Good clinical outcomes achieved in young dogs with tibial tuberosity avulsion fracture repairs when implants were left in situ past skeletal maturity.

OBJECTIVE: To evaluate outcomes of tibial tuberosity avulsion fractures (TTAF) in dogs with implants left in situ past skeletal maturity and to compare clinical outcomes with published outcomes in dogs whose implants were removed 4 to 6 weeks postoperatively. ANIMALS: 47 client-owned dogs. PROCEDURES: In this retrospective study, 47 dogs had surgery to correct a TTAF before 10 months of age and had the implants left in situ past skeletal maturity. Of these, 42 were followed for a median of 36 months postoperatively. Short- and long-term complications were recorded and compared with historically published data in which the implants were removed within 6 weeks of surgery. RESULTS: 14% (6/42) of our population experienced minor long-term complications (stiffness and lameness), 6% (3/47) experienced major short-term complications (repair failure), and 14% (6/24) experienced major long-term complications (implant removal). There was no difference in long-term outcomes when compared with results of historical reports in which implants were removed 4 to 6 weeks postoperatively. Client satisfaction was high, with 93% (38/41) grading outcomes as excellent and 95% (39/41) stating they would have surgery performed again in retrospect. CLINICAL RELEVANCE: Immature dogs with surgically repaired TTAFs have favorable long-term outcomes when the implants were left in situ past skeletal maturity. Dogs with TTAF repairs may not need implant removal unless it becomes clinically necessary. Avoiding a second procedure will decrease patient morbidity, recovery time, and cost.

Owner assessed outcomes following elbow arthroscopy with or without platelet rich plasma for fragmented medial coronoid process.

Objective: Document the outcomes of bilateral arthroscopic subtotal coronoidectomy for the fragmented medial coronoid process, quantify persistent lameness that required additional treatment (PRP), and document the outcomes of dogs that followed up with PRP injections. Study design: Retrospective study. Sample population: Overall, 115 dogs underwent arthroscopy alone and 31 received PRP at least 6 weeks after arthroscopy. The owner's response rate was ~50% (73 dogs). Methods: Collected data included signalment, unilateral or bilateral clinical signs, intra-articular chondroprotective injection during the procedure, if PRP intra-articular injection was received postoperatively, and if it was received, the time from the initial surgery to administration was recorded. Outcomes were assessed via standardized owner questionnaires using the Liverpool Osteoarthritis in Dogs (LOAD) score, the Canine Brief Pain Inventory (CBPI) score, and the overall quality of life (QOL) assessment. Results: Approximately 20% of the patients received PRP post-operatively due to persistent lameness following surgery. Similar pain scores were found between the two groups with an average of 11-13 LOAD score, 13-15 CBPI score, and good quality of life. Older animals at the time of surgery and those that received pain-relieving medications after the procedure were more painful and affected their functional outcome. PRP as an adjunctive therapy achieved a perceived good to excellent quality of life in ~90% of pets in this population. Conclusion: Arthroscopy and subtotal coronoidectomy followed by PRP, if needed, seemed to decrease pain, and improve lameness in the long term. Clinical significance: PRP should be considered as adjunctive therapy in dogs with the limited response to arthroscopy alone.

'The last thing you feel is the self-disgust'. The role of self-directed disgust in men who have attempted suicide: A grounded theory study.

OBJECTIVE: Globally, suicide affects more men than women. Emotional pain underpins many theoretical accounts of suicidality, yet little is known about the role of disgust in suicide. Self-directed disgust, whereby aspects of the self-serve as an object of disgust, has been hypothesised to factor in suicide. This research aimed to explore the processes which link self-disgust to attempted suicide in males. METHOD: Nine men who had attempted suicide completed semi-structured interviews. The interview data were analysed using a constructivist grounded theory methodology. RESULTS: Three concepts emerged out of the analysis: (1) self-disgust; (2) worthlessness; and (3) the endured emotional distress of 'the abyss'" - these concepts interweaved, leading the men to experience hopelessness, disconnection and an inability to cope, leading ultimately to their suicide attempt. Throughout this journey, various disgust-related processes worsened men's distress and increased their suicidal risk. Historic adversities prevailed across the data, as did the men's difficulties in understanding their emotions. CONCLUSION: Self-disgust was an important emotion in the men's experiences of suicide and shaped their views of themselves and their lives. The distancing and repellent properties of self-disgust, in addition to the fear of having their 'disgustingness' exposed, increased suicidal risk. Self-disgust appeared more pervasive in the suicidality of men with a history of multiple childhood adversities. The limitations of this research are discussed as implications for clinical practice and directions for future research.

A blood screening tool for detecting mild cognitive impairment and Alzheimer's disease among community-dwelling Mexican Americans and non-Hispanic Whites: A method for increasing representation of diverse populations in clinical research.

INTRODUCTION: Representation of Mexican Americans in Alzheimer's disease (AD) clinical research has been extremely poor. METHODS: Data were examined from the ongoing community-based, multi-ethnic Health & Aging Brain among Latino Elders (HABLE) study. Participants underwent functional exams, clinical labs, neuropsychological testing, and 3T magnetic resonance imaging of the brain. Fasting proteomic markers were examined for predicting mild cognitive impairment (MCI) and AD using support vector machine models. RESULTS: Data were examined from n = 1649 participants (Mexican American n = 866; non-Hispanic White n = 783). Proteomic profiles were highly accurate in detecting MCI (area under the curve [AUC] = 0.91) and dementia (AUC = 0.95). The proteomic profiles varied significantly between ethnic groups and disease state. Negative predictive value was excellent for ruling out MCI and dementia across ethnic groups. DISCUSSION: A blood-based screening tool can serve as a method for increasing access to state-of-the-art AD clinical research by bridging between community-based and clinic-based settings.

Artificial Intelligence in Toxicologic Pathology: Quantitative Evaluation of Compound-Induced Hepatocellular Hypertrophy in Rats.

Digital pathology evolved rapidly, enabling more systematic usage of image analysis and development of artificial intelligence (AI) applications. Here, combined AI models were developed to evaluate hepatocellular hypertrophy in rat liver, using commercial AI-based software on hematoxylin and eosin-stained whole slide images. In a first approach, deep learning-based identification of critical tissue zones (centrilobular, midzonal, and periportal) enabled evaluation of region-specific cell size. Mean cytoplasmic area of hepatocytes was calculated via several sequential algorithms including segmentation in microanatomical structures (separation of sinusoids and vessels from hepatocytes), nuclear detection, and area measurements. An increase in mean cytoplasmic area could be shown in groups given phenobarbital, known to induce hepatocellular hypertrophy when compared to control groups, in multiple studies. Quantitative results correlated with the gold standard: observation and grading performed by board-certified veterinary pathologists, liver weights, and gene expression. Furthermore, as a second approach, we introduce for the first time deep learning-based direct detection of hepatocellular hypertrophy with similar results. Cell hypertrophy is challenging to pick up, particularly in milder cases. Additional evaluation of mean cytoplasmic area or direct detection of hypertrophy, combined with histopathological observations and liver weights, is expected to increase accuracy and repeatability of diagnoses and grading by pathologists.

Micronized Dehydrated Human Amnion Chorion Membrane Injection in the Treatment of Knee Osteoarthritis-A Large Retrospective Case Series.

Osteoarthritis (OA) of the knee is a leading cause of chronic pain and disability in the United States. Current treatment options primarily target OA symptoms reserving surgical intervention and knee replacement for those who fail conservative measures. With average age of patients with knee OA decreasing, regenerative treatment approaches to reduce symptoms, increase quality of life, and delay the need for surgical intervention are increasingly sought. Human amniotic membrane contains growth factors and cytokines, which promote epithelial cell migration and proliferation, stimulate metabolic processes leading to collagen synthesis, and attract fibroblasts, while also reducing pain and inflammation. Micronization of the tissue allows for suspension in normal saline and injection. We conducted a retrospective review of 100 knees treated for symptomatic OA with micronized dehydrated human amnion/chorion membrane (mdHACM) and followed for 6 months. Our purpose is to present our experience and patient outcomes. Data were abstracted from electronic medical records of 82 consecutive OA patients (100 knees) injected with 100 mg mdHACM. Patient age, gender, adverse events and routinely collected Knee Injury and Osteoarthritis Outcome Score (KOOS) were evaluated. Effectiveness of mdHACM treatment was measured by serial KOOS at baseline, and posttreatment at 6 weeks, 3, and 6 months. Overall mean KOOS for the cohort was 40 at baseline, improving to 52, 62, and 65 at 6 weeks, 3 months, and 6 months post-mdHACM injection. Percent increases were 32, 56, and 65%, respectively. Quality of life and sports/recreation domains improved by 111 and 118%, respectively, at 6 months. Pain scores improved by 67% at 6 months. All scores improved throughout the observation period. The most common adverse event was pain after injection lasting 2 to 7 days, observed in 68% of cases. This represents the largest single-physician experience with mdHACM for treatment of knee OA reported to date. Injectable mdHACM appears to be a potentially useful treatment option for knee OA patients. Controlled studies are underway to confirm these observations.

Use of the Polo-like kinase 4 (PLK4) inhibitor centrinone to investigate intracellular signalling networks using SILAC-based phosphoproteomics.

Polo-like kinase 4 (PLK4) is the master regulator of centriole duplication in metazoan organisms. Catalytic activity and protein turnover of PLK4 are tightly coupled in human cells, since changes in PLK4 concentration and catalysis have profound effects on centriole duplication and supernumerary centrosomes, which are associated with aneuploidy and cancer. Recently, PLK4 has been targeted with a variety of small molecule kinase inhibitors exemplified by centrinone, which rapidly induces inhibitory effects on PLK4 and leads to on-target centrosome depletion. Despite this, relatively few PLK4 substrates have been identified unequivocally in human cells, and PLK4 signalling outside centriolar networks remains poorly characterised. We report an unbiased mass spectrometry (MS)-based quantitative analysis of cellular protein phosphorylation in stable PLK4-expressing U2OS human cells exposed to centrinone. PLK4 phosphorylation was itself sensitive to brief exposure to the compound, resulting in PLK4 stabilisation. Analysing asynchronous cell populations, we report hundreds of centrinone-regulated cellular phosphoproteins, including centrosomal and cell cycle proteins and a variety of likely 'non-canonical' substrates. Surprisingly, sequence interrogation of ∼300 significantly down-regulated phosphoproteins reveals an extensive network of centrinone-sensitive [Ser/Thr]Pro phosphorylation sequence motifs, which based on our analysis might be either direct or indirect targets of PLK4. In addition, we confirm that NMYC and PTPN12 are PLK4 substrates, both in vitro and in human cells. Our findings suggest that PLK4 catalytic output directly controls the phosphorylation of a diverse set of cellular proteins, including Pro-directed targets that are likely to be important in PLK4-mediated cell signalling.

Spontaneous pneumomediastinum secondary to electronic cigarette use.

Vaping, the use of electronic cigarettes, involves different mechanics than conventional combustion cigarettes. Consumers who vape tend to overinhale and then forcefully exhale to eliminate the vapor, which is usually produced in much greater quantity than generated by a regular cigarette. Effectively, they are performing an exaggerated Valsalva maneuver. This can increase their risk for developing potential spontaneous pneumomediastinum. Here we present a case of spontaneous pneumomediastinum secondary to electronic cigarette use.

Differentiated thyroid cancer mortality by disease stage in northern England.

OBJECTIVE: Mortality from thyroid cancer is reported to be higher in the UK compared with several other European countries, though UK data on mortality by disease stage have not been published. The aim of this study was to ascertain disease-specific mortality by stage in our centre. DESIGN, PATIENTS AND MEASUREMENTS: This was a cohort study of all patients presenting to a single centre. Four hundred and twenty patients treated between 2000 and 2010 were identified. The medical records and causes of deaths were reviewed and analysed. RESULTS: Overall disease-specific mortality at 5 and 10 years was 1.4% and 5.8%, respectively. The observed mortality was 58 against 66.3 expected deaths (CI 43.8-75.4) thus yielding an age-standardized mortality rate of 0.87. There were no deaths due to thyroid cancer in patients with stage I disease at 5 or 10 years. The 10-year disease-specific mortality rose with stage (stage II 3.1%, stage III 28.6%, stage IV 30%). CONCLUSIONS: Thyroid cancer mortality of patients treated at our centre was lower than the official national UK registry and most European figures.

Tracheal resection for tracheal stenosis.

Anatomically, patients with refractory tracheal stenosis benefit from tracheal resection, depending on the medical comorbidities or challenging tracheal anatomy, which is often the reason for denial of this option in these patients. We evaluated 15 patients undergoing tracheal resection at our institution from May 2016 through December 2017. Eleven patients had a history of previous tracheostomy, six in place at the time of resection. One had idiopathic stenosis with no known comorbidities. Major comorbidities included chronic obstructive pulmonary disease, non-insulin-dependent diabetes mellitus, hypertension, and cardiovascular disease. One had a left ventricular assist device, and one was a lung transplant recipient. All had primary resection through the cervical approach with a median length of 3.5 cm. Fourteen patients were eventually decannulated. One patient had re-resection 1 year later for recurrent stenosis. Twelve were alive at a median follow-up of 15 months with patent airways. In conclusion, tracheal stenosis patients have significant comorbidities that increase the risks after resection. However, these patients should still be considered for surgery for an improved quality of life and eventual resolution of severe stenosis.

Obesity, transplantation, and bariatric surgery: An evolving solution for a growing epidemic.

The increasing obesity epidemic has major implications in the realm of transplantation. Patients with obesity face barriers in access to transplant and unique challenges in perioperative and postoperative outcomes. Because of comorbidities associated with obesity, along with the underlying end-stage organ disease leading to transplant candidacy, these patients may not even be referred for transplant evaluation, much less be waitlisted or actually undergo transplant. However, the use of bariatric surgery in this population can help optimize the transplant candidacy of patients with obesity and end-stage organ disease and improve perioperative and postoperative outcomes. We review the impact of obesity on kidney, liver, and cardiothoracic transplant candidates and recipients and explore potential interventions to address obesity in these populations.

Bicuspid valve aortopathy is associated with distinct patterns of matrix degradation.

OBJECTIVE: To explore the micromechanical, biochemical, and microstructural differences between bicuspid aortic valve aneurysm (BAV-A) and tricuspid aortic valve idiopathic degenerative aneurysm (DA), compared with normal aorta. METHODS: Aortic tissue was obtained from patients undergoing aneurysmal repair surgery (BAV-A; n = 15 and DA; n = 15). Control tissue was obtained from aortic punch biopsies during coronary artery bypass graft surgery (n = 9). Nanoindentation was used to determine the elastic modulus on the medial layer. Glycosaminoglycan, collagen, and elastin levels were measured using biochemical assays. Verhoeff Van Gieson-stained cross-sections were imaged for elastin microstructural quantification. RESULTS: The elastic modulus was more than 20% greater for BAV-A relative to control and DA (signifying a loss of compliance). No significance difference between control and DA were observed. Collagen levels for BAV-A (36.9 ± 7.4 µg/mg) and DA (49.9 ± 10.9 µg/mg) were greater compared with the control (30.2 ± 13.1 µg/mg). Glycosaminoglycan and elastin levels were not significant between the groups. Elastin segments were uniform throughout the control. Aneurysmal tissues had less elastin segments close to the intima and adventitia layers. Both BAV-A and DA had elastin segments compacted in the media; however, elastin segments were highly fragmented in DA. CONCLUSIONS: BAV-A has a greater loss of aortic wall compliance relative to DA and the control. Although elastin levels were equal for all groups, spatial distribution of elastin provided a unique profile of matrix degradation for BAV-A. Elastin compaction within the media of BAV-A may have resulted from the altered hemodynamic pressure against the wall, which could explain for the stiffness of the tissue.

Intra-abdominal complications following intestinal anastomoses by suture and staple techniques in dogs.

OBJECTIVE To compare the incidence of intra-abdominal complications in dogs following resection and functional end-to-end stapled anastomosis (FEESA) versus anastomosis with an end-to-end sutured technique for treatment of enteric lesions. DESIGN Multicenter, retrospective descriptive cohort study. ANIMALS 180 dogs. PROCEDURES Medical records of dogs undergoing intestinal resection and anastomosis at 3 nonaffiliated private practice specialty centers were retrospectively reviewed. Preoperative clinical variables, indication for surgery, surgical technique (sutured end-to-end anastomosis vs FEESA), and evidence of postoperative anastomosis site leakage (dehiscence) were recorded. Variables of interest were analyzed for associations with dehiscence. RESULTS Dehiscence rates of sutured and stapled anastomoses were 12 of 93 (13%) and 4 of 87 (5%), respectively; odds of postoperative dehiscence were significantly lower for dogs with FEESAs than for dogs with sutured anastomoses (OR, 0.28; 95% confidence interval, 0.09 to 0.94). Among dogs that underwent surgery for treatment of intestinal dehiscence after surgery at another facility, subsequent dehiscence developed in 3 of 5 with sutured anastomoses and 0 of 11 with stapled anastomoses. Dehiscence rates varied significantly among clinics. No other variable was associated with risk of dehiscence. Eleven of 16 dogs with dehiscence were euthanized without additional surgery. Impaction at the anastomosis site was identified months or years after surgery in 3 dogs (4 anastomosis sites) that had FEESAs. CONCLUSIONS AND CLINICAL RELEVANCE Odds for dehiscence were significantly greater for sutured end-to-end anastomoses than FEESAs, and dogs undergoing surgery for previous dehiscence were significantly more likely to experience a subsequent dehiscence with a sutured anastomosis. However, variability of procedure types and dehiscence rates among clinics suggested further research is needed to confirm these findings. Obstruction at the anastomosis site was identified as a potential long-term complication of FEESA.

Live Imaging of Cell Invasion Using a Multicellular Spheroid Model and Light-Sheet Microscopy.

Three-dimensional cellular assays are becoming increasingly popular as a fundamental tool to bridge the gap between tissue culture systems and in vivo tissue. In particular, spheroids are recognised today as a necessary intermediate model between testing in monolayer cultures and testing in animals. This chapter describes a straightforward protocol, from sample preparation to image acquisition and initial post-processing, based on one of most widely used commercial light-sheet fluorescence microscopy platform, the Zeiss Lightsheet Z.1.

Postpneumonectomy Bronchopleural Fistula Closure With Biologic Mesh and Diaphragm Flap.

A 77-year-old man with clinical stage II squamous cell carcinoma underwent right intrapericardial pneumonectomy. After an initially uneventful course he was readmitted with right-sided empyema, bronchopleural fistula, and pulmonary embolus. This was managed with initial resuscitation and anticoagulant agents, followed by debridement and closure of the fistula with biologic mesh reinforced with a pedicled diaphragm muscle flap.

Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine.

Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.

Transcriptional responses to hyperplastic MRL signalling in Drosophila.

Recent work has implicated the actin cytoskeleton in tissue size control and tumourigenesis, but how changes in actin dynamics contribute to hyperplastic growth is still unclear. Overexpression of Pico, the only Drosophila Mig-10/RIAM/Lamellipodin adapter protein family member, has been linked to tissue overgrowth via its effect on the myocardin-related transcription factor (Mrtf), an F-actin sensor capable of activating serum response factor (SRF). Transcriptional changes induced by acute Mrtf/SRF signalling have been largely linked to actin biosynthesis and cytoskeletal regulation. However, by RNA profiling, we find that the common response to chronic mrtf and pico overexpression in wing discs was upregulation of ribosome protein and mitochondrial genes, which are conserved targets for Mrtf/SRF and are known growth drivers. Consistent with their ability to induce a common transcriptional response and activate SRF signalling in vitro, we found that both pico and mrtf stimulate expression of an SRF-responsive reporter gene in wing discs. In a functional genetic screen, we also identified deterin, which encodes Drosophila Survivin, as a putative Mrtf/SRF target that is necessary for pico-mediated tissue overgrowth by suppressing proliferation-associated cell death. Taken together, our findings raise the possibility that distinct targets of Mrtf/SRF may be transcriptionally induced depending on the duration of upstream signalling.