Effect of Stress-Related Neural Pathways on the Cardiovascular Benefit of Physical Activity.

BACKGROUND: The mechanisms underlying the psychological and cardiovascular disease (CVD) benefits of physical activity (PA) are not fully understood. OBJECTIVES: This study tested whether PA: 1) attenuates stress-related neural activity, which is known to potentiate CVD and for its role in anxiety/depression; 2) decreases CVD in part through this neural effect; and 3) has a greater impact on CVD risk among individuals with depression. METHODS: Participants from the Mass General Brigham Biobank who completed a PA survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygAC). CVD events were ascertained from electronic health records. RESULTS: A total of 50,359 adults were included (median age 60 years [Q1-Q3: 45-70 years]; 40.1% male). Greater PA was associated with both lower AmygAC (standardized ß: -0.245; 95% CI: -0.444 to -0.046; P = 0.016) and CVD events (HR: 0.802; 95% CI: 0.719-0.896; P < 0.001) in multivariable models. AmygAC reductions partially mediated PA's CVD benefit (OR: 0.96; 95% CI: 0.92-0.99; P < 0.05). Moreover, PA's benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; 95% CI: 0.810-0.915; vs HR: 0.929; 95% CI: 0.910-0.949; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023). CONCLUSIONS: PA appears to reduce CVD risk in part by acting through the brain's stress-related activity; this may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression.

Association of Angiotensin II Receptor Type 1 and Endothelin-1 Receptor Type A Agonistic Autoantibodies With Adverse Remodeling and Cardiovascular Events After Acute Myocardial Infarction.

BACKGROUND: The left ventricular remodeling (LVR) process has limited the effectiveness of therapies after myocardial infarction. The relationship between autoantibodies activating AT1R-AAs (angiotensin II receptor type 1-AAs) and ETAR-AAs (autoantibodies activating endothelin-1 receptor type A) with myocardial infarction has been described. Among patients with ST-segment-elevation myocardial infarction, we investigated the relationship between these autoantibodies with LVR and subsequent major adverse cardiac events. METHODS AND RESULTS: In this prospective observational study, we included 131 patients with ST-segment-elevation myocardial infarction (61±11 years of age, 112 men) treated with primary percutaneous coronary intervention. Within 48 hours of admission, 2-dimensional transthoracic echocardiography was performed, and blood samples were obtained. The seropositive threshold for AT1R-AAs and ETAR-AAs was >10 U/mL. Patients were followed up at 6 months, when repeat transthoracic echocardiography was performed. The primary end points were LVR, defined as a 20% increase in left ventricular end-diastolic volume index, and major adverse cardiac event occurrence at follow-up, defined as cardiac death, nonfatal re-myocardial infarction, and hospitalization for heart failure. Forty-one (31%) patients experienced LVR. The prevalence of AT1R-AAs and ETAR-AAs seropositivity was higher in patients with versus without LVR (39% versus 11%, P<0.001 and 37% versus 12%, P=0.001, respectively). In multivariable analysis, AT1R-AAs seropositivity was significantly associated with LVR (odds ratio [OR], 4.66; P=0.002) and represented a risk factor for subsequent major adverse cardiac events (OR, 19.6; P=0.002). CONCLUSIONS: AT1R-AAs and ETAR-AAs are associated with LVR in patients with ST-segment-elevation myocardial infarction. AT1R-AAs are also significantly associated with recurrent major adverse cardiac events. These initial observations may set the stage for a better pathophysiological understanding of the mechanisms contributing to LVR and ST-segment-elevation myocardial infarction prognosis.

PTSD increases risk for major adverse cardiovascular events through neural and cardio-inflammatory pathways.

While posttraumatic stress disorder (PTSD) is known to associate with an elevated risk for major adverse cardiovascular events (MACE), few studies have examined mechanisms underlying this link. Recent studies have demonstrated that neuro-immune mechanisms, (manifested by heightened stress-associated neural activity (SNA), autonomic nervous system activity, and inflammation), link common stress syndromes to MACE. However, it is unknown if neuro-immune mechanisms similarly link PTSD to MACE. The current study aimed to test the hypothesis that upregulated neuro-immune mechanisms increase MACE risk among individuals with PTSD. This study included N = 118,827 participants from a large hospital-based biobank. Demographic, diagnostic, and medical history data collected from the biobank. SNA (n = 1,520), heart rate variability (HRV; [n = 11,463]), and high sensitivity C-reactive protein (hs-CRP; [n = 15,164]) were obtained for a subset of participants. PTSD predicted MACE after adjusting for traditional MACE risk factors (hazard ratio (HR) [95 % confidence interval (CI)] = 1.317 [1.098, 1.580], ß = 0.276, p = 0.003). The PTSD-to-MACE association was mediated by SNA (CI = 0.005, 0.133, p < 0.05), HRV (CI = 0.024, 0.056, p < 0.05), and hs-CRP (CI = 0.010, 0.040, p < 0.05). This study provides evidence that neuro-immune pathways may play important roles in the mechanisms linking PTSD to MACE. Future studies are needed to determine if these markers are relevant targets for PTSD treatment and if improvements in SNA, HRV, and hs-CRP associate with reduced MACE risk in this patient population.

Reduced Stress-Related Neural Network Activity Mediates the Effect of Alcohol on Cardiovascular Risk.

BACKGROUND: Chronic stress associates with major adverse cardiovascular events (MACE) via increased stress-related neural network activity (SNA). Light/moderate alcohol consumption (ACl/m) has been linked to lower MACE risk, but the mechanisms are unclear. OBJECTIVES: The purpose of this study was to evaluate whether the association between ACl/m and MACE is mediated by decreased SNA. METHODS: Individuals enrolled in the Mass General Brigham Biobank who completed a health behavior survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography, enabling assessment of SNA. Alcohol consumption was classified as none/minimal, light/moderate, or high (<1, 1-14, or >14 drinks/week, respectively). RESULTS: Of 53,064 participants (median age 60 years, 60% women), 23,920 had no/minimal alcohol consumption and 27,053 ACl/m. Over a median follow-up of 3.4 years, 1,914 experienced MACE. ACl/m (vs none/minimal) associated with lower MACE risk (HR: 0.786; 95% CI: 0.717-0.862; P < 0.0001) after adjusting for cardiovascular risk factors. In 713 participants with brain imaging, ACl/m (vs none/minimal) associated with decreased SNA (standardized beta -0.192; 95% CI: -0.338 to -0.046; P = 0.01). Lower SNA partially mediated the beneficial effect of ACl/m on MACE (log OR: -0.040; 95% CI: -0.097 to -0.003; P < 0.05). Further, ACl/m associated with larger decreases in MACE risk among individuals with (vs without) prior anxiety (HR: 0.60 [95% CI: 0.50-0.72] vs 0.78 [95% CI: 0.73-0.80]; P interaction = 0.003). CONCLUSIONS: ACl/m associates with reduced MACE risk, in part, by lowering activity of a stress-related brain network known for its association with cardiovascular disease. Given alcohol's potential health detriments, new interventions with similar effects on SNA are needed.

Radionuclide Imaging of Heart-Brain Connections.

The heart and brain have a complex interplay wherein disease or injury to either organ may adversely affect the other. The mechanisms underlying this connection remain incompletely characterized. However, nuclear molecular imaging is uniquely suited to investigate these pathways by facilitating the simultaneous assessment of both organs using targeted radiotracers. Research within this paradigm has demonstrated important roles for inflammation, autonomic nervous system and neurohormonal activity, metabolism, and perfusion in the heart-brain connection. Further mechanistic clarification may facilitate greater clinical awareness and the development of targeted therapies to alleviate the burden of disease in both organs.

Variable exposure to echocardiography core competencies when applying minimum recommended procedural numbers for cardiology fellows in training.

BACKGROUND: The American College of Cardiology Core Cardiovascular Training Statement (COCATS) defined echocardiography core competencies and set the minimum recommend number of echocardiograms to perform (150) and interpret (300) for independent practice in echocardiography (level 2 training). Fellows may lack exposure to key pathologies that are relatively infrequent, however, even when achieving an adequate number of studies performed and interpreted. We hypothesized that cardiology fellows would lack exposure to 1 or more cardiac pathologies related to core competencies in COCATS when performing and interpreting the minimum recommend number of studies for level 2 training. METHODS: We retrospectively reviewed 11,250 reports from consecutive echocardiograms interpreted (7,500) and performed (3,750) by 25 cardiology fellows at a University tertiary referral hospital who graduated between 2015 and 2019. The first 300 echocardiograms interpreted and the first 150 echocardiograms performed by each fellow were included in the analysis. Echocardiography reports were reviewed for cardiac pathologies relating to core competencies defined in COCATS. RESULTS: All 25 fellows lacked exposure to 1 or more cardiac pathologies related to echocardiography core competencies despite meeting COCATS minimum recommended numbers for echocardiograms performed and interpreted. Pathologies for which 1 or more fellows encountered 0 cases despite meeting the minimum recommended numbers for both echocardiograms performed and interpreted included: pericardial constriction (16/25 fellows), aortic dissection (15/25 fellows), pericardial tamponade (4/25 fellows), valvular mass/thrombus (2/25 fellows), prosthetic valve dysfunction (1/25 fellows), and cardiac chamber mass/thrombus (1/25 fellows). CONCLUSIONS: Cardiology fellows who completed the minimum recommend number of echocardiograms performed and interpreted for COCATS level 2 training frequently lacked exposure to cardiac pathologies, even in a University tertiary referral hospital setting. These data suggest that fellowship programs should monitor pathology case counts for each fellow in training, in addition to the minimum recommend number of echocardiograms defined by COCATS, to ensure competency for independent practice in echocardiography.

How safe are paediatric emergency departments? A national prospective cohort study.

BACKGROUND: Despite the high number of children treated in emergency departments, patient safety risks in this setting are not well quantified. Our objective was to estimate the risk and type of adverse events, as well as their preventability and severity, for children treated in a paediatric emergency department. METHODS: Our prospective, multicentre cohort study enrolled children presenting for care during one of 168 8-hour study shifts across nine paediatric emergency departments. Our primary outcome was an adverse event within 21 days of enrolment which was related to care provided at the enrolment visit. We identified 'flagged outcomes' (such as hospital visits, worsening symptoms) through structured telephone interviews with patients and families over the 21 days following enrolment. We screened admitted patients' health records with a validated trigger tool. For patients with flags or triggers, three reviewers independently determined whether an adverse event occurred. RESULTS: We enrolled 6376 children; 6015 (94%) had follow-up data. Enrolled children had a median age of 4.3 years (IQR 1.6-9.8 years). One hundred and seventy-nine children (3.0%, 95% CI 2.6% to 3.5%) had at least one adverse event. There were 187 adverse events in total; 143 (76.5%, 95% CI 68.9% to 82.7%) were deemed preventable. Management (n=98, 52.4%) and diagnostic issues (n=36, 19.3%) were the most common types of adverse events. Seventy-nine (42.2%) events resulted in a return emergency department visit; 24 (12.8%) resulted in hospital admission; and 3 (1.6%) resulted in transfer to a critical care unit. CONCLUSION: In this large-scale study, 1 in 33 children treated in a paediatric emergency department experienced an adverse event related to the care they received there. The majority of events were preventable; most were related to management and diagnostic issues. Specific patient populations were at higher risk of adverse events. We identify opportunities for improvement in care.

Treatment of a Recalcitrant Non-union of the Clavicle.

Background: Plate fixation is the treatment of choice for a midshaft clavicle non-union. Those non-unions that require >1 surgical procedure to heal are termed recalcitrant non-union. Regardless of the number of previously failed procedures, our surgical strategy is aimed at achieving an optimal mechanical and biological environment to facilitate healing. Materials and methods: We performed a retrospective analysis of 14 patients with a recalcitrant clavicle non-union treated with open reduction and plate fixation combined with graft augmentation when indicated. Healing rates after index surgery were analysed. All patients were observed for at least 12 months. Results: All patients healed at a mean time of 193.2 days (range 90-390). Five of the 14 patients had at least one positive surprise culture, for which they received antibiotic treatment. At the latest follow-up, no patient reported pain or discomfort. Mean disability of the arm, shoulder and hand (DASH) score was 16.3 points (range 0-40), indicating only mild residual impairment. A possible link was found between the time between injury and definitive surgery and the time to healing [Pearson correlation 0.527, sig. (two-tailed) 0.000]. Conclusion: This study shows 100% bone healing and good functional outcomes after surgical revision for a recalcitrant clavicle non-union. How to cite this article: Grewal S, Baltes TPA, Wiegerinck E, et al. Treatment of a Recalcitrant Non-union of the Clavicle. Strategies Trauma Limb Reconstr 2022;17(1):1-6.

Oral Antibiotic Prophylaxis Reduces Surgical Site Infection and Anastomotic Leakage in Patients Undergoing Colorectal Cancer Surgery.

BACKGROUND: Surgical-site infection (SSI) and anastomotic leakage (AL) are major complications following surgical resection of colorectal carcinoma (CRC). The beneficial effect of prophylactic oral antibiotics (OABs) on AL in particular is inconsistent. We investigated the impact of OABs on AL rates and on SSI. METHODS: A systematic review and meta-analysis of recent RCTs and cohort studies was performed including patients undergoing elective CRC surgery, receiving OABs with or without mechanical bowel preparation (MBP). Primary outcomes were rates of SSI and AL. Secondarily, rates of SSI and AL were compared in broad-spectrum OABs and selective OABs (selective decontamination of the digestive tract (SDD)) subgroups. RESULTS: Eight studies (seven RCTs and one cohort study) with a total of 2497 patients were included. Oral antibiotics combined with MBP was associated with a significant reduction in SSI (RR = 0.46, 95% confidence interval (CI) 0.31-0.69), I2 = 1.03%) and AL rates (RR = 0.58, 95% CI 0.37-0.91, I2 = 0.00%), compared to MBP alone. A subgroup analysis demonstrated that SDD resulted in a significant reduction in AL rates compared to broad-spectrum OABs (RR = 0.52, 95% CI 0.30 to 0.91), I2 = 0.00%). CONCLUSION: OABs in addition to MBP reduces SSI and AL rates in patients undergoing elective CRC surgery and, more specifically, SDD appears to be more effective compared to broad-spectrum OABs in reducing AL.

Usefulness of Glucagon-Like Peptide-1 Receptor Agonists to Reduce Adverse Cardiovascular Disease Events in Patients with Type 2 Diabetes Mellitus.

Evidence suggests glucagon-like peptide-1 receptor agonists (GLP-1 RA) reduce cardiovascular disease (CVD) events. The objective of this study was to analyze randomized controlled trials (RCT) testing GLP-1 RA's effect on CVD events among participants with type 2 diabetes (T2DM). RCTs comparing GLP-1 RA versus placebo were identified using the PubMed and Cochrane databases. The endpoints in this study included major adverse cardiovascular events (MACE; a composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke), and the individual components of MACE. The primary analysis calculated risk ratios (RR) and 95% confidence intervals (CI) for each endpoint. Heterogeneity for each endpoint was calculated using Chi2 and I2 tests. For any endpoint with significant heterogeneity, a meta-regression was performed using mean baseline hemoglobin A1C (A1C) as the moderator and a R2 value was calculated. Seven RCTs (N = 56,004) were identified with 174,163 patient-years of follow-up. GLP-1 RA reduced MACE [RR 0.89, 95% CI 0.83 to 0.95], cardiovascular death [RR 0.88, 95% CI 0.81 to 0.95], and nonfatal stroke [RR 0.85, 95% CI 0.77 to 0.95]. There was no statistically significant heterogeneity among these RCTs. GLP-1 RA did not reduce nonfatal MI [RR 0.91, 95% CI 0.81 to 1.02]. However, there was significant heterogeneity among these RCTs (Chi2 = 12.68, p = 0.05, I2 = 53%). When accounting for baseline A1C in the regression model, there was no longer significant heterogeneity for this endpoint (p = 0.23, I2 = 27%). A potential linear relationship between baseline A1C and GLP-1 RA's effect on nonfatal MI (R2 = 0.64) was observed. In conclusion, GLP-1 RA reduced MACE, cardiovascular death, and nonfatal stroke; GLP-1 RA did not reduce nonfatal MI, however there may be a linear association between baseline A1C and GLP-1 RA's effect on nonfatal MI.

Surgery for Colorectal Cancer: A Trigger for Liver Metastases Development? New Insights into the Underlying Mechanisms.

Surgery is a crucial intervention and provides the best chance of cure for patients with colorectal cancer. Experimental and clinical evidence, however, suggests that paradoxically surgery itself may precipitate or accelerate tumor recurrence and/or liver metastasis development. This review addresses the various aspects of surgery-induced metastasis formation and sheds light on the role of inflammation as potential trigger for metastasis development. Understanding these mechanisms may provide potential new perioperative interventions to improve treatment outcomes, and as such could transform the perioperative timeframe from a facilitator of metastatic progression to a window of opportunity to reduce the risk of liver metastasis development. Ultimately, this can potentially improve long-term survival rates and quality of life in patients with colorectal cancer.

Risks of adverse events in patients with orthostatic intolerance undergoing surgery with general anesthesia.

INTRODUCTION: Orthostatic intolerance (OI) is a group of disorders characterized by symptoms that occur upon standing and resolve with recumbence. Although well established but not widely recognized, these diagnoses may create uncertainty for clinicians dealing with a patient affected by OI and requiring a surgical procedure. OBJECTIVES: To determine the rate of intra- and postoperative major adverse events in patients with OI undergoing surgery with general anesthesia. METHODS: The study was a retrospective study of patients with orthostatic intolerance who underwent surgery requiring general anesthesia from 1 January 2000 to 31 December 2018. RESULTS: A total 171 patients with OI underwent 190 surgeries. In patients with POTS and orthostatic-induced VVS, there were no major significant adverse events. There was one episode of AVNRT in a patient with POTS and one episode of bradycardia secondary to vasovagal reflex in a patient with orthostatic-induced VVS. Moreover, there were 13 (6.8%) episodes of postoperative hypotension. However, the majority of these episodes were related to bleeding, volume depletion or sepsis. All cases of hypotension responded well to appropriate therapy. In patients with OH, the rate of postoperative major adverse cardiac events was 4.7%, and the 30-day mortality rate was 6.1%. This is not significantly different from the calculated risk for patients without OH. There were no myocardial infarctions or deaths at 30 days in patients with POTS or orthostatic-induced VVS. CONCLUSION: Patients with OI may not experience higher rates of perioperative complications compared with patients without OI syndromes.

Disturbed remodeling and delayed fracture healing in pediatric pycnodysostosis patients.

Pycnodysostosis is an autosomal recessive disease caused by a gene mutation leading cathepsin K deficiency. Pathological fractures of the long bones are common, but guidelines on fracture treatment in these patients are still lacking. We have treated 5 fractures in 2 pediatric pycnodysostosis patients. We hypothesize that pycnodysostosis patients have an incomplete remodeling process in fracture healing because of cathepsin K deficiency. Therefore, to minimize the role of endochondral bone formation (indirect) after a fracture, it seems prudent to strive for direct bone healing (intramembranous) instead of indirect bone healing. Open reduction with internal fixation should be the goal.

Spillage of bacterial products during colon surgery increases the risk of liver metastases development in a rat colon carcinoma model.

Surgical resection of the primary tumor provides the best chance of cure for patients with colorectal carcinoma (CRC). However, bacterial translocation during intestinal surgery has been correlated with poor long-term oncological outcome. Therefore, we investigated the influence of bacterial contamination during colon surgery on CRC liver metastases development. Blood and liver samples of patients undergoing resection of primary CRC or liver metastases were collected. Cell numbers, activation markers and inflammatory mediators were determined. Tumor cell adhesion and outgrowth after sham- or colectomy operations were determined in a rat model, in which tumor cells had been injected into the portal vein. White blood cells and granulocytes were increased in per- and post-operative patient blood samples. IL-6 was also increased post-operatively compared to the preoperative level. Expression of NOX-2, NOX-4 and polymorphonuclear cells (PMNs) numbers were elevated in post-operative human liver samples. In vitro stimulation of macrophages with plasma of rats after colectomy resulted in production of reactive oxygen species (ROS). Colectomy in rats increased D-lactate levels in plasma, supporting bacterial translocation. Decreased expression of tight junction molecules and increased tumor cell adhesion and outgrowth was observed. Treatment with a selective decontamination of the digestive tract (SDD) cocktail decreased tumor cell adherence after colectomy. In conclusion, postoperative bacterial translocation may activate liver macrophages and PMNs, resulting in ROS production. As we previously showed that ROS release led to liver vasculature damage, circulating tumor cells may adhere to exposed extracellular matrix and grow out into liver metastases. This knowledge is pivotal for development of therapeutic strategies to prevent surgery-induced liver metastases development.

Corrective osteotomy in symptomatic clavicular malunion using computer-assisted 3-D planning and patient-specific surgical guides.

Surgical correction of a symptomatic clavicular malunion requires simultaneous adjustment of the translation as well as the rotation in multiple planes. We describe a corrective osteotomy for a clavicle malunion using 3-D computer assisted preoperative-planning combined with patient-specific surgical guides, along with the benefits and disadvantages of this approach. This method enabled quantifying the malunion by comparing the malunited bone with the normal contralateral clavicle as a template. The postoperative results were encouraging with symmetrical shoulder anatomy and functional improvement. Therefore, we recommend this technique in patients with a symptomatic clavicle malunion, as it allows successful correction of the deformity.

Human IgG3 with extended half-life does not improve Fc-gamma receptor-mediated cancer antibody therapies in mice.

BACKGROUND: Current anti-cancer therapeutic antibodies that are used in the clinic are predominantly humanized or fully human immunoglobulin G1 (IgG1). These antibodies bind with high affinity to the target antigen and are efficient in activating the immune system via IgG Fc receptors and/or complement. In addition to IgG1, three more isotypes are present in humans, of which IgG3 has been found to be superior compared to human IgG1 in inducing antibody dependent cell cytotoxicity (ADCC), phagocytosis or activation of complement in some models. Nonetheless, no therapeutic human IgG3 mAbs have been developed due to the short in vivo half-life of most known IgG3 allotypes. In this manuscript, we compared the efficacy of V-gene matched IgG1 and IgG3 anti-tumour mAb (TA99) in mice, using natural variants of human IgG3 with short- or long half-life, differing only at position 435 with an arginine or histidine, respectively. RESULTS: In vitro human IgG1 and IgG3 did not show any differences in opsonisation ability of B16F10-gp75 mouse melanoma cells. IgG1, however, was superior in inducing phagocytosis of tumour cells by mouse macrophages. Similarly, in a mouse peritoneal metastasis model we did not detect an improved effect of IgG3 in preventing tumour outgrowth. Moreover, replacing the arginine at position 435 for a histidine in IgG3 to enhance half-life did not result in better suppression of tumour outgrowth compared to wild type IgG3 when injected prior to tumour cell injection. CONCLUSION: In conclusion, human IgG3 does not have improved therapeutic efficacy compared to human IgG1 in a mouse tumour model.

Hypertonic saline for bronchiolitis in infants.

QUESTION: Recently, a 1-year-old patient returned from admission in the hospital for bronchiolitis, and the report I received indicated that he was treated with inhaled hypertonic saline, among other treatments. Is this therapy recommended for children in the acute care setting? ANSWER: Bronchiolitis, caused mostly by respiratory syncytial virus, is very common in the winter. It is the most frequent cause of hospitalization in infancy. Several good studies have been conducted in the past decade on the use of nebulized hypertonic saline for bronchiolitis management; however, they offer conflicting results. While there might be a role for the use of nebulized hypertonic saline in children who are hospitalized with bronchiolitis for more than 3 days, treatment in other settings does not confer enough benefit to recommend its use.