Development and validation of a frailty index compatible with three interRAI assessment instruments

BACKGROUND: a Frailty Index (FI) calculated by the accumulation of deficits is often used to quantify the extent of frailty in individuals in specific settings. This study aimed to derive a FI that can be applied across three standardised international Residential Assessment Instrument assessments (interRAI), used at different stages of ageing and the corresponding increase in support needs. METHODS: deficit items common to the interRAI Contact Assessment (CA), Home Care (HC) or Long-Term Care Facilities assessment (LTCF) were identified and recoded to form a cumulative deficit FI. The index was validated using a large dataset of needs assessments of older people in New Zealand against mortality prediction using Kaplan Meier curves and logistic regression models. The index was further validated by comparing its performance with a previously validated index in the HC cohort. RESULTS: the index comprised 15 questions across seven domains. The assessment cohort and their mean frailty (SD) were: 89,506 CA with 0.26 (0.15), 151,270 HC with 0.36 (0.15) and 83,473 LTCF with 0.41 (0.17). The index predicted 1-year mortality for each of the CA, HC and LTCF, cohorts with area under the receiver operating characteristic curves (AUCs) of 0.741 (95% confidence interval, CI: 0.718-0.762), 0.687 (95%CI: 0.684-0.690) and 0.674 (95%CI: 0.670-0.678), respectively. CONCLUSIONS: the results for this multi-instrument FI are congruent with the differences in frailty expected for people in the target settings for these instruments and appropriately associated with mortality at each stage of the journey of progressive ageing.</p

Stepwise engineering of a Pichia pastoris D-amino acid oxidase whole cell catalyst

<p>Abstract</p> <p>Background</p> <p><it>Trigonopsis variabilis </it><smcaps>D</smcaps>-amino acid oxidase (<it>Tv</it>DAO) is a well characterized enzyme used for cephalosporin C conversion on industrial scale. However, the demands on the enzyme with respect to activity, operational stability and costs also vary with the field of application. Processes that use the soluble enzyme suffer from fast inactivation of <it>Tv</it>DAO while immobilized oxidase preparations raise issues related to expensive carriers and catalyst efficiency. Therefore, oxidase preparations that are more robust and active than those currently available would enable a much broader range of economically viable applications of this enzyme in fine chemical syntheses. A multi-step engineering approach was chosen here to develop a robust and highly active <it>Pichia pastoris Tv</it>DAO whole-cell biocatalyst.</p> <p>Results</p> <p>As compared to the native <it>T. variabilis </it>host, a more than seven-fold enhancement of the intracellular level of oxidase activity was achieved in <it>P. pastoris </it>through expression optimization by codon redesign as well as efficient subcellular targeting of the enzyme to peroxisomes. Multi copy integration further doubled expression and the specific activity of the whole cell catalyst. From a multicopy production strain, about 1.3 × 10³U/g wet cell weight (wcw) were derived by standard induction conditions feeding pure methanol. A fed-batch cultivation protocol using a mixture of methanol and glycerol in the induction phase attenuated the apparent toxicity of the recombinant oxidase to yield final biomass concentrations in the bioreactor of ≥ 200 g/L compared to only 117 g/L using the standard methanol feed. Permeabilization of <it>P. pastoris </it>using 10% isopropanol yielded a whole-cell enzyme preparation that showed 49% of the total available intracellular oxidase activity and was notably stabilized (by three times compared to a widely used <it>Tv</it>DAO expressing <it>Escherichia coli </it>strain) under conditions of <smcaps>D</smcaps>-methionine conversion using vigorous aeration.</p> <p>Conclusions</p> <p>Stepwise optimization using a multi-level engineering approach has delivered a new <it>P. pastoris </it>whole cell <it>Tv</it>DAO biocatalyst showing substantially enhanced specific activity and stability under operational conditions as compared to previously reported preparations of the enzyme. The production of the oxidase through fed-batch bioreactor culture and subsequent cell permeabilization is high-yielding and efficient. Therefore this <it>P. pastoris </it>catalyst has been evaluated for industrial purposes.</p

The Drug Burden Index and Level of Frailty as Determinants of Healthcare Costs in a Cohort of Older Frail Adults in New Zealand

OBJECTIVES: Frailty is common in older people and is associated with increased use of healthcare services and ongoing use of multiple medications. This study provides insights into the healthcare cost structure of a frail group of older adults in Aotearoa, New Zealand. Furthermore, we investigated the relationship between participants' anticholinergic and sedative medication burden and their total healthcare costs to explore the viability of deprescribing interventions within this cohort.METHODS: Healthcare cost analysis was conducted using data collected during a randomized controlled trial within a frail, older cohort. The collected information included participant demographics, medications used, frailty, cost of service use of aged residential care and outpatient hospital services, hospital admissions, and dispensed medications.RESULTS: Data from 338 study participants recruited between 25 September 2018 and 30 October 2020 with a mean age of 80 years were analyzed. The total cost of healthcare per participant ranged from New Zealand $15 (US dollar$10) to New Zealand $270 681 (US dollar$175 943) over 6 months postrecruitment into the study. Four individuals accounted for 26% of this cohort's total healthcare cost. We found frailty to be associated with increased healthcare costs, whereas the drug burden was only associated with increased pharmaceutical costs, not overall healthcare costs.CONCLUSIONS: With no relationship found between a patient's anticholinergic and sedative medication burden and their total healthcare costs, more research is required to understand how and where to unlock healthcare cost savings within frail, older populations.</p

Frailty of Māori, Pasifika, and non-Māori/non-Pasifika older people in New Zealand: a national population study of older people referred for home care services

Little is known about the prevalence of frailty in indigenous populations. We developed a frailty index for older New Zealand Māori and Pasifika who require publicly funded support services.A frailty index (FI) was developed for New Zealand adults aged ≥65 years who had an interRAI-Home Care assessment between 1 June 2012 and 30 October 2015. A frailty score for each participant was calculated by summing the number of deficits recorded and dividing by the total number of possible deficits. This created a FI with a potential range from 0 to 1. Linear regression models for FIs with ethnicity were adjusted for age and sex. Cox proportional hazards models were used to assess the association between the FI and mortality for Māori, Pasifika, and non-Māori/non-Pasifika.Of 54,345 participants, 3,096 (5.7%) identified as Māori, 1,846 (3.4%) were Pasifika, and 49,415 (86.7%) identified as neither Māori nor Pasifika. New Zealand Europeans (48,178, 97.5%) constituted most of the latter group. Within each sex, the mean FIs for Māori and Pasifika were greater than the mean FIs for non-Māori and non-Pasifika, with the difference being more pronounced in females. The FI was associated with mortality (Māori SHR 2.53, 95% CI 1.63 to 3.95; Pasifika SHR 6.03, 95% CI 3.06 to 11.90; non-Māori and non-Pasifika SHR 2.86, 95% 2.53 to 3.25).This study demonstrated differences in FI between the ethnicities in this select cohort. After adjustment for age and sex, increases in FI were associated with increased mortality. This suggests that FI is predictive of poor outcomes in these ethnic groups

Mechanism of completion of peptidyltransferase centre assembly in eukaryotes.

During their final maturation in the cytoplasm, pre-60S ribosomal particles are converted to translation-competent large ribosomal subunits. Here, we present the mechanism of peptidyltransferase centre (PTC) completion that explains how integration of the last ribosomal proteins is coupled to release of the nuclear export adaptor Nmd3. Single-particle cryo-EM reveals that eL40 recruitment stabilises helix 89 to form the uL16 binding site. The loading of uL16 unhooks helix 38 from Nmd3 to adopt its mature conformation. In turn, partial retraction of the L1 stalk is coupled to a conformational switch in Nmd3 that allows the uL16 P-site loop to fully accommodate into the PTC where it competes with Nmd3 for an overlapping binding site (base A2971). Our data reveal how the central functional site of the ribosome is sculpted and suggest how the formation of translation-competent 60S subunits is disrupted in leukaemia-associated ribosomopathies.Bloodwise, MRC, Wellcome Trus

Recent advances in cardio-oncology:a report from the 'Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019'

While anti-cancer therapies, including chemotherapy, immunotherapy, radiotherapy, and targeted therapy, are constantly advancing, cardiovascular toxicity has become a major challenge for cardiologists and oncologists. This has led to an increasing demand of cardio-oncology units in Europe and a growing interest of clinicians and researchers. The Heart Failure 2019 meeting of the Heart Failure Association of the European Society of Cardiology in Athens has therefore created a scientific programme that included four dedicated sessions on the topic along with several additional lectures. The major points that were discussed at the congress included the implementation and delivery of a cardio-oncology service, the collaboration among cardio-oncology experts, and the risk stratification, prevention, and early recognition of cardiotoxicity. Furthermore, sessions addressed the numerous different anti-cancer therapies associated with cardiotoxic effects and provided guidance on how to treat cancer patients who develop cardiovascular disease before, during, and after treatment

Burkitt lymphoma masquerading as cardiac tamponade

A 61 year old man presented with diffuse large B cell lymphoma of the skin of the back of the shoulder which was excised and treated with chemotherapy (CHOP regime) in 1998. He was in complete remission till he presented in 2002 with extranodal marginal zone lymphoma of the parotid gland for which he underwent superficial parotidectomy and radiotherapy. He continued in remission till 2006 when he presented with recurrent pericardial effusion and tamponade. At median sternotomy, pericardial effusion was drained, an anterior pericardiectomy was done and a left posterior pericardial window made, and an enlarged hard paraaortic lymph node excised. Histology, immunocytochemistry and chromosome analysis revealed Burkitt lymphoma. Patient underwent chemotherapy with CODOX-M regime and continues in remission. This report is unusual on account of the highly atypical presentation of Burkitt lymphoma as cardiac tamponade, only a few cases having been reported previously, the occurrence of three lymphomas of different pathological and genomic profiles in one patient over a period of eight years and the relatively slow rate of growth of an otherwise fulminant tumour with high tumour doubling time. A review of literature with special emphasis on chromosomal diagnosis, transformation of other lymphomas into Burkitt lymphoma and mediastinal and cardiac involvement with Burkitt lymphoma is presented

Aortic stiffness as a marker of cardiac function and myocardial strain in patients undergoing aortic valve replacement

Background: Cardiac function and myocardial strain are affected by cardiac afterload, which is in part due to the stiffness of the aortic wall. In this study, we hypothesize that aortic pulse wave velocity (PWV) as a marker of aortic stiffness correlates with conventional clinical and biochemical markers of cardiac function and perioperative myocardial strain in aortic valve replacement (AVR). Methods: Patients undergoing AVR for aortic stenosis between June 2010 and August 2012 were recruited for inclusion in this study. PWV, NYHA class and left ventricular (LV) function were assessed pre-operatively. PWV was analysed both as a continuous and dichotomous variable according to age-standardized reference values. B-type natriuretic peptide (BNP) was measured pre-operatively, and at 3 h and 18-24 h after cardiopulmonary bypass (CPB). NYHA class, leg edema, and LV function were recorded at follow-up (409 ± 159 days). Results: Fifty-six patients (16 females) with a mean age of 71 ± 8.4 years were included, with 50 (89%) patients completing follow-up. The NYHA class of PWV-norm patients was significantly lower than PWV-high patients both pre- and post-operatively. Multiple logistic regression also highlighted PWV-cut off as an independent predictor of NYHA class pre- and post-operatively (OR 8.3, 95%CI [2.27,33.33] and OR 14.44, 95%CI [1.49,139.31] respectively). No significant relationship was observed between PWV and either LV function or plasma BNP. Conclusion: In patients undergoing AVR for aortic stenosis, PWV is independently related to pre- and post-operative NYHA class but not to LV function or BNP. These findings provisionally support the use of perioperative PWV as a non-invasive marker of clinical functional status, which when used in conjunction with biomarkers of myocardial strain such as BNP, may provide a holistic functional assessment of patients undergoing aortic valve surgery. However, in order for PWV assessment to be translated into clinical practice and utilised as more than simply a research tool, further validation is required in the form of larger prospective studies specifically designed to assess the relationship between PWV and these functional clinical outcomes