The International Consortium on Primary Graft Dysfunction: Redefining Clinical Risk Factors in the Contemporary Era of Heart Transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality early after heart transplantation (HT). The International Consortium on PGD is a multicenter collaboration dedicated to identifying the clinical risk factors for PGD in the contemporary era of HT. The objectives of the current report were (1) to assess the incidence of severe PGD in an international cohort; (2) to evaluate the performance of the most strongly validated PGD risk tool, the RADIAL score, in a contemporary cohort; and (3) to redefine clinical risk factors for severe PGD in the current era of HT. METHODS: This is a retrospective, observational study of consecutive adult HT recipients between 2010 and 2020 in 10 centers in the United States, Canada and Europe. Patients with severe PGD were compared to those without severe PGD (comprising those with no, mild and moderate PGD). The RADIAL score was calculated for each transplant recipient. The discriminatory power of the RADIAL score was evaluated using receiver operating characteristic (ROC) analysis, and its calibration was assessed by plotting the percentage of PGD predicted vs that which was observed. To identify clinical risk factors associated with severe PGD, we performed multivariable mixed-effects logistic regression modeling to account for among-center variability. RESULTS: A total of 2746 patients have been enrolled in the registry to date, including 2015 (73.4%) from North America, and 731 (26.6%) from Europe; 215 participants (7.8%) met the criteria for severe PGD. There was an increase in the incidence of severe PGD over the study period (P value for trend by difference sign test = 0.004). The Kaplan-Meier estimate for 1-year survival was 75.7% (95% CI 69.4-80.9%) in patients with severe PGD as compared to 94.4% (95% CI 93.5-95.2%) in those without severe PGD (log-rank P value < 0.001). The RADIAL score performed poorly in our contemporary cohort and was not associated with severe PGD; it had an AUC of 0.53 (95% CI 0.48-0.58). In the multivariable regression model, acute preoperative dialysis (OR 2.41, 95% CI 1.31-4.43), durable left ventricular assist device support (OR 1.77, 95% CI 1.13-2.77), and total ischemic time (OR 1.20 for each additional hour, 95% CI 1.02-1.41) were associated with an increased risk of severe PGD. CONCLUSIONS: Our consortium has identified an increasing incidence of PGD in the modern transplant era. We identified contemporary risk factors for this early post-transplant complication, which confers a high mortality risk. These results may enable the identification of patients at high risk for developing severe PGD in order to inform peri-transplant donor and recipient management practices.

"I Like and Prefer to Work Alone": Social Anxiety, Academic Self-Efficacy, and Students' Perceptions of Active Learning.

Although active learning improves student outcomes in science, technology, engineering, and mathematics (STEM) programs, it may provoke anxiety in some students. We examined whether two psychological variables, social anxiety (psychological distress relating to the fear of negative evaluation by others) and academic self-efficacy (confidence in one's ability to overcome academic challenges), interact with student perceptions of evidence-based instructional practices (EBIPs) and associate with their final grades in a STEM-related course. Human anatomy and physiology students in community college courses rated various EBIPs for their perceived educational value and their capacity to elicit anxiety (N = 227). In general, practices causing students the most anxiety (e.g., cold calling) were reported by students as having the least educational value. When controlling for students' self-reported grade point averages, socially anxious students rated several EBIPs as more anxiety inducing, whereas high-efficacy students reported less anxiety surrounding other EBIPs. Furthermore, mediation analysis revealed that individual differences in academic self-efficacy at the beginning of the term explained some of the negative association between students' social anxiety levels and final grades in the course. Our results, obtained in a community college context, support a growing body of evidence that social anxiety and academic self-efficacy are linked with how students perceive and perform in an active-learning environment.

Mandatory reporting legislation in Canada: improving systems for patient safety?

Patient safety is a complex systems issue. In this study, we used a scoping review of peer-reviewed literature and a case study of provincial and territorial legislation in Canada to explore the influence of mandatory reporting legislation on patient safety outcomes in hospital settings. We drew from a conceptual model that examines the components of mandatory reporting legislation that must be in place as a part of a systems governance approach to patient safety and used this model to frame our results. Our results suggest that mandatory reporting legislation across Canada is generally designed to gather information about - rather than respond to and prevent - patient safety incidents. Overall, we found limited evidence of impact of mandatory reporting legislation on patient safety outcomes. Although legislation is one lever among many to improve patient safety outcomes, there are nonetheless several considerations for patient safety legislation to assist in broader system improvement efforts in Canada and elsewhere. Legislative frameworks may be enhanced by strengthening learning systems, accountability mechanisms and patient safety culture.

Balloon Eustachian tuboplasty treatment of longstanding Eustachian tube dysfunction.

BACKGROUND: Eustachian tube dysfunction is a poorly defined condition associated with various symptoms and it can predispose to middle-ear disease. Balloon dilation Eustachian tuboplasty has been proposed as a treatment for Eustachian tube dysfunction. OBJECTIVE: To evaluate the subjective and objective outcomes of balloon dilation Eustachian tuboplasty in patients with recurrent, previously treated chronic Eustachian tube dysfunction. METHODS: The study was conducted on 11 patients (13 ears) who had undergone previous unsuccessful medical and surgical treatment. Tympanometry was the primary outcome measure. Secondary outcome measures included pure tone audiogram assessment and seven-item Eustachian Tube Dysfunction Questionnaire score. RESULTS: Balloon dilation Eustachian tuboplasty resulted in significant improvements in 11 patients' subjective but not objective outcome measures. CONCLUSION: The objective abnormality and subjective symptoms in Eustachian tube dysfunction may represent two distinct pathological processes, which may nevertheless influence and exacerbate each other.

High grade angiosarcoma fifteen years after breast conservation therapy with radiation therapy: A case report.

INTRODUCTION: Angiosarcoma is a rare tumor of the breast. Secondary angiosarcoma of the breast refers specifically to a tumor that arises after a latency period following radiation. With breast conservation therapy gaining significant popularity to that of mastectomy, more cases of secondary angiosarcoma continue to arise in the irradiated fields of these patients. PRESENTATION OF CASE: The authors describe the case of an 80 year old female who presented fifteen years after her surgery and radiation treatment with two bleeding skin lesions in her breast. These lesions were found to be high grade angiosarcoma upon excision. Due to high cardiac co-morbidity she was treated with re-excision and surveillance. DISCUSSION: This case is an example of a rare sequela to a common procedure. Breast conservation therapy with lumpectomy and radiation has become a popular technique in treating localized breast cancer. Radiation like all therapy has its known adverse effects. Further work is needed with the small amount of published cases of angiosarcoma after breast irradiation so that we may find optimal treatment plans for these patients. Like any rare entity, difficulty lies in accruing enough cases to compare prognosis and results. CONCLUSION: Secondary breast angiosarcoma diagnosis requires frequent follow ups and a high index of suspicion. With mastectomy giving the best chance of treatment in these cases, early detection is crucial in this rare sequela.

Lymphoma presenting as neck lumps: causes of waiting time target breaches and potential solutions.

OBJECTIVES: This study aimed to assess the speed of referral, diagnosis and treatment of patients with lymphoma presenting with a neck lump, and to identify where delays are occurring that prevent UK national targets from being met. METHOD: The study entailed a retrospective survey of patients presenting with a neck lump secondary to lymphoma between 2006 and 2008 in Gloucestershire, UK. RESULTS: Forty-seven of 54 patients (87 per cent) were seen within 2 weeks of referral. However, the 62-day rule, which covers the time from referral to the initiation of treatment, was met in only 32 of the 54 cases (59 per cent). There were no breaches of the 31-day target, which concerned the time from decision to treat to the initiation of treatment. Subsequent target breaches were due to longer waiting times for radiological and pathological investigations. CONCLUSION: Radiological examinations should be ordered at the first consultation and biopsies performed as soon as possible. Establishing one-stop, rapid access clinics should improve the achievement of a maximum 62-day wait for patients with lymphoma presenting with neck lumps.

Flexibility within the middle ears of vertebrates.

INTRODUCTION AND AIMS: Tympanic middle ears have evolved multiple times independently among vertebrates, and share common features. We review flexibility within tympanic middle ears and consider its physiological and clinical implications. COMPARATIVE ANATOMY: The chain of conducting elements is flexible: even the 'single ossicle' ears of most non-mammalian tetrapods are functionally 'double ossicle' ears due to mobile articulations between the stapes and extrastapes; there may also be bending within individual elements. SIMPLE MODELS: Simple models suggest that flexibility will generally reduce the transmission of sound energy through the middle ear, although in certain theoretical situations flexibility within or between conducting elements might improve transmission. The most obvious role of middle-ear flexibility is to protect the inner ear from high-amplitude displacements. CLINICAL IMPLICATIONS: Inter-ossicular joint dysfunction is associated with a number of pathologies in humans. We examine attempts to improve prosthesis design by incorporating flexible components.

A case of paraganglioma of the hypoglossal nerve.

INTRODUCTION: Paragangliomas are rare tumours arising from the paraganglia of the autonomic nervous system. CASE REPORT: We present a case of a paraganglioma arising from the hypoglossal nerve and producing an unusual clinical picture at presentation. DISCUSSION: We supply radiological evidence of a paraganglioma originating from the hypoglossal nerve, and thus extend the evidence base for this rare site of origin. Our patient presented as an emergency with long tract neurological symptoms and progressive brainstem involvement. This presentation is not characteristic of paragangliomas in general, which usually have an indolent growth pattern and often demonstrate benign symptoms for a number of years prior to diagnosis. The location of a hypoglossal paraganglioma differs significantly from more common paragangliomas described in the neck and skull base, and this should inform the surgical approach undertaken.

Short waitlist time does not adversely impact outcome following liver transplantation for hepatocellular carcinoma.

It has been suggested that patients with hepatocellular carcinoma (HCC) undergoing living donor liver transplantation (LDLT) have worse recurrence-free survival compared to deceased donor liver transplantation (CLT), leading to the hypothesis that short waitlist time or fast-tracking may include more aggressive tumors that would have been selected out by traditionally longer waitlist time. The primary aim of the present study was to evaluate the impact of waitlist time on HCC recurrence. The study cohort included 100 patients meeting T2 criteria by imaging before undergoing CLT (n = 90) or LDLT (n = 10). The 5-year recurrence-free probability was 89.9% for the entire cohort, and 91.9%, 90.5% and 86.6%, respectively, for waitlist time of 3 months or less, 3-6 months and > 6 months (p = 0.81). In the Cox proportional hazards model, waitlist time was also not a significant predictor of HCC recurrence. Tumor under-staging was observed in 20.5% of patients with waitlist time 3 months or less and 23.0% for waitlist time > 3 months (p = 0.81). In conclusion, our results failed to show an association between waitlist time and outcome after CLT or LDLT for HCC, and provided evidence disputing a significant role of waitlist time in the selection against HCC with unfavorable tumor biology.

Automated PCR setup for forensic casework samples using the Normalization Wizard and PCR Setup robotic methods.

Human genome, pharmaceutical and research laboratories have long enjoyed the application of robotics to performing repetitive laboratory tasks. However, the utilization of robotics in forensic laboratories for processing casework samples is relatively new and poses particular challenges. Since the quantity and quality (a mixture versus a single source sample, the level of degradation, the presence of PCR inhibitors) of the DNA contained within a casework sample is unknown, particular attention must be paid to procedural susceptibility to contamination, as well as DNA yield, especially as it pertains to samples with little biological material. The Virginia Department of Forensic Science (VDFS) has successfully automated forensic casework DNA extraction utilizing the DNA IQ(trade mark) System in conjunction with the Biomek 2000 Automation Workstation. Human DNA quantitation is also performed in a near complete automated fashion utilizing the AluQuant Human DNA Quantitation System and the Biomek 2000 Automation Workstation. Recently, the PCR setup for casework samples has been automated, employing the Biomek 2000 Automation Workstation and Normalization Wizard, Genetic Identity version, which utilizes the quantitation data, imported into the software, to create a customized automated method for DNA dilution, unique to that plate of DNA samples. The PCR Setup software method, used in conjunction with the Normalization Wizard method and written for the Biomek 2000, functions to mix the diluted DNA samples, transfer the PCR master mix, and transfer the diluted DNA samples to PCR amplification tubes. Once the process is complete, the DNA extracts, still on the deck of the robot in PCR amplification strip tubes, are transferred to pre-labeled 1.5 mL tubes for long-term storage using an automated method. The automation of these steps in the process of forensic DNA casework analysis has been accomplished by performing extensive optimization, validation and testing of the software methods.

Subacute airway obstruction from a tracheal mucosal flap.

We report the case of a 15-year-old girl with a near fatal obstructive tracheal lesion following tracheal intubation. The patient developed stridor and acute respiratory distress 29 h following tracheal extubation, after 35 h intubation in the intensive care unit. The failure of conventional management of stridor, including re-intubation, to provide a satisfactory airway prompted an urgent bronchoscopy, which revealed a tracheal mucosal flap causing 80% obstruction of the subglottic trachea. The fibreoptic bronchoscope allowed careful placement of a tracheal tube distal to the obstruction. The patient eventually made a full recovery. The low incidence of similar lesions and the lack of distinguishing clinical features from other causes of post-extubation stridor make diagnosis and appropriate management of this life-threatening condition difficult. We discuss how early consideration of the diagnosis and optimal initial management reduce the risk of an adverse outcome.

Vaccination against hepatitis B infection in patients with end stage renal disease.

BACKGROUND: Experience of hepatitis B vaccination in a contemporary renal replacement programme is reported. METHODS: A total of 406 patients were involved: 214 on haemodialysis, 97 on continuous ambulatory peritoneal dialysis, 67 predialysis (serum creatinine >400 micromol/l), and 28 with a failing transplant. Primary vaccination comprised recombinant hepatitis B vaccine (Engerix B) 40 microg intramuscularly at 0, 1, 2, and 3 months. Booster doses were administered three monthly if anti-HBs titre was <100 IU/l. RESULTS: Uptake of vaccine was 61% (haemodialysis 70%, continuous ambulatory peritoneal dialysis 62%, predialysis 31%, transplant 61%, p<0.0001). Primary seroconversion occurred in 64% of vaccinated patients (anti-HBs; 10-100 U/l, 33%; >100 U/l, 31%). Booster doses led to further improvement in immunity in 66/115 (57%) patients after a first and 8/20 (40%) patients after a second booster dose, but uptake was again poor (first booster 74%, second 31%). Seroprotection declined unexpectedly rapidly; after a mean of 16 months 71/115 patients (62 %) had a significant fall in their anti-HBs titres; 30/115 (26%) lost detectable antibody. CONCLUSIONS: Routine hepatitis B vaccination of patients with end stage renal failure is logistically difficult to administer on a large scale; primary seroconversion is relatively poor, but improves after repeated booster doses; protective anti-HBs titres decline rapidly, and yearly antibody checks with selective booster doses will be required to maintain seroprotection. The cost effectiveness of a vaccination programme will vary greatly depending on the prevalence of hepatitis B in the population at risk.

MMP-TIMP interaction depends on residue 2 in TIMP-4.

Extracellular matrix remodeling and degradation are of great importance in both physiological and pathological situations. Matrix metalloproteinases (MMPs) and their natural occurring inhibitors - tissue inhibitors of metalloproteinases (TIMPs) - are involved in matrix turnover. Among the TIMPs there is only little specificity for inhibiting individual MMPs. In this report we describe the mutational analysis of the interaction of human TIMP-4 with several MMPs. The effects of different substitutions of residue 2 (Ser(2)) in the inhibitory domain of TIMP-4 were determined by kinetic measurements. Size, charge and polarity of residue 2 in the TIMP structure are key factors in MMP inhibition.

Characterization of C-terminally truncated human tissue inhibitor of metalloproteinases-4 expressed in Pichia pastoris.

The tight regulation of extracellular matrix remodeling and degradation is of great importance in physiological processes like development and morphogenesis, as well as in pathological situations like tumor invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) are the naturally occuring inhibitors of matrix metalloproteinases, which are involved in matrix turnover. In this report we describe the cloning of human TIMP-4 from a human adenocarcinoma and an osteosarcoma cell line and the expression of the inhibitory domain in the methylotrophic yeast Pichia pastoris. The inhibition of MMP-8, -9, -12, -13 and -14 by the N-terminal domain of TIMP-4 was analysed. Using a fluorescent MCA-peptide, Ki values for each subclass of MMPs were determined. With dissociation constants in the nanomolar range, TIMP-4 seems to be a good inhibitor for all classes of MMPs without remarkable preference for special MMPs.

Direct interactions between immunocytes and neurons after axotomy in Aplysia.

Axon growth during development and after injury has processes in common, but also differs in that regeneration requires the participation of cells of the immune system. To investigate how neuron-immunocyte interactions might influence regeneration, we developed an in vitro model whereby neurons and hemocytes from Aplysia californica were cocultured. The hemocytes, which behave like vertebrate macrophages, migrated randomly throughout the dish. When a neuron was encountered, some hemocytes exhibited an avoidance response, whereas others formed stable contacts. Hemocytes did not distinguish between neurons from different animals. Stable contacts occurred on neurites and growth cones, but not the cell soma, and were benign in that the hemocytes did not impede neurite growth. When hemocytes attached to the cell body, it presaged the destruction of the neuron. Destruction was a dynamic process that was initiated when groups of one to three hemocytes adhered to various regions of the cell soma. Each group was then joined by other hemocytes. They did not contact the neuron, but interconnected the initial groups, forming a network around the neuron. The network then contracted to dismember the cell. Once a neuron was destroyed, hemocytes removed the debris by phagocytosis. Both damaged neurons and those without apparent damage were targets for destruction. Severing neurites with a needle resulted in the destruction of only one of six cells. Our studies suggest that hemocytes, and by extrapolation, vertebrate macrophages, exhibit highly complex interactions with neurons that can exert a variety of influences on the course of nerve regeneration.

Pregnancy-associated plasma protein-E (PAPP-E).

A full-length cDNA encoding a novel human protein was cloned from placenta cDNA. The corresponding 1542 amino acid protein sequence was termed 'pregnancy-associated plasma protein-E' (PAPP-E) as it shows a 62% homology to the human pregnancy-associated plasma protein-A (PAPP-A) that is a diagnostic marker for trisomies, especially Down syndrome. The conserved domain structure contains five motifs related to the short consensus repeats of complement proteins and selectins, three motifs related to the lin-notch motifs of proteins regulating early tissue differentiation, and a putative zinc-binding motif and active site of the metzincin-superfamily of metalloproteases. The PAPP-E gene was localized to chromosome 1q23-25. Northern blot analysis showed that PAPP-E is predominantly expressed in placenta.

Randomized prospective comparison of laparoscopic and open peritoneal dialysis catheter insertion.

OBJECTIVE: To compare laparoscopic and conventional peritoneal dialysis catheter insertion with respect to post operative discomfort, complication rates, and catheter survival. DESIGN: Randomized prospective study. SETTING: Tertiary referral renal unit. PATIENTS: Fifty patients commencing peritoneal dialysis. INTERVENTION: Catheters were implanted laparoscopically or by a conventional surgical technique. MAIN OUTCOME MEASURES: The duration of surgery, hospital stay, pain scores, and analgesic requirements were recorded. Complications (early/late) and catheter survival were compared. RESULTS: The conventional procedure was faster than the laparoscopic (14.3 vs 21.9 minutes, p < 0.0001). There was no difference in any other parameter assessed. CONCLUSIONS: The data suggest that the insertion techniques are equivalent, and that laparoscopic insertion does not reduce early complication rates.

Inflammation causes a long-term hyperexcitability in the nociceptive sensory neurons of Aplysia.

Nerve injury, tissue damage, and inflammation all cause hyperalgesia. A factor contributing to this increased sensitivity is a long-term (>24 hr) hyperexcitability (LTH) in the sensory neurons that mediate the responses. Using the cluster of nociceptive sensory neurons in Aplysia californica as a model, we are examining how inflammation induces LTH. A general inflammatory response was induced by inserting a gauze pad into the animal Within 4 days, the gauze is enmeshed in an amorphous material that contains hemocytes, which comprise a cellular immune system. Concurrently, LTH appears in both ipsilateral and contralateral sensory neurons. The LTH is manifest as increased action potential discharge to a normalized stimulus. Immunocytochemistry revealed that hemocytes have antigens recognized by antibodies to TGFbeta1, IL-6, and 5HT. When a localized inflammation was elicited on a nerve, hemocytes containing the TGFbeta1 antigen were present near axons within the nerve and those containing the IL-6 were on the surface. Western blots of hemocytes, or of gauze that had induced a foreign body response, contained a 28-kD polypeptide recognized by the anti-TGFbeta1 antibody. Exposure of the nervous system to recombinant human TGFbeta1 elicited increased firing of the nociceptive neurons and a decrease in threshold. The TGFbeta1 also caused an activation of protein kinase C (PKC) in axons but did not affect a kinase that is activated in axons after injury. Our findings, in conjunction with previous results, indicate that a TGFbeta1-homolog can modulate the activity of neurons that respond to noxious stimuli. This system could also contribute to interactions between the immune and nervous systems via regulation of PKC.