Molecular insights on Eltrombopag: potential mitogen stimulants, angiogenesis, and therapeutic radioprotectant through TPO-R activation.

The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.

What is the context?● Chemotherapy, radiation treatment, or immunological disorders can cause a decrease in platelet count (thrombocytopenia) or decrease all blood cell types (pancytopenia) in the bone marrow. This can make it challenging to choose the appropriate cancer treatment plan.● Eltrombopag (EPAG) is an oral non-peptide thrombopoietin (TPO) mimetic that activates the cMPL receptor in the body. This activation leads to cell differentiation and proliferation, stimulating platelet production and reducing thrombocytopenia. The cMPL receptor is present in liver cells, megakaryocytes, and hematopoietic cells. However, its effects on stem cell proliferation and differentiation are not entirely understood.What is the new?● This study delves into the molecular interactions and therapeutic applications of EPAG, a small molecule that activates cMPL (TPO-R).● The study offers a comprehensive analysis of the ligand-receptor complex formation, including an examination of downstream signaling elements. Furthermore, molecular dynamics simulations demonstrate the stability of the ligand when interacting with targeted proteins.● The research investigates the presence of TPO-R on stem cell-derived endothelial cells, shedding insight into the ability of EPAG TPO-mimetic to promote angiogenesis and vasculature formation.● The study revealed that EPAG has the potential to protect against UVB-induced radiation damage and stimulate stem cell growth.What is the implications?The study emphasizes the potential of EPAG as a promising option for addressing radiation injury and minimizing the adverse effects of radiotherapy. It could revolutionize treatments not only for thrombocytopenia but also for enhancing the growth of stem cells. Furthermore, the research deepens our understanding of EPAG's molecular mechanisms, providing valuable insights for developing future drugs and therapeutic approaches for cell therapy to treat radiation damage.

Conditioned medium-enriched umbilical cord mesenchymal stem cells: a potential therapeutic strategy for spinal cord injury, unveiling transcriptomic and secretomic insights.

INTRODUCTION: Spinal cord injury (SCI) leads to significant destruction of nerve tissue, causing the degeneration of axons and the formation of cystic cavities. This study aimed to examine the characteristics of human umbilical cord-derived mesenchymal stem cells (HUCMSCs) cultured in a serum-free conditioned medium (CM) and assess their effectiveness in a well-established hemitransection SCI model. MATERIALS AND METHODS: In this study, HUCMSCs cultured medium was collected and characterized by measuring IL-10 and identifying proteomics using mass spectroscopy. This collected serum-free CM was further used in the experiments to culture and characterize the HUMSCs. Later, neuronal cells derived from CM-enriched HUCMSC were tested sequentially using an injectable caffeic acid-bioconjugated gelatin (CBG), which was further transplanted in a hemitransection SCI model. In vitro, characterization of CM-enriched HUCMSCs and differentiated neuronal cells was performed using flow cytometry, immunofluorescence, electron microscopy, and post-transplant analysis using immunohistology analysis, qPCR, in vivo bioluminescence imaging, and behavioral analysis using an infrared actimeter. RESULTS: The cells that were cultured in the conditioned media produced a pro-inflammatory cytokine called IL-10. Upon examining the secretome of the conditioned media, the Kruppel-like family of KRAB and zinc-finger proteins (C2H2 and C4) were found to be activated. Transcriptome analysis also revealed an increased expression of ELK-1, HOXD8, OTX2, YY1, STAT1, ETV7, and PATZ1 in the conditioned media. Furthermore, the expression of Human Stem-101 confirmed proliferation during the first 3 weeks after transplantation, along with the migration of CBG-UCNSC cells within the transplanted area. The gene analysis showed increased expression of Nestin, NeuN, Calb-2, Msi1, and Msi2. The group that received CBG-UCNSC therapy showed a smooth recovery by the end of week 2, with most rats regaining their walking abilities similar to those before the spinal cord injury by week 5. CONCLUSIONS: In conclusion, the CBG-UCNSC method effectively preserved the integrity of the transplanted neuronal-like cells and improved locomotor function. Thus, CM-enriched cells can potentially reduce biosafety risks associated with animal content, making them a promising option for clinical applications in treating spinal cord injuries.

The health care and societal costs of inherited retinal diseases in Australia: a microsimulation modelling study.

OBJECTIVES: To estimate the health care and societal costs of inherited retinal diseases (IRDs) in Australia. DESIGN, SETTING, PARTICIPANTS: Microsimulation modelling study based on primary data - collected in interviews of people with IRDs who had ophthalmic or genetic consultations at the Children's Hospital at Westmead or the Save Sight Institute (both Sydney) during 1 January 2019 - 31 December 2020, and of their carers and spouses - and linked Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Schedule (PBS) data. MAIN OUTCOME MEASURES: Annual and lifetime costs for people with IRDs and for their carers and spouses, grouped by payer (Australian government, state governments, individuals, private health insurance) and type (health care costs; societal costs: social support, National Disability Insurance Scheme (NDIS), income and taxation, costs associated with caring for family members with IRDs); estimated annual national cost of IRDs. RESULTS: Ninety-four people (74 adults, 20 people under 18 years; 55 girls and women [59%]) and 30 carers completed study surveys (participation rate: adults, 66%; children, 66%; carers, 63%). Total estimated lifetime cost was $5.2 million per person with an IRD, of which 87% were societal and 13% health care costs. The three highest cost items were lost income for people with IRDs ($1.4 million), lost income for their carers and spouses ($1.1 million), and social spending by the Australian government (excluding NDIS expenses: $1.0 million). Annual costs were twice as high for people who were legally blind as for those with less impaired vision ($83 910 v $41 357 per person). The estimated total annual cost of IRDs in Australia was $781 million to $1.56 billion. CONCLUSION: As the societal costs associated with IRDs are much larger than the health care costs, both contributors should be considered when assessing the cost-effectiveness of interventions for people with IRDs. The increasing loss of income across life reflects the impact of IRDs on employment and career opportunities.

Healthcare resource utilization of patients with mitochondrial disease in an outpatient hospital setting.

BACKGROUND AND OBJECTIVES: Mitochondrial diseases present as multi-system disorders requiring a comprehensive multidisciplinary approach. The data on healthcare resource utilization associated with mitochondrial diseases and the clinical drivers of these costs are limited including for the out-patient setting where the majority of the clinical care for mitochondrial disease patients occurs. We performed a cross-sectional retrospective study of out-patient healthcare resource utilization and costs for patients with a confirmed diagnosis of mitochondrial disease. METHODS: We recruited participants from the Mitochondrial Disease Clinic in Sydney and stratified them into three groups: those with mitochondrial DNA (mtDNA) mutations (Group 1), those with nuclear DNA (nDNA) mutations and the predominant phenotype of chronic progressive external ophthalmoplegia (CPEO) or optic atrophy (Group 2) and those without a confirmed genetic diagnosis but clinical criteria and muscle biopsy findings supportive of a diagnosis of mitochondrial disease (Group 3). Data was collected through retrospective chart review and out-patient costs were calculated using the Medicare Benefits Schedule. RESULTS: We analyzed the data from 91 participants and found that Group 1 had the greatest average out-patient costs per person per annum ($838.02; SD 809.72). Neurological investigations were the largest driver of outpatient healthcare costs in all groups (average costs per person per annum:-Group 1: $364.11; SD 340.93, Group 2: $247.83; SD 113.86 and Group 3: $239.57; SD 145.69) consistent with the high frequency (94.5%) of neurological symptoms. Gastroenterological and cardiac-related out-patient costs were also major contributors to out-patient healthcare resource utilization in Groups 1 and 3. In Group 2, ophthalmology was the second-most resource intensive specialty ($136.85; SD 173.35). The Group 3 had the greatest average healthcare resource utilization per person over the entire duration of out-patient clinic care ($5815.86; SD 3520.40) most likely due to the lack of a molecular diagnosis and a less customized management approach. CONCLUSION: The drivers of healthcare resource utilization are dependent on the phenotype-genotype characteristics. Neurological, cardiac, and gastroenterological costs were the top three drivers in the out-patient clinics unless the patient had nDNA mutations with predominant phenotype of CPEO and/or optic atrophy wherein ophthalmological-related costs were the second most resource intensive driver.

Economic evaluation of population-based, expanded reproductive carrier screening for genetic diseases in Australia.

PURPOSE: This study aimed to evaluate the cost effectiveness of population-based, expanded reproductive carrier screening (RCS) for a 300 recessive gene panel from health service and societal perspectives. METHODS: A microsimulation model (PreConMod) was developed using 2016 Australian Census data as the base population. Epidemiologic, health, and indirect cost data were based on literature review. The study assessed the incremental cost effectiveness ratio of expanded RCS compared with (1) no population screening and (2) 3-condition screening for cystic fibrosis, spinal muscular atrophy, and fragile X syndrome in a single birth cohort. Averted affected births and health service savings with expanded RCS were projected to year 2061. Both one-way and probability sensitivity analyses were conducted to assess the uncertainty of the parameter inputs. RESULTS: Expanded RCS was cost saving compared with no population screening and cost effective compared with the 3-condition screening (incremental cost effectiveness ratio of Australian dollar [AUD] 6287 per quality-adjusted life year gained) at an uptake rate of 50% for RCS, 59% for in vitro fertilization and preimplantation genetic testing, 90% for prenatal diagnosis testing, and 50% for elective termination of affected pregnancies and a cost of AUD595 per couple screened. Our model predicts that expanded RCS would avert one-third of affected births in a single birth cohort and reduce lifetime health service spending by AUD632.0 million. Expanded RCS was estimated to be cost saving from the societal perspective. CONCLUSION: Expanded RCS is cost effective from health service and societal perspectives. Expanded RCS is projected to avert significantly more affected births and result in health service saving beyond those expected from 3-condition screening or no population screening.

Return to work and productivity loss after surgery: A health economic evaluation.

BACKGROUND: We aimed to identify preoperative psychosocial factors associated with return-to-work (RTW) and the associated cost of productivity loss due to work absenteeism following surgery. Research demonstrates a high economic burden from productivity loss after surgery, but the comparative cost of productivity loss relative to income across different operations has not been examined. MATERIALS AND METHODS: A mixed surgical cohort recruited for a randomized controlled trial were prospectively followed for up to two years following surgery with daily phone assessments to three months, weekly assessments thereafter to six months, then monthly assessments thereafter to determine RTW status, opioid use and pain. RESULTS: 183 of 207 (88.3%) patients in paid employment prior to surgery, who provided at least one day of follow-up, were included in this analysis. The average cost of productivity loss due to work absenteeism was $13 761 (median $9064). Patients who underwent total knee replacement incurred the highest income loss. Medical claims filed before surgery were significantly associated with relative income loss (AOR 5.09; 95% CI 1.73-14.96; p < 0.01) and delayed postoperative RTW. Elevated preoperative PTSD symptoms were associated with delayed RTW (HR 0.78; 95%CI 0.63-0.96; p-value = 0.02) while male gender (HR 1.63; 95%CI 1.11-2.38; p-value = 0.01) was associated with faster postoperative RTW. CONCLUSION: Surgery places a high economic burden on individuals due to postoperative productivity loss. Multidisciplinary approaches, such as pathways, that facilitate the operation and recovery may mitigate the economic consequences for patients, employers, and the healthcare system.

An Analysis of Hospital Costs for Childhood Cancer Care.

BACKGROUND: This study used a linked dataset consisting of all childhood cancers recorded over the course of 10 years in New South Wales (NSW), Australia, to evaluate the hospital and emergency department costs (from a payer perspective) and resources used by patients with childhood cancer. We also analyzed determinants responsible for high-frequency hospital admissions, hospital length of stay (LoS), and hospital costs. METHODS: We analyzed linked data at the individual patient level for a retrospective cohort of 2,966 patients with cancer aged <18 years with a diagnosis date between 2001 and 2012 from the NSW Central Cancer Registry, Australia. We reported costs and use of hospitalization and emergency department presentation 1 year before the date of diagnosis, 1 year after diagnosis, and 2 to 5 years after diagnosis. We also examined the association between cancer types and hospital admission and hospital costs from the payer perspective. Patient characteristics associated with the frequency of hospital admissions, hospital LoS, and hospital costs were also determined using a generalized linear model. RESULTS: Most hospital admission costs occurred in the first year after diagnosis, accounting for >70% of hospital costs within 5 years after diagnosis. The estimated median annual cost of hospitalization in the first year after diagnosis was A$88,964 (interquartile range [IQR], A$34,399-A$163,968) for patients diagnosed at age 0 to 14 years and A$23,384 (IQR, A$5,585-A$91,565) for those diagnosed at age 15 to 17 years. Higher frequency of hospital admissions, hospital LoS, and hospital costs were significantly associated with younger age at cancer diagnosis, cancer metastases, and living in remote/disadvantaged socioeconomic areas. CONCLUSIONS: Our study represents one of the first in Australia to include detailed hospitalization cost information for all childhood cancer cases. This study highlights the high hospital use by pediatric patients and the importance of early diagnosis. Our findings also demonstrate the health inequities experienced by patients from remote areas and the lowest socioeconomic areas.

Induced pluripotent stem cells and derivative photoreceptor precursors as therapeutic cells for retinal degenerations.

The visual impairment associated with inherited retinal degeneration and age-related degeneration of photoreceptors is causing substantial challenges in finding effective therapies. However, induced pluripotent stem cell (iPSC)-derived therapeutic cells such as photoreceptor and retinal pigment epithelium (RPE) cells provide the ultimate options in the rescue of lost photoreceptors to improve the visual function in end-stage degeneration. Retinal cells derived from iPSC are therapeutic cells that could be promising in the field of cell replacement therapy and regenerative medicine. This review presents an overview of the photoreceptor degeneration, methods of iPSC generation, iPSC in retinal disease modeling, summarizes the photoreceptor differentiation protocols, and challenges remained with photoreceptor cell replacement for the treatment of retinal diseases. Thus, the burden and increased incidence of visual impairment emphasizes the need of novel therapy, where iPSC-derived photoreceptor and RPE cells proved to be promising for curing the retinal dysfunction and act as renovation in approach to improve visual function.

Effective Differentiation and Biological Characterization of Retinal Pigment Epithelium Derived from Human Induced Pluripotent Stem Cells.

PURPOSE: Human induced pluripotent stem cells (hiPSC)-derived retinal pigment epithelium (RPE) cells are therapeutic cells that have been shown to be promising in the rescue of lost photoreceptors. In this study, we generated hiPSC from human epidermal keratinocytes and subsequently differentiated them into RPE cells to investigate their ability to influence the retinal functions of the Royal College of Surgeon (RCS) rats. METHODS: Keratinocytes were reprogrammed to hiPSC using a non-integrating Sendai reprogramming system. Established hiPSCs were differentiated into RPE cells, and complete characterization was performed. Next, the suspension of hiPSC-RPE cells was transplanted into the subretinal space of 3-week-old RCS rats (n = 12). Posttransplantation evaluations were performed using optical coherence tomography (OCT), electroretinography, and immunohistochemical analysis. RESULTS: The hiPSC colonies were identical to embryonic stem-like cells that revealed the expression of pluripotency markers and retention of the normal genome. These cells exhibited the ability to differentiate into an amalgam of germ layers and produce RPE cells. The differentiated RPE cells exhibited an identical pigmented morphology that expressed RPE-specific markers, such as CRALBP, BESTROPHIN, RPE65, and MERTK. At 8 weeks of longitudinal culture, the RPE cells exhibited maximum pigmentation with in vitro phagocytotic activity. Furthermore, transplantation data showed improved retinal function till week 12 post-transplantation and a significantly higher number of rod/cone ratios in transplanted eyes compared to non-surgery control eyes. CONCLUSION: hiPSC-derived RPE cells exhibited naïve RPE cell properties and functionality that provided trophic support and the transient rescue of photoreceptor cells.

Impact of molecular testing on thyroid nodule neoplastic diagnosis, stratified by 4-cm size, in a surgical series.

Whether molecular testing adds diagnostic value to the evaluation of thyroid nodules 4-cm or larger is unknown. The impact of molecular testing on cytopathologic-histopathologic diagnosis of neoplasm (adenoma or malignant), stratified by nodule size

Semiquantitative assessment of cytomorphologic features can predict mutation status of thyroid nodules with indeterminate cytologic diagnosis.

Molecular diagnostics increasingly direct the management of thyroid nodules with an indeterminate cytologic diagnosis. This study was undertaken to correlate cytomorphologic features with the molecular profiles in an effort to identify features predictive of molecular aberrations. One hundred eighty-nine thyroid nodules with an indeterminate thyroid cytology diagnosis (atypia of undetermined significance, suspicious for follicular lesion, and suspicious for malignancy) with an adequate sample submitted for targeted mutation detection by polymerase chain reaction or next-generation sequencing were assessed semiquantitatively for the following cytomorphologic parameters: cellularity, Hurthle cell changes, microfollicles, nuclear elongation, nuclear grooves, nuclear enlargement, nuclear atypia, extent of atypia, and colloid. Based on this evaluation, a cumulative cytomorphologic score (CCS) and a more simplified overall atypia score (OAS) were assigned to each case. Associations among mutational status and each of the aforementioned parameters, CCS, and OAS were determined. Of the 189 nodules with indeterminate cytology, 63 (33.3%) harbored at least 1 mutation. RAS and BRAF were the most common mutations, found in 34 (18.0%) and 13 (6.9%) cases, respectively. Both CCS and OAS were highly associated with the presence of all mutations (P < .0001) and with the presence of BRAF and RAS mutations in particular (all P < .01). Semiquantitative assessment of various cytomorphologic features in indeterminate thyroid cytology cases showed a strong association of higher OAS and CCS and incidence of BRAF and RAS mutations. Using a more objective approach to thyroid cytology can potentially decrease the overall number of indeterminate diagnoses, leading to fewer repeat procedures and unnecessary surgical procedures.

Systematic Review and Meta-analysis of the Impact of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) on Cytological Diagnosis and Thyroid Cancer Prevalence.

A re-named diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) likely impacts the prevalence of thyroid cancer and risk of malignancy in populations based on the established Bethesda System of Reporting Thyroid Cytopathology (TBSRTC). This study was done to investigate the prevalence and cytological distribution of NIFTP. PRISMA guided systematic review was done from a database search of Pubmed, EMBASE, and Medline using the search terms "non-invasive follicular thyroid neoplasm with papillary-like nuclear features", "non-invasive follicular variant of papillary carcinoma", "niftp", and "Bethesda" until November 2018. Original articles with surgically proven diagnoses of NIFTP using strict NIFTP criteria were included. Twenty-nine studies with 1563 cases of NIFTP were included. The pooled prevalence of NIFTP in cases which would be classified previously as the follicular variant of papillary thyroid cancer (FVPTC) and papillary thyroid cancer (PTC) were 43.5% (95% CI 33.5-54.0%) and 4.4% (95% CI 2.0-9.0%) respectively. The pooled TBSRTC distribution of cases diagnosed as NIFTP was: from the non-diagnostic category 3.6% (95% CI 2.4-5.3%), benign 10.0% (95% CI 7.2-13.6%), AUS/FLUS 34.2% (95% CI 28.2-40.8%), FN/SFN 22.7% (95% CI 17.2-29.4%), suspicious for malignancy 22.4% (95% CI 17.7-27.9%), and malignant 7.5% (95% CI 4.2-12.9%). While a significant reduction in FVPTC prevalence is anticipated, a modest reduction of PTC prevalence is also expected with adoption of the NIFTP terminology that would be distributed mainly among lesions classified as indeterminate thyroid nodules. Further studies are needed to identify unique clinical characteristics of these lesions preoperatively.

Thyroid nodules over 4 cm do not have higher malignancy or benign cytology false-negative rates.

PURPOSE: Whether thyroid nodules 4 cm or larger with benign cytology carry a higher risk of malignancy, and should be managed differently than smaller nodules remains controversial. We aimed to evaluate the malignancy rate and benign cytology false-negative rate in thyroid nodules ≥4 cm compared with those <4 cm. METHODS: All thyroidectomies between January 2010 and December 2014 were reviewed. Patient demographics, preoperative sonographic nodule size, fine needle aspiration cytology (FNAC), and final surgical pathology results were compared for index nodules ≥4 vs. <4 cm. RESULTS: A total of 490 index nodules with preoperative FNAC were identified. A total of 137 nodules were ≥4 cm and 353 nodules were <4 cm. The prevalence of carcinoma was lower (23 vs. 53%) in nodules ≥4 vs. <4 cm (p < 0.0001). The false-negative rate of benign FNAC for ≥4 and <4 cm index nodule was 5.2% and 5.9%, respectively (p = 1.000). CONCLUSIONS: This study shows that thyroid nodules ≥4 cm do not have a higher malignancy rate at surgery nor higher benign cytology false-negative rate than smaller nodules. Thyroid nodules over 4 cm do not require resection, to rule out malignancy, based on size alone.

Cytomorphology of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and the Impact of New Nomenclature on Molecular Testing.

The re-naming of noninvasive follicular variant papillary thyroid cancer to the apparently non-malignant, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) impacts the prevalence of malignancy rates, thereby affecting mutation frequency in papillary thyroid cancer. Preoperative assessment of such nodules could affect management in the future. The original publications following the designation of the new nomenclature have been extensively reviewed. With the adoption of NIFTP terminology, a reduction in the follicular variant of papillary thyroid cancer (FVPTC) prevalence is anticipated, as is a modest reduction of papillary thyroid cancer (PTC) prevalence that would be distributed mainly across indeterminate thyroid nodules. Identifying NIFTP preoperatively remains challenging. RAS mutations are predominant but the presence of BRAF V600E mutation has been observed and could indicate inclusion of the classical PTC. The histological diagnosis of NIFTP to designate low-risk encapsulated follicular variant papillary thyroid cancers (EFVPTCs) would impact malignancy rates, thereby altering the mutation prevalence. The histopathologic criteria have recently been refined with an exclusion of well-formed papillae. The preoperative identification of NIFTP using cytomorphology and gene testing remains challenging.

USE OF A CONTINUOUS GLUCOSE MONITOR FOR PREOPERATIVE MONITORING AND TREATMENT OF HYPOGLYCEMIA IN A CASE OF PANCREATIC NEUROENDOCRINE TUMOR.

OBJECTIVE: Pancreatic neuroendocrine tumors secreting proinsulin and insulin could lead to life-threatening hypoglycemia. We aim to show this can be avoided by utilizing continuous glucose monitoring. METHODS: We describe a case of a 55-year-old female with hypoglycemia unawareness and seizures diagnosed with proinsulinoma. She utilized an intermittently scanned continuous glucose monitor (isCGM) to monitor hypoglycemia preoperatively. RESULTS: The patient underwent biochemical and radiographic evaluation to confirm the diagnosis of proinsulinoma. Utilizing isCGM to monitor blood glucose, she was able to prevent hypoglycemia-related seizures prior to definitive surgery. CONCLUSION: In the time leading up to a definitive surgery, patients with proinsulinomas are at risk of hypoglycemic events leading to falls, seizures, and even death. isCGMs can be utilized for preoperative monitoring and treatment of hypoglycemia in these patients.

Role of Relative Malnutrition in Exercise Hypogonadal Male Condition.

OBJECTIVE: Exercise hypogonadal male condition is a well-recognized condition in women but much less understood in men. The aim of this case report is to highlight exercise-induced hypogonadotropic hypogonadism in a male who recovered with lifestyle modifications. METHODS: We report a case of an adolescent male who developed hypogonadotropic hypogonadism secondary to excessive exercise and malnutrition that was followed up for a year without exogenous testosterone supplementation. Informed consent was obtained from the patient for his information to be used in a manuscript submitted to a journal. RESULTS: An 18-yr-old adolescent male presented to the clinic with symptoms of fatigue and low endurance, low libido, and lack of morning erections. At the time of his presentation, he was running about 60 miles per week for school cross-country team in addition to cross training with kickboxing. Physical examination was remarkable for low body mass index of 19 kg·m but was otherwise normal. Biochemical workup confirmed hypogonadotropic hypogonadism and a mild pancytopenia. Other pituitary laboratory values and MRI of the brain were unremarkable. Bone marrow biopsy performed for anemia showed features consistent with malnutrition. With a working diagnosis of exercise hypogonadal male condition, he was advised to reduce the frequency and intensity of his exercise and increase calorie intake. Cell counts and testosterone levels normalized, and his symptoms resolved without any further interventions. CONCLUSION: Significant reversible hypogonadism can develop after intensive and prolonged exercise. One of the mechanisms of hypogonadism in endurance athletes performing intensive exercise could be relative malnutrition. Further studies to evaluate the role of nutrition and body mass index in male endurance athletes presenting with hypogonadism are needed to identify the underlying mechanism of this condition.

The economic impacts of using adalimumab (Humira® ) for reducing pain in people with ankylosing spondylitis: A microsimulation study for Australia.

AIM: The onset and progression of ankylosing spondylitis (AS) usually occurs during the life stage when individuals are more likely to be working and receiving an income, but little is known about the effects of interventions that reduce pain and improve the economic circumstances of patients out of the labour force due to AS. This study evaluates the economic benefits of pain reduction among people aged 19-64 with AS using adalimumab (Humira® ) from the patient and governmental perspectives. METHODS: We estimated the benefits of adalimumab for reducing pain in people aged 19-64 with AS in terms of labor force participation and earnings, and to the Australian Government in terms of income tax revenue and welfare payments using economic simulation. The simulation model integrated data from the Adalimumab Trial Evaluating Long-Term Safety and Efficacy for Ankylosing Spondylitis (ATLAS), the Household Income and Labour Dynamics in Australia (HILDA) Survey - Wave 10, and Static Incomes Model (STINMOD). All benefits are expressed in 2014 real Australian dollars. RESULTS: We estimated an additional 131 people aged 19-64 with AS (111 males, 20 females) would be in the labour force after using adalimumab for 24 weeks. National benefits consisted of an increase in annual earnings of AU$7.4 million for patients through increased labour force participation, savings of $2 million in annual welfare payments, and an increase of $1.3 million in income tax revenue in 2014 (after 24 weeks). CONCLUSION: Adalimumab therapy generates substantial economic benefits in addition to health benefits for individuals, and savings for government.

Cost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseases.

Childhood-onset muscle disorders are genetically heterogeneous. Diagnostic workup has traditionally included muscle biopsy, protein-based studies of muscle specimens, and candidate gene sequencing. High throughput or massively parallel sequencing is transforming the approach to diagnosis of rare diseases; however, evidence for cost-effectiveness is lacking. Patients presenting with suspected congenital muscular dystrophy or nemaline myopathy were ascertained over a 15-year period. Patients were investigated using traditional diagnostic approaches. Undiagnosed patients were investigated using either massively parallel sequencing of a panel of neuromuscular disease genes panel, or whole exome sequencing. Cost data were collected for all diagnostic investigations. The diagnostic yield and cost effectiveness of a molecular approach to diagnosis, prior to muscle biopsy, were compared with the traditional approach. Fifty-six patients were analysed. Compared with the traditional invasive muscle biopsy approach, both the neuromuscular disease panel and whole exome sequencing had significantly increased diagnostic yields (from 46 to 75% for the neuromuscular disease panel, and 79% for whole exome sequencing), and reduced the cost per diagnosis from USD$16,495 (95% CI: $12,413-$22,994) to USD$3706 (95% CI: $3086-$4453) for the neuromuscular disease panel and USD $5646 (95% CI: $4501-$7078) for whole exome sequencing. The neuromuscular disease panel was the most cost-effective, saving USD$17,075 (95% CI: $10,654-$30,064) per additional diagnosis, over the traditional diagnostic pathway. Whole exome sequencing saved USD$10,024 (95% CI: $5795-$17,135) per additional diagnosis. This study demonstrates the cost-effectiveness of investigation using massively parallel sequencing technologies in paediatric muscle disease. The findings emphasise the value of implementing these technologies in clinical practice, with particular application for diagnosis of Mendelian diseases, and provide evidence crucial for government subsidy and equitable access.

Association of Biotin Ingestion With Performance of Hormone and Nonhormone Assays in Healthy Adults.

Importance: Biotinylated antibodies and analogues, with their strong binding to streptavidin, are used in many clinical laboratory tests. Excess biotin in blood due to supplemental biotin ingestion may affect biotin-streptavidin binding, leading to potential clinical misinterpretation. However, the degree of interference remains undefined in healthy adults. Objective: To assess performance of specific biotinylated immunoassays after 7 days of ingesting 10 mg/d of biotin, a dose common in over-the-counter supplements for healthy adults. Design, Setting, and Participants: Nonrandomized crossover trial involving 6 healthy adults who were treated at an academic medical center research laboratory. Exposure: Administration of 10 mg/d of biotin supplementation for 7 days. Main Outcomes and Measures: Analyte concentrations were compared with baseline (day 0) measures on the seventh day of biotin treatment and 7 days after treatment had stopped (day 14). The 11 analytes included 9 hormones (ie, thyroid-stimulating hormone, total thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine, parathyroid hormone, prolactin, N-terminal pro-brain natriuretic peptide, 25-hydroxyvitamin D) and 2 nonhormones (prostate-specific antigen and ferritin). A total of 37 immunoassays for the 11 analytes were evaluated on 4 diagnostic systems, including 23 assays that incorporated biotin and streptavidin components and 14 assays that did not include biotin and streptavidin components and served as negative controls. Results: Among the 2 women and 4 men (mean age, 38 years [range, 31-45 years]) who took 10 mg/d of biotin for 7 days, biotin ingestion-associated interference was found in 9 of the 23 (39%) biotinylated assays compared with none of the 14 nonbiotinylated assays (P = .007). Results from 5 of 8 biotinylated (63%) competitive immunoassays tested falsely high and results from 4 out of 15 (27%) biotinylated sandwich immunoassays tested falsely low. Conclusions and Relevance: In this preliminary study of 6 healthy adult participants and 11 hormone and nonhormone analytes measured by 37 immunoassays, ingesting 10 mg/d of biotin for 1 week was associated with potentially clinically important assay interference in some but not all biotinylated assays studied. These findings should be considered for patients taking biotin supplements before ordering blood tests or when interpreting results. Trial Registration: clinicaltrials.gov Identifier: NCT03034707.

The long-term productivity impacts of all cause premature mortality in Australia.

OBJECTIVE: To estimate the long-term productivity impacts of all-cause premature mortality in Australia by age, sex and cause of death. METHODS: Using a human capital approach, a model was developed to estimate both the working years and present value of lifetime income (PVLI) lost due to premature deaths that occurred in 2003. Outcomes were modelled on individual level data to the year 2030. A discount rate of 3% was applied and results are presented in 2015 Australian dollars. RESULTS: Premature deaths occurring in 2003 accounted for about 284,000 working years lost and $13.8 billion in PVLI lost when modelled to 2030. Deaths from cancer and cardiovascular disease accounted for more than half the total PVLI impact. Injuries and mental disorders were associated with the highest average PVLI loss per death. CONCLUSIONS: The productivity-related impacts of premature mortality are substantial. This study provides an assessment of relative impact of these costs across specific age, sex and cause of death categories. IMPLICATIONS: Policies and interventions that prevent premature mortality would improve both health and economic outcomes. An awareness of the productivity costs associated with all-cause mortality may assist decision makers in identifying population and disease subgroups where cost-effective health care investment can achieve the greatest economic gains to society.