Four-factor Prothrombin Complex Concentrate During Liver Transplantation: A Retrospective Cohort Study.

Background: Four-factor prothrombin complex concentrate (PCC) is a plasma product that contains factors II, VII, IX, X, protein C, and protein S. PCC can be used off-label to treat coagulopathy during orthotopic liver transplantation (OLT). However, its use comes with safety concerns regarding thrombosis. The purpose of our study is to determine the safety of PCC in OLT. Methods: We conducted a retrospective cohort study of patients who received 4-factor PCC during OLT at our institution from January 1, 2018, to May 1, 2022, with a 1:1 match of 83 patients who received PCC and 83 patients who did not. We evaluated 30-d mortality, 1-y mortality, prevalence of thrombotic complications (portal vein thrombosis, deep venous thrombosis, myocardial infarction, and pulmonary embolus), and postoperative intensive care (ICU) length of stay (LOS). Results: There was no significant difference in 30-d mortality (odds ratio [OR] 5; 95% confidence interval [CI], 0.58-42.8; P = 0.14), 1-y mortality (OR 3; 95% CI, 0.61-14.86; P = 0.18), or ICU LOS (OR -13.8; 95% CI, -39.2 to 11.6; P = 0.29). There was no increased incidence of thrombotic complications among patients receiving PCC 90 d after surgery, including portal vein thrombosis (OR 1.5; 95% CI, 0.42-5.32; P = 0.53), pulmonary embolus (OR 1; 95% CI, 0.14-7.1; P = 0.99), deep venous thrombosis (OR 0.67; 95% CI, 0.11-3.99; P = 0.66), and myocardial infarction (OR 1.67; 95% CI, 0.4-6.97; P = 0.48). Conclusions: Although there was a statistically insignificant increase in mortality after PCC administration during OLT, we did not see a significant increase in perioperative complications, including thrombotic events and increased ICU LOS.

Sensitivity of the Social Behavior Observer Checklist to Early Symptoms of Patients With Frontotemporal Dementia.

BACKGROUND AND OBJECTIVES: Changes in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes. METHODS: Asymptomatic individuals and neurodegenerative disease patients were selected from the multisite ALLFTD cohort study. In a sample of participants with at least one timepoint of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy. RESULTS: 1082 FTLD mutation carriers and non-carriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 non-fluent variant primary progressive aphasia, 137 progressive supranuclear palsy, 113 Alzheimer's clinical syndrome). The Disorganized score increased between asymptomatic to very mild (p=0.016, estimate=-1.10, 95%CI=[-1.99, -0.22]), very mild to mild (p=0.013, -1.17, [-2.08, -0.26]), and mild to moderate/severe (p<0.001, -2.00, [-2.55, -1.45]) disease stages in behavioral variant frontotemporal dementia regardless of mutation status. Asymptomatic GRN pathogenic gene variant carriers showed more Reactive behaviors (preoccupation with time: p=0.001, 1.11, [1.06, 1.16]; self-consciousness: p=0.003, 1.77, [1.52, 2.01]) than asymptomatic non-carriers (1.01, [0.98, 1.03]; 1.31, [1.20, 1.41]). Insensitive score increased to a clinically abnormal level in advanced stages of behavioral variant frontotemporal dementia (p=0.003, -0.73, [-1.18, -0.29]). Higher scores on each subscale corresponded with higher caregiver burden (p<0.001). Greater change over time corresponded to greater fronto-subcortical atrophy in the semantic-appraisal and fronto-parietal intrinsically connected networks. DISCUSSION: The SBOCL is sensitive to early symptoms and reflects disease severity, with some evidence for progression across asymptomatic and symptomatic stages of FTLD syndromes; thus it may hold promise for early measurement and monitoring of behavioral symptoms in clinical practice and treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the Social Behavior Observer Checklist is sensitive to early behavioral changes in FTLD pathogenic variants and early symptomatic individuals in a highly educated patient cohort.

Experiences of Pain in Hospitalized Children During Hematopoietic Stem Cell Transplantation Therapy.

Children undergoing hematopoietic stem cell transplantation (HSCT) are vulnerable to pain due to the intensity and toxicity of this treatment. An instrumental case study design of two qualitative phases was conducted to examine the pain experiences of hospitalized children during HSCT therapy and how contextual factors related to the pediatric HSCT environment influenced their experience of pain. The Social Communication Model of Pain provided the conceptual framework for the study. In Phase 1, semi-structured interviews were conducted with parents of a child undergoing HSCT therapy at two time points. Phase 2 was conducted as a naturalistic observational study of the clinical care provided to children and semi-structured interviews with health-care providers. Children experienced complex and multifaceted pain with physical, psychological, and contextual contributors. Understanding the many factors contributing to the child's pain experience can inform strategies to improve the management of pain during HSCT therapy.

A practical and ethical toolkit for last-minute refusal of anesthetic in children.

Children's fear of a procedure, including the anesthetic, is a common issue that operating theatre staff face. This fear is generally mitigated by preesthetic preparation and information sharing. Last-minute refusal of a procedure creates unique difficulties for the anesthetist and proceduralist. Refusal for a procedure raises issues of whether the dissent is binding, and if not, how best to get the child to theatre without creating moral injury. In this case review of a young adolescent who refuses to go to the operating theatre, we explore practical and ethical options to resolve the situation. We discuss respect for persons (including assent and consent), best interests, truth-telling, harm minimization, and restraint. The importance of a postevent debrief is discussed. We also assess the value of a clinical ethics service with team members embedded in clinical teams.

A custom, functional and lifelike passive prosthetic hand for infants and small toddlers: Clinical note.

BACKGROUND AND AIM: For infants and small toddlers with congenital upper limb deficiencies, terminal devices mainly provide either cosmesis or functionality. We report a clinical note about fitting a child with a low-cost passive hand targeting both functionality and cosmesis. TECHNIQUE: An elastomeric, alloy-wire-reinforced hand was fabricated using additive manufacturing to allow independent positioning of the digits. A clinical pilot in-home evaluation was conducted on a child with upper limb loss. DISCUSSION: The fabricated hand met the functional requirements but required a cover for cosmesis due to a poor surface finish associated with the fabrication technique. The participant child was comfortable using the prosthesis for various tasks. The parents were satisfied with the hand's function and cosmesis when covered with a cosmetic glove. This work demonstrated a new design and process that may in the future improve the utilization of prosthetic hands to promote early prosthesis use and a child's development. CLINICAL RELEVANCE: Early prosthesis use is important for infants and toddlers. Additive manufacturing may enable the fabrication of custom passive prosthetic hands that provide both cosmesis and functionality.

Identification of barriers and enablers to rapid diagnosis along the paediatric stroke chain of recovery using Value-Focused Process Engineering.

Coordinated systems of care are required to improve access to reperfusion therapies in paediatric stroke. A conceptual model was developed to map the process-of-care from symptom onset to confirmation of diagnosis. Value-Focused Process Engineering with event-driven process modelling was used to identify barriers and enablers to timely and accurate paediatric stroke diagnosis. Stakeholder interviews were conducted to inform model design, development, demonstration and validation. Barriers included: (i) ambulance dispatcher failure to allocate high-priority response, (ii) childrens' exclusion from paramedic clinical practice guidelines, (ii) non-allocation of high triage category on hospital arrival, (iii) absence of emergency department guidelines for focal neurological deficits, and (iv) computed tomography as the first imaging investigation. Enablers included: (i) public awareness programs, (ii) childrens' inclusion in prehospital emergency stroke algorithms, (iii) re-organisation of health services, with primary paediatric stroke centres, (iv) implementation of triage and neuroimaging decision support tools, and (iv) rapid stroke MRI imaging protocols.

Remarkable Stability of Myelinating Oligodendrocytes in Mice.

New myelin-forming oligodendrocytes (OLs) are generated in the mouse central nervous system during adulthood. These adult-born OLs might augment the existing population, contributing to neural plasticity, or else replace OLs that die in use (turnover). To distinguish between these alternatives, we induced genetic labeling of mature myelinating OLs in young adult mice and tracked their subsequent survival. OL survival rates were region dependent, being higher in corpus callosum (∼90% survival over 20 months) and motor cortex (∼70% survival) than in corticospinal tract or optic nerve (50%-60% survival). Survival rates over the first 8 months were 90%-100% in all regions except the optic nerve. In the corpus callosum, new OLs accumulate during young adulthood and are therefore likely to participate in adaptive myelination. We also found that the number of myelin internodes maintained by individual cortical OLs is stable for at least 8 months but declines ∼12% in the following year.

Pain assessment and management in paediatric oncology: a cross-sectional audit.

AIMS AND OBJECTIVES: To describe the pain assessment and management practices documented by health professionals within a tertiary-level Children's Cancer Centre and to evaluate how these practices were compared with international recommendations. BACKGROUND: Children with cancer are vulnerable to pain due to the intensity of antineoplastic therapy. Therefore, it is imperative to ensure that current pain management practices provided to paediatric oncology inpatients are of a high quality. DESIGN: A single-site cross-sectional audit. METHODS: A 24-hour period of documented pain-related care in randomly selected inpatients of an Australian tertiary-level Children's Cancer Centre was examined. The current pain management practices were audited over a two-month period resulting in 258 episodes of pain-related care being reviewed. RESULTS: Pain related to medical treatment for cancer was common (n = 146/258, 57%) and persistent. The presence of pain was not consistently recorded by health professionals (n = 75/146, 51%). Pain was mild (n = 26/75, 35%) and opioids were the mainstay of pain management interventions (n = 63/112, 56%). Adjuvants were an important component of pain management (n = 47/112, 42%), and nonpharmacological methods of managing pain were under-represented in this audit (n = 38/146, 26%). According to the Pain Management Index, pain was appropriately managed for the majority of children (n = 65/76, 87%). CONCLUSIONS: Pain management practices did not fully reflect the recommendations of contemporary paediatric pain management. Due to limitations in the documentation of children's pain, it was difficult to determine the effectiveness of pain management interventions. RELEVANCE TO CLINICAL PRACTICE: This study highlights the ongoing problem of pain for children receiving antineoplastic therapy. It is recommended that health professionals routinely screen for the presence of pain during hospitalisation and assess the efficacy of pain-related care.

Cellular Mucins: Targets for Immunotherapy.

Mucins are attracting great interest as potential targets for immunotherapy in the development of vaccines for cancers expressing Mucinl (MUC1) (e.g., breast, pancreas, ovary, and others) as there is (1) a 10-fold increase in the amount in adenocarcinomas; (2) an alteration in expression where they become ubiquitous, and (3) due to altered glycosylation, new epitopes appear on the cell surface that are absent in normal tissues. These new epitopes can be carbohydrate; others are peptide in nature. The cloning of the cDNAs from mucins, particularly MUC1, has led to rapid advances being made, and it is clear that a highly immunogenic peptide exists within the variable number of tandem repeats (VNTR) found in all mucins. This peptide is immunogenic in mice, giving rise to strong antibody production, and most monoclonal antibodies made to breast cancer, which react with the protein core, react with the peptide APDTR. It is now also clear that humans with breast cancer have, in their draining lymph nodes, precursors of cytotoxic T cells that can be stimulated in vitro to react against breast cancer and indeed against the APDTR or a closely related peptide - shown from antibody-blocking studies. These CTLs are unique in that they are non-MHC restricted. The identification of suitable targets, coupled with the known immunogenicity of both the peptide and neo-carbohydrate epitopes, has led to the development of several different programs to immunize humans against breast cancer using either synthetic carbohydrates or peptides conjugated with adjuvants, and clinical trials are now in progress to evaluate their immunogenicity and anti-cancer effects.

MUC1 immunotherapy against a metastatic mammary adenocarcinoma model: Importance of IFN-gamma.

Immunotherapy using mucin 1 (MUC1) linked to oxidised mannan (MFP) was investigated in an aggressive MUC1+ metastatic tumour, DA3-MUC1 because, unlike many MUC1+ tumour models, DA3-MUC1 is not spontaneously rejected in mice making it an alternative model for immunotherapy studies. Further, DA3-MUC1 cells are resistant to lysis by anti-MUC1 cytotoxic T cells (CTLs). The inability of DA3-MUC1 tumours to be rejected in naïve mice as well as vaccination to MUC1 was attributed to a deficiency of expression of MHC class I molecules on the tumour cell surface. In vitro and in vivo analysis of subcutaneous tumours and lung metastases demonstrated that DA3-MUC1 tumour cells have a low expression (< 6%) of MHC class I which can be upregulated (> 90%) following culturing with IFN-γ. Results from flow cytometry analysis and immunoperoxidase staining indicated that the in vitro up-regulation of MHC class I could be maintained for up to seven days in vivo, without affecting the expression levels of MUC1 antigen. Interestingly, MUC1-specific CTL that lyse DA3-MUC1 targets in vitro were induced in MFP immunised mice but failed to protect mice from a DA3-MUC1 tumour challenge. These results highlight the importance of MHC class I molecules in the induction of anti-tumour immunity and the MFP immune response.

Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning.

We identified mRNA encoding the ecto-enzyme Enpp6 as a marker of newly forming oligodendrocytes, and used Enpp6 in situ hybridization to track oligodendrocyte differentiation in adult mice as they learned a motor skill (running on a wheel with unevenly spaced rungs). Within just 2.5 h of exposure to the complex wheel, production of Enpp6-expressing immature oligodendrocytes was accelerated in subcortical white matter; within 4 h, it was accelerated in motor cortex. Conditional deletion of myelin regulatory factor (Myrf) in oligodendrocyte precursors blocked formation of new Enpp6(+) oligodendrocytes and impaired learning within the same ∼2-3 h time frame. This very early requirement for oligodendrocytes suggests a direct and active role in learning, closely linked to synaptic strengthening. Running performance of normal mice continued to improve over the following week accompanied by secondary waves of oligodendrocyte precursor proliferation and differentiation. We concluded that new oligodendrocytes contribute to both early and late stages of motor skill learning.

Pre-Existing Mature Oligodendrocytes Do Not Contribute to Remyelination following Toxin-Induced Spinal Cord Demyelination.

Remyelination is the regenerative response to demyelination. Although the oligodendrocyte progenitor is established as the major source of remyelinating cells, there is no conclusive evidence on whether mature, differentiated oligodendrocytes can also contribute to remyelination. Using two different inducible myelin-CreER mouse strains in which mature oligodendrocytes were prelabeled by the expression of membrane-bound Green fluorescent protein, we found that after focal spinal cord demyelination, the surrounding surviving labeled oligodendrocytes did not proliferate but remained at a consistent density. Furthermore, existing (prelabeled) oligodendrocytes showed no evidence of incorporation or migration into the lesioned area, or of process extension from the peripheral margins into the lesion. Thus, mature oligodendrocytes do not normally contribute to remyelination and are therefore not a promising target for regenerative therapy.

Dendritic cell immunotherapy: clinical outcomes.

The use of tumour-associated antigens for cancer immunotherapy studies is exacerbated by tolerance to these self-antigens. Tolerance may be broken by using ex vivo monocyte-derived dendritic cells (DCs) pulsed with self-antigens. Targeting tumour-associated antigens directly to DCs in vivo is an alternative and simpler strategy. The identification of cell surface receptors on DCs, and targeting antigens to DC receptors, has become a popular approach for inducing effective immune responses against cancer antigens. Many years ago, we demonstrated that targeting the mannose receptor on macrophages using the carbohydrate mannan to DCs led to appropriate immune responses and tumour protection in animal models. We conducted Phase I, I/II and II, clinical trials demonstrating the effectiveness of oxidised mannan-MUC1 in patients with adenocarcinomas. Here we summarise DC targeting approaches and their efficacy in human clinical trials.

Motor skill learning requires active central myelination.

Myelin-forming oligodendrocytes (OLs) are formed continuously in the healthy adult brain. In this work, we study the function of these late-forming cells and the myelin they produce. Learning a new motor skill (such as juggling) alters the structure of the brain's white matter, which contains many OLs, suggesting that late-born OLs might contribute to motor learning. Consistent with this idea, we show that production of newly formed OLs is briefly accelerated in mice that learn a new skill (running on a "complex wheel" with irregularly spaced rungs). By genetically manipulating the transcription factor myelin regulatory factor in OL precursors, we blocked production of new OLs during adulthood without affecting preexisting OLs or myelin. This prevented the mice from mastering the complex wheel. Thus, generation of new OLs and myelin is important for learning motor skills.

A phase 2, single-arm study of an autologous dendritic cell treatment against mucin 1 in patients with advanced epithelial ovarian cancer.

BACKGROUND: Mucin 1 antigen, highly expressed by epithelial ovarian cancer (EOC), is a potential target for immunotherapy. A previous successful phase 1 trial was conducted in patients with adenocarcinoma who were injected with Cvac, autologous monocyte-derived dendritic cells (DCs) incubated with mannosylated mucin 1 protein (M-FP). The present study was a phase 2 trial of Cvac in patients with advanced EOC. METHODS: Eligible patients had EOC with progressive disease, defined as an increase in CA125 of ≥ 25% in 1 month. The primary endpoint was CA125 response or stabilization. Peripheral blood mononuclear cells were collected by leukapheresis and cultured to generate DCs. The DC were incubated with M-FP, and after washing were prepared for injection into the patient intradermally every 4 weeks for 3 doses, then every 10 weeks for up to 12 months. RESULTS: All 28 patients recruited were evaluable for safety and 26 for efficacy. All had undergone surgery and platinum-based chemotherapy, and 57% of patients received ≥ 3 chemotherapy regimens. There were no Grade 3 or 4 toxicities considered related to Cvac. Four patients showed CA125 response or stabilization (2 patients with major responses, 1 minor response, 1 stabilization) of median duration 10.3 months (5.3-16.3 months). An additional patient had > 25% CA125 reduction (not confirmed). CONCLUSIONS: Cvac immunotherapy was well tolerated. Clinical activity in EOC was evident based on decline or stabilization of CA125 in some patients, supporting ongoing development of Cvac in ovarian carcinoma and planning of additional trials of patients in remission is currently underway.

Up to 15-year clinical follow-up of a pilot Phase III immunotherapy study in stage II breast cancer patients using oxidized mannan-MUC1.

BACKGROUND: Targeting antigens to dendritic cell receptors has recently become a popular approach to inducing effective immune responses against cancer antigens. Almost 20 years ago, however, we demonstrated that targeting the mannose receptor on macrophages and dendritic cells leads to strong cellular immune responses. We conducted numerous human clinical trials demonstrating the effectiveness of oxidized mannan-MUC1 (M-FP) in MUC1(+) adenocarcinoma patients. In one trial, the 5-8-year follow-up of breast cancer patients vaccinated with M-FP was published previously; we now report here the 12-15-year follow-up. Details regarding the preparation of the vaccine, inclusion and exclusion criteria, immunotherapy and follow-up schedule, were published previously. RESULTS: The follow-up at 12-15 years showed that the recurrence rate in patients receiving placebo was 60% (nine of 15). In those receiving immunotherapy (M-FP), the rate was 12.5% (two of 16). The time of recurrence in the placebo group ranged from 7 to 180 months (mean: 65.8 months) and in the two patients of the vaccine group, the recurrence appeared at 95 and 141 months (mean: 118 months) after surgery. These findings are statistically significant (p = 0.02 for survival and p = 0.009 for percentage of patients cancer-free). All patients injected with M-FP showed no evidence of toxic effects or signs of autoimmunity during the 12-15-year follow-up. DISCUSSION: The preliminary evidence indicates that M-FP is beneficial in the overall survival of early-stage breast cancer patients. This long-term clinical follow-up of patients strongly supports the necessity for a large Phase III study of direct M-FP injection in early-stage breast cancer patients, to evaluate immunotherapy as an adjuvant treatment for breast cancer.

Remote ischemic preconditioning in cyanosed neonates undergoing cardiopulmonary bypass: a randomized controlled trial.

OBJECTIVE: The myocardial protective effect of remote ischemic preconditioning has been demonstrated in heterogeneous groups of patients undergoing cardiac surgery. No studies have examined this technique in neonates. The present study was performed to examine the remote ischemic preconditioning efficacy in this high-risk patient group. METHODS: A preliminary, randomized, controlled trial was conducted to investigate whether remote ischemic preconditioning in cyanosed neonates undergoing cardiac surgery confers protection against cardiopulmonary bypass. Two groups of neonates undergoing cardiac surgery were recruited for the present study: patients with transposition of the great arteries undergoing the arterial switch procedure and patients with hypoplastic left heart syndrome undergoing the Norwood procedure. The subjects were randomized to the remote ischemic preconditioning or sham control groups. Remote ischemic preconditioning was induced by four 5-minute cycles of lower limb ischemia and reperfusion using a blood pressure cuff. Troponin I and the biomarkers for renal and cerebral injury were measured pre- and postoperatively. RESULTS: A total of 39 neonates were recruited-20 with transposition of the great arteries and 19 with hypoplastic left heart syndrome. Of the 39 neonates, 20 were randomized to remote ischemic preconditioning and 19 to the sham control group. The baseline demographics appeared similar between the randomized groups. The cardiopulmonary bypass and crossclamp times were not significantly different between the 2 groups. The troponin I levels were not significantly different at 6 hours after cardiopulmonary bypass nor were the postoperative inotrope requirements. Markers of renal (neutrophil gelatinase-associated lipocalin) and cerebral injury (S100b, neuron-specific enolase) were not significantly different between the 2 groups. CONCLUSIONS: Our data suggest that remote ischemic preconditioning in hypoxic neonates undergoing cardiopulmonary bypass surgery does not provide myocardial, renal, or neuronal protection. Additional studies are needed to examine the relationships among developmental age, hypoxia, and the molecular mechanisms of ischemic preconditioning.

Testicular vasculitis - literature review and case report in queensland.

A 21-year-old male presented with acute onset, sharp right sided testicular pain. The testicle was removed with a histological diagnosis of testicular vasculitis. Anti-neutrophil cytoplasmic antibodies were negative. Although rare, males who present with acute onset pain should be screened for testicular vasculitis with a scrotal ultrasound and blood investigations including tumor markers and anti-neutrophil cytoplasmic antibodies.

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer.

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer.