Search

Demyelination within the central nervous system (CNS) is a significant feature of debilitating neurological diseases such as multiple sclerosis and administering the copper-selective chelatorcuprizone to mice is widely used to model demyelination in vivo. Conspicuous demyelination within the corpus callosum is generally attributed to cuprizone's ability to restrict copper availability in this vulnerable brain region. However, the small number of studies that have assessed copper in brain tissue from cuprizone-treated mice have produced seemingly conflicting outcomes, leaving the role of CNS copper availability in demyelination unresolved. Herein we describe our assessment of copper concentrations in brain samples from mice treated with cuprizone for 40 d. Importantly, we applied an inductively coupled plasma mass spectrometry methodology that enabled assessment of copper partitioned into soluble and insoluble fractions within distinct brain regions, including the corpus callosum. Our results show that cuprizone-induced demyelination in the corpus callosum was associated with decreased soluble copper in this brain region. Insoluble copper in the corpus callosum was unaffected, as were pools of soluble and insoluble copper in other brain regions. Treatment with the blood-brain barrier permeant copper compound CuII(atsm) increased brain copper levels and this was most pronounced in the soluble fraction of the corpus callosum. This effect was associated with significant mitigation of cuprizone-induced demyelination. These results provide support for the involvement of decreased CNS copper availability in demyelination in the cuprizone model. Relevance to human demyelinating disease is discussed.

BACKGROUND: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved. METHODS: To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1G37R mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo. RESULTS: We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1G37R mouse model where treatment with a CNS-permeant ferroptosis inhibitor, CuII(atsm), ameliorated these markers and was neuroprotective. CONCLUSIONS: By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pat

Demyelination within the central nervous system (CNS) is a significant feature of debilitating neurological diseases such as multiple sclerosis and administering the copper-selective chelatorcuprizone to mice is widely used to model demyelination in vivo. Conspicuous demyelination within the corpus callosum is generally attributed to cuprizone's ability to restrict copper availability in this vulnerable brain region. However, the small number of studies that have assessed copper in brain tissue from cuprizone-treated mice have produced seemingly conflicting outcomes, leaving the role of CNS copper availability in demyelination unresolved. Herein we describe our assessment of copper concentrations in brain samples from mice treated with cuprizone for 40 d. Importantly, we applied an inductively coupled plasma mass spectrometry methodology that enabled assessment of copper partitioned into soluble and insoluble fractions within distinct brain regions, including the corpus callosum. Our results show that cuprizone-induced demyelination in the corpus callosum was associated with decreased soluble copper in this brain region. Insoluble copper in the corpus callosum was unaffected, as were pools of soluble and insoluble copper in other brain regions. Treatment with the blood-brain barrier permeant copper compound CuII(atsm) increased brain copper levels and this was most pronounced in the soluble fraction of the corpus callosum. This effect was associated with significant mitigation of cuprizone-induced demyelination. These results provide support for the involvement of decreased CNS copper availability in demyelination in the cuprizone model. Relevance to human demyelinating disease is discussed.

Demyelination within the central nervous system (CNS) is a significant feature of debilitating neurological diseases such as multiple sclerosis and administering the copper-selective chelatorcuprizone to mice is widely used to model demyelination in vivo. Conspicuous demyelination within the corpus callosum is generally attributed to cuprizone's ability to restrict copper availability in this vulnerable brain region. However, the small number of studies that have assessed copper in brain tissue from cuprizone-treated mice have produced seemingly conflicting outcomes, leaving the role of CNS copper availability in demyelination unresolved. Herein we describe our assessment of copper concentrations in brain samples from mice treated with cuprizone for 40 d. Importantly, we applied an inductively coupled plasma mass spectrometry methodology that enabled assessment of copper partitioned into soluble and insoluble fractions within distinct brain regions, including the corpus callosum. Our results show that cuprizone-induced demyelination in the corpus callosum was associated with decreased soluble copper in this brain region. Insoluble copper in the corpus callosum was unaffected, as were pools of soluble and insoluble copper in other brain regions. Treatment with the blood-brain barrier permeant copper compound CuII(atsm) increased brain copper levels and this was most pronounced in the soluble fraction of the corpus callosum. This effect was associated with significant mitigation of cuprizone-induced demyelination. These results provide support for the involvement of decreased CNS copper availability in demyelination in the cuprizone model. Relevance to human demyelinating disease is discussed.

BACKGROUND: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved. METHODS: To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1G37R mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo. RESULTS: We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1G37R mouse model where treatment with a CNS-permeant ferroptosis inhibitor, CuII(atsm), ameliorated these markers and was neuroprotective. CONCLUSIONS: By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pat

The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.

OBJECTIVE: (1) To estimate the pooled prevalence of multimorbidity in all age groups, globally. (2) To examine how measurement of multimorbidity impacted the estimated prevalence. METHODS: In this systematic review and meta-analysis, we conducted searches in nine bibliographic databases (PsycINFO, Embase, Global Health, Medline, Scopus, Web of Science, Cochrane Library, CINAHL and ProQuest Dissertations and Theses Global) for prevalence studies published between database inception and 21 January 2020. Studies reporting the prevalence of multimorbidity (in all age groups and in community, primary care, care home and hospital settings) were included. Studies with an index condition or those that did not include people with no long-term conditions in the denominator were excluded. Retrieved studies were independently reviewed by two reviewers, and relevant data were extracted using predesigned pro forma. We used meta-analysis to pool the estimated prevalence of multimorbidity across studies, and used random-effects meta-regression and subgroup analysis to examine the association of heterogeneous prevalence estimates with study and measure characteristics. RESULTS: 13 807 titles were screened, of which 193 met inclusion criteria for meta-analysis. The pooled prevalence of multimorbidity was 42.4% (95% CI 38.9% to 46.0%) with high heterogeneity (I2 >99%). In adjusted meta-regression models, participant mean age and the number of conditions included in a measure accounted for 47.8% of heterogeneity in effect sizes. The estimated prevalence of multimorbidity was significantly higher in studies with older adults and those that included larger numbers of conditions. There was no significant difference in estimated prevalence between low-income or middle-income countries (36.8%) and high-income countries (44.3%), or between self-report (40.0%) and administrative/clinical databases (52.7%). CONCLUSIONS: The pooled prevalence of multimorbidity was significantly higher in older

OBJECTIVE: To develop international consensus on the definition and measurement of multimorbidity in research. DESIGN: Delphi consensus study. SETTING: International consensus; data collected in three online rounds from participants between 30 November 2020 and 18 May 2021. PARTICIPANTS: Professionals interested in multimorbidity and people with long term conditions were recruited to professional and public panels. RESULTS: 150 professional and 25 public participants completed the first survey round. Response rates for rounds 2/3 were 83%/92% for professionals and 88%/93% in the public panel, respectively. Across both panels, the consensus was that multimorbidity should be defined as two or more long term conditions. Complex multimorbidity was perceived to be a useful concept, but the panels were unable to agree on how to define it. Both panels agreed that conditions should be included in a multimorbidity measure if they were one or more of the following: currently active; permanent in their effects; requiring current treatment, care, or therapy; requiring surveillance; or relapsing-remitting conditions requiring ongoing care. Consensus was reached for 24 conditions to always include in multimorbidity measures, and 35 conditions to usually include unless a good reason not to existed. Simple counts were preferred for estimating prevalence and examining clustering or trajectories, and weighted measures were preferred for risk adjustment and outcome prediction. CONCLUSIONS: Previous multimorbidity research is limited by inconsistent definitions and approaches to measuring multimorbidity. This Delphi study identifies professional and public panel consensus guidance to facilitate consistency of definition and measurement, and to improve study comparability and reproducibility.

OBJECTIVES: This study aimed to examine the differences in multimorbidity between Aboriginal and Torres Strait Islander people and non-Indigenous Australians, and the effect of multimorbidity on health service use and work productivity. SETTING: Cross-sectional sample of the Household, Income and Labour Dynamics in Australia wave 17. PARTICIPANTS: A nationally representative sample of 16 749 respondents aged 18 years and above. OUTCOME MEASURES: Multimorbidity prevalence and pattern, self-reported health, health service use and employment productivity by Indigenous status. RESULTS: Aboriginal respondents reported a higher prevalence of multimorbidity (24.2%) compared with non-Indigenous Australians (20.7%), and the prevalence of mental-physical multimorbidity was almost twice as high (16.1% vs 8.1%). Multimorbidity pattern varies significantly among the Aboriginal and non-Indigenous Australians. Multimorbidity was associated with higher health service use (any overnight admission: adjusted OR=1.52, 95% CI=1.46 to 1.58), reduced employment productivity (days of sick leave: coefficient=0.25, 95% CI=0.19 to 0.31) and lower perceived health status (SF6D score: coefficient=-0.04, 95% CI=-0.05 to -0.04). These associations were found to be comparable in both Aboriginal and non-Indigenous populations. CONCLUSIONS: Multimorbidity prevalence was significantly greater among Aboriginal and Torres Strait Islanders compared with the non-Indigenous population, especially mental-physical multimorbidity. Strategies are required for better prevention and management of multimorbidity for the aboriginal population to reduce health inequalities in Australia.

BACKGROUND: Population health has stagnated or is declining in many high-income countries. We analysed whether nationally administered austerity cuts in England were associated with prevalence of multimorbidity (individuals with two or more long-term conditions) and health-related quality of life. METHODS: We conducted an observational, longitudinal study on 147 local authorities in England. We examined associations of changes in spending over time (2009/10-2017/18), in total and by budget line, with (i) prevalence of multimorbidity, 2+ conditions (2011/12-2017/18), and (ii) health-related quality of life (EQ-5D-5L) score (2012/13-2016/17). We estimated linear, log-log regression models, incorporating local authority fixed-effects, time-varying demographic and socio-economic confounders, and time trends. FINDINGS: All local authorities experienced real spending cuts, varying from 42% (Barking and Dagenham) to 0·3% (Sefton). A 1% cut in per capita total service expenditure was associated with a 0·10% (95% CI 0·03 to 0·16) increase in prevalence of multimorbidity. We found no association (0·003%; 95% CI -0·01 to 0·01) with health-related quality of life. By budget line, after controlling for other spending, a 1% cut in public health expenditure was associated with a 0·15% (95% CI 0·11 to 0·20) increase in prevalence of multimorbidity, and a 1% cut in adult social care expenditure was associated with a 0·01% (95% CI 0·002 to 0·02) decrease in average health-related quality of life. INTERPRETATION: Fiscal austerity is associated with worse multimorbidity and health-related quality of life. Policymakers should consider the potential health consequences of local government expenditure cuts and knock-on effects for health systems. FUNDING: Medical Research Council.

The co-occurrence of mental and physical chronic conditions is a growing concern and a largely unaddressed challenge in low-and-middle-income countries. This study aimed to investigate the independent and multiplicative effects of depression and physical chronic conditions on health-related quality of life (HRQoL) in China, and how it varies by age and gender. We used two waves of the China Health and Retirement Longitudinal Study (2011, 2015), including 9227 participants aged ≥ 45 years, 12 physical chronic conditions and depressive symptoms. We used mixed-effects linear regression to assess the effects of depression and physical multimorbidity on HRQoL, which was measured using a proxy measure of Physical Component Scores (PCS) and Mental Component Scores (MCS) of the matched SF-36 measure. We found that each increased number of physical chronic conditions, and the presence of depression were independently associated with lower proxy PCS and MCS scores. There were multiplicative effects of depression and physical chronic conditions on PCS (- 0.83 points, 95% CI - 1.06, - 0.60) and MCS scores (- 0.50 points, 95% CI - 0.73, - 0.27). The results showed that HRQoL decreased markedly with multimorbidity and was exacerbated by the presence of co-existing physical and mental chronic conditions.

India is witnessing an increase in the prevalence of multimorbidity. Oral health is related to overall health but is seldom included in the assessment of multimorbidity. Hence, this study aimed to estimate the prevalence of oral morbidity and explore its association with physical multimorbidity using data from Longitudinal Ageing Study in India (LASI). LASI is a nationwide survey amongst adults aged ≥ 45 years conducted in 2018. Descriptive analysis was performed on included participants (n = 59,764) to determine the prevalence of oral morbidity. Multivariable logistic regression assessed the association between oral morbidity and physical multimorbidity. Self-rated health was compared between multimorbid participants with and without oral morbidity. Oral morbidity was prevalent in 48.56% of participants and physical multimorbidity in 50.36%. Those with multimorbidity were at a higher risk of having any oral morbidity (AOR: 1.60 (1.48-1.73)) than those without multimorbidity. Participants who had only oral morbidity rated their health to be good more often than those who had physical multimorbidity and oral morbidity (40.84% vs. 32.98%). Oral morbidity is significantly associated with physical multimorbidity. Multimorbid participants perceived their health to be inferior to those with only oral morbidity. The findings suggest multidisciplinary health teams in primary care should include the management of oral morbidity and physical multimorbidity.

BACKGROUND: Patients with multimorbidities have the greatest healthcare needs and generate the highest expenditure in the health system. There is an increasing focus on identifying specific disease combinations for addressing poor outcomes. Existing research has identified a small number of prevalent "clusters" in the general population, but the limited number examined might oversimplify the problem and these may not be the ones associated with important outcomes. Combinations with the highest (potentially preventable) secondary care costs may reveal priority targets for intervention or prevention. We aimed to examine the potential of defining multimorbidity clusters for impacting secondary care costs. METHODS AND FINDINGS: We used national, Hospital Episode Statistics, data from all hospital admissions in England from 2017/2018 (cohort of over 8 million patients) and defined multimorbidity based on ICD-10 codes for 28 chronic conditions (we backfilled conditions from 2009/2010 to address potential undercoding). We identified the combinations of multimorbidity which contributed to the highest total current and previous 5-year costs of secondary care and costs of potentially preventable emergency hospital admissions in aggregate and per patient. We examined the distribution of costs across unique disease combinations to test the potential of the cluster approach for targeting interventions at high costs. We then estimated the overlap between the unique combinations to test potential of the cluster approach for targeting prevention of accumulated disease. We examined variability in the ranks and distributions across age (over/under 65) and deprivation (area level, deciles) subgroups and sensitivity to considering a smaller number of diseases. There were 8,440,133 unique patients in our sample, over 4 million (53.1%) were female, and over 3 million (37.7%) were aged over 65 years. No clear "high cost" combinations of multimorbidity emerged as possible targets for inter

BACKGROUND: The co-occurrence of mental and physical chronic conditions (mental-physical multimorbidity) is a growing and largely unaddressed challenge for health systems and wider economies in low-and middle-income countries. This study investigated the independent and combined (additive or synergistic) effects of mental and physical chronic conditions on disability, work productivity, and social participation in China. METHODS: Panel data study design utilised two waves of the China Health and Retirement Longitudinal Study (2011, 2015), including 5616 participants aged ≥45 years, 12 physical chronic conditions and depression. We used a panel data approach of random-effects regression models to assess the relationships between mental-physical multimorbidity and outcomes. RESULTS: After adjusting for socio-economic and demographic factors, an increased number of physical chronic conditions was independently associated with a higher likelihood of disability (Adjusted odds ratio (AOR) = 1.39; 95% CI: 1.33, 1.45), early retirement (AOR = 1.37 [1.26, 1.49]) and increased sick leave days (1.25 days [1.16, 1.35]). Depression was independently associated with disability (AOR = 3.78 [3.30, 4.34]), increased sick leave days (2.18 days [1.72, 2.77]) and a lower likelihood of social participation (AOR = 0.57 [0.47, 0.70]), but not with early retirement (AOR = 1.24 [0.97, 1.58]). There were small and statistically insignificant interactions between physical chronic conditions and mental health on disability, work productivity and social participation, suggesting an additive effect of mental-physical multimorbidity on productivity loss. CONCLUSION: Mental-physical multimorbidity poses substantial negative health and economic effects on individuals, health systems, and societies. More research that addresses the challenges of mental-physical multimorbidity is needed to inform the development of interventions that can be applied to the workplace and the wider community in China.

BACKGROUND: The burden of non-communicable diseases (NCDs) is rising rapidly in middle-income countries (MICs), where NCDs are often undiagnosed, untreated and uncontrolled. How comorbidity impacts diagnosis, treatment, and control of NCDs is an emerging area of research inquiry and have important clinical implications as highlighted in the recent National Institute for Health and Care Excellence guidelines for treating patients suffering from multiple NCDs. This is the first study to examine the association between increasing numbers of comorbidities with being undiagnosed, untreated, and uncontrolled for NCDs, in 6 large MICs. METHODS: Cross-sectional analysis of the World Health Organisation Study of Global Ageing and Adult Health (WHO SAGE) Wave 1 (2007-10), which consisted of adults aged ≥18 years from 6 populous MICs, including China, Ghana, India, Mexico, Russia and South Africa (overall n = 41, 557). RESULTS: A higher number of comorbidities was associated with better odds of diagnosis for hypertension, angina, and arthritis, and higher odds of having treatment for hypertension and angina. However, more comorbidities were associated with increased odds of uncontrolled hypertension, angina, arthritis, and asthma. Comorbidity with concordant conditions was associated with improved diagnosis and treatment of hypertension and angina. CONCLUSION: Patients with more comorbidities have better diagnosis of chronic conditions, but this does not translate into better management and control of these conditions. Patients with multiple NCDs are high users of health services and are at an increased risk of adverse health outcomes. Hence, improving their access to care is a priority for healthcare systems.

OBJECTIVES: The UK faces major problems in retaining general practitioners (GPs). Scotland introduced a new GP contract in April 2018, intended to better support GPs. This study compares the career intentions and working lives of GPs in Scotland with GPs in England, shortly after the new Scotland contract was introduced. DESIGN AND SETTING: Comparison of cross-sectional analysis of survey responses of GPs in England and Scotland in 2017 and 2018, respectively, using linear regression to adjust the differences for gender, age, ethnicity, urbanicity and deprivation. PARTICIPANTS: 2048 GPs in Scotland and 879 GPs in England. MAIN OUTCOME MEASURES: Four intentions to reduce work participation (5-point scales: 1='none', 5='high'): reducing working hours; leaving medical work entirely; leaving direct patient care; or continuing medical work but outside the UK. Four domains of working life: job satisfaction (7-point scale: 1='extremely dissatisfied', 7='extremely satisfied'); job stressors (5-point-scale: 1='no pressure', 5='high pressure); positive and negative job attributes (5-point scales: 1='strongly disagree', 5='strongly agree'). RESULTS: Compared with England, GPs in Scotland had lower intention to reduce work participation, including a lower likelihood of reducing work hours (2.78 vs 3.54; adjusted difference=-0.52; 95% CI -0.64 to -0.41), a lower likelihood of leaving medical work entirely (2.11 vs 2.76; adjusted difference=-0.32; 95% CI -0.42 to -0.22), a lower likelihood of leaving direct patient care (2.23 vs 2.93; adjusted difference=-0.37; 95% CI -0.47 to -0.27), and a lower likelihood of continuing medical work but outside of the UK (1.41 vs 1.61; adjusted difference=-0.2; 95% CI -0.28 to -0.12). GPs in Scotland reported higher job satisfaction, lower job stressors, similar positive job attributes and lower negative job attributes. CONCLUSION: Following the introduction of the new contract in Scotland, GPs in Scotland reported significantly better working l

BACKGROUND: Multimorbidity, the presence of two or more mental or physical chronic non-communicable diseases, is a major challenge for the health system in China, which faces unprecedented ageing of its population. Here we examined the distribution of physical multimorbidity in relation to socioeconomic status; the association between physical multimorbidity, health-care service use, and catastrophic health expenditures; and whether these associations varied by socioeconomic group and social health insurance schemes. METHODS: In this population-based, panel data analysis, we used data from three waves of the nationally representative China Health and Retirement Longitudinal Study (CHARLS) for 2011, 2013, and 2015. We included participants aged 50 years and older in 2015, who had complete follow-up for the three waves. We used 11 physical non-communicable diseases to measure physical multimorbidity and annual per-capita household consumption spending as a proxy for socioeconomic status. FINDINGS: Of 17 708 participants in CHARLS, 11 817 were eligible for inclusion in our analysis. The median age of participants was 62 years (IQR 56-69) in 2015, and 5766 (48·8%) participants were male. 7320 (61·9%) eligible participants had physical multimorbidity in China in 2015. The prevalence of physical multimorbidity was increased with older age (odds ratio 2·93, 95% CI 2·71-3·15), among women (2·70, 2·04-3·57), within a higher socioeconomic group (for quartile 4 [highest group] 1·50, 1·24-1·82), and higher educational level (5·17, 3·02-8·83); however, physical multimorbidity was more common in poorer regions than in the more affluent regions. An additional chronic non-communicable disease was associated with an increase in the number of outpatient visits (incidence rate ratio 1·29, 95% CI 1·27-1·31), and number of days spent in hospital as an inpatient (1·38, 1·35-1·41). We saw similar effects in health service use of an additional chronic non-communicable disease in different

Background Multimorbidity, the coexistence of multiple health conditions, is a growing public health challenge. Research and intervention development are hampered by the lack of consensus regarding defining and measuring multimorbidity. The aim of this systematic review was to pool the findings of systematic reviews examining definitions and measures of multimorbidity. Methods Medline, Embase, PubMed and Cochrane were searched from database inception to February 2017. Two authors independently screened titles, abstracts and full texts and extracted data from the included papers. Disagreements were resolved with a third author. Reviews were quality assessed. Results Of six reviews, two focussed on definitions and four on measures. Multimorbidity was commonly defined as the presence of multiple diseases or conditions, often with a cut-off of two or more. One review developed a holistic definition including biopsychosocial and somatic factors as well as disease. Reviews recommended using measures validated for the outcome of interest. Disease counts are an alternative if no validated measure exists. Conclusions To enable comparison between studies and settings, researchers and practitioners should be explicit about their choice of definition and measure. Using a cut-off of two or more conditions as part of the definition is widely adopted. Measure selection should be based on tools validated for the outcome being considered. Where there is no validated measure, or where multiple outcomes or populations are being considered, disease counts are appropriate.

Objective Multimorbidity (the co-existence of two or more health conditions) is increasingly prevalent. No long-term cohort study has examined the impact of contemporaneously measured birth social class and educational attainment upon adult self-reported multimorbidity. We investigated the impact of educational attainment on the relationship between social class at birth and adult self-reported multimorbidity in the Aberdeen Children of the 1950s (ACONF) cohort. Methods A prospective cohort study using the ACONF cohort. ACONF included 12,150 individuals born in Aberdeen, Scotland 1950-1956. In 2001, 7,184 (64%) responded to a questionnaire providing information including self-reported morbidity and educational attainment. The exposure was father’s social class at birth from birth records and the outcome was self-reported multimorbidity. Logistic regression assessed the association between social class and multimorbidity with adjustment for gender, then by educational attainment and finally by childhood cognition and secondary school type. Odds ratios (ORs) and 95% confidence intervals were presented. Results Of 7,184 individuals (mean age 48, 52% female), 5.4% reported multimorbidity. Birth social class was associated with adult multimorbidity. For example the OR of multimorbidity adjusted by gender was 0.62 (95% CI 0.39-1.00) in the highest social class group (I/II) in relation to the reference group (III (manual)) and was 1.85 (95% CI 1.19-2.88) in the lowest social class group. This was partially attenuated in all social class categories by educational attainment, for example the OR was 0.74 (95% CI 0.45-1.21) in group I/II following adjustment. Conclusion Lower social class at birth was associated with developing multimorbidity in middle age. This was partially mediated by educational attainment and future research should consider identifying the other explanatory variables. The results are relevant to researchers and to those aiming to reduce the impact of mult

Background Multimorbidity, the coexistence of multiple health conditions, is a growing public health challenge. Research and intervention development are hampered by the lack of consensus regarding defining and measuring multimorbidity. The aim of this systematic review was to pool the findings of systematic reviews examining definitions and measures of multimorbidity. Methods Medline, Embase, PubMed and Cochrane were searched from database inception to February 2017. Two authors independently screened titles, abstracts and full texts and extracted data from the included papers. Disagreements were resolved with a third author. Reviews were quality assessed. Results Of six reviews, two focussed on definitions and four on measures. Multimorbidity was commonly defined as the presence of multiple diseases or conditions, often with a cut-off of two or more. One review developed a holistic definition including biopsychosocial and somatic factors as well as disease. Reviews recommended using measures validated for the outcome of interest. Disease counts are an alternative if no validated measure exists. Conclusions To enable comparison between studies and settings, researchers and practitioners should be explicit about their choice of definition and measure. Using a cut-off of two or more conditions as part of the definition is widely adopted. Measure selection should be based on tools validated for the outcome being considered. Where there is no validated measure, or where multiple outcomes or populations are being considered, disease counts are appropriate.

Objective Multimorbidity (the co-existence of two or more health conditions) is increasingly prevalent. No long-term cohort study has examined the impact of contemporaneously measured birth social class and educational attainment upon adult self-reported multimorbidity. We investigated the impact of educational attainment on the relationship between social class at birth and adult self-reported multimorbidity in the Aberdeen Children of the 1950s (ACONF) cohort. Methods A prospective cohort study using the ACONF cohort. ACONF included 12,150 individuals born in Aberdeen, Scotland 1950-1956. In 2001, 7,184 (64%) responded to a questionnaire providing information including self-reported morbidity and educational attainment. The exposure was father’s social class at birth from birth records and the outcome was self-reported multimorbidity. Logistic regression assessed the association between social class and multimorbidity with adjustment for gender, then by educational attainment and finally by childhood cognition and secondary school type. Odds ratios (ORs) and 95% confidence intervals were presented. Results Of 7,184 individuals (mean age 48, 52% female), 5.4% reported multimorbidity. Birth social class was associated with adult multimorbidity. For example the OR of multimorbidity adjusted by gender was 0.62 (95% CI 0.39-1.00) in the highest social class group (I/II) in relation to the reference group (III (manual)) and was 1.85 (95% CI 1.19-2.88) in the lowest social class group. This was partially attenuated in all social class categories by educational attainment, for example the OR was 0.74 (95% CI 0.45-1.21) in group I/II following adjustment. Conclusion Lower social class at birth was associated with developing multimorbidity in middle age. This was partially mediated by educational attainment and future research should consider identifying the other explanatory variables. The results are relevant to researchers and to those aiming to reduce the impact of mult

Background Multimorbidity, the coexistence of multiple health conditions, is a growing public health challenge. Research and intervention development are hampered by the lack of consensus regarding defining and measuring multimorbidity. The aim of this systematic review was to pool the findings of systematic reviews examining definitions and measures of multimorbidity. Methods Medline, Embase, PubMed and Cochrane were searched from database inception to February 2017. Two authors independently screened titles, abstracts and full texts and extracted data from the included papers. Disagreements were resolved with a third author. Reviews were quality assessed. Results Of six reviews, two focussed on definitions and four on measures. Multimorbidity was commonly defined as the presence of multiple diseases or conditions, often with a cut-off of two or more. One review developed a holistic definition including biopsychosocial and somatic factors as well as disease. Reviews recommended using measures validated for the outcome of interest. Disease counts are an alternative if no validated measure exists. Conclusions To enable comparison between studies and settings, researchers and practitioners should be explicit about their choice of definition and measure. Using a cut-off of two or more conditions as part of the definition is widely adopted. Measure selection should be based on tools validated for the outcome being considered. Where there is no validated measure, or where multiple outcomes or populations are being considered, disease counts are appropriate.

Objective Multimorbidity (the co-existence of two or more health conditions) is increasingly prevalent. No long-term cohort study has examined the impact of contemporaneously measured birth social class and educational attainment upon adult self-reported multimorbidity. We investigated the impact of educational attainment on the relationship between social class at birth and adult self-reported multimorbidity in the Aberdeen Children of the 1950s (ACONF) cohort. Methods A prospective cohort study using the ACONF cohort. ACONF included 12,150 individuals born in Aberdeen, Scotland 1950-1956. In 2001, 7,184 (64%) responded to a questionnaire providing information including self-reported morbidity and educational attainment. The exposure was father’s social class at birth from birth records and the outcome was self-reported multimorbidity. Logistic regression assessed the association between social class and multimorbidity with adjustment for gender, then by educational attainment and finally by childhood cognition and secondary school type. Odds ratios (ORs) and 95% confidence intervals were presented. Results Of 7,184 individuals (mean age 48, 52% female), 5.4% reported multimorbidity. Birth social class was associated with adult multimorbidity. For example the OR of multimorbidity adjusted by gender was 0.62 (95% CI 0.39-1.00) in the highest social class group (I/II) in relation to the reference group (III (manual)) and was 1.85 (95% CI 1.19-2.88) in the lowest social class group. This was partially attenuated in all social class categories by educational attainment, for example the OR was 0.74 (95% CI 0.45-1.21) in group I/II following adjustment. Conclusion Lower social class at birth was associated with developing multimorbidity in middle age. This was partially mediated by educational attainment and future research should consider identifying the other explanatory variables. The results are relevant to researchers and to those aiming to reduce the impact of mult

Background Multimorbidity, the coexistence of multiple health conditions, is a growing public health challenge. Research and intervention development are hampered by the lack of consensus regarding defining and measuring multimorbidity. The aim of this systematic review was to pool the findings of systematic reviews examining definitions and measures of multimorbidity. Methods Medline, Embase, PubMed and Cochrane were searched from database inception to February 2017. Two authors independently screened titles, abstracts and full texts and extracted data from the included papers. Disagreements were resolved with a third author. Reviews were quality assessed. Results Of six reviews, two focussed on definitions and four on measures. Multimorbidity was commonly defined as the presence of multiple diseases or conditions, often with a cut-off of two or more. One review developed a holistic definition including biopsychosocial and somatic factors as well as disease. Reviews recommended using measures validated for the outcome of interest. Disease counts are an alternative if no validated measure exists. Conclusions To enable comparison between studies and settings, researchers and practitioners should be explicit about their choice of definition and measure. Using a cut-off of two or more conditions as part of the definition is widely adopted. Measure selection should be based on tools validated for the outcome being considered. Where there is no validated measure, or where multiple outcomes or populations are being considered, disease counts are appropriate.

Objective Multimorbidity (the co-existence of two or more health conditions) is increasingly prevalent. No long-term cohort study has examined the impact of contemporaneously measured birth social class and educational attainment upon adult self-reported multimorbidity. We investigated the impact of educational attainment on the relationship between social class at birth and adult self-reported multimorbidity in the Aberdeen Children of the 1950s (ACONF) cohort. Methods A prospective cohort study using the ACONF cohort. ACONF included 12,150 individuals born in Aberdeen, Scotland 1950-1956. In 2001, 7,184 (64%) responded to a questionnaire providing information including self-reported morbidity and educational attainment. The exposure was father’s social class at birth from birth records and the outcome was self-reported multimorbidity. Logistic regression assessed the association between social class and multimorbidity with adjustment for gender, then by educational attainment and finally by childhood cognition and secondary school type. Odds ratios (ORs) and 95% confidence intervals were presented. Results Of 7,184 individuals (mean age 48, 52% female), 5.4% reported multimorbidity. Birth social class was associated with adult multimorbidity. For example the OR of multimorbidity adjusted by gender was 0.62 (95% CI 0.39-1.00) in the highest social class group (I/II) in relation to the reference group (III (manual)) and was 1.85 (95% CI 1.19-2.88) in the lowest social class group. This was partially attenuated in all social class categories by educational attainment, for example the OR was 0.74 (95% CI 0.45-1.21) in group I/II following adjustment. Conclusion Lower social class at birth was associated with developing multimorbidity in middle age. This was partially mediated by educational attainment and future research should consider identifying the other explanatory variables. The results are relevant to researchers and to those aiming to reduce the impact of mult

Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex CuII(atsm) tested for therapeutic efficacy in mice expressing SOD1G93A on a mixed genetic background. Oral administration of CuII(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1G93A mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the CuII(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with CuII(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for CuII(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1.

Glutaredoxins are a family of small molecular weight proteins that have a central role in cellular redox regulation. Human GRX1 (hGRX1) has also been shown to play an integral role in copper homeostasis by regulating the redox activity of the metalated sites of copper chaperones such as ATOX1 and SOD1, and the copper efflux proteins ATP7A and ATP7B. To further elucidate the role of hGRX1 in copper homeostasis, we examined the impact of RNA interference-mediated knockdown of CG6852, a putative Drosophila orthologue of hGRX1. CG6852 shares ~41 % amino acid identity with hGRX1 and key functional domains including the metal-binding CXXC motif are conserved between the two proteins. Knockdown of CG6852 in the adult midline caused a thoracic cleft and reduced scutellum, phenotypes that were exacerbated by additional knockdown of copper uptake transporters Ctr1A and Ctr1B. Knockdown of CG6852 in the adult eye enhanced a copper-deficiency phenotype caused by Ctr1A knockdown while ubiquitous knockdown of CG6852 resulted a mild systemic copper deficiency. Therefore we conclude that CG6852 is a putative orthologue of hGRX1 and may play an important role in Drosophila copper homeostasis.

BACKGROUND: Visual impairment is common in older people and the presence of additional health conditions can compromise health and rehabilitation outcomes. A small number of studies have suggested that comorbities are common in visual impairment; however, those studies have relied on self-report and have assessed a relatively limited number of comorbid conditions. METHODS: We conducted a cross-sectional analysis of a dataset of 291,169 registered patients (65-years-old and over) within 314 primary care practices in Scotland, UK. Visual impairment was identified using Read Code ever recorded for blindness and/or low vision (within electronic medical records). Prevalence, odds ratios (from prevalence rates standardised by stratifying individuals by age groups (65 to 69 years; 70 to 74; 75 to 79; 80 to 84; and 85 and over), gender and deprivation quintiles) and 95% confidence intervals (95% CI) of 37 individual chronic physical/mental health conditions and total number of conditions were calculated and compared for those with visual impairment to those without. RESULTS: Twenty seven of the 29 physical health conditions and all eight mental health conditions were significantly more likely to be recorded for individuals with visual impairment compared to individuals without visual impairment, after standardising for age, gender and social deprivation. Individuals with visual impairment were also significantly more likely to have more comorbidities (for example, five or more conditions (odds ratio (OR) 2.05 95% CI 1.94 to 2.18)). CONCLUSIONS: Patients aged 65 years and older with visual impairment have a broad range of physical and mental health comorbidities compared to those of the same age without visual impairment, and are more likely to have multiple comorbidities. This has important implications for clinical practice and for the future design of integrated services to meet the complex needs of patients with visual impairment, for example, embedding depression and he

BACKGROUND: Multimorbidity occurs at a younger age in individuals in areas of high socioeconomic deprivation but little is known about the 'typology' of multimorbidity in different age groups and its association with socioeconomic status. AIM: To characterise multimorbidity type and most common conditions in a large nationally representative primary care dataset in terms of age and deprivation. DESIGN AND SETTING: Cross-sectional analysis of 1 272 685 adults in Scotland. METHOD: Multimorbidity type of participants (physical-only, mental-only, mixed physical, and mental) and most common conditions were analysed according to age and deprivation. RESULTS: Multimorbidity increased with age, ranging from 8.1% in those aged 25-34 to 76.1% for those aged ≥75 years. Physical-only (56% of all multimorbidity) was the most common type of multimorbidity in those aged ≥55 years, and did not vary substantially with deprivation. Mental-only was uncommon (4% of all multimorbidity), whereas mixed physical and mental (40% of all multimorbidity) was the most common type of multimorbidity in those aged <55 years and was two- to threefold more common in the most deprived compared with the least deprived in most age groups. Ten conditions (seven physical and three mental) accounted for the top five most common conditions in people with multimorbidity in all age groups. Depression and pain featured in the top five conditions across all age groups. Deprivation was associated with a higher prevalence of depression, drugs misuse, anxiety, dyspepsia, pain, coronary heart disease, and diabetes in multimorbid patients at different ages. CONCLUSION: Mixed physical and mental multimorbidity is common across the life-span and is exacerbated by deprivation from early adulthood onwards.

Multimorbidity is a major challenge for patients and healthcare providers. The limited evidence of the effectiveness of interventions for people with multimorbidity means that there is a need for much more research and trials of potential interventions. Here we present a consensus view from a group of international researchers working to improve care for people with multimorbidity to guide future studies of interventions. We suggest that there is a need for careful consideration of whom to include, how to target interventions that address specific problems and that do not add to treatment burden, and selecting outcomes that matter both to patients and the healthcare system. Innovative design of these interventions will be necessary as many will be introduced in service settings and it will be important to ensure methodological rigour, relevance to service delivery, and generalizability across healthcare systems. Journal of Comorbidity 2013;3:10-17.