Investigation and management of young-onset hypertension: British and Irish hypertension society position statement.

National and international hypertension guidelines recommend that adults with young-onset hypertension (aged <40 years at diagnosis) are reviewed by a hypertension specialist to exclude secondary causes of hypertension and optimise therapeutic regimens. A recent survey among UK secondary care hypertension specialist physicians highlighted variations in the investigation of such patients. In this position statement, the British and Irish Hypertension Society seek to provide clinicians with a practical approach to the investigation and management of adults with young-onset hypertension. We aim to ensure that individuals receive consistent and high-quality care across the UK and Ireland, to highlight gaps in the current evidence, and to identify important future research questions.

Screening and management of hypertensive patients with chronic kidney disease referred to Hypertension Excellence Centres among 27 countries. A pilot survey based on questionnaire.

OBJECTIVE: Real-life management of hypertensive patients with chronic kidney disease (CKD) is unclear. METHODS: A survey was conducted in 2023 by the European Society of Hypertension (ESH) to assess management of CKD patients referred to ESH-Hypertension Excellence Centres (ESH-ECs) at first referral visit. The questionnaire contained 64 questions with which ESH-ECs representatives were asked to estimate preexisting CKD management quality. RESULTS: Overall, 88 ESH-ECs from 27 countries participated (fully completed surveys: 66/88 [75.0%]). ESH-ECs reported that 28% (median, interquartile range: 15-50%) had preexisting CKD, with 10% of them (5-30%) previously referred to a nephrologist, while 30% (15-40%) had resistant hypertension. The reported rate of previous recent (<6 months) estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) testing were 80% (50-95%) and 30% (15-50%), respectively. The reported use of renin-angiotensin system blockers was 80% (70-90%). When a nephrologist was part of the ESH-EC teams the reported rates SGLT2 inhibitors (27.5% [20-40%] vs. 15% [10-25], P = 0.003), GLP1-RA (10% [10-20%] vs. 5% [5-10%], P = 0.003) and mineralocorticoid receptor antagonists (20% [10-30%] vs. 15% [10-20%], P = 0.05) use were greater as compared to ESH-ECs without nephrologist participation. The rate of reported resistant hypertension, recent eGFR and UACR results and management of CKD patients prior to referral varied widely across countries. CONCLUSIONS: Our estimation indicates deficits regarding CKD screening, use of nephroprotective drugs and referral to nephrologists before referral to ESH-ECs but results varied widely across countries. This information can be used to build specific programs to improve care in hypertensives with CKD.

Cytokeratin-18 is a sensitive biomarker of alanine transaminase increase in a placebo-controlled, randomized, crossover trial of therapeutic paracetamol dosing (PATH-BP biomarker substudy).

Drug-induced liver injury (DILI) is a challenge in clinical medicine and drug development. Highly sensitive novel biomarkers have been identified for detecting DILI following a paracetamol overdose. The study objective was to evaluate biomarker performance in a 14-day trial of therapeutic dose paracetamol. The PATH-BP trial was a double-blind, placebo-controlled, crossover study. Individuals (n = 110) were randomized to receive 1 g paracetamol 4× daily or matched placebo for 2 weeks followed by a 2-week washout before crossing over to the alternate treatment. Blood was collected on days 0 (baseline), 4, 7, and 14 in both arms. Alanine transaminase (ALT) activity was measured in all patients. MicroRNA-122 (miR-122), cytokeratin-18 (K18), and glutamate dehydrogenase (GLDH) were measured in patients who had an elevated ALT on paracetamol treatment (≥50% from baseline). ALT increased in 49 individuals (45%). All 3 biomarkers were increased at the time of peak ALT (K18 paracetamol arm: 18.9 ± 9.7 ng/ml, placebo arm: 11.1 ± 5.4 ng/ml, ROC-AUC = 0.80, 95% CI 0.71-0.89; miR-122: 15.1 ± 12.9fM V 4.9 ± 4.7fM, ROC-AUC = 0.83, 0.75-0.91; and GLDH: 24.6 ± 31.1U/l V 12.0 ± 11.8U/l, ROC-AUC = 0.66, 0.49-0.83). All biomarkers were correlated with ALT (K18 r = 0.68, miR-122 r = 0.67, GLDH r = 0.60). To assess sensitivity, biomarker performance was analyzed on the visit preceding peak ALT (mean 3 days earlier). K18 identified the subsequent ALT increase (K18 ROC-AUC = 0.70, 0.59-0.80; miR-122 ROC-AUC = 0.60, 0.49-0.72, ALT ROC-AUC = 0.59, 0.48-0.70; GLDH ROC-AUC = 0.70, 0.50-0.90). Variability was lowest for ALT and K18. In conclusion, K18 was more sensitive than ALT, miR-122, or GLDH and has potential significant utility in the early identification of DILI in trials and clinical practice.

Inter-observer variance of examiner scoring in urology Objective Structured Clinical Examinations.

INTRODUCTION: The Objective Structured Clinical Examination (OSCE) is an attractive tool of competency assessment in a high-stakes summative exam. An advantage of the OSCE is the ability to assess more realistic context, content, and procedures. Each year, the Queen's Urology Exam Skills Training (QUEST) is attended by graduating Canadian urology residents to simulate their upcoming board exams. The exam consists of a written component and an OSCE. The aim of this study was to determine the inter-observer consistency of scoring between two examiners of an OSCE for a given candidate. METHODS: Thirty-nine participants in 2020 and 37 participants in 2021 completed four stations of OSCEs virtually over the Zoom platform. Each candidate was examined and scored independently by two different faculty urologists in a blinded fashion at each station. The OSCE scoring consisted of a checklist rating scale for each question. An intra-class correlation (ICC) analysis was conducted to determine the inter-rater reliability of the two examiners for each of the four OSCE stations in both the 2020 and 2021 OSCEs. RESULTS: For the 2020 data, the prostate cancer station scores were most strongly correlated (ICC 0.746, 95% confidence interval [CI] 0.556-0.862, p<0.001). This was followed by the general urology station (ICC 0.688, 95% CI 0.464-0.829, p<0.001), the urinary incontinence station (ICC 0.638, 95% CI 0.403-0.794, p<0.001), and finally the nephrolithiasis station (ICC 0.472, 95% CI 0.183-0.686, p<0.001). For the 2021 data, the renal cancer station had the highest ICC at 0.866 (95% CI 0.754-0.930, p<0.001). This was followed by the nephrolithiasis station (ICC 0.817, 95% CI 0.673-0.901, p<0.001), the pediatric station (ICC 0.809, 95% CI 0.660-0.897, p<0.001), and finally the andrology station (ICC 0.804, 95% CI 0.649-0.895, p<0.001). A Pearson correlation coefficient was calculated for all stations, and all show a positive correlation with global exam scores. It is noteworthy that some stations were more predictive of overall performance, but this did not necessarily mean better ICC scores for these stations. CONCLUSIONS: Given a specific clinical scenario in an OSCE exam, inter-rater reliability of scoring can be compromised on occasion. Care should be taken when high-stakes decisions about promotion are made based on OSCEs with limited standardization.

The effect of daily UVA phototherapy for 2 weeks on clinic and 24-h blood pressure in individuals with mild hypertension.

Latitude and season determine exposure to ultraviolet radiation and correlate with population blood pressure. Evidence for Vitamin D causing this relationship is inconsistent, and temperature changes are only partly responsible for BP variation. In healthy individuals, a single irradiation with 20 J/cm2 UVA mobilises NO from cutaneous stores to the circulation, causes arterial vasodilatation, and elicits a transient fall in BP. We, therefore, tested whether low-dose daily UVA phototherapy might be an effective treatment for mild hypertension. 13 patients with untreated high-normal or stage 1 hypertension (BP 130-159/85-99 mm Hg), confirmed by 24-h ambulatory blood pressure (ABP), were recruited. Using home phototherapy lamps they were either exposed to 5 J/cm2 full body UVA (320-410 nm) radiation each day for 14 days, or sham-irradiated with lamps filtered to exclude wavelengths <500 nm. After a washout period of 3 ± 1 week, the alternate irradiation was delivered. 24-h ABP was measured on day 0 before either irradiation sequence and on day 14. Clinic BP was recorded on day 0, and within 90 min of irradiation on day 14. There was no effect on 24-h ABP following UVA irradiation. Clinic BP shortly after irradiation fell with UVA (-8.0 ± 2.9/-3.8 ± 1.1 mm Hg p = 0.034/0.029) but not sham irradiation (1.1 ± 3.0/0.9 ± 1.5 mm Hg). Once daily low-dose UVA does not control mildly elevated BP although it produces a transient fall shortly after irradiation. More frequent exposure to UVA might be effective. Alternatively, UVB, which photo-releases more NO from skin, could be tried.

John Goodsir (1814-1867) and his neurological illness.

John Goodsir, conservator and professor of anatomy at the University of Edinburgh, suffered an unidentified illness described by experts after his death as tabes. The features that led to this diagnosis, the understanding of tabes at that time and its relationship in some cases to syphilis, are discussed. It is concluded that the most likely diagnoses are subacute combined degeneration of the cord as a result of malnutrition or tabes dorsalis resulting from earlier syphilis. The presence of 'lightning pains' leans towards the latter diagnosis but evidence for a means of acquisition of syphilis is lacking. The disadvantages of retrospective diagnosis are discussed.

Robert Lawson Tait (1845-1899): The true innovator of aseptic surgery?

Robert Lawson Tait was an original thinker, a surgical innovator, a controversialist and an iconoclast. He made important contributions to surgery, was an eloquent supporter of Darwinian evolution and women in medicine and opposed vivisection. He is probably best remembered for his high-profile opposition to Listerian antisepsis which continued until his death. While Lister went on to receive the country's highest honours and was lauded throughout the world, Tait received much more modest honours and little subsequent recognition by historians. Yet it could be argued that Tait's system rather than Lister's was the basis of modern aseptic surgery. Tait never changed his views on asepsis over his lifetime and relied on surgical cleanliness, which, combined with his extensive clinical experience, enabled him to achieve outcomes as good or better than with antisepsis. By contrast, Listerism evolved over 30 years, claimed to be based on laboratory data and adopted the new discoveries of the germ theory of disease as they emerged. We compare the systems of Tait and Lister, explore the basis of Tait's opposition to Listerian methods and conclude that Tait's thinking underlies modern surgical practice and that he should receive greater acknowledgement for his contribution to the prevention of surgical infections.

Surgeon-anatomist to robotic technician? The evolving role of the surgeon over three centuries.

In the 18th century, anatomy was the principal science underlying surgical practice. Over the next three centuries, the scientific basis of surgery changed dramatically. Morbid anatomy led to the understanding of organ-based pathologies that allowed surgeons to remove, reconstruct and in some cases replace internal organs. In the 19th century, the new science of microbiology facilitated antisepsis, then asepsis as surgery progressed from a craft to a scientific discipline. Yet many surgeons believed that surgery was not merely a science but also an art, in which the creativity of the doctor was necessary for progress. Surgical advancement depended on creative individuals with innovative flair, prepared to pioneer often risky procedures in the face of mainstream opposition. The 20th century saw a series of changes that made such individualism more difficult. 'Scientific Management' when applied to surgery decreed that procedures be performed according to predetermined schedules, a drive to uniformity producing better outcomes and diminishing individual variation. Yet inventive individuals continued to produce surgical advances. In the 21st century, moves toward standardisation developed further. The escalating safety culture in surgery moderates the introduction of novel, potentially riskier procedures, while more and more regulation increasingly requires surgeons to adhere to guidelines and protocols, further restricting surgical individualism. Moreover, the role of the individual is further diminished, as surgical care is delivered by teams, both in deciding management in major cases and in the operating theatre. The introduction of robotics into surgery has led to the suggestion that the role of the surgeon may become that of a technician. Will these constraints, and greater patient involvement in decisions, allow tomorrow's surgeons the freedom to innovate? We believe that the pioneering spirit, imagination and flair will not be lost. Tomorrow's surgeons must remain doctors, showing the compassion and empathy that robots cannot provide.

Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial.

BACKGROUND: Acetaminophen is widely used as first-line therapy for chronic pain because of its perceived safety and the assumption that, unlike nonsteroidal anti-inflammatory drugs, it has little or no effect on blood pressure (BP). Although observational studies suggest that acetaminophen may increase BP, clinical trials are lacking. We, therefore, studied the effects of regular acetaminophen dosing on BP in individuals with hypertension. METHODS: In this double-blind, placebo-controlled, crossover study, 110 individuals were randomized to receive 1 g acetaminophen 4× daily or matched placebo for 2 weeks followed by a 2-week washout period before crossing over to the alternate treatment. At the beginning and end of each treatment period, 24-hour ambulatory BPs were measured. The primary outcome was a comparison of the change in mean daytime systolic BP from baseline to end of treatment between the placebo and acetaminophen arms. RESULTS: One-hundred three patients completed both arms of the study. Regular acetaminophen, compared with placebo, resulted in a significant increase in mean daytime systolic BP (132.8±10.5 to 136.5±10.1 mm Hg [acetaminophen] vs 133.9±10.3 to 132.5±9.9 mm Hg [placebo]; P<0.0001) with a placebo-corrected increase of 4.7 mm Hg (95% CI, 2.9-6.6) and mean daytime diastolic BP (81.2±8.0 to 82.1±7.8 mm Hg [acetaminophen] vs 81.7±7.9 to 80.9±7.8 mm Hg [placebo]; P=0.005) with a placebo-corrected increase of 1.6 mm Hg (95% CI, 0.5-2.7). Similar findings were seen for 24-hour ambulatory and clinic BPs. CONCLUSIONS: Regular daily intake of 4 g acetaminophen increases systolic BP in individuals with hypertension by ≈5 mm Hg when compared with placebo; this increases cardiovascular risk and calls into question the safety of regular acetaminophen use in this situation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01997112. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2013-003204-40.

Effects of Spironolactone and Chlorthalidone on Cardiovascular Structure and Function in Chronic Kidney Disease: A Randomized, Open-Label Trial.

BACKGROUND AND OBJECTIVES: In a randomized double-blind, placebo-controlled trial, treatment with spironolactone in early-stage CKD reduced left ventricular mass and arterial stiffness compared with placebo. It is not known if these effects were due to BP reduction or specific vascular and myocardial effects of spironolactone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective, randomized, open-label, blinded end point study conducted in four UK centers (Birmingham, Cambridge, Edinburgh, and London) comparing spironolactone 25 mg to chlorthalidone 25 mg once daily for 40 weeks in 154 participants with nondiabetic stage 2 and 3 CKD (eGFR 30-89 ml/min per 1.73 m2). The primary end point was change in left ventricular mass on cardiac magnetic resonance imaging. Participants were on treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and had controlled BP (target ≤130/80 mm Hg). RESULTS: There was no significant difference in left ventricular mass regression; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was -3.8 g (95% confidence interval, -8.1 to 0.5 g, P=0.08). Office and 24-hour ambulatory BPs fell in response to both drugs with no significant differences between treatment. Pulse wave velocity was not significantly different between groups; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was 0.04 m/s (-0.4 m/s, 0.5 m/s, P=0.90). Hyperkalemia (defined ≥5.4 mEq/L) occurred more frequently with spironolactone (12 versus two participants, adjusted relative risk was 5.5, 95% confidence interval, 1.4 to 22.1, P=0.02), but there were no patients with severe hyperkalemia (defined ≥6.5 mEq/L). A decline in eGFR >30% occurred in eight participants treated with chlorthalidone compared with two participants with spironolactone (adjusted relative risk was 0.2, 95% confidence interval, 0.05 to 1.1, P=0.07). CONCLUSIONS: Spironolactone was not superior to chlorthalidone in reducing left ventricular mass, BP, or arterial stiffness in nondiabetic CKD.

Prolonged SARS-CoV-2 viral shedding in patients with chronic kidney disease.

Recent World Health Organization guidance has aimed to provide pragmatic guidance acknowledging the role of sequential nasopharyngeal swabs taken >24 hours apart for SARS-CoV-2 in high-risk populations. Patients with chronic kidney disease (CKD) are known to have an altered immune milieu which may be associated with a delay in viral clearance. Here, a cross-sectional observational study of 138 patients admitted with SARS-CoV-2 infection at two large regional hospitals in Scotland, UK examined the median time to two consecutive negative nasopharyngeal swabs for SARS-CoV-2 in an inpatient population. The median time from admission to the first of two consecutive negative nasopharyngeal swabs was 18 days (range = 1-44) in patients with CKD, compared with 11 days (range: 1-71) in patients without CKD (P = .0007). Multivariable linear regression analysis using explanatory variables of age, sex, SARS-CoV-2 disease severity, key comorbidities and renal function showed that declining estimated glomerular filtration rate was independently associated with prolonged time to viral clearance. Our data suggest that patients with CKD who are admitted to hospital with SARS-CoV-2 take longer to achieve sequential negative nasopharyngeal swab reverse transcription-polymerase chain reaction results than those without CKD. This has implications for renal service provision, discharge planning and hospital capacity as well as a direct impact on patients due to extended hospital stay, anxiety and stigmatisation.

The life and legacy of William Keiller (1861-1931), anatomist, artist and curator.

After graduating in medicine from the Edinburgh Extramural School of Medicine, William Keiller trained in obstetrics and became anatomy lecturer at the Edinburgh College of Medicine for Women, where he successfully devised and developed an anatomical curriculum. In 1891, Keiller was appointed as the Professor of anatomy at the state medical department of the University of Texas, at the age of 30. He built up a nationally recognised anatomy department, museum and teaching curriculum informed by his experience in Edinburgh. Keiller left the University of Texas Medical Branch at Galveston a rich legacy, including anatomical specimens and drawings.

Rationale and Design of the Genotype-Blinded Trial of Torasemide for the Treatment of Hypertension (BHF UMOD).

BACKGROUND: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the uromodulin gene (UMOD) affecting uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb (TAL) of the loop of Henle and its effect on BP appears to be mediated via the TAL sodium transporter, NKCC2. Loop-diuretics block NKCC2 but are not commonly used in hypertension management. Volume overload is one of the primary drivers for uncontrolled hypertension, so targeting loop-diuretics to individuals who are more likely to respond to this drug class, using the UMOD genotype, could be an efficient precision medicine strategy. METHODS: The BHF UMOD Trial is a genotype-blinded, multicenter trial comparing BP response to torasemide between individuals possessing the AA genotype of the SNP rs13333226 and those possessing the G allele. 240 participants (≥18 years) with uncontrolled BP, on ≥1 antihypertensive agent for ≥3 months, will receive treatment with Torasemide, 5 mg daily for 16 weeks. Uncontrolled BP is average home systolic BP (SBP) >135 mmHg and/or diastolic BP >85 mmHg. The primary outcome is the change in 24-hour ambulatory SBP area under the curve between baseline and end of treatment. Sample size was calculated to detect a 4 mmHg difference between groups at 90% power. Approval by West of Scotland Research Ethics Committee 5 (16/WS/0160). RESULTS: The study should conclude August 2021. CONCLUSIONS: If our hypothesis is confirmed, a genotype-based treatment strategy for loop diuretics would help reduce the burden of uncontrolled hypertension. CLINICAL TRIALS REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03354897.

George Hogarth Pringle and the mystery of the first antiseptic operation in Australia.

EARLY LIFE: George Hogarth Pringle, later an associate of Joseph Lister, was born in Kintail, Scotland in 1830. In 1854, he worked as a dresser at the Royal Infirmary, Edinburgh with Joseph Lister. After serving in the Crimean War, he settled in New South Wales and began practice in Parramatta. PRINGLE AND ANTISEPTIC SURGERY: In October 1867, Pringle performed the first operation in Australia using the antiseptic principles advocated 6 months previously in the first of a series of articles published in The Lancet by Joseph Lister. Mystery surrounds how Pringle was able to adopt Lister's principles so quickly. Lister and Pringle had been friends in Edinburgh and previous writers have hypothesized that the two men corresponded whilst another has suggested Pringle was using antiseptic principles prior to Lister's work being published. Both these scenarios are unlikely. The Lancet appears to have been available in Australia within 4 months of publication. CONCLUSION: The conjunction of an appropriate case and the arrival of a recent copy of The Lancet highlighting Lister's work is the likely source of Pringle's decision to apply antiseptic principles.

A pioneer in two worlds: Thomas Keith (1827-1895) photographer and surgeon.

Thomas Keith, an Edinburgh surgeon, was an early and successful exponent of the operation of ovariotomy (ovarian cystectomy). He published detailed accounts of all of the patients on whom he carried out this procedure and his published success rate proved to be amongst the best in the world. The leading American surgeon J Marion Sims, who visited Keith to determine the reasons for this success, concluded that Keith's achievement resulted from meticulous attention to detail and his emphasis on the cleanliness of the instruments and the operating field, before this was generally adopted. His friendship with Joseph Lister led to his early use of Listerian antisepsis, which further improved these results. Yet, his medical colleagues and his obituarists seemed unaware of his other significant pioneering contribution, as a gifted photographer and pioneer of the waxed paper technique of photographic processing. That same attention to detail resulted in photographs of the highest quality whose significance has since been appreciated by photographic historians.

Pheromone-Induced Odor Associative Fear Learning in Rats.

Alarm pheromones alert conspecifics to the presence of danger. Can pheromone communication aid in learning specific cues? Such facilitation has an evident evolutionary advantage. We use two associative learning paradigms to test this hypothesis. The first is stressed cage mate-induced conditioning. One pair-housed adult rat received 4 pairings of terpinene + shock over 30 min. Ten minutes after return to the home cage, its companion rat was removed and exposed to terpinene. Single-housed controls were exposed to either terpinene or shock only. Companion rats showed terpinene-specific freezing, which was prevented by ß-adrenoceptor blockade. Using Arc to index neuronal activation in response to terpinene re-exposure, stressed cage-mate induced associative learning was measured. Companion rats showed increased neuronal activity in the accessory olfactory bulb, while terpinene + shock-conditioned rats showed increased activity in the main olfactory bulb. Both groups had enhanced activity in the anterior basolateral amygdala and central amygdala. To test involvement of pheromone mediation, in the 2nd paradigm, we paired terpinene with soiled bedding from odor + shock rats or a rat alarm pheromone. Both conditioning increased rats' freezing to terpinene. Blocking NMDA receptors in the basolateral amygdala prevented odor-specific learning suggesting shock and pheromone-paired pathways converge in the amygdala. An alarm pheromone thus enables cue-specific learning as well as signalling danger.