spatial resolution/contrast performance. The materials and procedures required to address each of the phantoms are described.

Quality assurance testing of transoesophageal echocardiography probes.

INTRODUCTION: In response to an ultrasound imaging issue with transoesophageal echocardiography probes, a testing protocol was developed to check features pertinent to the operation of these probes. The imaging problem was detected in multiple probes of the same make and model. METHODS: Over a two-year period, a series of 26 probes of this model were tested at acceptance, then three to six months later before being replaced due to a defect. A range of visual, mechanical and electrical tests were performed. Image tests comprised low-contrast penetration measurements and a comparison of phantom images at regular intervals to highlight artefacts in both B-mode and colour Doppler imaging. RESULTS: Of the 26 defective probes replaced, 7 suffered mechanical/electrical problems, 5 of which prevented imaging results being obtained. Low-contrast penetration reduction of greater than 5% occurred in 14 probes. B-mode artefacts were observed on 12 probes and Doppler noise artefacts on 6 probes. No faults were found on five probes. The manufacturer addressed the imaging problem identified and of the seven subsequent probes supplied, only one suffered an imaging fault. CONCLUSIONS: The implementation of a quality assurance protocol for transoesophageal echocardiography probes resulted in cost savings on replacements/repairs. When provided with the evidence gathered, the manufacturer supplied 23 probes under warranty or as loan equipment. The regular testing of the probes substantially reduced the impact of downtime and poor diagnosis from this equipment on the clinical service.

The androgen receptor gene CAG repeat in relation to 4-year changes in androgen-sensitive endpoints in community-dwelling older European men.

CONTEXT: The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive. OBJECTIVE: To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-aged and elderly European men. DESIGN: Multinational European observational prospective cohort study. PARTICIPANTS: A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic-pituitary-testicular (HPT) axis. MAIN OUTCOME MEASURES: Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6-20; 21-23; 24-39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels. RESULTS: The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels. CONCLUSION: Within a 4-year time frame, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, which might be associated with the age-related decline in T levels.

Detecting failed elements on phased array ultrasound transducers using the Edinburgh Pipe Phantom.

AIMS: Imaging faults with ultrasound transducers are common. Failed elements on linear and curvilinear array transducers can usually be detected with a simple image uniformity or 'paperclip' test. However, this method is less effective for phased array transducers, commonly used in cardiac imaging. The aim of this study was to assess whether the presence of failed elements could be detected through measurement of the resolution integral (R) using the Edinburgh Pipe Phantom. METHODS: A 128-element paediatric phased array transducer was studied. Failed elements were simulated using layered polyvinyl chloride (PVC) tape as an attenuator and measurements of resolution integral were carried out for several widths of attenuator. RESULTS: All widths of attenuator greater than 0.5 mm resulted in a significant reduction in resolution integral and low contrast penetration measurements compared to baseline (p < 0.05). CONCLUSIONS: Measurements of resolution integral and low contrast penetration both have the potential to be used as straightforward and inexpensive tests to detect failed elements on phased array transducers. Particularly encouraging is the result for low contrast penetration as this is a quick and simple measurement to make and can be performed with many different test objects, thus enabling 'in-the-field' checks.

Natural history, risk factors and clinical features of primary hypogonadism in ageing men: Longitudinal Data from the European Male Ageing Study.

OBJECTIVE: In ageing men, the incidence and clinical significance of testosterone (T) decline accompanied by elevated luteinizing hormone (LH) are unclear. We describe the natural history, risk factors and clinical features associated with the development of biochemical primary hypogonadism (PHG, T < 10·5 nmol/l and LH>9·4U/l) in ageing men. DESIGN, PATIENTS AND MEASUREMENTS: A prospective observational cohort survey of 3,369 community-dwelling men aged 40-79 years, followed up for 4·3 years. Men were classified as incident (i) PHG (eugonadal [EUG, T ≥ 10·5 nmol/l] at baseline, PHG at follow-up), persistent (p) PHG (PHG at baseline and follow-up), pEUG (EUG at baseline and follow-up) and reversed (r) PHG (PHG at baseline, EUG at follow-up). Predictors and changes in clinical features associated with the development of PHG were analysed by regression models. RESULTS: Of 1,991 men comprising the analytical sample, 97·5% had pEUG, 1·1% iPHG, 1·1% pPHG and 0·3% rPHG. The incidence of PHG was 0·2%/year. Higher age (>70 years) [OR 12·48 (1·27-122·13), P = 0·030] and chronic illnesses [OR 4·24 (1·08-16·56); P = 0·038] predicted iPHG. Upon transition from EUG to PHG, erectile function, physical vigour and haemoglobin worsened significantly. Men with pPHG had decreased morning erections, sexual thoughts and haemoglobin with increased insulin resistance. CONCLUSIONS: Primary testicular failure in men is uncommon and predicted by old age and chronic illness. Some clinical features attributable to androgen deficiency, but not others, accompanied the T decline in men who developed biochemical PHG. Whether androgen replacement can improve sexual and/or physical function in elderly men with PHG merits further study.

Oral glucocorticoid therapy and all-cause and cause-specific mortality in patients with rheumatoid arthritis: a retrospective cohort study.

Previous studies of glucocorticoid (GC) therapy and mortality have had inconsistent results and have not considered possible perimortal bias-a type of protopathic bias where illness in the latter stages of life influences GC exposure, and might affect the observed relationship between GC use and death. This study aimed to investigate all-cause and cause-specific mortality in association with GC therapy in patients with rheumatoid arthritis (RA), and explore possible perimortal bias. A retrospective cohort study using the primary care electronic medical records. Oral GC exposure was identified from prescriptions. Mortality data were obtained from the UK Office for National Statistics. Multivariable Cox proportional hazards regression models assessed the association between GC use models and death. Several methods to explore perimortal bias were examined. The cohort included 16,762 patients. For ever GC use there was an adjusted hazard ratio for all-cause mortality of 1.97 (95 % CI 1.81-2.15). Current GC dose of below 5 mg per day (prednisolone equivalent dose) was not associated with an increased risk of death, but a dose-response association was seen for higher dose categories. The association between ever GC use and all-cause mortality was partly explained by perimortal bias. GC therapy was associated with an increased risk of mortality for all specific causes considered, albeit to a lesser extent for cardiovascular causes. GC use was associated with an increased risk of death in RA, at least partially explained by perimortal bias. Importantly, GC doses below 5 mg were not associated with an increased risk of death.