Evaluation of treatment and outcome for patients with haemophilia A and haemophilia B on extended half-life (EHL) factor products: A 12-month data analysis.

INTRODUCTION: Extended half-life (EHL) factor VIII and IX concentrates as prophylaxis against bleeds have been available to selected persons with haemophilia (PWH) in Australia since March 2018. Preliminary analysis of switching to EHL demonstrated increased treatment adherence, fewer injections and improved bleeding outcomes. AIMS: To characterise clinical practices regarding the use of EHL in Australia, to further evaluate treatment regimens and bleeding outcomes, and to analyse the influence of EHL product pharmacokinetics on clinical decision-making. METHODS: A national, retrospective study was conducted using the Australian Bleeding Disorders Registry (ABDR). Patients on EHL products during the entire 2019 calendar year were included for analysis. RESULTS: A complete and validated dataset of 174 PWH was analysed, 115 Haemophilia A (HA) and 59 Haemophilia B (HB). Adherence to EHL therapy was 85.7% in HA and 87.2% in HB. About 63.5% of HA and 64.4% of HB PWH reported zero spontaneous bleeds over 12months. Ankles were the most frequent spontaneous bleed site. Approximately one-third patients underwent dose adjustments, with most frequent reasons being pharmacokinetics, body weight change and breakthrough bleeds. About 19.5% of PWH had target joint history, with spontaneous bleeds reported in 58% of that cohort on EHL. Multivariate regression showed significant impact of non-adherence, target joint history and short half-life on spontaneous bleeds in the HA cohort; however only short half-life had significant impact in the HB cohort. CONCLUSION: EHL usage in Australia shows excellent treatment adherence and bleeding outcomes. This study affirms the use and value of widely available population-based pharmacokinetics as a clinical tool.

Haemophilia joint health score (HJHS) usage, patterns and outcome data in patients with haemophilia A and haemophilia B in Australia: A descriptive study using the Australian Bleeding Disorders Registry (ABDR).

INTRODUCTION: Assessment of joint health is an essential component of haemophilia management. A variety of clinical tools have been developed to standardise this assessment process. One such tool, the Haemophilia Joint Health Score (HJHS), is embedded for use within the Australian Bleeding Disorders Registry (ABDR). This provides a unique opportunity to analyse patterns of tool usage as well as associations between scores, demographics and clinical outcome factors. AIMS: To characterise clinician practices regarding use of HJHS in routine clinical assessment of persons with haemophilia (PWH), to examine relationships between HJHS, and age, inhibitor status and body mass index (BMI), and to identify potential barriers to HJHS tool usage. METHODS: A national, retrospective study was conducted using data extracted from the ABDR between 2014 and 2020, complemented by a qualitative questionnaire exploring haemophilia treatment centre (HTC) structure, resourcing and clinician perspectives about HJHS. RESULTS: 28.1% (622/2220) of PWH had at least one HJHS recorded in the ABDR during the defined study period (546 haemophilia A, 76 haemophilia B). HJHS were recorded more in children than adults and performed more in severe than non-severe haemophilia. Multivariate analysis demonstrated significant association of age, severity and inhibitor status with HJHS. No association was identified between BMI and HJHS. Qualitative surveys revealed significant variation in physiotherapy funding, availability and methods of tool use between HTCs. CONCLUSION: This study provides valuable insights into joint health assessment in Australia. It improved our understanding of factors influencing long-term joint outcomes. Practical limitations of HJHS tool were also discussed.

Sickle cell disease in Australia: a snapshot from the Australian Haemoglobinopathy Registry.

BACKGROUND: Sickle cell disease (SCD) is the most common monogenic disorder worldwide. In deoxygenated conditions, the altered beta chain (haemoglobin S [HbS]) polymerises and distorts the erythrocyte, resulting in pain crises, vasculopathy and end-organ damage. Clinical complications of SCD cause substantial morbidity, and therapy demands expertise and resources. Optimising care for patients and planning resource allocation for the future requires an understanding of the disease in the Australian population. The Australian Haemoglobinopathy Registry (HbR) is a collaborative initiative of specialist centres collating and analysing data on patients with haemoglobin disorders. AIMS: To provide a snapshot of SCD in Australia over a 12-month period based on data from the HbR. METHODS: Patients with a clinically significant sickling disorder across 12 clinical sites were included for analysis. Data include demographic and diagnostic details, as well as details of the clinical management of the condition over a 12-month period. RESULTS: Data on 359 SCD patients demonstrate a shift in the demographic of patients in Australia, with a growing proportion of sub-Saharan African ethnicities associated with the HbSS genotype. Acute and chronic complications are common, and patients require significant outpatient and inpatient support. Prevalence of disease complications and therapeutic trends are in keeping with other high-income countries. CONCLUSIONS: This study provides the first national picture of SCD in Australia, describing the characteristics and needs of SCD patients, elucidating demand for current and novel therapy and facilitating the planning of services for this vulnerable population.

Australian and New Zealand consensus guideline for paediatric newly diagnosed immune thrombocytopaenia endorsed by Australian New Zealand Children's Haematology and Oncology Group.

In children, the majority of cases are self-limiting and thus many paediatric patients can be managed conservatively with minimal complications. This varies considerably compared to adult newly diagnosed immune thrombocytopaenia (NDITP) where, in most cases, thrombocytopaenia persists with higher risk of moderate to severe bleeding complications. In the past decade, local and international guidelines have emerged to support approaches to the investigation and management of NDITP, with a focus primarily on adult immune thrombocytopaenia (ITP). International consensus guidelines on paediatric NDITP have been developed, however gaps remain, and approaches vary between North American, Asia, Europe and the UK. There are no current Australian or New Zealand paediatric ITP guidelines readily available, rather differing guidelines for each state, territory or island. These inconsistencies cause uncertainty for patients, families and physicians managing cases. Subsequently, physicians, including paediatric haematologists and general paediatricians, have come together to provide a consensus approach guideline specific to paediatric NDITP for Australian or New Zealand. Persistent or chronic paediatric ITP remains a complex and separate entity and are not discussed here.

Incidence of NUT carcinoma in Western Australia from 1989 to 2014: a review of pediatric and adolescent cases from Perth Children's Hospital.

BACKGROUND: NUT carcinoma (NC), previously known as NUT midline carcinoma, is a rare and very aggressive cancer that occurs in both children and adults. NC is largely chemoresistant, with an overall survival of less than 7 months. Because the carcinoma is not restricted to a particular organ, diagnosis is often a challenge. In the absence of a clearly determined incidence for NC, we sought to study the diagnosis of patients in a well-defined population. METHODS: We systematically reviewed records of all patients that presented to the Oncology Department of the Princess Margaret Hospital for Children from 1989 to 2014. This institution in the geographically isolated state of Western Australia has a catchment population of around 2 million. We then identified all high grade undifferentiated sarcomas or carcinomas in the 0-16 year age group. RESULTS: Over 26 years, we found 14 patients of 16 years or younger with undifferentiated malignant tumors. Of these, five tumors were positive by immunohistochemistry for the NUT/NUTM1 (Nuclear Protein in Testis) protein and/or the translocation t(15;19). Three patients presented with thoracic tumors, one with a para-spinal tumor, and one had an upper airway nasopharyngeal carcinoma. In all five cases, there was an initial response to therapy and then progression. This 26-year survey was conducted in a geographically isolated state with a well-defined population, and we determined an estimated incidence of NC of around 0.41 per million child years (0-16 yrs. of age) at risk. From three patients it was feasible to derive cell lines for further genetic analyses and drug screening. CONCLUSIONS: For the first time, the incidence of NC could be determined in a well-defined geographic area. The calculated rate of NC incidence is consistent with a history of under-recognition for this malignancy. These findings indicate that improved diagnostic detection of NC would enable better management and counselling of patients. Our findings emphasize the heterogeneity of NC, and they highlight the need to develop personalised therapy options, and to consider a diagnosis of NC in undifferentiated malignant tumors.

Optimized peripheral blood progenitor cell mobilization for autologous hematopoietic cell transplantation in children with high-risk and refractory malignancies.

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) using hematopoietic progenitor cells (HPCs) has become an important therapeutic modality for patients with high-risk malignancies. Current literature on standardized method for HPC apheresis in children is sparse and failure rate reported as high as 30%. PATIENTS/METHODS: A retrospective study of 125 pediatric patients with high-risk malignancies undergoing aHSCT in Western Australia between 1997 and 2016 was conducted. RESULTS: Mobilization was achieved by means of chemotherapy and granulocyte colony-stimulating factor (G-CSF). Patients underwent apheresis the day after CD34+ counts reached ≥20/µL and an additional dose of G-CSF. Peripheral arterial and intravenous lines were inserted in pediatric intensive care unit under local anesthetic and/or sedation, omitting the need for general anesthesia as well as facilitating an uninterrupted apheresis flow. Larger apheresis total blood volumes were processed in patients weighing ≤20 kg. The minimal dose of ≥2 × 106 CD34+ cells/kg was successfully collected in 98.4% of all patients. The optimal dose of 3-5 × 106 CD34+ cells/kg was collected in 96% of patients scheduled for a single aHSCT, 87.5% for tandem, and 100% for triple aHSCT. All HPC collections were completed in one apheresis session. Mobilization after ≤3 chemotherapy cycles and cycles including cyclophosphamide resulted in a significantly higher yield of CD34+ cells. CONCLUSION: Our approach to HPC mobilization by means of chemotherapy and single myeloid growth factor combined with optimal collection timing facilitated by continuous apheresis flow resulted in highly effective HPC harvest in children and adolescents with high-risk cancers.

Aplastic anaemia: Current concepts in diagnosis and management.

Aplastic anaemia is a rare, previously fatal condition with a significantly improved survival rate owing to advances in understanding of the pathophysiology and improved treatment strategies including haematopoietic stem cell transplantation. Although a rare condition, aplastic anaemia continues to present a high burden for affected patients, their families and the health system due to the prolonged course of disease often associated with high morbidity and the uncertainty regarding clinical outcome. Modern molecular and genetic techniques including next-generation sequencing have contributed to a better understanding of this heterogeneous group of conditions, albeit at a cost of increased complexity of clinical decision-making regarding prognosis and choice of treatment for individual patients. Here we present a concise and comprehensive review of aplastic anaemia and closely related conditions based on extensive literature review and long-standing clinical experience. The review takes the reader across the complex pathophysiology consisting of three main causative mechanisms of bone marrow destruction resulting in aplastic anaemia: direct injury, immune mediated and bone marrow failure related including inherited and clonal disorders. A comprehensive diagnostic algorithm is presented and an up-to-date therapeutic approach to acquired immune aplastic anaemia, the most represented type of aplastic anaemia, is described. Overall, the aim of the review is to provide paediatricians with an update of this rare, heterogeneous and continuously evolving condition.

Vaccine-preventable disease following allogeneic haematopoietic stem cell transplant in Western Australia.

AIM: Infection is an important and frequent cause of mortality and morbidity following allogeneic haematopoietic stem cell transplantation (HSCT). This study was conducted to determine the epidemiology and clinical phenotype of vaccine-preventable disease in children who have undergone HSCT following the implementation of a standard revaccination programme. METHODS: Children receiving first allogeneic HSCT in Western Australia between January 2005 and December 2014 were eligible for recruitment. Patients received standard antimicrobial prophylaxis and were vaccinated according to the West Australian post-HSCT immunisation schedule, commencing 6 months following HSCT. Children who developed any illness post-HSCT were reviewed, and investigations for infectious disease were undertaken as clinically indicated. Positive identification of vaccine-preventable disease was documented with the clinical course of the illness. RESULTS: A total of 71 patients were enrolled in the study. The overall incidence of vaccine-preventable disease following HSCT was 19.7%; influenza accounted for 50% of all cases, herpes zoster for 42.9%. All episodes occurred late, beyond day 100 post-HSCT. Overall survival for matched-sibling donor transplants was 83.3 and 75.0% at 1 and 5 years, respectively, and was 72.3 and 63.3% for alternative donor transplants. Mortality due to vaccine-preventable disease was low, with one death from disseminated herpes zoster. CONCLUSIONS: There is a high incidence of vaccine-preventable morbidity post-allogeneic HSCT in West Australian children. Viral aetiology constitutes the main burden, namely, influenza infection and varicella zoster virus reactivation. Further efforts are required to identify the most appropriate preventative strategies.

Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis.

Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.

Development of a miniaturized mechanoacoustic sensor for continuous, objective cough detection, characterization and physiologic monitoring in children with cystic fibrosis.

Cough is an important symptom in children with acute and chronic respiratory disease. Daily cough is common in Cystic Fibrosis (CF) and increased cough is a symptom of pulmonary exacerbation. To date, cough assessment is primarily subjective in clinical practice and research. Attempts to develop objective, automatic cough counting tools have faced reliability issues in noisy environments and practical barriers limiting long-term use. This single-center pilot study evaluated usability, acceptability and performance of a mechanoacoustic sensor (MAS), previously used for cough classification in adults, in 36 children with CF over brief and multi-day periods in four cohorts. Children whose health was at baseline and who had symptoms of pulmonary exacerbation were included. We trained, validated, and deployed custom deep learning algorithms for accurate cough detection and classification from other vocalization or artifacts with an overall area under the receiver-operator characteristic curve (AUROC) of 0.96 and average precision (AP) of 0.93. Child and parent feedback led to a redesign of the MAS towards a smaller, more discreet device acceptable for daily use in children. Additional improvements optimized power efficiency and data management. The MAS's ability to objectively measure cough and other physiologic signals across clinic, hospital, and home settings is demonstrated, particularly aided by an AUROC of 0.97 and AP of 0.96 for motion artifact rejection. Examples of cough frequency and physiologic parameter correlations with participant-reported outcomes and clinical measurements for individual patients are presented. The MAS is a promising tool in objective longitudinal evaluation of cough in children with CF.

Outcomes of hematopoietic stem cell transplantation in primary immunodeficiency: a report from the Australian and New Zealand Children's Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry.

We performed a retrospective analysis on the outcomes of 135 hematopoietic stem cell transplantations (HSCTs) for primary immunodeficiency disorders in Australian and New Zealand Children's Haematology Oncology Group transplantation centers between 1992 and 2008. The most common indications for HSCT were severe combined immunodeficiency, Wiskott-Aldrich syndrome, and chronic granulomatous disease. Five-year overall survival (OS) was 72% for the entire cohort. Disease-specific 5-year OS was 70% for severe combined immunodeficiency, 81% for Wiskott-Aldrich syndrome, and 69% for chronic granulomatous disease. Transplantation-related mortality (TRM) was 10% at day +100. TRM and OS were equivalent in recipients of related and unrelated donor transplants. Source of stem cells had no impact on TRM or OS with outcomes following unrelated umbilical cord blood similar to unrelated bone marrow. The presence of interstitial pneumonitis, active cytomegalovirus infection, or veno-occlusive disease were all independent variables that significantly decreased OS. This large series supports the use of HSCT as curative therapy for a range of primary immunodeficiency disorders, demonstrating excellent survival after both related and unrelated donor transplantation.

Health screening dialouges.

Nurses can play an important role in community-based health screenings, which are a practical resource to empower people living with mental and substance use disorders to make positive lifestyle changes. The experiences, struggles, and strengths of screening participants provides insights for nurses to engage people in health and wellness dialogues.

Use of bisphosphonates for the treatment of osteonecrosis as a complication of therapy for childhood acute lymphoblastic leukaemia (ALL).

BACKGROUND: Osteonecrosis is a well-recognised complication of current childhood acute lymphoblastic leukaemia (ALL) therapy. There are few studies on the medical management of osteonecrosis in this setting. We studied the therapeutic and radiological effects of oral and intravenous bisphosphonate use compared with standard care as treatment for osteonecrosis in this population. METHOD: Patients who developed osteonecrosis as a complication of ALL therapy between 1994 and 2007 were treated at a single paediatric institution. Of 17 patients, 9 were commenced on bisphosphonates and 8 treated conservatively. Both groups were observed with time. Pain, analgesic requirement and musculoskeletal function were assessed monthly. Affected joints were radiologically imaged at set intervals. Each scan was graded using an ellipsoid method to give the total volume of osteonecrosis, by blinded radiologic examination. RESULTS: Three of six patients treated with oral alendronate showed clinical improvement. The three patients that had no improvement were subsequently treated with intravenous pamidronate. All six patients treated with intravenous pamidronate showed clinical improvement. Seven of eight conservatively treated patients deteriorated clinically. All patients demonstrated reduction in the radiological burden of osteonecrosis with time. There was no difference in the rate of reduction between conservative and bisphosphonate arms. CONCLUSION: Bisphosphonate use, in particular pamidronate, improved pain scores, analgesic requirement and musculoskeletal function in patients with osteonecrosis occurring as a complication of childhood ALL therapy. Objective radiologic benefit of bisphosphonate treatment could not be demonstrated. Risks, benefits and long-term outcome of bisphosphonate use in this population should be addressed in a larger prospective, randomised trial.

Promoting self-determination and financial security through innovative asset building approaches.

TOPIC: Studies indicate that asset development programs such as Individual Development Accounts (IDAs) can enhance the economic security of low-income populations; however, only a handful of asset development programs have been implemented specifically to serve people with psychiatric disabilities, and larger programs have not collected disability-specific information. PURPOSE: The purpose of this article is to increase our knowledge about the use of IDAs to enhance self-determination and recovery for people with psychiatric disabilities. SOURCES USED: Background information about IDAs is presented followed by case studies of two IDA programs that serve people with psychiatric disabilities. CONCLUSIONS: The use of IDA programs in enhancing self-determination among people with psychiatric disabilities is discussed, along with barriers and future directions.

Automated enumeration of lymphoid and plasma cells in bone marrow to establish normal reference ranges.

AIMS: The number of precursor and mature lymphoid cells and plasma cells in normal bone marrow trephine (BMT) biopsies throughout the human lifespan is unknown. Reference ranges have been established from aspirated marrow, but due to haemodilution errors, these do not accurately reflect the native marrow milieu. We aimed to define age-specific, normal reference ranges for lymphoid and plasma cells in BMT biopsy specimens using a combined immunophenotyping and digital enumeration approach. METHODS: Morphologically normal BMT biopsy specimens (n=483) were obtained from patients aged 1 month to 90 years of age. Immunohistochemistry was performed to identify lymphoid progenitors , T-lymphocytes (CD3), B-lymphocytes (CD20) and plasma cells (CD138 and MUM1). Positive cells were counted using digital enumeration software, and the percent positivity for each antigen was determined per case. Mean values were generated for specific age groups, and age-defined reference ranges were determined for each antigen using normalised data. RESULTS: A mean of 16 609 cells (range: 7210-34 097) were counted per biopsy. Infant marrows showed a predominance of immature lymphoid progenitors and B cells. With increasing age, an increase in mean T cell and plasma cell numbers were observed. The results showed the same trends to flow cytometry references for aspirate material although the absolute values differed. CONCLUSIONS: Combined immunohistochemistry and automated enumeration gives an accurate, reproducible number of antigen-positive cells and has generated normal reference ranges for these cell types in BMT biopsies. The method and ranges we have established have the potential to be applied in routine clinical practice.

Correlates of Co-Occurring Diabetes and Obesity Among Community Mental Health Program Members With Serious Mental Illnesses.

OBJECTIVE: This study examined the prevalence and correlates of co-occurring obesity and diabetes among community mental health program members. METHODS: Medical screenings of 457 adults with serious mental illnesses were conducted by researchers and peer wellness specialists in four U.S. states. Body mass index was measured directly. Diabetes was assessed via glycosylated hemoglobin and interview self-report. Multivariable logistic regression analysis examined associations with known predictors. RESULTS: In the sample, 59% were obese, 25% had diabetes, and 19% had both conditions. When gender, diagnosis, and site were controlled, co-occurring diabetes and obesity was almost three times as likely among African Americans (OR=2.93) as among participants from other racial groups and half as likely among smokers as among nonsmokers (OR=.58). Older persons and those with poorer self-rated physical health also were more likely to have these co-occurring conditions. CONCLUSIONS: Results support the need for culturally competent treatment and for smoking cessation options with sensitivity to the potential for weight gain.