Health-related quality of life among Indigenous Australians diagnosed with cancer.

PURPOSE: Health-related quality of life (HRQoL) and associated factors were assessed among 155 Indigenous Australian adult cancer patients 6 months post-diagnosis. METHODS: The Assessment of Quality of Life-4D Questionnaire was used to assess HRQoL. Differences in the median utility score among subgroups of interest were examined using nonparametric tests. Factors associated with excellent HRQoL were assessed through logistic regression. RESULTS: Participants' mean age was 52 years (range 20-78), and the majority were female (60 %), unemployed (72 %), and recruited from outpatients clinics (64 %). Breast cancer (27 %) was the most common diagnosis. The median HRQoL score was 0.62; 14 % of participants reported excellent HRQoL (>0.90). After adjusting for age, admission status, and treatment, excellent HRQoL was more likely among participants of Torres Strait Islander origin [adjusted odds ratio (AOR) 3.68; 95 % CI 1.23-11.01], those living in regional areas (AOR 5.59; 95 % CI 1.42-22.06), and those whose main language spoken at home was not English (AOR 3.60; 95 % CI 1.08-11.99) and less likely among those reporting less contact with Indigenous people (AOR 0.23; 95 % CI 0.68-0.81). CONCLUSION: Assessing HRQoL is important to identifying and improving the length and quality of cancer survivorship, especially in groups that have significantly poorer cancer outcomes, such as Indigenous Australians. Acknowledging the study's observational nature, we found HRQoL was lower than reported for other Australians, and we identified some socio-demographic factors that were associated with excellent HRQoL. Such assessments are an important component of identifying and evaluating appropriate interventions to improve the health and well-being of Indigenous cancer patients.

Evaluation of therapeutic enoxaparin in a pregnant population at a tertiary hospital.

BACKGROUND: Therapeutic anticoagulation with enoxaparin in pregnancy is complex due to varying pharmacokinetics and the increasing prevalence of obesity. There is limited evidence to support current dosing and monitoring strategies of enoxaparin in this population. AIM: To describe the current practice in therapeutic anticoagulation in the pregnant population at a tertiary institution. METHODS: A retrospective study of pregnant women on therapeutic enoxaparin between January 2007 and December 2011. RESULTS: Forty-four pregnant women requiring therapeutic anticoagulation were identified and divided into two groups, monitored with anti-factor Xa (AXA) concentrations and unmonitored. Fifty-five percent of monitored women were initiated on the recommended 1 mg/kg twice a day (bd) enoxaparin dose-strategy. Eighty-two percent of women were monitored; however, there was variability regarding the timing, frequency and subsequent dose adjustments from monitoring. Overall, as pregnancies progressed, there was both increasing dose adjustments and increasing frequency of monitoring. Fourteen women had a BMI over 30 kg/m(2) , and 13 of these women were monitored. Nine monitored obese women required doses less than 1 mg/kg/bd to maintain a therapeutic AXA level. Management appeared to be individualised. There were small numbers of toxicity events. CONCLUSION: Variation exists in dosing and monitoring practices for therapeutic enoxaparin in the pregnant population. Dosing obese patients using 1 mg/kg twice daily can lead to toxic AXA concentrations, and dose reductions are required to maintain a therapeutic range. A larger prospective study reviewing dose, AXA concentrations and outcome data is necessary to make dosing recommendations in this group.

Off-label use of tumour necrosis factor-alpha inhibitors and anakinra at an Australian tertiary hospital.

BACKGROUND: Tumour necrosis factor-alpha inhibitors (anti-TNFα) and anakinra are monoclonal antibodies against pro-inflammatory cytokines overexpressed in many systemic inflammatory diseases. In Australia, they are registered for the treatment of several rheumatological, gastroenterological and dermatological indications. Despite increasing observational evidence for their use in off-label indications, there is a paucity of outcome research from the Australian hospital sector. AIMS: To describe the off-label use of anti-TNFα and anakinra at a tertiary referral hospital in Queensland, Australia and consideration of a drug register to inform future clinical decision-making. METHODS: We performed an in-depth retrospective chart audit of off-label treatment with anti-TNFα or anakinra at the Royal Brisbane and Women's Hospital from mid-2010 to mid-2014, linking demographic, phenotypic, pathology and outcome data with these drugs. RESULTS: Off-label use was identified in 10 patients. The most frequent indications were sarcoidosis and dermatological conditions. Three patients required sequential therapy with a second anti-TNFα (total responses = 13). Complete response occurred in 46%, partial response in 38% and primary non-response in 8%. Response was unable to be determined in 8%. We recorded 14 adverse events (infections most common). CONCLUSION: This study suggests that anti-TNFα may be beneficial for some off-label indications (e.g. sarcoidosis). However, the observational design of this study (and pre-existing research) limits the ability to infer causality and generalise results. We propose the creation of a mandatory drug register to monitor off-label use. Whilst comparative efficacy cannot be established without a matched placebo arm, a register would enable some reporting on effectiveness in rare diseases and identify infrequent but serious adverse events.

Health professional's perspectives of the barriers and enablers to cancer care for Indigenous Australians.

To investigate health professionals' perspectives about factors that impede or facilitate cancer care for Indigenous people. Semi-structured interviews with 22 health professionals involved in Indigenous cancer care. Data were interpreted using an inductive thematic analysis approach. Participants presented their perspectives on a number of barriers and enablers to Indigenous cancer care. Barriers were related to challenges with communication, the health system and coordination of care, issues around individual and community priorities and views of cancer treatment and health professional judgement. Enablers to cancer care were related to the importance of trust and rapport as well as health care system and support factors. The findings highlighted the need for recording of Indigenous status in medical records and a coordinated approach to the provision of evidence-based and culturally appropriate cancer care. This could go some way to improving Indigenous patient's engagement with tertiary cancer care services.

Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration.

OBJECTIVES: Interleukin 1 (IL-1) is potentially important in the pathogenesis of intervertebral disc (IVD) degeneration; increasing production of matrix degradation enzymes and inhibiting matrix synthesis. Although IL-1 polymorphisms have been linked to increased risk of IVD degeneration, it is still unclear whether IL-1 drives IVD degeneration in vivo or is a secondary feature of degeneration. Here, we investigated whether IVD degeneration could be induced spontaneously by the removal of the natural inhibitor of IL-1 (IL-1 receptor antagonist) in mice that lack a functional IL-1rn gene. METHODS: Histological staining and immunohistochemistry was performed on BALB/c IL-1rn(+/+) and IL-1rn(-/-) mice to examine degeneration and to localise and detect IL-1, matrix metalloproteinases (MMP)3, MMP7, a disintigrin and MMP with thrombospondin motifs (ADAMTS)4 protein production. In addition, IVD cells were isolated using collagenase and proliferation potential determined. RESULTS: IL-1rn(-/-) knockout mice displayed typical features of human disc degeneration: loss of proteoglycan and normal collagen structure and increased expression of matrix degrading enzymes: MMP3; MMP7 and ADAMTS4. Histological grade of degeneration increased in IL-1rn(-/-) mice which was more evident within older mice. In addition IVD cells isolated from IL-1rn(-/-) mice displayed reduced proliferation potential. CONCLUSIONS: Here, we show that IL-1rn(-/-) mice develop spinal abnormalities that resemble characteristic features associated with human disc degeneration. The current evidence is consistent with a role for IL-1 in the pathogenesis of IVD degeneration. The imbalance between IL-1 and IL-1Ra which is observed during human IVD degeneration could therefore be a causative factor in the degeneration of the IVD, and as such, is an appropriate pharmaceutical target for inhibiting degeneration.

Interleukin-1ß regulates CXCL8 release and influences disease outcome in response to Streptococcus pneumoniae, defining intercellular cooperation between pulmonary epithelial cells and macrophages.

The success of Streptococcus pneumoniae (the pneumococcus) as a pulmonary pathogen is related to its restriction of innate immune responses by respiratory epithelial cells. The mechanisms used to overcome this restriction are incompletely elucidated. Pulmonary chemokine expression involves complex cellular and molecular networks, involving the pulmonary epithelium, but the specific cellular interactions and the cytokines that control them are incompletely defined. We show that serotype 2 or 4 pneumococci induce only modest levels of CXCL8 expression from epithelial cell lines, even in the absence of a polysaccharide capsule. In contrast, coculture of A549 cells with the macrophage-like THP-1 cell line, differentiated with vitamin D, or monocyte-derived macrophages enhanced CXCL8 release. Supernatants from the THP-1 cell line prime A549 cells to release CXCL8 at levels similar to cocultures. Interleukin-1Ra (IL-1Ra) inhibits CXCL8 release from cocultures and reduces the activity of macrophage-conditioned media, but inhibition of tumor necrosis factor alpha (TNF-α) had only a minimal effect on CXCL8 release. Release of IL-1ß but not TNF-α was upregulated in cocultures. IL-1 type 1 receptor knockout C57BL/6 and BALB/c mice confirmed the importance of IL-1 signaling in CXC chemokine expression and neutrophil recruitment in vivo. In fulminant disease, increased IL-1 signaling resulted in increased neutrophils in the airway and more invasive disease. These results demonstrate that IL-1 is an important component of the cellular network involving macrophages and epithelial cells, which facilitates CXC chemokine expression and aids neutrophil recruitment during pneumococcal pneumonia. They also highlight a potential clinical role for anti-IL-1 treatment to limit excessive neutrophilic inflammation in the lung.

Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis.

TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial or host-derived ligands found in arthritic joints. Here, we show that TLR2 and TLR4, but not TLR9, are involved in the pathogenesis of autoimmune arthritis and play distinct roles in the regulation of T cells and cytokines. We investigated the involvement of TLR2, TLR4, and TLR9 in the progression of arthritis using IL-1 receptor antagonist-knockout (IL1rn-/-) mice, which spontaneously develop an autoimmune T cell-mediated arthritis. Spontaneous onset of arthritis was dependent on TLR activation by microbial flora, as germ-free mice did not develop arthritis. Clinical and histopathological evaluation of IL1rn-/-Tlr2-/- mice revealed more severe arthritis, characterized by reduced suppressive function of Tregs and substantially increased IFN-gamma production by T cells. IL1rn-/-Tlr4-/- mice were, in contrast, protected against severe arthritis and had markedly lower numbers of Th17 cells and a reduced capacity to produce IL-17. A lack of Tlr9 did not affect the progression of arthritis. While any therapeutic intervention targeting TLR2 still seems complicated, the strict position of TLR4 upstream of a number of pathogenic cytokines including IL-17 provides an interesting potential therapeutic target for rheumatoid arthritis.

How reliable is eGFR when calculating drug dosage in acute medical admissions?

BACKGROUND: The Modification of Diet in Renal Disease-derived estimation of glomerular filtration rate (eGFR) is used widely. Although validated in stable chronic kidney disease (CKD) outpatients, it is not known how it performs in those presenting with acute medical illness. AIM: We aimed to compare eGFR with Cockroft Gault (CG) - the renal function assessment tool available prior to eGFR - to assess the difference in clinical outcome that would occur when one over another estimation is used in practice. In particular, we wished to assess whether use of eGFR would have resulted in a change of dose of commonly used acutely administered medications. METHODS: Acute medical admissions presenting to a tertiary hospital between August and December 2008 were included. Serum creatinine concentration, age, sex, height and weight were collected. Renal function was estimated by both estimates. Movement from CKD class 3 to 4 or 5 was measured - a clinically used cut-off point for changes in management. RESULTS: A total of 54 patients was included. eGFR values were higher than those estimated by CG. Almost half of patients categorized as CKD stage 4-5 using CG were only categorized as CKD stage 3 using eGFR. CONCLUSION: Although we did not use a gold standard estimation of GFR, this study shows that estimates of renal function vary in a clinically significant manner. As estimates of GFR are used to adjust drug dosages and to stratify for many other treatments, it is imperative that we find a method of estimating kidney function that is readily available, consistent and accurate.

Incretin-based therapies--review of the physiology, pharmacology and emerging clinical experience.

Diabetes therapies based on manipulation of the incretin system are now widely available, with millions of people receiving treatment. The incretin hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 are released from endocrine cells in the small intestinal mucosa primarily in response to oral nutrient ingestion. They have various effects, but those most relevant to metabolic dysfunction include stimulation of insulin and suppression of glucagon secretion, with resultant reduction in fasting and postprandial glucose. Incretin secretion and/or action is impaired in type 2 diabetes, leading to development of strategies aimed at redressing this abnormality. These strategies include pharmacological inhibition of dipeptidyl peptidase-4, the enzyme responsible for the short half-life of endogenous incretins, and administration of long-acting dipeptidyl peptidase-4-resistant peptides that bind to and activate the glucagon-like peptide-1 receptor. In this review, we address aspects of incretin biology and pharmacotherapy with a view to highlighting potentially clinically relevant issues and areas of basic research that may impinge on these.

Pitfalls of using estimations of glomerular filtration rate in an intensive care population.

BACKGROUND: Accurate knowledge of the glomerular filtration rate (GFR) is imperative in the intensive care unit (ICU) as renal status is important for medical decisions, including drug dosing. AIMS: Recently, an estimation of GFR (eGFR) was suggested as a method of estimating GFR. How well this formula predicts GFR in unwell patients with normal initial serum creatinine concentrations has not been examined. METHODS: The accuracy of the eGFR (before and after adjustment for actual body surface area (BSA)) was compared with measured and with estimated creatinine clearance using the Cockcroft Gault (CG) formula adjusted for total and lean body weight. RESULTS: A total of 237 observations was recorded in 47 subjects. These were initially analysed independently, and then using the first observation only. Overall the mean difference between measured creatinine clearance and eGFR was -12 mL/min (95% confidence interval (CI) -20 to -3), between measured creatinine clearance and CG +17 mL/min (95% CI 9-24), between measured creatinine clearance and CG adjusted for ideal body weight +12 mL/min (95% CI 4-21) and between measured creatinine clearance and eGFR 'unadjusted' for BSA 5 mL/min (95% CI -2-13). CONCLUSIONS: Using either eGFR or CG formulae to estimate renal function in ICU subjects with normal serum creatinine concentrations is inaccurate. Although correcting for BSA improves the eGFR, this requirement to measure height and weight removes a major attraction for its use. We suggest that eGFR should not be automatically calculated in the ICU setting.

ACE2-Independent Interaction of SARS-CoV-2 Spike Protein with Human Epithelial Cells Is Inhibited by Unfractionated Heparin.

Coronaviruses such as SARS-CoV-2, which is responsible for COVID-19, depend on virus spike protein binding to host cell receptors to cause infection. The SARS-CoV-2 spike protein binds primarily to ACE2 on target cells and is then processed by membrane proteases, including TMPRSS2, leading to viral internalisation or fusion with the plasma membrane. It has been suggested, however, that receptors other than ACE2 may be involved in virus binding. We have investigated the interactions of recombinant versions of the spike protein with human epithelial cell lines that express low/very low levels of ACE2 and TMPRSS2 in a proxy assay for interaction with host cells. A tagged form of the spike protein containing the S1 and S2 regions bound in a temperature-dependent manner to all cell lines, whereas the S1 region alone and the receptor-binding domain (RBD) interacted only weakly. Spike protein associated with cells independently of ACE2 and TMPRSS2, while RBD required the presence of high levels of ACE2 for interaction. As the spike protein has previously been shown to bind heparin, a soluble glycosaminoglycan, we tested the effects of various heparins on ACE2-independent spike protein interaction with cells. Unfractionated heparin inhibited spike protein interaction with an IC50 value of <0.05 U/mL, whereas two low-molecular-weight heparins were less effective. A mutant form of the spike protein, lacking the arginine-rich putative furin cleavage site, interacted only weakly with cells and had a lower affinity for unfractionated and low-molecular-weight heparin than the wild-type spike protein. This suggests that the furin cleavage site might also be a heparin-binding site and potentially important for interactions with host cells. The glycosaminoglycans heparan sulphate and dermatan sulphate, but not chondroitin sulphate, also inhibited the binding of spike protein, indicating that it might bind to one or both of these glycosaminoglycans on the surface of target cells.

Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust.

BACKGROUND: We aimed to measure SARS-CoV-2 seroprevalence in a cohort of healthcare workers (HCWs) during the first UK wave of the COVID-19 pandemic, explore risk factors associated with infection, and investigate the impact of antibody titres on assay sensitivity. METHODS: HCWs at Sheffield Teaching Hospitals NHS Foundation Trust (STH) were prospectively enrolled and sampled at two time points. SARS-CoV-2 antibodies were tested using an in-house assay for IgG and IgA reactivity against Spike and Nucleoprotein (sensitivity 99·47%, specificity 99·56%). Data were analysed using three statistical models: a seroprevalence model, an antibody kinetics model, and a heterogeneous sensitivity model. FINDINGS: As of 12th June 2020, 24·4% (n=311/1275) HCWs were seropositive. Of these, 39·2% (n=122/311) were asymptomatic. The highest adjusted seroprevalence was measured in HCWs on the Acute Medical Unit (41·1%, 95% CrI 30·0-52·9) and in Physiotherapists and Occupational Therapists (39·2%, 95% CrI 24·4-56·5). Older age groups showed overall higher median antibody titres. Further modelling suggests that, for a serological assay with an overall sensitivity of 80%, antibody titres may be markedly affected by differences in age, with sensitivity estimates of 89% in those over 60 years but 61% in those ≤30 years. INTERPRETATION: HCWs in acute medical units working closely with COVID-19 patients were at highest risk of infection, though whether these are infections acquired from patients or other staff is unknown. Current serological assays may underestimate seroprevalence in younger age groups if validated using sera from older and/or more symptomatic individuals. RESEARCH IN CONTEXT: Evidence before this study: We searched PubMed for studies published up to March 6th 2021, using the terms "COVID", "SARS-CoV-2", "seroprevalence", and "healthcare workers", and in addition for articles of antibody titres in different age groups against coronaviruses using "coronavirus", "SARS-CoV-2, "antibody", "antibody tires", "COVID" and "age". We included studies that used serology to estimate prevalence in healthcare workers. SARS-CoV-2 seroprevalence has been shown to be greater in healthcare workers working on acute medical units or within domestic services. Antibody levels against seasonal coronaviruses, SARS-CoV and SARS-CoV-2 were found to be higher in older adults, and patients who were hospitalised.Added value of this study: In this healthcare worker seroprevalence modelling study at a large NHS foundation trust, we confirm that those working on acute medical units, COVID-19 "Red Zones" and within domestic services are most likely to be seropositive. Furthermore, we show that physiotherapists and occupational therapists have an increased risk of COVID-19 infection. We also confirm that antibody titres are greater in older individuals, even in the context of non-hospitalised cases. Importantly, we demonstrate that this can result in age-specific sensitivity in serological assays, where lower antibody titres in younger individuals results in lower assay sensitivity.Implications of all the available evidence: There are distinct occupational roles and locations in hospitals where the risk of COVID-19 infection to healthcare workers is greatest, and this knowledge should be used to prioritise infection prevention control and other measures to protect healthcare workers. Serological assays may have different sensitivity profiles across different age groups, especially if assay validation was undertaken using samples from older and/or hospitalised patients, who tend to have higher antibody titres. Future seroprevalence studies should consider adjusting for age-specific assay sensitivities to estimate true seroprevalence rates.

Acidosis in the hospital setting: is metformin a common precipitant?

BACKGROUND: Acidosis is commonly seen in the acute hospital setting, and carries a high mortality. Metformin has been associated with lactic acidosis, but it is unclear how frequently this is a cause of acidosis in hospitalized inpatients. The aim of this study is to explore the underlying comorbidities and acute precipitants of acidosis in the hospital setting, including the relationship between type 2 diabetes (T2DM) and metformin use. METHODS: Retrospective review. Cases of acidosis were identified using the hospital discharge code for acidosis for a 3-month period: October-December 2005. RESULTS: A total of 101 episodes of acidosis were identified: 29% had isolated respiratory acidosis, 31% had metabolic acidosis and 40% had a mixed respiratory and metabolic acidosis. There were 28 cases of confirmed lactic acidosis. Twenty-nine patients had T2DM, but only five of the subjects with T2DM had lactic acidosis; two were on metformin. The major risk factors for development of lactic acidosis were hepatic impairment (OR 33.8, P = 0.01), severe left ventricular dysfunction (OR 25.3, P = 0.074) and impaired renal function (OR 9.7, P = 0.09), but not metformin use. CONCLUSION: Most cases of metabolic and lactic acidosis in the hospital setting occur in patients not taking metformin. Hepatic, renal and cardiac dysfunction are more important predictors for the development of acidosis.

Giant-cell centrioles.

The giant cell of osteoclastic origin and the giant cell produced in response to foreign bodies are characterized by multiple nuclei. Electron microscopy of these multinucleated cells reveals a special centrosphere in the osteoclast, which is not typical of other types of giant cells.

Nitric oxide decreases motility and increases adhesion in human breast cancer cells.

Our previous results have suggested that increasing aggressiveness of breast tumour cells is associated with the down-regulation of the expression of nitric oxide synthase (NOS). As increasing aggressiveness is associated with a propensity for metastasis, this study aimed to investigate whether our theory applied to the processes of motility and invasion. Although the well-established dual roles of nitric oxide (NO) were evident, most of the results are consistent with our theory. We demonstrated that basal motility is higher in the MCF-7-ADR multidrug-resistant variant cell line compared to the MCF-7 parent cell line and that treatment with NOS inhibitors increased motility in MDA-MB-231 and T47D cells. Exogenous NO was associated with a trend to increase adhesion in the MCF-7 and MDA-MB-231 cell lines. These results are consistent with the theory that loss of NOS expression may be associated with the progression of breast cancers via increase in motility and loss of adhesion.

p493F12 kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system.

Monoclonal antibody 3F12 identifies a cytoplasmic antigen of 49 kDa in human hippocampus and neocortex. The distribution of 3F12 immunoreactive neurons closely matches that of Alzheimer's disease (AD) targeted neurons in these areas. In some hippocampal neurons of AD patients, this antigen colocalizes with ALZ-50, indicating the presence of AD pathology in these neurons. Molecular characterization of the 3F12 cDNA revealed it to be a member of the MAP kinase family, showing 43% amino acid sequence identity to human extracellular related kinase 2 (p42mapk). We have confirmed that p493F12 kinase autophosphorylates both threonine and tyrosine residues, as expected for a MAP kinase. The p49 mRNA is expressed exclusively in the nervous system. In the brain, the distribution of these neurons closely corresponds to 3F12 antigen-bearing neurons. The p493F12 gene maps to the human chromosome 21q21 region, a region that may be important in the pathogenesis of AD and Down's syndrome.