Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients With COVID-19: COVID-PACT.

BACKGROUND: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain. METHODS: COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit-level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit-level COVID-19 rates. RESULTS: At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08-3.55]; P=0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32-0.99]; P=0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose (P=0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%; P=0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56-1.48]; P=0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy. CONCLUSIONS: In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04409834.

The orthopaedic and traumatology scenario during Covid-19 outbreak in Italy: chronicles of a silent war.

BACKGROUND: From February 21, the day of hospitalisation in ICU of the first diagnosed case of Covid-19, the social situation and the hospitals' organisation throughout Italy dramatically changed. METHODS: The CIO (Club Italiano dell'Osteosintesi) is an Italian society devoted to the study of traumatology that counts members spread in public and private hospitals throughout the country. Fifteen members of the CIO, Chairmen of 15 Orthopaedic and Trauma Units of level 1 or 2 trauma centres in Italy, have been involved in the study. They were asked to record data about surgical, outpatients clinics and ER activity from the 23rd of February to the 4th of April 2020. The data collected were compared with the data of the same timeframe of the previous year (2019). RESULTS: Comparing with last year, overall outpatient activity reduced up to 75%, overall Emergency Room (ER) trauma consultations up to 71%, elective surgical activity reduced up to 100% within two weeks and trauma surgery excluding femoral neck fractures up to 50%. The surgical treatment of femoral neck fractures showed a stable reduction from 15 to 20% without a significant variation during the timeframe. CONCLUSIONS: Covid-19 outbreak showed a tremendous impact on all orthopaedic trauma activities throughout the country except for the surgical treatment of femoral neck fractures, which, although reduced, did not change in percentage within the analysed timeframe.

Non-unions.

Non-union of long bones is a significant consequence of fracture treatment. Bone regeneration is a complex physiological process of bone formation which can be seen during normal fracture healing. An improved understanding of the molecular and cellular events that occur during bone repair and remodelling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Currently, there are different strategies to augment the impaired or "insufficient" bone-regeneration process, including the "gold standard" autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications.

Proximal femoral fractures in elderly people: time to surgery. The experience of Milan's "ASST Pini/CTO".

Proximal femoral fractures in elderly patients represent a rapidly increasing socio-economic problem. The functional recovery and the mortality rate are influenced by a substantial quantity of variables, including the waiting time for surgical treatment ("time to surgery"). This study aims at investigating the average waiting time, and ascertaining the causes and effects, together with other non-modifiable variables, on the outcome for patients admitted to Milan's Istituto Ortopedico Gaetano Pini (Gaetano Pini Orthopaedic Institute) with a proximal femoral fracture. Data have been collected from 234 patients, between May and November 2015. Parameters recorded and analysed included fracture type, presence of comorbidities (Charlson Index (CCI)), the ASA (American Society of Anesthesiology) score, day of the week presenting to hospital, the type of treatment received, the functional recovery, and the patient's condition on discharge. In 46.4% of cases, the duration of preoperative stay prior to surgery was found to be in line with what is recommended in the literature (<48 h). In 20% of cases, the time to surgery was found to exceed 96 hours. The data collected that pertain to the distribution of the sample and the comorbidities were shown to be in line with the literature. A statistical significant difference was found between day of the week that the patient was admitted to hospital and the waiting time for surgery.

Treatment of an atrophic clavicle non-union with the chamber induction technique: a case report.

The gold standard technique for treating non-union of the clavicle is based on corticocancellous bone graft harvested from the iliac crest and fixation with a plate. In cases of large clavicular defects, this surgical procedure becomes ineffective and only a complex bone reconstruction can be considered. In the herein study we report on a clavicular non-union which was associated with a 4cm bone defect that was managed successfully with optimum fixation and the Chamber Induction Technique (C.I.T)-formation of the masquelet membrane- and subsequent biological augmentation with a composite bone graft.

Core decompression and biotechnologies in the treatment of avascular necrosis of the femoral head.

Avascular necrosis (AVN) of the femoral head (FH) causes 5% to 12% of total hip arthroplasties (THA). It especially affects active male adults between the third and fifth decades of life. The exact worldwide incidence is unknown. There are only few data related to each country, but most of it relates to the United States.Non-surgical management has a very limited role in the treatment of AVN of the FH and only in its earliest stages. Core decompression (CD) of the hip is the most common procedure used to treat the early stages of AVN of the FH. Recently, surgeons have considered combining CD with autologous bone-marrow cells, demineralised bone matrix or bone morphogenetic proteins or methods of angiogenic potential to enhance bone repair in the FH.Manuscripts were deemed eligible for our review if they evaluated treatment of early stage AVN of the FH with biotechnology implanted via CD. After application of eligibility criteria, we selected 19 reports for final analysis.The principal results showed that only by correctly mastering the therapeutic principles and adopting proper methods specifically oriented to different stages can the best therapeutic effect be achieved. Combining CD with biotechnology could result in a novel long-lasting hip- preserving treatment option.Furthermore, more refined clinical studies are needed to establish the effectiveness of biotechnology treatments in AVN of the FH. Cite this article: EFORT Open Rev 2017;2:41-50. DOI: 10.1302/2058-5241.2.150006.

Complications in proximal humeral fractures.

Necrosis of the humeral head, infections and non-unions are among the most dangerous and difficult-to-treat complications of proximal humeral fractures. The aim of this work was to analyse in detail non-unions and post-traumatic bone defects and to suggest an algorithm of care. Treatment options are based not only on the radiological frame, but also according to a detailed analysis of the patient, who is classified using a risk factor analysis. This method enables the surgeon to choose the most suitable treatment for the patient, thereby facilitating return of function in the shortest possible time. The treatment of such serious complications requires the surgeon to be knowledgeable about the following possible solutions: increased mechanical stability; biological stimulation; and reconstructive techniques in two steps, with application of biotechnologies and prosthetic substitution.

Reconstruction of patellar tendon following implantation of proximal tibia megaprosthesis for the treatment of post-traumatic septic bone defects.

INTRODUCTION: Latest advances made in joint replacement implants allows reconstruction of entire limbs. These special prostheses or megaprostheses were originally designed for the treatment of severe oncological bone loss. Nowadays, however, the indications and applications of these devices are expanding to other orthopaedic and trauma clinical conditions. Since 2008 we have implanted 152 megaprostheses in non-oncological conditions: 87 were implanted for post-traumatic failures aseptic/septic (represented by complex non-unions and critical size bone defects); 26 total femur, 52 distal femur and 9 proximal tibia. In this group of patients bone and soft tissues conditions are completely different compared to patients with oncological back ground. The presence of infection and previous surgeries can lead to adhesion, scar interference, muscular and tendon impairment and skin problems that lead to reduced function and severe joint stiffness. The purpose of this study is to evaluate the results of treatment of reconstruction of patellar tendon during implantation of proximal tibia megaprosthesis for the treatment of septic post traumatic critical bone defects. PATIENTS AND METHODS: In this retrospective study, we evaluated 9 patients treated with proximal tibia megaprosthesis who underwent patellar tendon reconstruction. All patients presented a complete patellar tendon disruption at the time of prosthesis implantation. Procedures of reconstruction included a tendon-plasty of quadriceps and/or patellar tendons, a pie crusting of quadriceps fascia, a reinforcement of the apparatus with synthetic tendon graft substitutes (LARS) and a medial gastrocnemius muscular flap to reconstruct the extensor mechanism and obtain skin coverage when needed. The average follow up was 18 months (9-36). For each of the cases, we analysed the complications occurred regarding septic recurrence, patellar fracture, quadriceps and patellar tendon rupture and number of reinterventions. The clinical outcome was assessed by the WOMAC Score. RESULTS: In all cases there was no infection recurrence or skin related problems. None of the patients require prosthesis revision due to loosening or device failure. No patellar fracture or quadriceps tendon failure was recorded. One patient presented a rupture of the reconstructed patellar tendon due to a trauma incident 18 months after the implantation and he required revision surgery. From a clinical point of view the average WOMAC score was 62.4 at 1 month rising to 72.6 at 3 months, 78.2 at 6 months, 76.4 at 1 year and 74.8 at 18 months. CONCLUSION: When proximal tibia megaprosthesis is implanted and there are soft tissue and patellar tendon deficiency, soft tissue reconstruction can be achieved by appropriate lengthening of the tendon and a gastrocnemius flap reinforced by LARS. Such an approach allows restoration of the extensor mechanism and coverage of the prosthesis in an area where skin problems are frequently very common.

Clinical effectiveness of Osigraft in long-bones non-unions.

Current evidence, based primarily on case series, suggest that the eptotermin alfa (recombinant bone morphogenetic protein-7 (rhBM-7)), which is commercialized as Osigraft with an indication for tibial non-union, used in monotherapy or polytherapy, is a safe and effective therapy for long bones non-unions of lower and upper limbs. No previous study has compared the safety and the efficacy of Osigraft and the "gold standard" treatment for recalcitrant long-bones non-union, autologous bone graft (ABG). This study aims to compare the effectiveness of Osigraft and ABG in the treatment of post-traumatic, persistent long bone non-unions. In particular, the present study will focus exclusively on complex persistent non-unions, excluding simpler cases, in which it is likely that a simple revision of the osteosynthesis will be sufficient to promote union, and extremely severe cases in which there is an indication for amputation and prosthesis. The study addresses the following research question: 1. Is the effectiveness of eptotermin alfa comparable to that of ABG in the treatment of complex long bone non-unions? 2. Are there significant differences in the prevalence of adverse events between patients treated with eptotermin alfa and those treated with ABG? The study is an observational, retrospective study, located in one Experimental Recruiting Center (Ospedale Universitario G. PINI - Milano). The study was conducted with ethics approval and according with the existing Italian law. Demographic and clinical data were collected from patients Clinical Medical Records and other existing documentation, through a web based eCRF. The treatment (surgery with Osigraft or ABG) effectiveness was evaluated comparing the number of success cases (primary endpoint) and the length for clinical and radiological healing (secondary end-points). The treatment safety was evaluating comparing the prevalence of Adverse Events. Osigraft was demonstrated to be statistically equivalent to ABG with respect to the primary and secondary end point of surgical success. The treatment success was statistically comparable across all the anatomical regions considered, both in patients treated with Osigraft and in patients treated with ABG. The use of Osigraft when compared to autograft was associated with statistically lower intraoperative blood loss and shorter operative times. In addition patients treated with Osigraft developed statistically less peri-operative and late onset adverse events, compared to ABG. The difference was substantially due to the occurrence of pain at donor site in patients treated with ABG.

Heme oxygenase is necessary for the excitatory response of cultured neonatal rat rostral ventrolateral medulla neurons to hypoxia.

Heme oxygenase has been linked to the oxygen-sensing function of the carotid body, pulmonary vasculature, cerebral vasculature, and airway smooth muscle. We have shown previously that the cardiorespiratory regions of the rostral ventrolateral medulla are excited by local hypoxia and that heme oxygenase-2 (HO-2) is expressed in the hypoxia-chemosensitive regions of the rostral ventrolateral medulla (RVLM), the respiratory pre-Bötzinger complex, and C1 sympathoexcitatory region. To determine whether heme oxygenase is necessary for the hypoxic-excitation of dissociated RVLM neurons (P1) cultured on confluent medullary astrocytes (P5), we examined their electrophysiological responses to hypoxia (NaCN and low Po(2)) using the whole-cell perforated patch clamp technique before and after blocking heme oxygenase with tin protoporphyrin-IX (SnPP-IX). Following the electrophysiological recording, immunocytochemistry was performed on the recorded neuron to correlate the electrophysiological response to hypoxia with the expression of HO-2. We found that the responses to NaCN and hypoxia were similar. RVLM neurons responded to NaCN and low Po(2) with either depolarization or hyperpolarization and SnPP-IX blocked the depolarization response of hypoxia-excited neurons to both NaCN and low Po(2) but had no effect on the hyperpolarization response of hypoxia-depressed neurons. Consistent with this observation, HO-2 expression was present only in the hypoxia-excited neurons. We conclude that RVLM neurons are excited by hypoxia via a heme oxygenase-dependent mechanism.

Selective loss of catecholaminergic wake active neurons in a murine sleep apnea model.

The presence of refractory wake impairments in many individuals with severe sleep apnea led us to hypothesize that the hypoxia/reoxygenation events in sleep apnea permanently damage wake-active neurons. We now confirm that long-term exposure to hypoxia/reoxygenation in adult mice results in irreversible wake impairments. Functionality and injury were next assessed in major wake-active neural groups. Hypoxia/reoxygenation exposure for 8 weeks resulted in vacuolization in the perikarya and dendrites and markedly impaired c-fos activation response to enforced wakefulness in both noradrenergic locus ceruleus and dopaminergic ventral periaqueductal gray wake neurons. In contrast, cholinergic, histaminergic, orexinergic, and serotonergic wake neurons appeared unperturbed. Six month exposure to hypoxia/reoxygenation resulted in a 40% loss of catecholaminergic wake neurons. Having previously identified NADPH oxidase as a major contributor to wake impairments in hypoxia/reoxygenation, the role of NADPH oxidase in catecholaminergic vulnerability was next addressed. NADPH oxidase catalytic and cytosolic subunits were evident in catecholaminergic wake neurons, where hypoxia/reoxygenation resulted in translocation of p67(phox) to mitochondria, endoplasmic reticulum, and membranes. Treatment with a NADPH oxidase inhibitor, apocynin, throughout hypoxia/reoxygenation exposures conferred protection of catecholaminergic neurons. Collectively, these data show that select wake neurons, specifically the two catecholaminergic groups, can be rendered persistently impaired after long-term exposure to hypoxia/reoxygenation, modeling sleep apnea; wake impairments are irreversible; catecholaminergic neurons are lost; and neuronal NADPH oxidase contributes to this injury. It is anticipated that severe obstructive sleep apnea in humans destroys catecholaminergic wake neurons.

Sex differences in susceptibility to oxidative injury and sleepiness from intermittent hypoxia.

STUDY OBJECTIVES: Adult male mice exposed to long-term intermittent hypoxia (LTIH), modeling sleep apnea oxygenation patterns, develop nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent residual hypersomnolence and oxidative injury in select brain regions, including wake-active regions. Premenopausal females are less susceptible to selective oxidative brain injuries. We sought to determine whether female mice exposed to LTIH would confer resistance to LTIH-induced wake impairments and oxidative injuries. SUBJECTS AND SETTING: Young adult male and female C57BI/6J mice were studied in a university laboratory. INTERVENTIONS: Mice were randomly assigned to either LTIH or sham LTIH for 8 weeks. Total (24-h) wake time and mean sleep latency were measured under 2 conditions: rested and following 6 hours of enforced wakefulness. NADPH oxidase activation, carbonylation, and lipid peroxidation assays were also performed to assess sex differences in oxidative responses to LTIH. RESULTS: In contrast with the significant LTIH-induced wake impairments observed in male mice, females following LTIH showed normal wake times and sleep latencies. Female mice revealed less baseline carbonylation and less carbonylation following LTIH but showed robust NADPH oxidase activation and lipid peroxidation. In contrast with the female relative resistance to LTIH sleepiness, female mice showed more-pronounced sleepiness and delta response after enforced wakefulness. CONCLUSIONS: Despite a robust oxidative response to LTIH, age-matched female mice may be protected, at least temporarily, from LTIH wake impairments by lower basal carbonylation. In contrast, females show greater wake impairments after sleep deprivation. We hypothesize sex differences in polysomnographic predictors of sleepiness and residual sleepiness in humans with sleep apnea.