Prospective cohort study of nonspecific deprescribing in older medical inpatients being discharged to a nursing home.

Background: Older patients from nursing homes are commonly exposed to polypharmacy before a hospital admission. Deprescribing has been promoted as a solution to this problem, though systematic reviews have not found benefit. The aim of this study was to understand if in-hospital deprescribing of certain classes of medications is associated with certain benefits or risks. Methods: We conducted a prospective, multicentre, cohort study in 239 medical inpatients ⩾75 years (mean age 87.4 years) who were exposed to polypharmacy (⩾5 medications) prior to admission and discharged to a nursing home for permanent placement. Patients were categorised by whether deprescribing occurred, mortality and readmissions were assessed 30 and 90 days after hospital discharge. The EQ-5D-5 L health survey assessed changes in health-related quality of life (HRQOL) at 90 days, with comparison to EQ-5D-5 L results at day 30. Latent class analysis (LCA) was used to investigate associations between patterns of prescribed and deprescribed medications and mortality. Results: Patients for whom deprescribing occurred had a higher Charlson Index; there were no differences between the groups in principal diagnosis, total or Beers list number of medications on admission. The number of Beers list medications increased in both groups before discharge. Patients who had medications deprescribed had nonsignificantly greater odds of dying within 90 days [odds ration (OR) = 3.23 (95% confidence interval (CI): 0.68, 14.92; p = 0.136]. Deprescribing of certain classes was associated with higher 90-day mortality: antihypertensives (OR = 2.27, 95% CI: 1.004, 5; p = 0.049) and statins (OR = 5, 95% CI: 1.61, 14.28; p = 0.005). Readmissions and 1-year mortality rates were similar. There was no deterioration in HRQOL when medications were deprescribed. LCA showed that patients with the least medication changes had the lowest mortality. Conclusion: Deprescribing certain classes of medications during hospitalisation was associated with worse mortality, but not readmissions or overall HRQOL. Larger controlled deprescribing studies targeting specific medications are warranted to further investigate these findings.This study was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN1 2616001336471. Plain language summary: Background: When an older person living in a nursing home is admitted to hospital, does stopping long-term medications help them?Many older people from nursing homes take a large number of medications each day to treat symptoms and prevent adverse events. "Polypharmacy" is a term used to describe taking multiple long-term medications, and it is associated with many negative outcomes such as increased number of falls, cognitive decline, hospital readmission, even death. Deprescribing of nonessential medications - whether stopping or reducing the dose - is promoted as good hospital practice and is assumed to help older frail people live longer and feel better. However, we often don't fully understand what is and is not essential.We wanted to better understand the effect of deprescribing long-term medications for older frail patients during an unplanned hospital admission as they were going to a nursing home to live.Methods: While admitted to hospital, medications are often reviewed by a clinical pharmacist and specialist physician. Sometimes medications are ceased; sometimes they are not. This gave us the opportunity to study two groups of older frail people from nursing homes: those who had regular, long-term medications ceased or reduced and those who did not. We wanted to see if one group did better. For example, did they feel worse if we stopped certain medications? Did they suffer other bad events compared with those patients for whom no medications were ceased? Were they readmitted to hospital earlier or more often?Results and conclusion: Despite the assumption that stopping medications for this type of patient is good practice, we found no benefit. We were also surprised to find stopping or reducing certain drug classes (e.g. antihypertensives and cholesterol-lowering drugs) was associated with greater mortality. Larger, randomised studies will better answer these important questions.

Hospital admission as a deprescribing triage point for patients discharged to Residential Aged Care Facilities.

BACKGROUND: Deprescribing may benefit older frail patients experiencing polypharmacy. We investigated the scope for deprescribing in acutely hospitalised patients and the long-term implications of continuation of medications that could potentially be deprescribed. METHODS: Acutely hospitalised patients (n = 170) discharged to Residential Aged Care Facilities, ≥75 years and receiving ≥5 regular medications were assessed during admission to determine eligibility for deprescribing of key drug classes, along with the actual incidence of deprescribing. The impact of continuation of nominated drug classes (anticoagulants, antidiabetics, antiplatelets, antipsychotics, benzodiazepines, proton pump inhibitors (PPIs), statins) on a combined endpoint (death/readmission) was determined. RESULTS: Hyperpolypharmacy (>10 regular medications) was common (49.4%) at admission. Varying rates of deprescribing occurred during hospitalisation for the nominated drug classes (8-53%), with considerable potential for further deprescribing (34-90%). PPI use was prevalent (56%) and 89.5% of these had no clear indication. Of the drug classes studied, only continued PPI use at discharge was associated with increased mortality/readmission at 1 year (hazard ratio 1.54, 95% confidence interval (1.06-2.26), P = 0.025), driven largely by readmission. CONCLUSION: There is considerable scope for acute hospitalisation to act as a triage point for deprescribing in older patients. PPIs in particular appeared overprescribed in this susceptible patient group, and this was associated with earlier readmission. Polypharmacy in older hospitalised patients should be targeted for possible deprescribing during hospitalisation, especially PPIs.

A pilot cohort study of deprescribing for nursing home patients acutely admitted to hospital.

BACKGROUND: Patients from residential aged care facilities are commonly exposed to inappropriate polypharmacy. Unplanned inpatient admissions can provide an opportunity for review of complex medical regimens and deprescribing of inappropriate or nonbeneficial medications. The aim of this study was to assess the efficacy, safety and sustainability of in-hospital deprescribing. METHODS: We followed a prospective, multi-centre, cohort study design, with enrolment of 106 medical inpatients age 75 years and older (mean age was 88.8 years) who were exposed to polypharmacy prior to admission and with a planned discharge to a nursing home for permanent placement. Descriptive statistics were calculated for relevant variables. The Short Form-8 (SF-8) health survey was used to assess changes in health-related quality of life (HRQOL) at 90-day follow up, in comparison with SF-8 results at day 30. RESULTS: Deprescribing occurred in most, but not all patients. There were no differences between the groups in principal diagnosis, Charlson index, number of medications on admission or number of Beers list medications on admission. At 90 days, mortality and readmissions were similar, though the deprescribed group had significantly higher odds of better emotional wellbeing than the nondeprescribed group [odds ratio (OR) = 5.08, 95% confidence interval (CI): 1.93, 13.39; p = 0.001]. In the deprescribing group, 31% of the patients still alive at 90 days had medications restarted in primary care. One-year mortality rates were similar. CONCLUSIONS: Deprescribing medications during an unplanned hospital admission was not associated with mortality, readmissions, or overall HRQOL.

Evaluation of a bone morphogenetic protein 6 variant as a cause of iron loading.

BACKGROUND: Atypical iron overload without variation in the five clinically associated hereditary hemochromatosis genes is now recognized; however, their etiology remains unknown. Since the identification of iron overload in the bone morphogenetic protein 6 (Bmp6) knockout mouse, the search has been on for clinically pathogenic variants in the BMP6 gene. A recent report proposes that variants in the pro-peptide region of BMP6 are the underlying cause of several cases of iron overload. We performed targeted next-generation sequencing on three cases of atypical iron overload with Asian ethnicity and identified a p.Q118dup (aka p.E112indelEQ, p.Q115dup, p.Q118_L119insQ) variant in BMP6. The purpose of this study was to characterize the molecular function of the identified BMP6 variant. Molecular characterization by immunofluorescence microscopy and Western blotting of transfected cells, bioinformatics, and population analyses was performed. RESULTS: In contrast to reports for other BMP6 pro-peptide variants in this region, our data indicates that this variant does not affect the function of the mature BMP6 protein. CONCLUSIONS: Our data suggest that assignment of disease causation in clinical cases of iron overload to pro-peptide variants in BMP6 should thus be treated with caution and requires biological characterization.

Reversal of end-stage heart failure in juvenile hemochromatosis with iron chelation therapy: a case report.

BACKGROUND: Juvenile hemochromatosis is the most severe form of iron overloading phenotype. Although rare, it should be suspected in patients who present with hypogonadotropic hypogonadism, diabetes mellitus, or cardiomyopathy without a clear cause. CASE PRESENTATION: A young Serbian male presenting with end-stage heart failure was referred for extracorporeal membrane oxygenation. An endomyocardial biopsy revealed cytoplasmic iron deposits in myocytes. His condition was stabilized with biventricular assist devices and he was listed for heart transplantation. Iron chelation therapy was commenced and resulted in rapid removal of iron burden. Serial outpatient echocardiograms demonstrated myocardial recovery such that a successful biventricular assist device explant occurred 131 days after initial implant. Targeted gene sequencing revealed a loss-of-function mutation within the HJV gene, which is consistent with juvenile hemochromatosis. CONCLUSIONS: This rare case of a patient with juvenile hemochromatosis associated with a HJV mutation provides histologic evidence documenting the reversal of associated end-stage heart failure, requiring emergent mechanical circulatory support, with iron chelation therapy.

The dynamics of hepcidin-ferroportin internalization and consequences of a novel ferroportin disease mutation.

The hepcidin-ferroportin axis underlies the pathophysiology of many iron-associated disorders and is a key target for the development of therapeutics for treating iron-associated disorders. The aims of this study were to investigate the dynamics of hepcidin-mediated ferroportin internalization and the consequences of a novel disease-causing mutation on ferroportin function. Specific reagents for ferroportin are limited; we developed and characterized antibodies against the largest extracellular loop of ferroportin and developed a novel cell-based assay for studying hepcidin-ferroportin function. We show that hepcidin-mediated ferroportin internalization is a rapid process and could be induced using low concentrations of hepcidin. Targeted next-generation sequencing utilizing an iron metabolism gene panel developed in our group identified a novel ferroportin p.D84E variant in a patient with iron overload. Wild-type and mutant ferroportin constructs were generated, transfected into HEK293 cells and analysed using an all-in-one flow-cytometry-based assay to study the effects on hepcidin-mediated internalization and iron transport. Consistent with the classical phenotype of ferroportin disease, the p.D84E mutation results in an inability to transport iron and hepcidin insensitivity. These results validate a recently proposed 3D-structural model of ferroportin and highlight the significance of this variant in the structure and function of ferroportin. Our novel ferroportin antibody and assay will be valuable tools for investigating the regulation of hepcidin/ferroportin function and the development of novel approaches for the therapeutic modulation of iron homeostasis.

Interactive Exploration, Analysis, and Visualization of Complex Phenome-Genome Datasets with ASPIREdb.

Identifying variants causal for complex genetic disorders is challenging. With the advent of whole-exome and whole-genome sequencing, computational tools are needed to explore and analyze the list of variants for further validation. Correlating genetic variants with subject phenotype is crucial for the interpretation of the disease-causing mutations. Often such work is done by teams of researchers who need to share information and coordinate activities. To this end, we have developed a powerful, easy to use Web application, ASPIREdb, which allows researchers to search, organize, analyze, and visualize variants and phenotypes associated with a set of human subjects. Investigators can annotate variants using publicly available reference databases and build powerful queries to identify subjects or variants of interest. Functional information and phenotypic associations of these genes are made accessible as well. Burden analysis and additional reporting tools allow investigation of variant properties and phenotype characteristics. Projects can be shared, allowing researchers to work collaboratively to build queries and annotate the data. We demonstrate ASPIREdb's functionality using publicly available data sets, showing how the software can be used to accomplish goals that might otherwise require specialized bioinformatics expertise. ASPIREdb is available at http://aspiredb.chibi.ubc.ca.

Lean body mass change over 6 years is associated with dietary leucine intake in an older Danish population.

Higher protein intake, and particularly higher leucine intake, is associated with attenuated loss of lean body mass (LBM) over time in older individuals. Dietary leucine is thought to be a key mediator of anabolism. This study aimed to assess this relationship over 6 years among younger and older adult Danes. Dietary leucine intake was assessed at baseline and after 6 years in men and women, aged 35-65 years, participating in the Danish cohort of the WHO-MONICA (Multinational MONItoring of trends and determinants in CArdiovascular disease) study (n 368). Changes in LBM over the 6 years were measured by bioelectrical impedance using equations developed for this Danish population. The association between leucine and LBM changes was examined using multivariate linear regression and ANCOVA analyses adjusted for potential confounders. After adjustment for baseline LBM, sex, age, energy intake and physical activity, leucine intake was associated with LBM change in those older than 65 years (n 79), with no effect seen in those younger than 65 years. Older participants in the highest quartile of leucine intake (7·1 g/d) experienced LBM maintenance, whereas lower intakes were associated with LBM loss over 6 years (for trend: ß=0·434, P=0·03). Sensitivity analysis indicated no effect modification of sex or the presence of CVD. Greater leucine intake in conjunction with adequate total protein intake was associated with long-term LBM retention in a healthy older Danish population. This study corroborates findings from laboratory investigations in relation to protein and leucine intakes and LBM change. A more diverse and larger sample is needed for confirmation of these results.

Next-generation sequencing: Application of a novel platform to analyze atypical iron disorders.

The development of targeted next-generation sequencing (NGS) applications now promises to be a clinically viable option for the diagnosis of rare disorders. This approach is proving to have significant utility where standardized testing has failed to identify the underlying molecular basis of disease. We have developed a unique targeted NGS panel for the systematic sequence-based analysis of atypical iron disorders. We report the analysis of 39 genes associated with iron regulation in eight cases of atypical iron dysregulation, in which five cases we identified the definitive causative mutation, and a possible causative mutation in a sixth. We further provide a molecular and cellular characterization study of one of these mutations (TFR2, p.I529N) in a familial case as proof of principle. Cellular analysis of the mutant protein indicates that this amino acid substitution affects the localization of the protein, which results in its retention in the endoplasmic reticulum and thus failure to function at the cell surface. Our unique NGS panel presents a rapid and cost-efficient approach to identify the underlying genetic cause in cases of atypical iron homeostasis disorders.

Functional analysis of matriptase-2 mutations and domains: insights into the molecular basis of iron-refractory iron deficiency anemia.

Mutations in the TMPRSS6 gene are associated with severe iron-refractory iron deficiency anemia resulting from an overexpression of hepcidin, the key regulator of iron homeostasis. The matriptase (MT)-2 protein (encoded by the TMPRSS6 gene) regulates hepcidin expression by cleaving hemojuvelin [HJV/hemochromatosis type 2 (HFE2)], a bone morphogenetic protein (BMP) coreceptor in the hepcidin regulatory pathway. We investigated the functional consequences of five clinically associated TMPRSS6 variants and the role of MT-2 protein domains by generating epitope-tagged mutant and domain-swapped MT-2-MT-1 (encoded by the ST14 gene) chimeric constructs and expressing them in HepG2/C3A cells. We developed a novel cell culture immunofluorescence assay to assess the effect of MT-2 on cell surface HJV expression levels, compatible with HJV cleavage. The TMPRSS6 variants Y141C, I212T, G442R, and C510S were retained intracellularly and were unable to inhibit BMP6 induction of hepcidin. The R271Q variant, although it has been associated with iron-refractory iron deficiency anemia, appears to remain functional. Analysis of the chimeric constructs showed that replacement of sperm protein, enterokinase, and agrin (SEA), low-density-lipoprotein receptor class A (LDLRA), and protease (PROT) domains from MT-2 with those from MT-1 resulted in limited cell surface localization, while the complement C1r/C1s, Uegf, Bmp1 (CUB) domain chimera retained localization at the cell surface. The SEA domain chimera was able to reduce cell surface HJV expression, while the CUB, LDLRA, and PROT domain chimeras were not. These studies suggest that the SEA and LDLRA domains of MT-2 are important for trafficking to the cell surface and that the CUB, LDLRA, and PROT domains are required for cleavage of HJV.

Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload.

UNLABELLED: To identify polymorphisms associated with variability of iron overload severity in HFE-associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n = 22; cases) or with normal or mildly increased iron stores (n = 13; controls). The 35 participants, residents of the United States, Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single-nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload (P = 3 × 10(-6) ; P = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty-two participants with severe iron overload had glyceronephosphate O-acyltransferase (GNPAT) polymorphism p.D519G (rs11558492; 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed small interfering RNA-based knockdown of GNPAT in the human liver-derived cell line, HepG2/C3A. This knockdown resulted in a >17-fold decrease in expression of the messenger RNA encoding the iron-regulatory hormone, hepcidin. CONCLUSION: GNPAT p.D519G is associated with a high-iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation.

A critical role for murine transferrin receptor 2 in erythropoiesis during iron restriction.

Effective erythropoiesis requires an appropriate supply of iron and mechanisms regulating iron homeostasis and erythropoiesis are intrinsically linked. Iron dysregulation, typified by iron-deficiency anaemia and iron overload, is common in many clinical conditions and impacts the health of up to 30% of the world's population. The proteins transmembrane protease, serine 6 (TMPRSS6; also termed matriptase-2), HFE and transferrin receptor 2 (TFR2) play important and opposing roles in systemic iron homeostasis, by regulating expression of the iron regulatory hormone hepcidin. We have performed a systematic analysis of mice deficient in these three proteins and show that TMPRSS6 predominates over HFE and TFR2 in hepcidin regulation. The phenotype of mice lacking TMPRSS6 and TFR2 is characterized by severe anaemia and extramedullary haematopoiesis in the spleen. Stress erythropoiesis in these mice results in increased expression of the newly identified erythroid iron regulator erythroferrone, which does not appear to overcome the hepcidin overproduction mediated by loss of TMPRSS6. Extended analysis reveals that TFR2 plays an important role in erythroid cells, where it is involved in terminal erythroblast differentiation and the regulation of erythropoietin. In conclusion, we have identified an essential role for TFR2 in erythropoiesis that may provide new targets for the treatment of anaemia.

An international comparison of spontaneous adverse event reports and potentially inappropriate medicine use associated with dabigatran.

PURPOSE: The objective of this study was to analyse spontaneous adverse event (SAE) reports associated with the oral anticoagulant dabigatran from Australia, Canada and USA and to examine concomitant medicine use. METHODS: Spontaneous adverse event national databases from Australia, Canada and the USA were used to examine all reports of adverse events associated with dabigatran from 1st August 2005 to 31st March 2013. Disproportionality analysis was conducted for the quantitative detection of signals using the USA database. Concomitant medicine use was examined to identify potentially inappropriate medicines, which may place the patient at increased risk for adverse events. RESULTS: There were a total of 1039, 1333 and 13 788 SAE reports associated with dabigatran from Australia, Canada and USA, respectively. Gastrointestinal (GI) disorders were the most commonly reported adverse event, ranging from 27.5% for Australia and up to 40.5% for USA. Of these, GI haemorrhage accounted for 81.5% of Australian, 71.5% of Canadian and 42% of the USA adverse event reports for GI disorders. Positive signals were confirmed in the USA data (GI haemorrhage; PRR 18.18, χ2 40993.51 and ROR 19.55 95% CI 18.77-20.36). Use of concomitant medicines with the potential to increase bleeding risk across all three countries ranged from 34.1% for Australia to 51.1% for the USA. CONCLUSIONS: A large proportion of adverse events were associated with concomitant therapies, which may have placed the patient at increased risk of harm. This highlights the need for pharmacovigilance by the prescribing clinician to minimise risk and ensure the safe and effective integration of dabigatran into routine clinical practice.

A cross-country comparison of rivaroxaban spontaneous adverse event reports and concomitant medicine use with the potential to increase the risk of harm.

BACKGROUND: Concerns with the safety profiles of the newer anticoagulants have been raised because of differences in treatment populations between pre-marketing studies (randomized controlled trials) and clinical practice. Little is known about the potential safety issues and the reporting in spontaneous adverse event databases associated with rivaroxaban. OBJECTIVES: To analyse spontaneous adverse event reports associated with the oral anticoagulant rivaroxaban from Australia, Canada and the USA; and to examine concomitant medicine use that may increase the risk of adverse events. METHODS: Spontaneous adverse event report databases from Australia, Canada and the USA were examined for all reports of adverse events associated with rivaroxaban and concomitant medicines from 1 August 2005 to 31 March 2013. Disproportionality analysis (the proportional reporting ratio [PRR] and reporting odds ratio [ROR]) was conducted for quantitative detection of signals, using the US database. RESULTS: There were 244 spontaneous adverse event reports associated with rivaroxaban from Australia, 536 from Canada and 1,638 from the USA. Reporting of haemorrhage (any type) was common, ranging from 30.7% for Australia to 37.5% for Canada. Gastrointestinal haemorrhage was the most commonly reported haemorrhage, accounting for 13.9% of Australian, 16.4% of Canadian and 11.1% of US adverse event reports. Positive signals were confirmed in the US data (haemorrhage [any type] PRR 11.93, χ (2) 4,414.78 and ROR 13.41, 95% confidence interval [CI] 12.13-14.81; gastrointestinal haemorrhage PRR 12.52, χ (2) 2,018.48 and ROR 13.15, 95% CI 11.36-15.21). Reporting of concomitant use of medicines with the potential to increase bleeding risk ranged from 63.7% in Australia to 89.2% in Canada. CONCLUSION: A large proportion of adverse event reports for rivaroxaban were associated with use of concomitant medicines, which may have increased the risk of adverse events-in particular, haemorrhage. Increased awareness of a patient's comorbidity and associated medicine use is needed when rivaroxaban is used in clinical practice.

The muscle mass, omega-3, diet, exercise and lifestyle (MODEL) study - a randomised controlled trial for women who have completed breast cancer treatment.

BACKGROUND: Loss of lean body mass (LBM) is a common occurrence after treatment for breast cancer and is related to deleterious metabolic health outcomes [Clin Oncol, 22(4):281-288, 2010; Appl Physiol Nutr Metab, 34(5):950-956, 2009]. The aim of this research is to determine the effectiveness of long chain omega-3 fatty acids (LCn-3s) and exercise training alone, or in combination, in addressing LBM loss in breast cancer survivors. METHODS/DESIGN: A total of 153 women who have completed treatment for breast cancer in the last 12 months, with a Body Mass Index (BMI) of 20 to 35 kg/m2, will be randomly assigned to one of 3 groups: 3g/d LCn-3s (N-3), a 12-week nutrition and exercise education program plus olive oil (P-LC) or the education program plus LCn-3s (EX+N-3). Participants randomised to the education groups will be blinded to treatment, and will receive either olive oil placebo (OO+N-3) or LCn-3 provision, while the N-3 group will be open label. The education program includes nine 60-75 min sessions over 12 weeks that will involve breast cancer specific healthy eating advice, plus a supervised exercise session run as a resistance exercise circuit. They will also be advised to conduct the resistance training and aerobic training 5 to 7 days per week collectively. Outcome measures will be taken at baseline, 12-weeks and 24-weeks. The primary outcome is % change in LBM as measured by the air displacement plethysmograhy. Secondary outcomes include quality of life (FACT-B + 4) and inflammation (C-Reactive protein: CRP). Additional measures taken will be erythrocyte fatty acid analysis, fatigue, physical activity, menopausal symptoms, dietary intake, joint pain and function indices. DISCUSSION: This research will provide the first insight into the efficacy of LCn-3s alone or in combination with exercise in breast cancer survivors with regards to LBM and quality of life. In addition, this study is designed to improve evidence-based dietetic practice, and how specific dietary prescription may link with appropriate exercise interventions. TRIALS REGISTRATION: ACTRN12610001005044; and World Health Organisation Universal trial number: U1111-1116-8520.

Parenteral vs. oral iron: influence on hepcidin signaling pathways through analysis of Hfe/Tfr2-null mice.

Treatment for iron deficiency anemia can involve iron supplementation via dietary or parenteral routes that result in different cellular iron distributions. The effect of the administered iron on the iron regulatory system and hepcidin in the liver has not been well studied. Hepcidin, the liver-expressed central iron-regulatory peptide, is itself regulated through the bone morphogenetic protein (BMP)/SMAD signaling pathway. Specifically, Bmp6 expression is upregulated in response to iron and induces hepcidin through phosphorylation of Smad1/5/8. The hemochromatosis-associated proteins Hfe and transferrin receptor 2 (Tfr2) are known upstream regulators of hepcidin, although their precise roles are still unclear. To investigate the mechanisms of this regulation and the roles of the Hfe and Tfr2, we subjected wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice to iron loading via dietary or parenteral routes. Systematic analysis demonstrated that Tfr2 is required for effective upregulation of Bmp6 in response to hepatocyte iron, but not nonparenchymal iron. Hfe is not required for Bmp6 upregulation, regardless of iron localization, but rather, is required for efficient downstream transmission of the regulatory signal. Our results demonstrate that Hfe and Tfr2 play separate roles in the regulatory responses to iron compartmentalized in different cell types and further elucidates the regulatory mechanisms controlling iron homeostasis.

Omega-3 fatty acids and changes in LBM: alone or in synergy for better muscle health?

Myopenia or muscle wasting due to ageing, chronic disease, and various medical interventions has been associated with increased mortality, morbidity, and poorer physical function. Attempts through nutrient and exercise interventions have been made to prevent this deterioration. In addition, while a measure of lean body mass (LBM) is associated with health outcomes, LBM function may be a better prognostic tool. Long-chain omega-3 fatty acids (LCn-3s) are nutrients that may mitigate LBM losses in noncancer populations. The purpose of this review is to determine whether LCn-3s have a role in LBM sparing in noncancer populations, to establish a minimum dose and duration of LCn-3s that will result in LBM change, and to summarise the potential effects of LCn-3s on LBM function when combined with an anabolic stimulus. Overall, in noncancer populations, LCn-3s have limited utility in sparing LBM during energy balance, energy restriction, or in conjunction with aerobic exercise. Further investigations are required to determine the appropriate dose and duration of LCn-3s for optimal LBM function. Finally, compelling evidence exists for LCn-3s in conjunction with an anabolic stimulus to improve LBM function and quality. Functionality of LBM tissue is an important outcome for population health, and LCn-3s show some promise, albeit pending further study.

Iron storage disease in Asia-Pacific populations: the importance of non-HFE mutations.

Hereditary hemochromatosis (HH) is a widely recognized and well-studied condition in European populations. This is largely due to the high prevalence of the C282Y mutation of HFE. Although less common than in Europe, HH cases have been reported in the Asia-Pacific region because of mutations in both HFE and non-HFE genes. Mutations in all of the currently known genes implicated in non-HFE HH (hemojuvelin, hepcidin, transferrin receptor 2, and ferroportin) have been reported in patients from the Asia-Pacific region. This review discusses the molecular basis of HH and the genes and mutations known to cause non-HFE HH with particular reference to the Asia-Pacific region. Challenges in the genetic diagnosis of non-HFE HH are also discussed and how new technologies such as next generation sequencing may be informative in the future.

Muscle function and omega-3 fatty acids in the prediction of lean body mass after breast cancer treatment.

BACKGROUND: Decreased lean body mass (LBM) is common in breast cancer survivors yet currently there is a lack of information regarding the determinants of LBM after treatment, in particular, the effect of physical activity and dietary factors, such as long-chain omega-3 fatty acids (LCn-3) on LBM and LBM function. This cross-sectional study explored associations of LBM and function with LCn-3 intake, dietary intake, inflammation, quality of life (QOL) and physical fitness in breast cancer survivors to improve clinical considerations when addressing body composition change. METHODS: Forty-nine women who had completed treatment (surgery, radiation and/or chemotherapy) were assessed for body composition (BODPOD), LCn-3 content of erythrocytes, C-reactive protein (CRP), QOL, dietary intake, objective physical activity, 1-min push-ups, 1-min sit-stand, sub-maximal treadmill (TM) test, and handgrip strength. RESULTS: After adjustment for age, LBM was associated with push-ups (r = 0.343, p = 0.000), stage reached on treadmill (StageTM) (r = 0.302, 0.001), % time spent ≥ moderate activity (Mod + Vig) (r = 0.228, p = 0.024). No associations were seen between anthropometric values and any treatment, diagnostic and demographical variables. Body mass, push-ups and StageTM accounted for 76.4% of the variability in LBM (adjusted r-square: 0.764, p = 0.000). After adjustment docosahexanoic acid (DHA) was positively associated with push-ups (ß=0.399, p = 0.001), eicosapentanoic acid (EPA) was negatively associated with squats (r = -0.268, p = 0.041), with no other significant interactions found between LCn-3 and physical activity for LBM or LBM function. CONCLUSION: This is the first investigation to report that a higher weight adjusted LBM is associated with higher estimated aerobic fitness and ability to perform push-ups in breast cancer survivors. Potential LCn-3 and physical activity interactions on LBM require further exploration.