[Vascular occlusion following profile harmonization of the chin with hyaluronic acid fillers]. / Vasculaire occlusie na profielharmonisatie van de kin met hyaluronzuur fillers.

The use of dermal fillers for cosmetic procedures has increased rapidly both worldwide and in the Netherlands in recent years, which has led to an absolute increase in reported side effects and complications. Although most of these complications are mild, serious complications such as vascular occlusion can also occur. In this article, we describe a case of a 35-year-old woman who showed signs of reduced tissue perfusion and the early stage of skin necrosis following injection of hyaluronic acid fillers in the chin. This complication was successfully treated by ultrasound-guided injection of hyaluronidase, resulting in a full recovery without residual symptoms. To minimize the risk of serious complications treatment with hyaluronic acid fillers should be carried out by an experienced practitioner.

Diagnóstico y tratamiento de enfermedad vascular periférica. Revisión bibliográfica / Diagnosis and treatment of peripheral vascular disease. Literature review

La enfermedad arterial periférica tiene lugar debido a la obstrucción a nivel arterial. Esta obstrucción está dadaprincipalmente por la ateroesclerosis resultante a su vez de la acumulación de lípidos y de material fibroso entrela túnica íntima y muscular propia de la pared de los vasos sanguíneos. La consecuente disminución del flujosanguíneo puede presentarse de manera asintomática o manifestarse con síntomas de insuficiencia arterial como:claudicación intermitente, dolor en reposo en el grupo muscular afectado o pérdida tisular (úlceras). Esta última esuno de los signos más evidentes de isquemia de la extremidad. Los factores de riesgo son similares a los factoresde riesgo cardiovascular (hipertensión arterial, tabaquismo, hiperlipidemias, diabetes o síndrome metabólico). Parallevar a cabo su diagnóstico se requiere una adecuada historia clínica, un examen físico exhaustivo (disminuciónde pulsos periféricos), el índice tobillo-brazo (ITB) y, además, la utilización de herramientas diagnósticas como son:dúplex, la tomografía computarizada y la resonancia magnética. El manejo dependerá del estadio de la enfermedady va dirigido al alivio de los síntomas y a la disminución del riesgo de progresión de enfermedad cardiovascular.(AU)

Peripheral arterial disease occurs due to obstruction at the arterial level. This obstruction is mainly due to atheroscle-rosis resulting in turn from the accumulation of lipids and fibrous material between the tunica intima and muscularispropria of the blood vessel wall. The consequent decrease in blood flow can present asymptomatically or manifestwith symptoms of arterial insufficiency such as: intermittent claudication, pain at rest in the affected muscle group,tissue loss (ulcers), the latter being one of the most evident signs of ischemia of the the limb. The risk factors aresimilar to cardiovascular risk factors (hypertension, smoking, hyperlipidemia, diabetes or metabolic syndrome). Tocarry out the diagnosis of it, an adequate clinical history is required, an exhaustive physical examination (decreasedperipheral pulses), the ankle-brachial index (ABI) and also the use of diagnostic tools such as: duplex, tomographycomputed and magnetic resonance imaging. Management will depend on the stage of the disease and is aimedat relieving symptoms and reducing the risk of progression of cardiovascular disease.(AU)

Cardiovascular risk of gabapentin and pregabalin in patients with diabetic neuropathy.

BACKGROUND: Gabapentin and pregabalin are commonly prescribed medications to treat pain in patients with diabetic neuropathy. Gabapentin and pregabalin can cause fluid retention, which is hypothesized to be associated with cardiovascular diseases. However, whether long-term use of gabapentin and pregabalin is associated with adverse cardiovascular diseases remains unknown. This study aims to examine the association between gabapentin use, pregabalin use and several adverse cardiovascular events. METHODS: This retrospective cohort study used propensity score matching within patient electronic health records (EHRs) from a multicenter database with 106 million patients from 69 health care organizations in the US. The study population comprised 210,064 patients who had a diagnosis of diabetic neuropathy and were prescribed diabetic neuropathy medications in their EHRs. The exposure cohort comprised patients who were prescribed gabapentin or pregabalin to treat diabetic neuropathy. The comparison cohort comprised patients who were not prescribed either gabapentin or pregabalin but were prescribed other drugs to treat diabetic neuropathy. The outcomes of interest were myocardial infarcts, strokes, heart failure, peripheral vascular disease, and venous thromboembolic events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for 3-month and 5-year risk for adverse cardiovascular events between the propensity score-matched cohorts. RESULTS: Both gabapentin and pregabalin were associated with increased risk of 5-year adverse cardiovascular events compared with the comparison group. In patients prescribed gabapentin, the highest risk was observed for deep venous thrombosis (HR: 1.58, 95% CI 1.37-1.82), followed by pulmonary embolism (HR: 1.5, 95% CI 1.27-1.76), peripheral vascular disease (HR: 1.37, 95% CI 1.27-1.47), stroke (HR: 1.31, 95% CI 1.2-1.43), myocardial infarction (HR: 1.25, 95% CI 1.14-1.38) and heart failure (HR: 1.14, 95% CI 1.07-1.21). In patients prescribed pregabalin, the highest risk was observed for deep venous thrombosis (HR: 1.57, 95% CI 1.31-1.88), followed by peripheral vascular disease (HR: 1.35, 95% CI 1.22-1.49), myocardial infarction (HR: 1.29, 95% CI 1.13-1.47), pulmonary embolism (HR: 1.28, 95% CI 1.04-1.59), stroke (HR: 1.26, 95% CI 1.12-1.42), and heart failure (HR: 1.2, 95% CI 1.11-1.3). There were significant associations between short-term (3 month) gabapentin use and heart failure, myocardial infarction, peripheral vascular disease, deep venous thrombosis, and pulmonary embolism. Short-term (3 month) pregabalin use was associated with deep venous thrombosis, peripheral vascular disease. CONCLUSION: In patients with diabetic neuropathy who were prescribed gabapentin and pregabalin, there is an increased risk for heart failure, myocardial infarction, peripheral vascular disease, stroke, deep venous thrombosis, and pulmonary embolism with long-term use. Our findings suggest that increased risk for adverse cardiovascular events, along with other side effects, the efficacy of pain control and the degree of tolerance of the patient, should be considered when prescribing gabapentin and pregabalin long-term in patients with diabetic neuropathy.

Carnosine as a potential therapeutic for the management of peripheral vascular disease.

AIMS: To evaluate the potential role of carnosine in the management of peripheral vascular disease. DATA SYNTHESIS: Peripheral vascular disease is growing in its burden and impact; however it is currently under researched, and there are a lack of strong, non-invasive therapeutic options for the clinicians. Carnosine is a dipeptide stored particularly in muscle and brain tissue, which exhibits a wide range of physiological activities, which may be beneficial as an adjunct treatment for peripheral vascular disease. Carnosine's strong anti-inflammatory, antioxidant and antiglycating actions may aid in the prevention of plaque formation, through protective actions on the vascular endothelium, and the inhibition of foam cells. Carnosine may also improve angiogenesis, exercise performance and vasodilatory response, while protecting from ischemic tissue injury. CONCLUSIONS: Carnosine may have a role as an adjunct treatment for peripheral vascular disease alongside typical exercise and surgical interventions, and may be used in high risk individuals to aid in the prevention of atherogenesis. CLINICAL RECOMMENDATION: This review identifies a beneficial role for carnosine supplementation in the management of patients with peripheral vascular disease, in conjunction with exercise and revascularization. Carnosine as a supplement is safe, and associated with a host of beneficial effects in peripheral vascular disease and its key risk factors.

The Intervention of Nano-targeted Drugs & Angioplastryin Treatment and Prevention of Vascular Restenosis and its Influence on Monocyte Chemotactic Protein-1 in Lower Extremity Angiopathy.

It was to make use of the nano-targeted drugs and angioplastry to treat and prevent the vascular restenosis and analyze its influence on monocyte chemotactic protein 1 (MCP-1) of lower extremity angiopathy (LEA) patients since the patients with diabetic lower extremity angiopathy may be easily infected with vascular restenosis. In this article, the dexamethasone nano drugs were firstly prepared. After that, its related physical and chemical properties were tested, then, dexamethasone nano drugs were applied in treating patients with diabetic lower extremity angiopathy. The results showed that the prepared dexamethasone nanoparticles' encapsulation rate attained 99.2%. The laser light scattering experiment manifested that the particle size of the nanoparticles ranged from 200 to 300nm, and the average particle size was 258nm. The MCP-1 of the control group, conventional group, and observation group were 33.28±1.93 µg/mL, 78.27±9.73 µg/mL, and 75.29±8.99 µg/mL, respectively. The MCP-1 values of the conventional and observation groups were higher than that of the control group, and there was a notable difference (P<0.05). After interventional treatment, the MCP-1 level of the conventional group was 57.82±5.82 µg/mL, and that of the observation group was 41.93±6.92 µg/mL. The MCP-1 level of the group which received the treatment of nano-targeted drugs and angioplastry was superior to that of the conventional group which received the traditional operation, and there was a notable difference (P<0.05). In conclusion, MCP-1 is one of the major causes of lower extremity angiopathy. The nano-targeted drugs and angioplastry can raise the expression level of MCP-1 in patients with lower extremity angiopathy. The experimental results had a high application value and the nano-targeted drugs & angioplastry can be promoted clinically.

The correlation between platelet responsiveness to clopidogrel and CYP2C19 polymorphism in patients with peripheral vascular disease.

OBJECTIVE: Several patients undergoing endovascular intervention and bypass surgery present with high platelet reactivity following clopidogrel treatment. We aimed to determine the frequency of the genetic polymorphism of CYP2C19*2 and the contribution of this polymorphism along with other clinical parameters to clopidogrel response in an Egyptian population. PATIENTS AND METHODS: A total of 50 patients receiving clopidogrel at a maintenance dose of 75 mg daily post vascular intervention from January 1, 2019, to May 30, 2020, were enrolled in this study. Clopidogrel resistance was determined through platelet aggregation analysis using Chrono-Log® platelet aggregometer. Single-nucleotide polymorphism (SNP) genotyping was performed using quantitative real-time polymerase chain reaction (QRT-PCR). RESULTS: The incidence of clopidogrel resistance among this Egyptian population is about 22%. Univariate analysis demonstrated that CYP2C19*2 genotype (p = 0.001), high body mass index (BMI; p = 0.025), diabetes (p = 0.037),  high fasting blood glucose (FBG) level (p = 0.037), and high glycosylated hemoglobin (HbA1c) level (p = 0.004) were significantly associated with clopidogrel resistance. Multivariate analysis showed that CYP2C19*2 genotype (odds ratio (OR), 927.71; 95% confidence interval (CI), 1.915-449496.2; p = 0.030) and high BMI (OR, 1.789; 95% CI, 1.044-3.064; p = 0.034) were the most powerful predictors of clopidogrel resistance. CONCLUSIONS: Clopidogrel resistance in patients with peripheral vascular disease is associated with the presence of CYP2C19*2 allele, obesity, and diabetes; these factors should be considered prior to clopidogrel administration.

Cilostazol for intermittent claudication.

BACKGROUND: Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent claudication (exercise-induced lower limb pain relieved by rest). These patients have a three- to six-fold increase in cardiovascular mortality.  Cilostazol is a drug licensed for the use of improving claudication distance and, if shown to reduce cardiovascular risk, could offer additional clinical benefits. This is an update of the review first published in 2007. OBJECTIVES: To determine the effect of cilostazol on initial and absolute claudication distances, mortality and vascular events in patients with stable intermittent claudication. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries, on 9 November 2020. SELECTION CRITERIA: We considered double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other drugs used to improve claudication distance in patients with stable intermittent claudication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We assessed the risk of bias with the Cochrane risk of bias tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) and for continuous outcomes we used mean differences (MDs) and 95% CIs. We pooled data using a fixed-effect model, or a random-effects model when heterogeneity was identified. Primary outcomes were initial claudication distance (ICD) and quality of life (QoL). Secondary outcomes were absolute claudication distance (ACD), revascularisation, amputation, adverse events and cardiovascular events. MAIN RESULTS: We included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies also compared cilostazol with pentoxifylline. Treatment duration ranged from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Cilostazol dose ranged from 100 mg to 300 mg; pentoxifylline dose ranged from 800 mg to 1200 mg. The certainty of the evidence was downgraded by one level for all studies because publication bias was strongly suspected. Other reasons for downgrading were imprecision, inconsistency and selective reporting. Cilostazol versus placebo Participants taking cilostazol had a higher ICD compared with those taking placebo (MD 26.49 metres; 95% CI 18.93 to 34.05; 1722 participants; six studies; low-certainty evidence). We reported QoL measures descriptively due to insufficient statistical detail within the studies to combine the results; there was a possible indication in improvement of QoL in the cilostazol treatment groups (low-certainty evidence). Participants taking cilostazol had a higher ACD compared with those taking placebo (39.57 metres; 95% CI 21.80 to 57.33; 2360 participants; eight studies; very-low certainty evidence). The most commonly reported adverse events were headache, diarrhoea, abnormal stools, dizziness, pain and palpitations. Participants taking cilostazol had an increased odds of experiencing headache compared to participants taking placebo (OR 2.83; 95% CI 2.26 to 3.55; 2584 participants; eight studies; moderate-certainty evidence).Very few studies reported on other outcomes so conclusions on revascularisation, amputation, or cardiovascular events could not be made. Cilostazol versus pentoxifylline There was no difference detected between cilostazol and pentoxifylline for improving walking distance, both in terms of ICD (MD 20.0 metres, 95% CI -2.57 to 42.57; 417 participants; one study; low-certainty evidence); and ACD (MD 13.4 metres, 95% CI -43.50 to 70.36; 866 participants; two studies; very low-certainty evidence). One study reported on QoL; the study authors reported no difference in QoL between the treatment groups (very low-certainty evidence). No study reported on revascularisation, amputation or cardiovascular events. Cilostazol participants had an increased odds of experiencing headache compared with participants taking pentoxifylline at 24 weeks (OR 2.20, 95% CI 1.16 to 4.17; 982 participants; two studies; low-certainty evidence). AUTHORS' CONCLUSIONS: Cilostazol has been shown to improve walking distance in people with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache. There is insufficient evidence about the effectiveness of cilostazol for serious events such as amputation, revascularisation, and cardiovascular events. Despite the importance of QoL to patients, meta-analysis could not be undertaken because of differences in measures used and reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance and data were too limited for any conclusions on other outcomes.

Successful Catheter-Directed Thrombolysis for Acute Lower Limb Ischemia Secondary to COVID-19 Infection.

A 49-year-old man was admitted to his local hospital with left leg pain and breathing difficulties. He had negative nasopharyngeal polymerase chain reaction tests for severe acute respiratory syndrome coronavirus 2. Chest X-ray and Computed tomography pulmonary angiogram displayed typical coronavirus disease 2019 (COVID-19) radiological features as ground-glass opacities and bronchovascular thickening. His respiratory symptoms resolved after four days of supportive treatment, whereas his left leg became more painful and discolored. He was referred to our center with acute left leg ischemia. computed tomography angiogram revealed eccentric mural thrombus at the aortic bifurcation, extending into left common iliac and an abrupt occlusion of left popliteal, tibioperoneal, and posterior tibial arteries. He was treated with catheter-directed thrombolysis for 48-hours that achieved successful revascularization of the ischemic limb with no intervention-related complications. At six-week follow-up, he showed full recovery. Our case demonstrates that catheter-directed thrombolysis is a successful and safe treatment option in a COVID-19 patient with acute arterial occlusion.

Cardiovascular and Renal Morbidity in Takayasu Arteritis: A Population-Based Retrospective Cohort Study From the United Kingdom.

OBJECTIVE: Cardiovascular disease (CVD) is a major complication and cause of mortality in Takayasu arteritis (TAK), but population-based controlled studies from the UK are lacking. We undertook the present study to investigate the frequency of morbidity and mortality related to CVD, as well as to cerebrovascular and kidney disease, among patients with TAK in the UK. METHODS: Yearly cohort and cross-sectional studies were performed from 2000 to 2017 to estimate annual incidence and prevalence, respectively, of TAK. Using a UK primary care database (IQVIA Medical Research Data), an open retrospective matched cohort study was conducted to estimate risk of hypertension, diabetes, cardiovascular morbidity, chronic kidney disease (CKD), and all-cause mortality in TAK. Risk (adjusted hazard ratio [HR]) of the assessed comorbidities among patients with TAK compared to age- and sex-matched controls was estimated. Changes in medication prescription over time were examined in both groups. RESULTS: One hundred forty-two patients with TAK (median age 53.4 years [interquartile range 33.8-70.7]) and 1,371 matched controls were included. The annual incidence and prevalence of TAK were 0.8 per million and 7.5 per million respectively. All-cause mortality was increased in TAK (adjusted HR 1.88 [95% confidence interval 1.29-2.76]). Patients with TAK had an increased risk of developing ischemic heart disease, stroke/transient ischemic attack, combined CVD, and peripheral vascular disease compared to controls, but no increase in risk of hypertension, CKD, heart failure, or diabetes. Only ~50% of patients with TAK requiring secondary CVD prevention were prescribed statins or antiplatelet agents within 1 year after study entry. CONCLUSION: Cardiovascular morbidity was increased among patients with TAK receiving primary care services in the UK. Treatment with statins and antiplatelet agents in these patients was suboptimal.

Digital Ischemia in COVID-19 Patients: Case Report.

As coronavirus 2019 (COVID-19) continues to cause an immense burden on the global health care systems, it is crucial to understand the breadth of this disease process. Recent reports identified hypercoagulability in a subset of critically ill patients and extremity ischemia in an even smaller cohort. Because abnormal coagulation parameters and extremity ischemia have been shown to correlate with poor disease prognosis, understanding how to treat these patients is crucial. To better describe the identification and management of this phenomenon, we present 2 cases of critically ill patients with COVID-19 who developed fingertip ischemia while in the intensive care unit.

Effects of modified Wenjing decoction on microcirculation in reproductive organs in rats with symptom patterns of cold coagulation and blood stasis.

OBJECTIVE: To investigate the relationship between symptom patterns of cold coagulation and blood stasis (CCBS) and microcirculation disturbance. In addition, we determined the efficacy of modified Wenjing decoction (WJD) for the treatment of CCBS. METHODS: CCBS was induced in rats with an ice-water bath treatment. The ovarian function, microvascular and circulatory status of reproductive organs, and function of local microvascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) were evaluated. RESULTS: Ovarian dysfunction was observed in the rats with CCBS. It was characterized by the presence of an estrous cycle disorder and a decrease in reproductive hormone levels. Microvascular circulation disorders were associated with an imbalance in vasoconstriction, relaxation substances, nitric oxide, abnormal blood flow in whole blood, and decreased blood flow in the auricle and uterus. VECs were damaged, and VSMCs contracted and proliferated in ovarian and uterine tissues. CONCLUSION: Our findings suggest that the dysfunctional reproductive organs observed in gynecological CCBS may be closely related to the microcirculation disturbance of local tissues, microvascular contraction, and vascular remodeling. Modified WJD can be used to treat CCBS by improving microcirculation in reproductive organs.

Experience of a 40-day (6 week) LMWH treatment for isolated distal deep vein thrombosis.

Clinical significance of distal deep vein thrombosis (DVT) is important as it can potentially result in pulmonary embolism (PE), DVT extension, DVT recurrence and post-thrombotic syndrome (PTS). Controversy remains about the necessity and modalities of anticoagulation in all distal DVT. Evaluation of the efficiency of a 40-day weight-based low molecular weight heparin (LMWH) treatment in a cohort of 119 consecutive patients with distal DVT. Compression ultrasonography of the lower limb was performed initially for diagnosis as well as at the end of the treatment to identify persistence or resolution of the blood clot. A 3-month follow-up estimated the rates of PE, DVT recurrence, DVT extension, PTS and bleeding. Risk factors for DVT were considered to evaluate a possible correlation between them and the outcomes. In 71.4% of the patients the blood clot was totally dissolved and thrombus persistence was statistically associated with the number of initially involved veins. DVT recurrence occurred in 5% of patients and was also associated with the number of initial clotted veins. DVT extension and PTS rates were present in 1.7% and 3.4% respectively and no patient was diagnosed with PE or bleeding. This retrospective study including a limited number of patients and no control group supports that a 40-day weight-based LMWH treatment after distal DVT seems to be efficient when one single vein is initially affected whereas for multiple vein distal DVT and to avoid potential DVT recurrence, longer than 6 weeks of anticoagulant treatment is required. Our results support safety of the treatment, its potential to prevent DVT extension and the occurrence of PE.

Targeting Uremic Toxins to Prevent Peripheral Vascular Complications in Chronic Kidney Disease.

Chronic kidney disease (CKD) exhibits progressive kidney dysfunction and leads to disturbed homeostasis, including accumulation of uremic toxins, activated renin-angiotensin system, and increased oxidative stress and proinflammatory cytokines. Patients with CKD are prone to developing the peripheral vascular disease (PVD), leading to poorer outcomes than those without CKD. Cumulative evidence has showed that the synergy of uremic milieu and PVD could exaggerate vascular complications such as limb ischemia, amputation, stenosis, or thrombosis of a dialysis vascular access, and increase mortality risk. The role of uremic toxins in the pathogenesis of vascular dysfunction in CKD has been investigated. Moreover, growing evidence has shown the promising role of uremic toxins as a therapeutic target for PVD in CKD. This review focused on uremic toxins in the pathophysiology, in vitro and animal models, and current novel clinical approaches in reducing the uremic toxin to prevent peripheral vascular complications in CKD patients.

Botulinum Toxin A Salvage of Ischemic Hand Trauma.

Posttraumatic hand injuries from crush injury, infusion, or iatrogenic vascular cannulation can cause ischemic finger damage that can progress to necrosis and digital amputation. Botulinum toxin type A (Botox) improves blood flow in chronic vasospastic disorders of the hand. Botox's efficacy in salvaging ischemic loss in digits in acute traumatic and iatrogenic injury has not been previously reported. From February of 2015 to December of 2016, 11 patients at a Level I trauma center (West Virginia University) presented to the hand surgery service with early ischemic injury and vascular compromise to hand and fingers as a result of crush, direct drug injection, or proximal arterial injury from drug injection or catheterization. Before 2015, all patients with vascular compromise were treated with standard protocol. After January of 2016, patients were treated with additional injection of 80 to 100 U of Botox into the palm and wrist. Before administration of Botox, six patients with vascular compromise of one or more fingers were treated with a conservative protocol and 83 percent had amputation of necrotic digits. After January of 2016, five patients with ischemia were treated with Botox into the palm and proximal arteries. All Botox-treated digits were preserved (100 percent salvage). Pain scores were lower in Botox-treated fingers. We conclude that (1) in the acute traumatic vascular hand injury, early Botox injection markedly increases digital salvage; (2) direct nerve effects after Botox injections improve postinjury pain scores; and (3) early use of Botox in finger injuries is our standard approach to impending ischemia in the hand.

The History of Testosterone and the Evolution of its Therapeutic Potential.

INTRODUCTION: Testosterone therapy has been controversial since its synthesis in the 1930s to the present day. Testosterone's history provides depth and context for current controversies. AIM: To review the history of testosterone therapy from its initial synthesis in the 1930s to the modern day. METHODS: Expert review of the literature. MAIN OUTCOME MEASURES: Impactful events in the history of testosterone. RESULTS: By the 1940s there was already a fascinating literature that described the many symptomatic benefits of testosterone therapy that are recognized today. Numerous early reports suggested testosterone therapy improved angina pectoris and peripheral vascular disease. The assertion by Huggins and Hodges (Cancer Res 1941;1:293-297) in 1941 that testosterone activated prostate cancer (PCa) cast a pall for the next 70 years. The introduction of the radioimmunoassay in the 1970s shifted the diagnosis of testosterone deficiency from signs and symptoms to an undue emphasis on blood test results. The fear of PCa was the primary obstacle to the adoption of testosterone therapy for decades. Prescription rates increased as accumulated evidence showed testosterone therapy was not associated with increased PCa risks. The observation that androgenic stimulation of PCa reaches a maximum at relatively low testosterone concentrations-the saturation model-provided the theoretical framework for understanding the relation between androgens and PCa and led to multiple case series documenting reassuring results of testosterone therapy in men with PCa. Recent concerns regarding cardiovascular risks also have diminished because new evidence suggests testosterone therapy might actually be cardioprotective. In 2016 the Testosterone Trials provided high-quality evidence of multiple benefits of testosterone therapy, nearly all of which had been recognized by clinicians by 1940. CONCLUSIONS: If the past has any lessons for the future, it is likely that research will continue to demonstrate health benefits of testosterone therapy, while it remains one of the most controversial topics in medicine. Morgentaler A, Traish A. The History of Testosterone and the Evolution of its Therapeutic Potential. Sex Med Rev 2020;8:286-296.

Guideline-directed therapies for comorbidities and clinical outcomes among individuals with atrial fibrillation.

BACKGROUND: Comorbidities are common in patients with atrial fibrillation (AF) and affect prognosis, yet are often undertreated. However, contemporary rates of use of guideline-directed therapies (GDT) for non-AF comorbidities and their association with outcomes are not well described. METHODS: We used the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) to test the association between GDT for non-AF comorbidities and major adverse cardiac or neurovascular events (MACNE; cardiovascular death, myocardial infarction, stroke/thromboembolism, or new-onset heart failure), all-cause mortality, new-onset heart failure, and AF progression. Adjustment was performed using Cox proportional hazards models and logistic regression. RESULTS: Only 6,782 (33%) of the 20,434 patients eligible for 1 or more GDT for non-AF comorbidities received all indicated therapies. Use of all comorbidity-specific GDT was highest for patients with hyperlipidemia (75.6%) and lowest for those with diabetes mellitus (43.1%). Use of "all eligible" GDT was associated with a nonsignificant trend toward lower rates of MACNE (HR 0.90 [0.79-1.02]) and all-cause mortality (HR 0.90 [0.80-1.01]). Use of GDT for heart failure was associated with a lower risk of all-cause mortality (HR 0.77 [0.67-0.89]), and treatment of obstructive sleep apnea was associated with a lower risk of AF progression (OR 0.75 [0.62-0.90]). CONCLUSIONS: In AF patients, there is underuse of GDT for non-AF comorbidities. The association between GDT use and outcomes was strongest in heart failure and obstructive sleep apnea patients where use of GDT was associated with lower mortality and less AF progression.