Additive effect of erythropoietin use on exercise-induced endothelial activation and hypercoagulability in athletes.

PURPOSE: Recombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping legislation, but this risk has not been investigated thoroughly. This analysis was designed to evaluate whether rHuEPO impacts hemostatic profile and endothelial and platelet activation markers in trained subjects, and whether the combination with exercise affects exercise induced alterations. METHODS: This double-blind, randomized, placebo-controlled trial enrolled healthy, trained male cyclists aged 18-50 years. Participants were randomly allocated (1:1) to receive subcutaneous injections of rHuEPO (epoetin-ß; mean dose 6000 IU per week) or placebo (0.9% NaCl) for 8 weeks. Subjects performed five maximal exercise tests and a road race, coagulation and endothelial/platelet markers were measured at rest and directly after each exercise effort. RESULTS: rHuEPO increased P-selectin (+ 7.8% (1.5-14.5), p = 0.02) and E-selectin (+ 8.6% (2.0-15.7), p = 0.01) levels at rest. Maximal exercise tests significantly influenced all measured coagulation and endothelial/platelet markers, and in the rHuEPO group maximal exercise tests led to 15.3% ((7.0-24.3%), p = 0.0004) higher E-selectin and 32.1% ((4.6-66.8%), p = 0.0207) higher Platelet factor 4 (PF4) levels compared to the placebo group. CONCLUSION: In conclusion, rHuEPO treatment resulted in elevated E- and P-selectin levels in trained cyclists, indicating enhanced endothelial activation and/or platelet reactivity. Exercise itself induces hypercoagulability, and the combination of rHuEPO and exercise increased E-selectin and PF4 levels more than either intervention alone. Based on this, exercise potentially increases thrombotic risk, a risk that might be enhanced in combination with rHuEPO use.

Lateral Process Fracture of the Talus: A Case Series and Review of the Literature.

Fracture of the lateral process of the talus (LPFT) is a frequently overlooked injury that can lead to severe complaints if not treated adequately. The aim of this study was to evaluate treatment and long-term outcomes of LPFT through a review of the literature. Furthermore, we propose a modified classification based on severity and intra- or extra-articular location of LPFT. Patients diagnosed with LPFT and treated at a Level 1 trauma center between 2001 and 2018 were included. Fracture and treatment characteristics were recorded in combination with functional outcome and quality of life after a mean follow-up of 5.5 (range 0.8 to 17.2) years. A comprehensive literature search was performed to identify all case series regarding patients with LPFT; 36 patients were included. According to our modified classification, 1 patient had type 1A (2.8%), 6 patients had type 1B (16.7%), 10 patients had type 2 (27.8%), 11 patients had type 3 (30.6%), 6 patients had type 4A (16.7%), and 2 patients had type 4B (5.6%). Twenty-eight patients underwent operative fixation (78%). The median American Orthopaedic Foot and Ankle Society Hindfoot Score was 75 (range 12 to 100). The median Foot Function Index was 2 (range 0 to 9). The median score for the EuroQol-5D was 0.8 (range -0.5 to 1), and the median score for health status component was 75 (range 30 to 98). There is some room for conservative treatment of LPFT; however, we strongly believe that this should be considered only for nondisplaced, small-fragment, and extra-articular fractures. Surgical treatment leads to an overall good (long-term) outcome.

Protease-activated receptors are potential regulators in the development of arterial endofibrosis in high-performance athletes.

OBJECTIVE: High-performance athletes can develop symptomatic arterial flow restriction during exercise caused by endofibrosis. The pathogenesis is poorly understood; however, coagulation enzymes, such as tissue factor (TF) and coagulation factor Xa, might contribute to the fibrotic process, which is mainly regulated through activation of protease-activated receptors (PARs). Therefore, the aim of this explorative study was to evaluate the presence of coagulation factors and PARs in endofibrotic tissue, which might be indicative of their potential role in the natural development of endofibrosis. METHODS: External iliac arterial specimens with endofibrosis (n = 19) were collected during surgical interventions. As control, arterial segments of the external iliac artery (n = 20) were collected post mortem from individuals with no medical history of cardiovascular disease who donated their body to medical science. Arteries were paraffinized and cut in tissue sections for immunohistochemical analysis. Positive staining within lesions was determined with ImageJ software (National Institutes of Health, Bethesda, Md). RESULTS: Endofibrotic segments contained a neointima, causing intraluminal stenosis, which was highly positive for collagen (+150%; P < .01) and elastin (+148%; P < .01) in comparison with controls. Intriguingly, endofibrosis was not limited to the intima because collagen (+213%) and elastin (+215%) were also significantly elevated in the media layer of endofibrotic segments. These findings were accompanied by significantly increased α-smooth muscle actin-positive cells, morphologically compatible with the presence of myofibroblasts. In addition, PAR1 and PAR4 and the membrane receptor TF were increased as well as coagulation factor X. CONCLUSIONS: We showed that myofibroblasts and the accompanying collagen and elastin synthesis might be key factors in the development of endofibrosis. The special association with increased presence of PARs, factor X, and TF suggests that protease-mediated cell signaling could be a contributing component in the mechanisms leading to endofibrosis.

Traumatic Epidermal Inclusion Cyst After Minimally Invasive Surgery of a Displaced Intra-Articular Calcaneal Fracture: A Case Report.

Epidermal inclusion cysts are common epithelial cysts of the skin. The latter classically originate from progressive cystic ectasia of the infundibular portion of hair follicle. Therefore, these cysts are usually found in hairy regions and rarely in glabrous skin such as the palms and soles. The etiology of glabrous epidermal inclusion cysts appear to be different from that of those located in hairy regions. It has been suggested that implantation of epithelial cells into subcutaneous tissue, such as during trauma, is most likely the pathophysiologic basis. Epidermal inclusion cysts on the palms and soles are often misdiagnosed, leading to improper treatment. Therefore, we report a rare case of an epidermal inclusion cyst of the heel after minimally invasive surgery of a displaced intra-articular calcaneal fracture.

The mode of delivery after operative fixation of pelvic ring fractures-a retrospective observational study.

PURPOSE: The purpose of this study is to investigate whether retained hardware after surgical treatment for a pelvic fracture prior to pregnancy affects the choice of delivery method. The study aims to provide insights into the rates of vaginal delivery and caesarean sections, understanding whether the mode of delivery was influenced by patient preference or the recommendations of obstetricians or surgeons, and examining the rate of complications during delivery and postpartum. METHODS: All women of childbearing age who underwent surgical fixation for a pelvic ring fracture between 1994 and 2021 were identified. A questionnaire was sent about their possible pregnancies and deliveries. Of the included patients, surgical data were collected and the fracture patterns were retrospectively classified. Follow-up was a minimum of 36 months. RESULTS: A total of 168 women with a pelvic fracture were identified, of whom 13 had a pregnancy after surgical stabilization. Eleven women had combined anterior and posterior fracture patterns and two had isolated sacral fractures. Four women underwent combined anterior and posterior fixation, the others either anterior or posterior fixation. Seven women had a total of 11 vaginal deliveries, and 6 women had 6 caesarean sections. The decision for vaginal delivery was often the wish of the mother (n = 4, 57%) while the decision to opt for caesarean section was made by the surgeon or obstetrician (n = 5, 83%). One woman in the vaginal delivery group suffered a postpartum complication possibly related to her retained pelvic hardware. CONCLUSION: Women with retained hardware after pelvic ring fixation can have successful vaginal deliveries. Complications during labor or postpartum are rare. The rate of primary caesarean sections is high (46%) and is probably influenced by physician bias. Future research should focus on tools that can predict labor outcomes in this specific population, and larger multicenter studies are needed. LEVEL OF EVIDENCE: Level III.

Muscle abnormalities worsen after post-exertional malaise in long COVID.

A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

Complications and Functional Outcome Following Operative Treatment of Talus Neck and Body Fractures: A Systematic Review.

Background: Central talar fractures are rare and often associated with impaired functional outcome. Despite recent advances in diagnosis and management of talus fractures, complications rates remain high and functional outcome is generally poor. This study aims to provide an overview of complication rates and functional outcome following operative treatment of talar neck and body fractures. This may help in clinical decision making by improving patients' expectation management and tailored treatment strategies. Methods: A systematic review of the literature was conducted of studies published from January 2000 to July 2021 reporting functional outcome and/or complications following operative treatment of talar neck, body, or combined neck and body fractures. Keywords used were (Talar fracture) or (Talus fracture). Data on complication rates and functional outcome was extracted from selected articles. Results: A total of 28 articles were included in our analysis reporting 1086 operative treated talar fractures (755 neck [70%], 227 body fractures [21%], and 104 combined body and neck fractures [9%]). The mean follow-up was 48 (range 4-192) months. Complications occurred frequently with; 6% surgical site infection, 8% nonunion, 29% avascular necrosis, 64% osteoarthritis, and in 16% a secondary arthrodesis was necessary. A wide variety in functional outcome was reported; however, there seems to be a correlation between fracture classification and postoperative complications. Conclusion: Operative treatment of central talar fractures is associated with a high incidence of early and late complications and often leads to an impaired functional outcome. Standardization of talar fracture classification and scoring systems in combination with large sample-sized prospective studies are warranted to detect further predictive factors influencing tailormade treatment strategies and patient expectation management. Level of Evidence: Level III, Systematic review of case series and case-control studies.

Functional Outcome and Quality of Life After Nonoperative Treatment of Posterior Process Fractures of the Talus.

BACKGROUND: Fractures of the posterior process of the talus are frequently overlooked, possibly leading to nonunion, arthritis, and chronic pain. Given the rare occurrence, previous case series have been small and without functional outcome scores. Therefore, we aimed to provide evidence on outcomes after nonoperative and operative management of posterior process fractures of the talus. METHODS: All patients treated at a level 1 trauma center between 2012 and 2018 were retrospectively evaluated. Patient, fracture, and treatment characteristics were collected, and functional outcome as well as quality of life were assessed. Twenty-nine patients with posterior process fractures of the talus were identified in our database. RESULTS: The most frequently seen mechanism of trauma was fall from height in 13 patients (44.8%). Twenty-two patients underwent primary arthrodesis or operative reduction and fixation of the fracture (75.9%). Eighty-two percent of the patients returned the questionnaires with a mean follow-up of 6 years. The 2 patients with primary arthrodesis were excluded from outcome analysis. The mean Foot Function Index score was 1.8 (range 0.0-10). The mean American Orthopaedic Foot & Ankle Society (AOFAS) score was 78.7 points (range 0-100). The mean quality of life EuroQol-5D (EQ-5D) index score was 0.78 (range -0.26 to 1). The mean visual analog scale (VAS) on overall patient satisfaction was 8.2 (range 1-10). CONCLUSION: Operative management of extended posterior talar fractures was found to provide good functional outcome, quality of life, and patient satisfaction. Although the patients treated nonoperatively were found to have less severe injuries, they demonstrated worse overall outcome, which is supportive of surgical management. Nonoperative treatment is therefore only justified in selected patients. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Gastrointestinal histoplasmosis mimicking peritonitis carcinomatosis: a rare case of an emergent surgical presentation of HIV de novo.

Gastrointestinal perforation due to infection, including disseminated histoplasmosis, is a rare cause of the surgical acute abdomen, especially in an apparently healthy patient. We describe a rare case of gastrointestinal histoplasmosis-induced small intestine perforation as the first manifestation of acquired immune deficiency syndrome in a healthy patient. Remarkably, the disease mimicked peritonitis carcinomatosis during explorative laparoscopy.

Targeting Coagulation Factor Xa Promotes Regression of Advanced Atherosclerosis in Apolipoprotein-E Deficient Mice.

Atherosclerosis is a progressive inflammatory vascular disorder, complicated by plaque rupture and subsequently atherothrombosis. In vitro studies indicate that key clotting proteases, such as factor Xa (FXa), can promote atherosclerosis, presumably mediated through protease activated receptors (PARs). Although experimental studies showed reduced onset of atherosclerosis upon FXa inhibition, the effect on pre-existing plaques has never been studied. Therefore, we investigated effects of FXa inhibition by rivaroxaban on both newly-formed and pre-existing atherosclerotic plaques in apolipoprotein-e deficient (ApoE-/-) mice. Female ApoE-/- mice (age: 8-9 weeks, n = 10/group) received western type diet (WTD) or WTD supplemented with rivaroxaban (1.2 mg/g) for 14 weeks. In a second arm, mice received a WTD for 14 weeks, followed by continuation with either WTD or WTD supplemented with rivaroxaban (1.2 mg/g) for 6 weeks (total 20 weeks). Atherosclerotic burden in aortic arch was assessed by haematoxilin & eosin immunohistochemistry (IHC); plaque vulnerability was examined by IHC against macrophages, collagen, vascular smooth muscle cells (VSMC) and matrix metalloproteinases (MMPs). In addition, PAR1 and -2 expressions and their main activators thrombin and FXa in the plaque were determined in the plaque. Administration of rivaroxaban at human therapeutic concentrations reduced the onset of atherosclerosis (-46%, p < 0.05), and promoted a regression of pre-existing plaques in the carotids (-24%, p < 0.001). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (-39.03%, p < 0.05), enhanced collagen deposition (+38.47%, p < 0.05) and diminished necrotic core (-31.39%, p < 0.05). These findings were accompanied with elevated vascular smooth muscle cells and reduced MMPs. Furthermore, expression of PARs and their activators, thrombin and FXa was diminished after rivaroxaban treatment. Pharmacological inhibition of FXa promotes regression of advanced atherosclerotic plaques and enhances plaque stability. These data suggest that inhibition of FXa may be beneficial in prevention and regression of atherosclerosis, possibly mediated through reduced activation of PARs.

Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Substances that potentially enhance performance (eg, recombinant human erythropoietin [rHuEPO]) are considered doping and are therefore forbidden in sports; however, the scientific evidence behind doping is frequently weak. We aimed to determine the effects of rHuEPO treatment in well trained cyclists on maximal, submaximal, and race performance and on safety, and to present a model clinical study for doping research on other substances. METHODS: We did this double-blind, randomised, placebo-controlled trial at the Centre for Human Drug Research in Leiden (Netherlands). We enrolled healthy, well trained but non-professional male cyclists aged 18-50 years and randomly allocated (1:1) them to receive abdominal subcutaneous injections of rHuEPO (epoetin ß; mean dose 6000 IU per week) or placebo (0·9% NaCl) for 8 weeks. Randomisation was stratified by age groups (18-34 years and 35-50 years), with a code generated by a statistician who was not masked to the study. The primary outcome was exercise performance, measured as maximal power output (Pmax), maximal oxygen consumption VO2 max, and gross efficiency in maximal exercise tests with 25 W increments per 5 min, as lactate threshold and ventilatory threshold 1 (VT1) and 2 (VT2) at submaximal levels during the maximal exercise test, and as mean power, VO2, and heart rate in the submaximal exercise tests at the highest mean power output for 45 min in a laboratory setting and in a race to the Mont Ventoux (France) summit, using intention-to-treat analyses. The trial is registered with the Dutch Trial Registry (Nederlands Trial Register), number NTR5643. FINDINGS: Between March 7, 2016, and April 13, 2016, we randomly assigned 48 participants to the rHuEPO group (n=24) or the placebo group (n=24). Mean haemoglobin concentration (9·6 mmol/L vs 9·0 mmol/L [estimated difference 0·6, 95% CI 0·4 to 0·8]) and maximal power output (351·55 W vs 341·23 W [10·32, 3·47 to 17·17]), and VO2 max (60·121 mL/min per kg vs 57·415 mL/min per kg [2·707, 0·911 to 4·503]) in a maximal exercise test were higher in the rHuEPO group compared with the placebo group. Submaximal exercise test parameters mean power output (283·18 W vs 277·28 W [5·90, -0·87 to 12·67]) and VO2 (50·288 mL/min per kg vs 49·642 mL/min per kg [0·646, -1·307 to 2·600]) at day 46, and Mont Ventoux race times (1 h 40 min 32 s vs 1 h 40 min 15 s [0·3%, -8·3 to 9·6]) did not differ between groups. All adverse events were grade 1-2 and were similar between both groups. No events of grade 3 or worse were observed. INTERPRETATION: Although rHuEPO treatment improved a laboratory test of maximal exercise, the more clinically relevant submaximal exercise test performance and road race performance were not affected. This study shows that clinical studies with doping substances can be done adequately and safely and are relevant in determining effects of alleged performance-enhancing drugs. FUNDING: Centre for Human Drug Research, Leiden.

Short- and Long-term exercise induced alterations in haemostasis: a review of the literature.

Although regular exercise is beneficial for health, exercise-related thrombotic events, such as venous thromboembolism and myocardial infarctions, are occasionally observed. These events are characterized by a prothrombotic condition in which interactions between coagulation factors, the vessel wall and the fibrinolytic system play an important role. Apparently, various durations and intensities of exercise have different effects on haemostasis and especially high intensity exercise tends to increase the risk of thrombotic events. However, the mechanisms behind this have not been entirely established. In this review we provide an overview of the various effects of the different intensities and durations of exercise on haemostasis. Overall, the haemostatic profile is mainly affected by the intensity of exercise; and is more pronounced after high (>80%) compared to low intensity (<60%), as reflected by increased platelet and coagulant activity. These findings are in line with the increased risk of exercise-induced thrombotic events during high intensity exercise.