The Effects of Verapamil, Hydralazine, and Doxazosin on Renin, Aldosterone, and the Ratio Thereof.

PURPOSE: Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio. METHODS: In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions. RESULTS: Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables. CONCLUSION: We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.

The Death of Pyotr Ilyich Tchaikovsky: The Result of Treatment with Arsenic?

No abstract applicable.

Control in the Hospital by Extensive Clinical rules for Unplanned hospitalizations in older Patients (CHECkUP); study design of a multicentre randomized study.

BACKGROUND: Due to ageing of the population the incidence of multimorbidity and polypharmacy is rising. Polypharmacy is a risk factor for medication-related (re)admission and therefore places a significant burden on the healthcare system. The reported incidence of medication-related (re)admissions varies widely due to the lack of a clear definition. Some medications are known to increase the risk for medication-related admission and are therefore published in the triggerlist of the Dutch guideline for Polypharmacy in older patients. Different interventions to support medication optimization have been studied to reduce medication-related (re)admissions. However, the optimal template of medication optimization is still unknown, which contributes to the large heterogeneity of their effect on hospital readmissions. Therefore, we implemented a clinical decision support system (CDSS) to optimize medication lists and investigate whether continuous use of a CDSS reduces the number of hospital readmissions in older patients, who previously have had an unplanned probably medication-related hospitalization. METHODS: The CHECkUP study is a multicentre randomized study in older (≥60 years) patients with an unplanned hospitalization, polypharmacy (≥5 medications) and using at least two medications from the triggerlist, from Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. Patients will be randomized. The intervention consists of continuous (weekly) use of a CDSS, which generates a Medication Optimization Profile, which will be sent to the patient's general practitioner and pharmacist. The control group will receive standard care. The primary outcome is hospital readmission within 1 year after study inclusion. Secondary outcomes are one-year mortality, number of emergency department visits, nursing home admissions, time to hospital readmissions and we will evaluate the quality of life and socio-economic status. DISCUSSION: This study is expected to add evidence on the knowledge of medication optimization and whether use of a continuous CDSS ameliorates the risk of adverse outcomes in older patients, already at an increased risk of medication-related (re)admission. To our knowledge, this is the first large study, providing one-year follow-up data and reporting not only on quality of care indicators, but also on quality-of-life. TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register on October 14, 2018, identifier: NL7449 (NTR7691). https://www.trialregister.nl/trial/7449 .

The posterior fibulotalocalcaneal ligament complex: a forgotten ligament.

PURPOSE: The purpose of the present anatomical study was to define the exact morphology of the posterior fibulotalocalcaneal ligament complex (PFTCLC), both for a better orientation and understanding of the anatomy, especially during hindfoot endoscopy. METHODS: Twenty-three fresh frozen specimens were dissected in order to clarify the morphology of the PFTCLC. RESULTS: In all specimens, the ligament originated from the posteromedial border of the lateral malleolus between the posterior tibiofibular ligament (superior border) and the calcaneofibular ligament (CFL), (inferior border). This origin functions as the floor for the peroneal tendon sheath. The origin of the PFTCLC can be subdivided into two parts, a superior and inferior part. The superior part forms an aponeurosis with the superior peroneal retinaculum and the lateral septum of the Achilles tendon. From this structure, two independent laminae can be identified. The inferior part of the origin has no role in the aponeurosis and ligamentous fibres run obliquely to insert in the lateral surface of the calcaneus, in the same orientation as the CFL, but slightly more posterior, which was a consistent finding in all examined specimens. The PFTCLC is maximally tensed with ankle dorsiflexion and is located within the fascia of the deep posterior compartment of the leg. CONCLUSIONS: The PFTCLC is part of the normal anatomy of the hindfoot and therefore should be routinely recognized and partly released to achieve access to the posterior ankle anatomical pathology, relevant for hindfoot endoscopy. The origin of the ligament complex forms the floor for the peroneal tendon sheath. The superior part of the origin plays a role in the formation of an aponeurosis with the superior peroneal retinaculum and the lateral septum of the Achilles tendon.

Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease.

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II-mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. METHODS: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2-infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). SUMMARY: The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2-infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally.

Surgical treatment for posteromedial talar process fractures.

PURPOSE: The first descriptions on medial talar tubercle fractures are attributed to Cedell. He described avulsion fractures of the insertion of the posterior talotibial ligament. However the true etiology has not been established. Since little is known about these fractures, they are easily misdiagnosed as simple ankle sprains. Untreated, these fractures may lead to chronic ankle pain. To improve the understanding of the etiology and outcome of these fractures a systematic review was conducted of all cases of isolated fractures of the medial tubercle of the posterior talar process. In addition we present the first series of competitive athletes treated by means of the two-portal hindfoot approach for isolated medial talar tubercle fractures. METHODS: A systematic search was performed to identify all cases of medial tubercle fractures. Data on trauma mechanism, clinical presentation, imaging and treatment were extracted. In addition we retrospectively report on the results of endoscopically treated patients in our institution over the last fifteen years. Of all patients Numeric Rating Scores (NRS) for Satisfaction, Pain and Function, Foot Ankle Outcome Scores (FAOS), return to sport and complications were reported. RESULTS: Eightteen articles were included reporting on 33 patients with an isolated fracture or avulsion of the posteromedial talar process. Most of the fractures occurred during sport activities (58%), followed by motor vehicle accidents (21%) and fall from height (12%). Of the activities during sport, 73% resulted following an ankle sprain. Reasonable to good outcomes are described in cases treated with immobilization, open reduction internal fixation or open excision. Of the nine patients treated in our institution, five were male and the median age was 29. All were participating in sports at a competitive level, with four of them being a professional athlete. In most patients the diagnosis was made more than a year after initial trauma. Ankle sprain was most common trauma mechanism. In some patients it was evident the avulsion was part or the deep portion of the deltoid ligament, however in two cases it was more likely an avulsion of the flexor hallucis longus (FHL) retinaculum. The median follow-up was 69 months (IQR 12.0-94.3). At final follow-up patients had little pain, NRS 1. Median NRS for satisfaction and function were 7 and 8, respectively. All patients did resume sport activities, however only four reached the preinjury level. Of the five patients that did not return to their pre-injury level of activity, two were professional athletes at the end of their career, and retired not due to ankle complaints. One complication was reported. CONCLUSION: Fractures of the medial tubercle are rare and based on the available literature there is not one distinct trauma mechanism. Based on literature no recommendation for treatment can be made. Our results show endoscopic excision of the fragment as a save alternative for open surgical treatment.

First International Consensus on the diagnosis and management of fibromuscular dysplasia.

This article is a comprehensive document on the diagnosis and management of fibromuscular dysplasia (FMD), which was commissioned by the working group 'Hypertension and the Kidney' of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM). This document updates previous consensus documents/scientific statements on FMD published in 2014 with full harmonization of the position of European and US experts. In addition to practical consensus-based clinical recommendations, including a consensus protocol for catheter-based angiography and percutaneous angioplasty for renal FMD, the document also includes the first analysis of the European/International FMD Registry and provides updated data from the US Registry for FMD. Finally, it provides insights on ongoing research programs and proposes future research directions for understanding this multifaceted arterial disease.

Study protocol for a multicentre prospective cohort study to identify predictors of adverse outcome in older medical emergency department patients (the Risk Stratification in the Emergency Department in Acutely Ill Older Patients (RISE UP) study).

BACKGROUND: Older patients (≥65 years old) experience high rates of adverse outcomes after an emergency department (ED) visit. Reliable tools to predict adverse outcomes in this population are lacking. This manuscript comprises a study protocol for the Risk Stratification in the Emergency Department in Acutely Ill Older Patients (RISE UP) study that aims to identify predictors of adverse outcome (including triage- and risk stratification scores) and intends to design a feasible prediction model for older patients that can be used in the ED. METHODS: The RISE UP study is a prospective observational multicentre cohort study in older (≥65 years of age) ED patients treated by internists or gastroenterologists in Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. After obtaining informed consent, patients characteristics, vital signs, functional status and routine laboratory tests will be retrieved. In addition, disease perception questionnaires will be filled out by patients or their caregivers and clinical impression questionnaires by nurses and physicians. Moreover, both arterial and venous blood samples will be taken in order to determine additional biomarkers. The discriminatory value of triage- and risk stratification scores, clinical impression scores and laboratory tests will be evaluated. Univariable logistic regression will be used to identify predictors of adverse outcomes. With these data we intend to develop a clinical prediction model for 30-day mortality using multivariable logistic regression. This model will be validated in an external cohort. Our primary endpoint is 30-day all-cause mortality. The secondary (composite) endpoint consist of 30-day mortality, length of hospital stay, admission to intensive- or medium care units, readmission and loss of independent living. Patients will be followed up for at least 30 days and, if possible, for one year. DISCUSSION: In this study, we will retrieve a broad range of data concerning adverse outcomes in older patients visiting the ED with medical problems. We intend to develop a clinical tool for identification of older patients at risk of adverse outcomes that is feasible for use in the ED, in order to improve clinical decision making and medical care. TRIAL REGISTRATION: Retrospectively registered on clinicaltrials.gov ( NCT02946398 ; 9/20/2016).

The Link Between Adipose Tissue Renin-Angiotensin-Aldosterone System Signaling and Obesity-Associated Hypertension.

Obese individuals frequently develop hypertension, which is for an important part attributable to renin-angiotensin-aldosterone system (RAAS) overactivity. This review summarizes preclinical and clinical evidence on the involvement of dysfunctional adipose tissue in RAAS activation and on the renal, central, and vascular mechanisms linking RAAS components to obesity-associated hypertension.

Atherosclerotic Renal Artery Stenosis: Should we Intervene Earlier?

PURPOSE OF REVIEW: Randomized trials have failed to show clinical benefit in patients with atherosclerotic renal artery stenosis who were treated with angioplasty with or without stenting. However, these studies were done in patients with a high-grade stenosis. This paper examines whether there are arguments to consider patients with low-grade stenosis for angioplasty. RECENT FINDINGS: Patients with low-grade (< 50%) atherosclerotic renal artery stenosis have an excess risk for cardiovascular and renal complications. This could be related to inflammatory factors being generated by the stenotic kidney. Moreover, even a kidney with low-grade stenosis clears less or produces more of the natural nitric oxide inhibitor ADMA. Patients with low-grade atherosclerotic renal artery stenosis have an increased risk for a variety of complications. In addition, the abnormality is progressive. There is a case for setting up a prospective trial to examine whether angioplasty confers benefit in patients with low-grade renal artery stenosis.

Talus bipartitus: a systematic review and report of two cases with arthroscopic treatment.

PURPOSE: The aim of this study was to provide a literature review on talus bipartitus and to introduce an arthroscopic treatment option. METHODS: A systematic review of published case reports and small case series was performed. Medline, Embase, CINAHL, Google Scholar and Web of Science databases were searched for relevant publications. In addition, three cases of talus bipartitus treated in our institute were discussed. RESULTS: Eleven articles were identified, reporting on 23 patients, of whom one patient had a bilateral talus bipartitus. Fourteen were males (61%). The median age at presentation was 15.5 years (IQR 14-24.3). In 21 of the symptomatic cases (96%), the patient experienced ankle pain, and 13 had a restricted range of motion (54%). In our institution, two patients were treated arthroscopically and had excellent short- and long-term outcomes. CONCLUSION: Talus bipartitus is a rare anatomical anomaly. Symptoms are characterized by pain and restricted subtalar motion in young patients. Surgical treatment is focused on either fixation or excision of the bony fragment. Our two cases have demonstrated that an arthroscopic approach can be a safe and effective treatment option in patients with a symptomatic talus bipartitus. LEVEL OF EVIDENCE: IV.

Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH).

In patients with end-stage renal disease (ESRD) treated with haemodialysis or peritoneal dialysis, hypertension is common and often poorly controlled. Blood pressure (BP) recordings obtained before or after haemodialysis display a J- or U-shaped association with cardiovascular events and survival, but this most likely reflects the low accuracy of these measurements and the peculiar haemodynamic setting related to dialysis treatment. Elevated BP detected by home or ambulatory BP monitoring is clearly associated with shorter survival. Sodium and volume excess is the prominent mechanism of hypertension in dialysis patients, but other pathways, such as arterial stiffness, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, endothelial dysfunction, sleep apnoea and the use of erythropoietin-stimulating agents may also be involved. Non-pharmacologic interventions targeting sodium and volume excess are fundamental for hypertension control in this population. If BP remains elevated after appropriate treatment of sodium and volume excess, the use of antihypertensive agents is necessary. Drug treatment in the dialysis population should take into consideration the patient's comorbidities and specific characteristics of each agent, such as dialysability. This document is an overview of the diagnosis, epidemiology, pathogenesis and treatment of hypertension in patients on dialysis, aiming to offer the renal physician practical recommendations based on current knowledge and expert opinion and to highlight areas for future research.

CD4+CD28null T Cells are related to previous cytomegalovirus infection but not to accelerated atherosclerosis in ANCA-associated vasculitis.

Previous studies have suggested an increased risk for cardiovascular events in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). We analyzed the presence of atherosclerotic damage in patients with AAV in relation to the presence of CD4+CD28null T cells and antibodies against cytomegalovirus (CMV) and human Heat-Shock Protein 60 (hHSP60). In this cross-sectional study, patients with inactive AAV were compared with healthy controls (HC). Carotid intima-media thickness (IMT) and aortic pulse-wave velocity (PWV) were measured. In addition, CD4+CD28null T cells, anti-CMV, and anti-hHSP60 levels were determined. Forty patients with AAV were included. Patients' spouses were recruited as HC (N = 38). CD4+CD28null T cells are present in patients with AAV in a higher percentage (median 3.1, range 0.01-85) than in HC (0.28, 0-36, P < 0.0001). No significant difference in IMT (mm) between patients and controls was detected (mean 0.77 ± standard deviation 0.15 and 0.73 ± 0.11, respectively, P = 0.20). PWV standardized for MAP was increased in AAV patients (9.80 ± 2.50 m/s, compared to 8.72 ± 1.68 in HC, P = 0.04). There was a strong association between a previous CMV infection and the presence and percentage of CD4+CD28null T cells (0.33 vs 13.8, P < 0.001). There was no relationship between CD4+CD28null T cells and/or a previous CMV infection and IMT or PWV. There was no relation between anti-hHSP60 and CD4+CD28null T cells. Increased PWV values suggest atherosclerotic damage in patients with AAV. Plaque size, as determined by IMT, did not differ. CD4+CD28null T cells are increased in AAV and related to the previous CMV infection.

A rare cause of lateral ankle pain: A symptomatic talus secundarius.

The talus secundarius is one of the rarest accessory tarsal bones, being present in 0.01% of all ankles. It is located at the lateral side of the talus, distally to the tip of the fibula. Hitherto, only five cases of a symptomatic talus secundarius have been described in literature. We presented a case of bilateral symptomatic talus secundarius in a young gymnast. There was a difference in size of the two accessory bones. The large talus secundarius in the left ankle was fixated, in the right ankle the fragment was excised. Both excision and fixation in the presented patient led to satisfactory results, both in the short and long term outcome.

Identification of the superficial peroneal nerve: Anatomical study with surgical implications.

PURPOSE: To prevent iatrogenic damage to the superficial peroneal nerve during ankle arthroscopy, it needs to be identified. The purpose of the present study was to determine which clinical test identified the superficial peroneal nerve most frequently and which determinants negatively affected the identification. METHODS: A total of 198 ankles (99 volunteers) were examined for identification of the superficial peroneal nerve. Race, gender, body mass index (BMI), shoe size and frequency of physical activity were collected. RESULTS: The best method to identify the superficial peroneal nerve was the maximal combined ankle plantar flexion and inversion test. In this position, the nerve was identified in 57% of the ankles by palpation. BMI was the only independently influential factor in the identification of the superficial peroneal nerve. CONCLUSION: Since in nearly six out of the ten ankles the superficial peroneal nerve can be identified, it is advised to assess its anatomy prior to portal placement. A higher BMI negatively influences the identification of the superficial peroneal nerve. LEVEL OF EVIDENCE: Diagnostic study, Level III.

Midterm results of posterior arthroscopic ankle fusion.

PURPOSE: The presented study was performed to evaluate the midterm clinical and radiological results and complication rates of the first 40 patients with an ankle fusion through a posterior arthroscopic approach. METHODS: Forty consecutive patients with end-stage post-traumatic ankle osteoarthritis were treated with posterior arthroscopic ankle fusion. All patients were assessed clinically as well as radiologically with a minimum follow-up of 2 years. The Foot and Ankle Ability Measure (FAAM) and Foot Function Index (FFI) were used to assess clinical improvement. RESULTS: Clinical fusion was achieved in 40 patients within 3 months (100%), and radiological fusion was achieved in 40 patients at 12 months. Two screw mal-placements occurred. Both complications were solved following revision surgery. A significant improvement was noted for both the FAAM [median 38 (range 17-56) to 63 (range 9-84)] and FFI scores [median 66 (range 31-89) to 32 (range 11-98)] for all 40 patients. CONCLUSION: The posterior arthroscopic ankle fusion is an effective and safe treatment option for end-stage post-traumatic ankle osteoarthritis at midterm follow-up. LEVEL OF EVIDENCE: Prospective cohort study, Level IV.

Anatomy of the ankle ligaments: a pictorial essay.

Understanding the anatomy of the ankle ligaments is important for correct diagnosis and treatment. Ankle ligament injury is the most frequent cause of acute ankle pain. Chronic ankle pain often finds its cause in laxity of one of the ankle ligaments. In this pictorial essay, the ligaments around the ankle are grouped, depending on their anatomic orientation, and each of the ankle ligaments is discussed in detail.

Posterior Ankle Impingement in Two Athletic Twin Brothers, Could Genetics Play a Role?

Pain posteriorly in the ankle can be caused by bony impingement of the posterolateral process of the talus. This process impinges between the tibia and calcaneus during deep forced plantar flexion. If this occurs it is called posterior ankle impingement syndrome. We report the case of 2 athletic monozygotic twin brothers with bony impingement posteriorly in the left ankle. Treatment consisted of ankle arthroscopy in both patients during which the symptomatic process was easily removed. At 3 months after surgery, both patients were completely free of pain, and 1 of the brothers had already returned to sports. The posterior ankle impingement syndrome is not a rare syndrome, but it has not been described in siblings thus far. That these 2 patients are monozygotic twin brothers suggests that genetics could play a role in the development of skeletal deformities that can result in posterior ankle impingement syndrome.

Dietary proteins improve endothelial function under fasting conditions but not in the postprandial state, with no effects on markers of low-grade inflammation.

Endothelial dysfunction (ED) and low-grade inflammation (LGI) have a role in the development of CVD. The two studies reported here explored the effects of dietary proteins and carbohydrates on markers of ED and LGI in overweight/obese individuals with untreated elevated blood pressure. In the first study, fifty-two participants consumed a protein mix or maltodextrin (3×20 g/d) for 4 weeks. Fasting levels and 12 h postprandial responses of markers of ED (soluble intercellular adhesion molecule 1 (sICAM), soluble vascular cell adhesion molecule 1 (sVCAM), soluble endothelial selectin and von Willebrand factor) and markers of LGI (serum amyloid A, C-reactive protein and sICAM) were evaluated before and after intervention. Biomarkers were also combined into mean Z-scores of ED and LGI. The second study compared 4 h postprandial responses of ED and LGI markers in forty-eight participants after ingestion of 0·6 g/kg pea protein, milk protein and egg-white protein. In addition, postprandial responses after maltodextrin intake were compared with a protein mix and sucrose. The first study showed significantly lower fasting ED Z-scores and sICAM after 4 weeks on the high-protein diet (P≤0·02). The postprandial studies found no clear differences of ED and LGI between test meals. However, postprandial sVCAM decreased more after the protein mix compared with maltodextrin in both studies (P≤0·04). In conclusion, dietary protein is beneficial for fasting ED, but not for fasting LGI, after 4 weeks of supplementation. On the basis of Z-scores, postprandial ED and LGI were not differentially affected by protein sources or carbohydrates.