A standard set of person-centred outcomes for diabetes mellitus: results of an international and unified approach.

AIMS: To select a core list of standard outcomes for diabetes to be routinely applied internationally, including patient-reported outcomes. METHODS: We conducted a structured systematic review of outcome measures, focusing on adults with either type 1 or type 2 diabetes. This process was followed by a consensus-driven modified Delphi panel, including a multidisciplinary group of academics, health professionals and people with diabetes. External feedback to validate the set of outcome measures was sought from people with diabetes and health professionals. RESULTS: The panel identified an essential set of clinical outcomes related to diabetes control, acute events, chronic complications, health service utilisation, and survival that can be measured using routine administrative data and/or clinical records. Three instruments were recommended for annual measurement of patient-reported outcome measures: the WHO Well-Being Index for psychological well-being; the depression module of the Patient Health Questionnaire for depression; and the Problem Areas in Diabetes scale for diabetes distress. A range of factors related to demographic, diagnostic profile, lifestyle, social support and treatment of diabetes were also identified for case-mix adjustment. CONCLUSIONS: We recommend the standard set identified in this study for use in routine practice to monitor, benchmark and improve diabetes care. The inclusion of patient-reported outcomes enables people living with diabetes to report directly on their condition in a structured way.

Hazard Group 3 agent decontamination using hydrogen peroxide vapour in a class III microbiological safety cabinet.

AIMS: This study investigated the efficacy of hydrogen peroxide vapour (HPV) at inactivating hazard group 3 bacteria that have been presented dried from their growth medium to present a realistic challenge. METHODS AND RESULTS: Hydrogen peroxide vapour technology (Bioquell) was used to decontaminate a class III microbiological safety cabinet containing biological indicators (BIs) made by drying standard working suspensions of the following agents: Bacillus anthracis (Ames) spores, Brucella abortus (strain S99), Burkholderia pseudomallei (NCTC 12939), Escherichia coli O157 ST11 (NCTC 12079), Mycobacterium tuberculosis (strain H37Rv) and Yersinia pestis (strain CO92) on stainless steel coupons. Extended cycles were used to expose the agents for 90 min. The HPV cycle completely inactivated B. anthracis spores, B. abortus, B. pseudomallei, E. coli O157 and Y. pestis when BIs were processed using quantitative and qualitative methods. Whilst M. tuberculosis was not completely inactivated, it was reduced by 4 log10 from a starting concentration of 106 colony-forming units. CONCLUSIONS: This study demonstrates that HPV is able to inactivate a range of HG3 agents at high concentrations with associated organic matter, but M. tuberculosis showed increased resistance to the process. SIGNIFICANCE AND IMPACT OF THE STUDY: This publication demonstrates that HPV can inactivate HG3 agents that have an organic load associated with them. It also shows that M. tuberculosis has higher resistance to HPV than other agents. This shows that an appropriate BI to represent the agent of interest should be chosen to demonstrate a decontamination is successful.

Can We Use Routinely Collected Healthcare Data for a Nationwide Trial on Venous Thromboembolism Prophylaxis Following Primary Joint Replacement? A Feasibility Study.

BACKGROUND: UK hospitals nationally report venous thromboembolism (VTE) within 90 days of hospital admission, with hospital-acquired thrombosis (HAT) registers at each center used for this. We assessed the accuracy of our HAT register in identifying VTE following primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: We assessed 982 elective admissions for primary THA and TKA at a large tertiary center during 2018. The primary outcome was any VTE (deep vein thrombosis and/or pulmonary embolism) within 90 days postsurgery. VTEs were identified by systematically searching hospital databases (including discharge and outpatient letters, readmissions, emergency department visits, and imaging) for every patient. VTEs were also collected using the HAT database at our center, which is maintained regularly by a specialist nursing team and used to report VTEs nationally. Diagnostic test characteristics were assessed for HAT in identifying VTEs compared to the gold standard (ie, VTEs from the hospital databases). RESULTS: The prevalence of VTE was 2.7% (n = 27), with 20 VTEs identified by HAT. The accuracy of HAT in identifying VTEs were as follows: sensitivity = 74.1% (95% confidence interval [CI] = 53.7-88.9), specificity = 100% (CI = 99.6-100), positive predictive value = 100% (CI = 83.2-100), and negative predictive value = 99.3% (CI = 98.5-99.7). CONCLUSION: One-quarter of VTEs occurring after THA and TKA were not identified by the HAT register. These cases would be missing when our hospital's data are sent for national VTE reporting, and therefore would have substantial implications if HAT was primarily used to identify VTEs in a trial. Further work is needed to improve the accuracy of HAT VTE reporting before this could be relied upon in this setting.

A critical appraisal of Monro's erroneous description of the cerebral interventricular foramina: Age-related magnetic resonance imaging spatial morphometry and a proposed new terminology.

Anatomic connections between the cerebral lateral and third ventricles have been mischaracterized since Monro's original erroneous description of his eponymous foramina (FoMs) as being only one T-shaped passage. Accurate knowledge of the in vivo three-dimensional (3D) configuration of FoM has important clinical neuroendoscopic, neurosurgical, and neuroimaging implications. We retrospectively analyzed volumetric high-resolution brain magnetic resonance imaging of 100 normal individuals to characterize the normal spatial anatomy and morphometry for each FoM. We measured the true anatomical 3D angulations of FoMs relative to standard neuroimaging orthogonal planes, and their minimum width, depth, and distance between the medial borders of bilateral FoMs. The right and left FoMs were separate, distinct, and in a V-shaped configuration. Each FoM was a round, oval, or crescent-shaped canal-like passage with well-defined borders formed by the semicircular concavity of the ipsilateral forniceal column. The plane of FoM was angled on average 56.8° ± 9.1° superiorly from the axial plane, 22.5° ± 10.7° laterally, and 37.0° ± 6.9° anteriorly from the midsagittal plane; all these angles changing significantly with increasing age. The mean narrowest diameter of FoM was 2.8 ± 1.2 mm, and its depth was 2.5 ± 0.2 mm. Thus, the true size and orientation of FoM differs from that depicted on standard neuroimaging. Notably, in young subjects, FoM has a diameter smaller than its depth, a configuration akin to a short, small canal. We propose that the eponym "Monro" no longer be associated with this structure, and the term "foramen" be abandoned. Instead, FoM should be more appropriately renamed as the "interventricular canaliculus," or IVC, for short.

Donepezil for gait and falls in mild cognitive impairment: a randomized controlled trial.

BACKGROUND AND PURPOSE: Cognitive enhancers are commonly prescribed to people with Alzheimer's disease and related dementias to improve cognition and function. However, their effectiveness for individuals in the pre-stages of dementia, particularly in functional motor outcomes, remains unknown. We aimed to determine the efficacy of donepezil, a cognitive enhancer that improves cholinergic neurotransmission, on gait performance in mild cognitive impairment (MCI). METHODS: This was a double-blind, placebo-controlled trial including 60 older adults with MCI, randomized to receive donepezil (10 mg/daily, maximal dose) or placebo. Primary outcome was gait speed (cm/s) under single and three dual-task conditions (counting backwards by 1 or 7 and naming animals) measured using an electronic walkway. Dual-task gait cost (DTC), a valid measure of motor-cognitive interaction, was calculated as the percentage change between single (S) and dual-task (D) gait speeds: [(S - D)/S] × 100. Secondary outcomes included attention, executive function, balance and falls. RESULTS: After 6 months, the donepezil group experienced an improvement in dual-task gait speed (range 4-11 cm/s), although this was not statistically significant. The donepezil group showed a significant reduction in DTC (improvement) by counting backwards by 1 and 7 compared with placebo (10.25% vs. 1.75%, P = 0.048; 21.38% vs. 14.64%, P = 0.037, intention-to-treat analysis). Per-protocol analyses showed that all three DTCs improved in the donepezil group, along with a non-significant reduction of rate of falls. CONCLUSIONS: Donepezil treatment improved dual-task gait speed and DTC in elderly patients with MCI. Our results support the concept of reducing falls in MCI by targeting the motor-cognitive interface.

The effect of exercise on bone mineral density in adult cancer survivors: a systematic review and meta-analysis.

PURPOSE: Certain cancer treatments are associated with bone loss and increased fracture risk. Weight-bearing impact exercise, resistance training or the combination, are recommended to preserve or improve bone mineral density (BMD) inhealthy older adults, but their efficacy in cancer survivors is less well understood. The aim of this systematic review with meta-analysis of randomised control trials (RCT) was to review the evidence regarding the role of exercise to counteract cancer treatment-induced bone loss. METHODS: Four databases were searched systematically with 12 RCTs of at least 6-month duration investigating the effects of exercise on BMD compared to a control group in adult cancer survivors identified. RESULTS: Meta-analysis was completed using available data from six studies enrolling 814 participants, with lumbar spine, femoral neck and/or total hip BMD as the primary outcome measures. Overall, there was no significant benefit of exercise compared to controls on BMD at the lumbar spine (0.0071 g/cm , 95% CI -0.0002 to 0.0145, p = 0.057), femoral neck (0.0044 g/cm , 95% CI -0.0005 to 0.0093, p = 0.077), or total hip (0.0024 g/cm , 95% CI -0.0038 to 0.0086, p = 0.443). Subgroup analysis revealed a positive effect on lumbar spine BMD in three studies implementing a combined resistance and impact exercise intervention (0.015 g/cm , 95% CI 0.003 to 0.028, p = 0.019). CONCLUSIONS: From the evidence available, exercise may not be sufficient to improve bone health in cancer survivors, but given the heterogeneity in the participant characteristics and several exercise programs which may not have been designed to specifically optimise bone health, these findings should be interpreted with caution.

Association between serum interleukin-17A and clinical response to tofacitinib and etanercept in moderate to severe psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory disease with a pathophysiology involving interleukin (IL)-17. Tofacitinib is an oral Janus kinase inhibitor. Etanercept is a tumour necrosis factor-α inhibitor used in the treatment of psoriasis. Neither agent inhibits IL-17 directly. AIM: To evaluate correlations between circulating IL-17A and clinical efficacy in patients with psoriasis treated with tofacitinib or etanercept. METHODS: Serum concentrations of IL-17A homodimer and IL-17A/F heterodimer were determined by immunoassays at weeks 0, 4 and 12 in patients with moderate to severe psoriasis treated with placebo (n = 60), tofacitinib 5 mg twice daily (n = 184), tofacitinib 10 mg twice daily (n = 190), or etanercept 50 mg subcutaneously twice weekly (n = 190). Disease severity was assessed using the Psoriasis Area and Severity Index (PASI) and clinical response was defined as patients achieving ≥ 75% improvement from baseline PASI (PASI75). RESULTS: Serum levels of IL-17A homodimer at week 0 showed moderate correlation with PASI, with a Spearman correlation coefficient of 0.43. Furthermore, serum levels of IL-17A homodimer showed a clear correlation with clinical response, with a decrease of 57.1% in patients achieving PASI75 at week 12, but only 15.9% decrease in nonresponders. PASI75 responders had lower median concentrations of IL-17A (range across treatments: 0.24-0.27 pg/mL) at week 12 vs. nonresponders (0.37-0.62 pg/mL), regardless of the treatment. Serum IL-17A/F heterodimer showed similar decreases at week 12 in responders and nonresponders. CONCLUSIONS: Baseline serum IL-17A correlates moderately with psoriasis severity. Reduction in circulating IL-17A is required for disease remission regardless of therapeutic agent.

Synthesis and Reactivity of a Low-Coordinate Iron(II) Hydride Complex: Applications in Catalytic Hydrodefluorination.

A low-coordinate iron hydride complex bearing an unsymmetrical NpN (enamido-phosphinimine) ligand scaffold was synthesized and fully characterized. Insertion reactivity with azobenzene, 3-hexyne, and 1-azidoadamantane was explored, and the isolated products were analogous to previously reported ß-diketiminate iron hydride insertion products. Surprisingly, the NpN iron hydride displays unprecedented reactivity toward hexafluorobenzene, affording an NpN iron fluoride complex and pentafluorobenzene as products. The NpN iron hydride is a precatalyst for catalytic hydro-defluorination of perfluorinated aromatics in the presence of silane. Kinetic studies indicated that the rate-determining step during catalysis involved silane.

Using a linked database for epidemiology across the primary and secondary care divide: acute kidney injury.

BACKGROUND: NHS England has mandated the use in hospital laboratories of an automated early warning algorithm to create a consistent method for the detection of acute kidney injury (AKI). It generates an 'alert' based on changes in serum creatinine level to notify attending clinicians of a possible incident case of the condition, and to provide an assessment of its severity. We aimed to explore the feasibility of secondary data analysis to reproduce the algorithm outside of the hospital laboratory, and to describe the epidemiology of AKI across primary and secondary care within a region. METHODS: Using the Hampshire Health Record Analytical database, a patient-anonymised database linking primary care, secondary care and hospital laboratory data, we applied the algorithm to one year (1st January-31st December 2014) of retrospective longitudinal data. We developed database queries to modularise the collection of data from various sectors of the local health system, recreate the functions of the algorithm and undertake data cleaning. RESULTS: Of a regional population of 642,337 patients, 176,113 (27.4%) had two or more serum creatinine test results available, with testing more common amongst older age groups. We identified 5361 (or 0.8%) with incident AKI indicated by the algorithm, generating a total of 13,845 individual AKI alerts. A cross-sectional assessment of each patient's first alert found that more than two-thirds of cases originated in the community, of which nearly half did not lead to a hospital admission. CONCLUSION: It is possible to reproduce the algorithm using linked primary care, secondary care and hospital laboratory data, although data completeness, data quality and technical issues must be overcome. Linked data is essential to follow the significant proportion of people with AKI who transition from primary to secondary care, and can be used to assess clinical outcomes and the impact of interventions across the health system. This study emphasises that the development of data systems bridging across different sectors of the health and social care system can provide benefits for researchers, clinicians, healthcare providers and commissioners.

RETROSTERNAL GOITRES: A PRACTICAL CLASSIFICATION.

BACKGROUND: There is no standard definition for goitres extending below the thoracic inlet and no clear guidelines for pre-operative planning of surgery. The aim of this study is a practical classification of retrosternal goitres (RSG) based on the anatomical , radiological shape and size of the thyroid. METHODS: Retrospective analysis of all thyroidectomies performed in a referral centre between January 2012 and December 2016. Patients with RSGs had a pre-operative CT scan of neck/thorax. Imaging was reviewed to establish features to predict the difficulty of delivering the goitre through the neck incision and to advise the best surgical approach. RESULTS: 847 thyroidectomies were performed with n=98 involving RSGs. TypeA (n=47) are RSG with a shape of a "cone" or pyramid with the apex pointing down. Cervicotomy is the usual approach. TypeB (n=39) are goitres with a shape of a "pyramid' with the apex pointing up, cervicotomy with ± manubriotomy or sternotomy ± thoracotomy maybe required. TypeC (n=6) are thyroid enlargements in the mediastinum connected by a pedicle with the thyroid in the neck. A cervical approach ± manubriotomy or sternotomy ± thoracotomy is needed. TypeD (n=6) are true intrathoracic or "forgotten" goitres. Sternotomy is indicated for thyroids in the anterior mediastinum though a thoracic approach for those located in the posterior mediastinum might be needed. CONCLUSION: The shape and size of goitres is important in carefully planning surgery. CT imaging with cross-sectional reconstruction should be analysed before operation. The proposed classification helps treatment planning and allows comparison of outcomes by anatomical complexity.

Understanding decisions made about hepatitis C treatment by couples who inject drugs.

Efforts to increase the number of people having hepatitis C virus (HCV) treatment require understanding how to best deliver services to meet consumers' needs. The general health literature has examined the role that partners can play in supporting health outcomes. This study examines the experiences of couples who inject drugs in relation to knowledge of, decisions about and management of HCV treatment. This is a qualitative interview study of people who inject drugs in couples. Participants were recruited from harm reduction services in two major Australian cities. Couples were interviewed separately. Data were examined using the couple as the unit of analysis and to identify patterns of experience related to the HCV serostatus of couples. Knowledge of HCV and HCV treatment was low and variable but showed some relationship to serostatus. Decisions about HCV treatment were deeply informed by concerns regarding treatment side effects. Positive concordant couples considered 'staging' treatment to ensure that each partner could (in turn) care for the other. People with HCV in serodiscordant relationships may need specific support regarding HCV treatment information. Within positive concordant partnerships, our data indicated the need to support the HCV-positive 'carer' during their partner's treatment. Changing treatment regimens, and their anticipated lower side effect profiles, will need to be actively promoted to ensure that couples understand how these changes affect their treatment options.

Copper(I) Complexes of Pyridine-Bridged Phosphaalkene-Oxazoline Pincer Ligands.

The synthesis of enantiomerically pure pyridine-bridged phosphaalkene-oxazolines ArP═C(Ph)(2,6-C5H3NOx) (1, Ar = Mes/Mes*, Ox = CNOCH(i-Pr)CH2/CNOCH(CH2Ph)CH2) is reported. This new ligand forms a κ(P), κ(2)(NN) dimeric complex with copper(I) (7) that dissociates into a cationic κ(3)(PNN) monomeric complex upon addition of a neutral ligand {[1a·CuL]OTf (8a-e): L = PPh3 (a), P(OPh)3 (b), 2,6-lutidine (c), 4-DMAP (d), 1-methylimidazole (e)}. The P-Cu bond lengths in 8 are influenced by the π-accepting/σ-donating properties of L, and this can be observed by changes in the δ(31)PP═C NMR shift. The donor-acceptor properties in complexes of type 8 have also been investigated by UV/vis spectroscopy and density functional theory calculations.

Synthesis of Iron and Cobalt Complexes of a Ferrocene-Linked Diphosphinoamide Ligand and Characterization of a Weak Iron-Cobalt Interaction.

A ferrocene-based bis(phosphinoamine) fc(NHP(i)Pr2)2 has been deprotonated and used in salt metathesis reactions to form dimeric complexes ([fc(NP(i)Pr2)2]M)2 (M = Fe, Co). A novel coordination environment for Co(II) is observed including a weak but significant Fe-Co interaction, which was characterized using X-ray crystallography, Mössbauer spectroscopy, and VT-magnetometry. Density functional theory (DFT) calculations including natural bond order analysis provides further support for the interaction and suggests a combination of Fe → Co and Co → Fe interactions.

BRAF(V600E) Mutation is Associated with Decreased Disease-Free Survival in Papillary Thyroid Cancer.

BACKGROUND: The BRAF (V600E) mutation is a recognised molecular marker in papillary thyroid cancer (PTC), reported incidence from 30 to 80 %. BRAF(V600E) aberrantly activates the MAPK pathway, a central regulator of cell growth and proliferation. Previous studies have reported conflicting data regarding the impact of BRAF(V600E) on clinicopathological features of PTC. The study aims to determine whether BRAF(V600E) is useful as a prognostic biomarker in PTC. METHODS: A cohort study of patients undergoing surgery for PTC was undertaken. The primary outcome measure was disease-free survival. Secondary outcome measures were tumour size, nodal positivity and radioactive iodine ablation rate. All cases were re-examined to confirm PTC. Immunohistochemistry for BRAF(V600E) was performed on tissue microarrays. A single endocrine pathologist, blinded to clinicopathological data, interpreted staining. RESULTS: 496 patients with PTC were included, and 309 (62 %) were BRAF(V600E) positive. Tumour size was similar for BRAF(V600E)-positive and -negative tumours (21.3 vs. 23.2 mm, p = 0.23). BRAF(V600E)-positive patients were significantly older at first operation (mean age 45 versus 49 years, p = 0.003). BRAF(V600E)-positive PTCs had a higher rate of disease recurrence (12.9 vs. 5.6 %, p = 0.004), lymph node metastasis (44 vs. 29.4 %, p = 0.004) and extra-thyroidal extension (44 vs. 22 %, p < 0.001). Five-year disease-free survival was 89.6 % for BRAF(V600E) positive and 96.3 % for negative tumours, p < 0.001. There was no difference between groups for vascular invasion or multifocality. The mean follow-up was 57 months for both groups. CONCLUSION: BRAF(V600E) in PTC predicts an increased risk of lymph node metastasis, extra-thyroidal extension and reduced disease-free survival. It is an additional useful prognostic biomarker.

The LEAP™ Gesture Interface Device and Take-Home Laparoscopic Simulators: A Study of Construct and Concurrent Validity.

AIM: To assess the potential of the LEAP™ infrared motion tracking device to map laparoscopic instrument movement in a simulated environment. Simulator training is optimized when augmented by objective performance feedback. We explore the potential LEAP has to provide this in a way compatible with affordable take-home simulators. METHOD: LEAP and the previously validated InsTrac visual tracking tool mapped expert and novice performances of a standardized simulated laparoscopic task. Ability to distinguish between the 2 groups (construct validity) and correlation between techniques (concurrent validity) were the primary outcome measures. RESULTS: Forty-three expert and 38 novice performances demonstrated significant differences in LEAP-derived metrics for instrument path distance (P < .001), speed (P = .002), acceleration (P < .001), motion smoothness (P < .001), and distance between the instruments (P = .019). Only instrument path distance demonstrated a correlation between LEAP and InsTrac tracking methods (novices: r = .663, P < .001; experts: r = .536, P < .001). Consistency of LEAP tracking was poor (average % time hands not tracked: 31.9%). CONCLUSION: The LEAP motion device is able to track the movement of hands using instruments in a laparoscopic box simulator. Construct validity is demonstrated by its ability to distinguish novice from expert performances. Only time and instrument path distance demonstrated concurrent validity with an existing tracking method however. A number of limitations to the tracking method used by LEAP have been identified. These need to be addressed before it can be considered an alternative to visual tracking for the delivery of objective performance metrics in take-home laparoscopic simulators.

Disinfection of human musculoskeletal allografts in tissue banking: a systematic review.

Musculoskeletal allografts are typically disinfected using antibiotics, irradiation or chemical methods but protocols vary significantly between tissue banks. It is likely that different disinfection protocols will not have the same level of microorganism kill; they may also have varying effects on the structural integrity of the tissue, which could lead to significant differences in terms of clinical outcome in recipients. Ideally, a disinfection protocol should achieve the greatest bioburden reduction with the lowest possible impact on tissue integrity. A systematic review of three databases found 68 laboratory and clinical studies that analyzed the microbial bioburden or contamination rates of musculoskeletal allografts. The use of peracetic acid-ethanol or ionizing radiation was found to be most effective for disinfection of tissues. The use of irradiation is the most frequently published method for the terminal sterilization of musculoskeletal allografts; it is widely used and its efficacy is well documented in the literature. However, effective disinfection results were still observed using the BioCleanse™ Tissue Sterilization process, pulsatile lavage with antibiotics, ethylene oxide, and chlorhexidine. The variety of effective methods to reduce contamination rate or bioburden, in conjunction with limited high quality evidence provides little support for the recommendation of a single bioburden reduction method.

Effect of overreaching on cognitive performance and related cardiac autonomic control.

The purpose of this study was to characterize the effect of a 2-week overload period immediately followed by a 1-week taper period on different cognitive processes including executive and nonexecutive functions, and related heart rate variability. Eleven male endurance athletes increased their usual training volume by 100% for 2 weeks, and decreased it by 50% for 1 week. A maximal graded test, a constant speed test at 85% of peak treadmill speed, and a Stroop task with the measurement of heart rate variability were performed at each period. All participants were considered as overreached. We found a moderate increase in the overall reaction time to the three conditions of the Stroop task after the overload period (816 ± 83 vs 892 ± 117 ms, P = 0.03) followed by a return to baseline after the taper period (820 ± 119 ms, P = 0.013). We found no association between cognitive performance and cardiac parasympathetic control at baseline, and no association between changes in these measures. Our findings clearly underscore the relevance of cognitive performance in the monitoring of overreaching in endurance athletes. However, contrary to our hypothesis, we did not find any relationship between executive performance and cardiac parasympathetic control.

Mapping domains of early life determinants of future multimorbidity across three UK longitudinal cohort studies.

Many studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We explored how potential multiple early life determinants of multimorbidity can be characterised across three UK cohort studies. We used the National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identified early life variables that fit into 12 conceptualised domains of early life determinants of multimorbidity. Variables were assigned into 12 domains; principal component analysis reduced the dimensionality of the data and structured variables into subgroups. The data audit identified 7 domains in ACONF, 10 domains in NCDS and 12 domains in BCS70. Dominant components included maternal fertility histories within the prenatal, antenatal and birth domain, long-term illnesses within the child health domain, educational ability within the child education and health literacy domain, ethnicity within the demography domain, parental health behaviours within the transgenerational domain, housing within the socioeconomic domain and parental-child interactions within the parental-family domain. We demonstrated that if multiple large scale longitudinal studies are used, there is enough data available for researchers to consider conceptualising early life risk factors of multimorbidity across groups or domains. Such conceptualisation can help challenge the existing understanding of disease aetiology and develop new ideas for prevention of multimorbidity.

Limited capacity of proximal tubular proteolysis in mice with proteinuria.

Albuminuria is associated with the additional loss in the urine of small molecular weight proteins normally degraded by the proximal convoluted tubule (PCT), and competition for binding to the megalin/cubilin reuptake system has been considered the likely cause. We have previously reported that deficiency of the intrinsic lysosomal protein Limp-2 causes tubular proteinuria due to reduced fusion of endosomes with lysosomes in the PCT leading to inadequate proteolysis. To determine whether this mechanism also contributes to the tubular proteinuria induced by albumin overload in normal mice, wild-type (WT) mice received daily BSA injections intraperitoneally for 10 days, using untreated Limp-2(-/-) mice as positive controls for inadequate proteolysis. BSA overload induced significant urinary loss of megalin and cubilin ligands in WT mice. Tubular uptake of Alexa-conjugated BSA, administered by intravenous injection, was not reduced in the PCT of mice receiving intraperitoneal BSA. Expression of the tubular protein receptor megalin was also unchanged. There was a delay in proteolysis of reabsorbed proteins in WT mice receiving BSA, evidenced by an increased quantity of retinol-binding protein (RBP) in the kidney cortex, increased basal distribution of endocytosed RBP in cells of the PCT, and persistence of exogenous Alexa-conjugated BSA and RBP after injection. Upregulation of cathepsin L and normal fusion of lysosomes with endosomes were apparently not sufficient to maintain normal clearance of endocytosed proteins. The data suggest that in the presence of competition from albumin overload, reabsorption of filtered proteins is limited by the capacity of lysosomal degradation rather than receptor-mediated endocytosis.

Insulin sensitivity not modulated 24 to 78 h after acute resistance exercise in type 2 diabetes patients.

Resistance exercise is recommended as part of the exercise guidelines to prevent and manage type 2 diabetes (T2D), however, the frequency of exercise required to improve glycaemic control and insulin sensitivity is not clear. We recruited and tested 10 individuals with T2D by collecting a fasting blood sample immediately prior to, a whole-body moderate-high intensity resistance exercise session, and 24, 48 and 72 h afterwards. No changes to estimates of insulin sensitivity (HOMA2), glucose or insulin were observed using a repeated measures analysis of variance (p > 0.05). Further, there were no changes observed to markers of inflammation at 24 h following the resistance exercise session (p > 0.05). These findings suggest that insulin sensitivity is not acutely modified, positively or negatively, at 24, 48 or 72 h after a bout of resistance exercise. Nor are markers of inflammation altered during this time frame in a way that could cause transient insulin resistance.