Characterization of a canine freeze-dried platelet-derived hemostatic agent: A preclinical model for surgical and traumatic hemorrhage.

INTRODUCTION: A freeze-dried, platelet-derived hemostatic agent (FPH) was developed for acute hemorrhage. The canine product (cFPH) was developed for use in preclinical models supporting human product (hFPH) investigations. MATERIALS AND METHODS: A carotid artery bypass graft (CABG) study in dogs compared 3 dosages of cFPH to canine liquid stored platelets (cLSP) and vehicle (VEH) control groups. Histopathological analysis and blood loss assessments were completed. A separate ex-vivo synthetic graft study assessed thrombogenicity via blood from human and canine donors that was combined with species-specific FPH or apheresis platelets. Characterization of cFPH and hFPH included thrombin generation, total thrombus formation, and scanning electron microscopy. RESULTS: Blood loss was reduced in CABG dogs receiving standard of care (cLSP) or cFPH treatment compared to VEH control; a cFPH dose effect signal was observed. Further, cFPH dosing up to 5 × 109 cells/kg was not associated with increased mortality or occlusion of the anastomosis sites, and histopathologic evidence of off-target thrombosis was not detected. When passed through a synthetic graft (ex vivo), whole blood combined with species-specific FPH did not result in thrombosis beyond that of whole blood control. In vitro testing and imaging of cFPH and FPH were comparable. CONCLUSIONS: A single dose of cFPH or cLSP reduced blood loss in a pilot surgical study and was well tolerated with no related adverse events. Further, the hemostatic activity and characteristics of cFPH are comparable to that of hFPH, suggesting that research findings from the canine product are likely to inform the development of the human product.

Mechanisms of action of an investigational new freeze-dried platelet-derived hemostatic product.

BACKGROUND: A safe and efficacious hemostatic product with a long shelf-life is needed to reduce mortality from hemorrhage due to trauma and improve surgical outcomes for persons with platelet deficiency or dysfunction. Thrombosomes, a trehalose-stabilized, leukoreduced, pooled blood group-O freeze-dried platelet-derived hemostatic (FPH) with a 3-year shelf-life, may satisfy this need. OBJECTIVES: To characterize the mechanism of action of FPH. METHODS: FPH's ability to adhere to collagen, aggregate with and without platelets, and form clots was evaluated in vitro. Nonobese diabetic-severe combined immunodeficiency mouse models were used to assess circulation persistence and hemostatic efficacy. RESULTS: FPH displays the morphology and surface proteins of activated platelets. FPH adheres to collagen, aggregates, and promotes clots, producing an insoluble fibrin mesh. FPH is rapidly cleared from circulation, has hemostatic efficacy comparable to apheresis platelets in a murine tail-cut, and acts in a dose-dependent manner. CONCLUSION: FPH is a first-in-class investigational treatment and shows strong potential as a hemostatic agent that is capable of binding exposed collagen, coaggregating with endogenous platelets, and promoting the coagulation cascade. These properties may be exploited to treat active platelet-related or diffuse vascular bleeding. FPH has the potential to fulfill a large unmet patient need as an acute hemostatic treatment in severe bleeding, such as surgery and trauma.

Design of the Randomized Controlled Trial Comparing Dimethyl Sulfoxide Cryopreserved Platelets to Liquid Stored Platelets in Patients Undergoing Cardiopulmonary Bypass Surgery.

Objective: Dimethylsulfoxide-cryopreserved platelets are being evaluated for treatment of acute hemorrhage in patients with thrombocytopenia or platelet dysfunction when liquid stored platelets are unavailable. Patients undergoing cardiac surgery with cardiopulmonary bypass with risk factors for significant bleeding represent a population for which determining efficacy and safety of cryopreserved platelets is ideal in the clinical trial setting. The primary objective is to compare blood loss in cardiopulmonary bypass patients receiving cryopreserved platelets or liquid stored platelets. Methods: In patients undergoing cardiac surgery utilizing cardiopulmonary bypass, a standardized algorithm with transfusion triggers will be used to guide the intra- and postoperative administration of study platelets, either cryopreserved platelets or liquid stored platelets, based on the clinical presentation. The primary efficacy end point was the volume of blood loss from completion of chest closure (time 0) until the time chest tubes were removed or 24 hours after chest closure, whichever is earlier. Results: This design article describes an ongoing multicenter, randomized, blinded trial to evaluate noninferiority or superiority of cryopreserved platelets with liquid stored platelets in controlling blood loss in patients undergoing cardiopulmonary bypass surgery. Conclusions: Frozen storage could substantially safely extend the shelf life of stored platelets. If efficacy and safety were demonstrated in this trial, current constraints on platelet use in low resource military and civilian settings would be relieved.

Bedside Ultrasound in the Emergency Department Enables Rapid Diagnosis of PUJ Obstruction Syndrome.

Presentation A 27-year-old male presented to the Emergency Department with acute severe left flank pain following ingestion of 5 pints of beer. Approximately 20 bouts of similar episodes over the past year, in the setting of alcohol ingestion. Despite attending GP, no diagnosis reached yet. Diagnosis "Pelvo-ureteric junction (PUJ) obstruction Syndrome". Bedside ultrasound in the Emergency Department during the acute pain crisis: massive hydronephrosis left kidney. Finding confirmed on CT scan. Subsequent 99m-Tec renogram showed markedly decreased renal function on the left. Treatment Interval Pyeloplasty two months later. Conclusion Delayed recognition is the norm for PUJ obstruction syndrome, as CT/MRI/US studies often do not display hydronephrosis if the patient is asymptomatic. We could not find any reports in the literature of diagnosing PUJ obstruction syndrome using bedside ultrasound in the Emergency Department. We advise acquiring rapid bedside ultrasound imaging in suspected cases of PUJ obstruction syndrome, enabling earlier diagnosis.

Children with congenital colorectal malformations during the UK Sars-CoV-2 pandemic lockdown: an assessment of telemedicine and impact on health.

PURPOSE: This pilot study was designed to assess bowel function and quality of life (QoL) in children and adolescents with congenital colorectal malformations (CCM) during the first UK COVID lockdown period. METHODS: Changes in health were assessed through semi-structured interviews, gastrointestinal functional outcomes using Krickenbeck scoring and QoL by the modified disease-specific HAQL (Hirschsprung's disease anorectal malformation quality of life questionnaire). The State-Trait Anxiety Inventory (STAI)™ for adults was used to assess parental anxiety. RESULTS: Thirty-two families were interviewed; 19 (59%) reported no change in their child's health during the lockdown, 5 (16%) a deterioration and 8 (25%) an improvement. Neither the severity of the CCM, nor the degree of bowel dysfunction, correlated with any deterioration. The HAQL score was not correlated to a change in health. Anxiety scores ranged from no anxiety to clinical concerns. Telemedicine was well accepted by 28/32 parents (88%); however, in-person appointments were preferred if there were clinical concerns. CONCLUSION: In the follow-up of children and adolescents with CCM during the first UK lockdown using telemedicine we found that over half had stable health conditions. Patients needing additional care could not be predicted by the severity of their disease or their bowel function alone.

Inadvertent Antegrade Urethral Placement of a Suprapubic Catheter.

Presentation A 55-year-old male patient with neuropathic bladder secondary to multiple sclerosis (MS) presented to the EmergencyDepartment (ED) with abdominal pain and no output from his suprapubic catheter (SPC) that was changed 24 hourspreviously. Diagnosis On examination, the SPC-tip was clearly visible at the external urethral meatus. Treatment The patient was managed by gently deflating the anchoring balloon, exchanging the SPC and a period of observationto ensure adequate catheter drainage. Conclusion Important learning points from this case are to observe urine draining after routine SPC change and to examine thegenitalia when a misplaced SPC is suspected.

Novel platelet products under development for the treatment of thrombocytopenia or acute hemorrhage.

Controlling hemorrhage has been a focus of survival since man recognized that the loss of blood led to death. Papyri from 1600 BCE describe methods for hemorrhage control including; direct pressure, ligature and the use of sutures. Multiple studies have demonstrated the survival advantage of early transfusion of whole blood or red cells and plasma. The added survival impact of early transfusion of platelets was recently reported in a substudy of the prospective Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial. Early transfusion of platelets demonstrated a statistically significant survival benefit at 24 h and 30 days post-injury. [1] Platelet availability is limited due to the short shelf life (5-7 days) and storage requirements (room temperature with constant agitation). Providing platelets or platelet derived products for prehospital treatment and to rural and some urban hospitals is an unmet medical need. The interest in novel and alternative platelet products has grown over the past decade and the status of novel platelet products is presented herein. Development, approval, and distribution of hemostatically effective approved platelet products for prehospital use and routine stockage in rural and urban centers could significantly increase survival rates in bleeding patients.

A prolonged outbreak of invasive meningococcal disease in an extended Irish Traveller family across three Health Service Executive (HSE) areas in Ireland, 2010 to 2013.

Between March 2010 and November 2013 eight laboratory-confirmed cases of serogroup B, invasive meningococcal disease (IMD) were identified in an extended Irish Traveller family across three Health Service Executive (HSE) areas of Ireland. Cases were aged between 5 and 46 months, and were either a cousin or sibling of another case. All eight cases survived. Chemoprophylaxis was given to relevant nuclear family members and close contacts on each occasion, but failed to prevent further cases. Neisseria meningitidis isolates from six cases were highly related, belonging to the ST-41/44 clonal complex, and shared the porA designation 7­2,4. In November 2013, the outbreak control team recommended that directly observed ciprofloxacin chemoprophylaxis be administered simultaneously to the extended family, and that the four component meningococcal B (4CMenB) vaccine be administered to family members aged 2 months to 23 years inclusive and relevant close contacts of the eighth case. Subsequently these recommendations were implemented at three regional clinics. Additionally pharyngeal swabs (n=112) were collected to assess carriage rates of N. meningitidis in this extended family. Pharyngeal carriage of N. meningitidis was detected in 15 (13%) family members. From the epidemiological investigation and carriage study overcrowding was the most likely risk factor identified in this outbreak. To date, the combination of directly observed ciprofloxacin chemoprophylaxis and use of 4CMenB vaccine have controlled the outbreak with no further cases diagnosed.

Describing readmissions to an Ebola case management centre (CMC), Sierra Leone, 2014.

Case management centres (CMCs) are part of the outbreak control plan for Ebola virus disease (EVD). A CMC in Sierra Leone had 33% (138/419) of primary admissions discharged as EVD negative (not a case). Fifteen of these were readmitted within 21 days, nine of which were EVD positive. All readmissions had contact with an Ebola case in the community in the previous 21 days indicating that the infection was likely acquired outside the CMC.

Staff support for the Health Service Executive (HSE) global health programme.

The Global Health programme (GHP) within the Health Service Executive (HSE) aims to improve health in developing countries by creating partnerships between Irish and developing world healthcare institutions. To ascertain the level of interest among HSE staff for the GHP a web-based survey was conducted. 1,028 responses were received. Medical professionals, 202 (27.7%) composed the largest category of respondents. The majority, 503 (69.3%) of respondents wished to actively participate in the GHP. 237 (23.1%) staff had previous experience of working in the developing world. This survey highlighted a number of themes respondents considered important for successful partnerships including: reciprocal staff exchange, joint scientific research, the avoidance of "brain drain" and utilising the Internet to link institutions. Less than 1% (2/203) of comments expressed a negative view of the GHP.

The first pulse of the extremely bright GRB 130427A: a test lab for synchrotron shocks.

Gamma-ray burst (GRB) 130427A is one of the most energetic GRBs ever observed. The initial pulse up to 2.5 seconds is possibly the brightest well-isolated pulse observed to date. A fine time resolution spectral analysis shows power-law decays of the peak energy from the onset of the pulse, consistent with models of internal synchrotron shock pulses. However, a strongly correlated power-law behavior is observed between the luminosity and the spectral peak energy that is inconsistent with curvature effects arising in the relativistic outflow. It is difficult for any of the existing models to account for all of the observed spectral and temporal behaviors simultaneously.

Characteristics of patients admitted to the intensive care unit following self-poisoning and their impact on resource utilisation.

BACKGROUND: Self-poisoning accounts for up to 10 % of hospital admissions, some of whom require admission to ICU. Few studies have looked at the epidemiology of these patients in an Irish setting. AIMS: To quantify the proportion of ICU admissions attributable to self-poisoning, to examine the characteristics and outcome of these patients, and to assess their ICU resource utilisation. METHODS: Retrospective review of ICU admissions from 2006 to 2010. Data were collected on patient age, sex, admission diagnosis, substances involved, APACHE II score, length of stay, organ support, and outcome. RESULTS: There were 80 admissions to ICU following self-poisoning accounting for 3.8 % of ICU admissions and 13 % of all hospital admissions for self-poisoning. M:F ratio was 0.9:1. Mean age 35 (range 16-75), APACHE II score 14 (2-36). Commonest substances involved were benzodiazepines, opioids, tricycle antidepressants. Median ICU stay was 2 days (IQR 0.96-4.5). 84 % of patients were ventilated, 27.5 % required inotropic support, 14 % renal replacement therapy. When opioids were involved requirement for inotropes and CRRT were higher. ICU mortality was 6.3 %. These patients consumed 280 bed days. CONCLUSION: Self-poisoning accounted for 3.8 % of ICU admissions. Patients tend to require a short period of ventilation, with a minority requiring additional organ support. The cost of ICU care is calculated based on previously published methodology to be 7,717 per patient. Extrapolated nationally the annual cost for ICU care for self-poisoning is estimated to be in the order of 5 m.

Thrombosomes: a platelet-derived hemostatic agent for control of noncompressible hemorrhage.

BACKGROUND: Uncontrolled hemorrhage is responsible for ∼80% of the potentially survivable deaths in combat and over 40% of early mortality in the under 65 age group in the United States. Providing an easily used infusible hemostatic agent to first responders could significantly reduce these fatalities. We report on an infusible lyophilized platelet-derived hemostatic agent stabilized with trehalose and polysucrose prior to and during lyophilization. STUDY DESIGN AND METHODS: Characterization included determining the particle population size range, surface marker expression GPIb, GPIIbIIIa, and Annexin V binding. Function was assessed by aggregation, thromboelastography, and thrombin generation. Pharmacokinetics, biodistribution, and immunogenicity established using Indium(111) labeled Thrombosomes in healthy New Zealand white rabbits (NZWRs), efficacy in thrombocytopenic NZWR, and safety in NZWRs, canines, and nonhuman primates. RESULTS: Thrombosomes retained GPIIbIIIa expression (98.71% ± 0.18 of the rehydrated particles), a reduced expression of GPIb (47.77% ± 6.65), and Annexin V binding (86.05% ± 2.65). Aggregation to all agonists except thrombin in buffer (78.15% ± 2.5) was <50%. Thrombin generation and thromboelastography results demonstrated a concentration gradient that was consistent from lot to lot. There were no observed adverse events in any safety study and blood loss was reduced by >80% in the thrombocytopenic ear bleed model. CONCLUSION: Our in vitro characterization studies in conjunction with preclinical animal safety and efficacy studies demonstrated lot consistency in manufacturing, maintenance of hemostatic functions of Thrombosomes, safety at high dose concentrations, and the potential to provide an effective hemostatic agent at the site of injury.

Use of a geographic information system to map cases of measles in real-time during an outbreak in Dublin, Ireland, 2011.

In 2011, there was a large measles outbreak in Dublin. Nationally 285 cases were notified to the end of December 2011, and 250 (88%) were located in the Dublin region. After the first case was notified in week 6, numbers gradually increased, with 25 notified in June and a peak of 53 cases in August. Following public health intervention including a measles-mumps-rubella (MMR) vaccination campaign, no cases were reported in the Dublin region in December 2011. Most cases (82%) were children aged between 6 months and 14 years, and 46 cases (18%) were under 12 months-old. This is the first outbreak in Dublin to utilise a geographic information system for plotting measles cases on a digital map in real time. This approach, in combination with the analysis of case notifications, assisted the department of public health in demonstrating the extent of the outbreak. The digital mapping documented the evolution of two distinct clusters of 87 (35%) cases. These measles cases were infected with genotype D4-Manchester recently associated with large outbreaks across Europe. The two clusters occurred in socio-economically disadvantaged areas and were attributable to inadequate measles vaccination coverage due in part to the interruption of a school-based MMR2 vaccination programme.

Alcohol, drug misuse and suicide attempts: unrecognised causes of out of hospital cardiac arrests admitted to intensive care units.

AIM: To assess the contribution of alcohol, drug abuse and suicide attempts to out of hospital cardiac arrests (OHCA) who are admitted to our intensive care unit (ICU). METHODS: Retrospective review of all OHCA admitted to the ICU over a 2-year period. RESULTS: There were 26 OHCA. Six patients survived, all of whom had a cardiac aetiology for their arrest. Ten patients arrested due to external factors (drug misuse n = 4, alcohol excess n = 1, suicide attempts n = 4 and accidental choking n = 1). All of the patients who arrested secondary to external factors were young (37.2 +/- 13.58 years), 90% were male and all died in hospital. All of the cases of drug misuse involved cocaine. CONCLUSION: Alcohol, drug misuse and suicide attempts contribute significantly to the number of OHCA which are admitted to ICU. Moreover, cocaine usage has contributed to a number of OHCA in our study.

Wound-healing properties of trehalose-stabilized freeze-dried outdated platelets.

BACKGROUND: The wound-healing applications of platelet (PLT)-derived cytokines, proteins, and membranes is accepted but continues to be investigated. In this study, it is demonstrated that stabilized freeze-dried PLTs prepared from outdated PLTs (FDPOs) accelerate wound healing and form tube structures as well as stabilized indated freeze-dried PLTs (FDPIs) and room-temperature fresh PLTs (RT-PLTs). STUDY DESIGN AND METHODS: Experiments were designed to compare in vitro and in vivo wound-healing properties of FDPI, FDPO, and RT-PLT preparations. The concentration of PLT-derived growth factor (PDGF)-betabeta and transforming growth factor (TGF)-beta1 was determined, and the abilities of FDPIs, FDPOs and RT-PLTs to induce endothelial cell proliferation and promote endothelial cell tube formation (cells formed solid spouts connecting neighboring cells to form tube structures) were observed. Wound-healing characteristics were measured by surgically inducing 1-cm(2), full-thickness wounds on db/db mice (n = 10 per group). The wounds were treated with single or multiple doses of FDPIs and FDPOs. Wound closure rate was determined, and histology samples were evaluated for cellular makeup. RESULTS: FDPOs retained the same levels of PDGF-betabeta and TGF-beta1 and were able to promote endothelial cell proliferation and tube formation in vitro as well as FDPIs or RT-PLTs. Multiple applications of FDPO accelerated wound closure and enhanced reepithelialization when compared to untreated wounds in db/db mice. CONCLUSION: FDPOs enhanced wound healing in db/db mice as well as FDPIs and RT-PLTs. Wound closure was obtained 6 days earlier than untreated wounds and histologic examination revealed reduced granulation and increased cellular angiogenesis.

Dialysis: prolonging life or prolonging dying? Ethical, legal and professional considerations for end of life decision making.

There are over 7,000 people on dialysis in Australia and this is predicted to increase due to the ageing population and the high incidence of diabetes mellitus. Discontinuation of dialysis is the second most frequent cause of death in dialysis patients in Australia. Risk factors for the discontinuation of dialysis include: co-morbidities (especially diabetes mellitus) and being older. Because the decision to discontinue dialysis is a major life choice, collaborative decision making should be encouraged, and the patient needs assurances of the continuation of care and kindness, a palliative care plan, and the alleviation of suffering. Patients decide to discontinue dialysis because of an unacceptable quality of life, depression and a chronic failure to thrive. Health professionals need to support end of life decision making using an ethical decision framework. A review of current literature was undertaken and revealed a paucity of information in regard to palliation in those with end stage renal disease who had discontinued dialysis. The fear of dying, pain, suffering, and abandonment that a patient and/or their family may perceive as being associated with death may create barriers to decisions to discontinue with dialysis treatments. Therefore health care personnel should provide information with honesty to allow patients to predict their quality of life and death. Support for the patient and family during the dying period should be multi-disciplinary, with clear and timely communication between all members of the team.