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Background Cohorts such as UK Biobank are increasingly used to study multimorbidity; however, there are concerns that lack of representativeness may lead to biased results. This study aims to compare associations between multimorbidity and adverse health outcomes in UK Biobank and a nationally representative sample. Methods and findings These are observational analyses of cohorts identified from linked routine healthcare data from UK Biobank participants (n = 211,597 from England, Scotland, and Wales with linked primary care data, age 40 to 70, mean age 56.5 years, 54.6% women, baseline assessment 2006 to 2010) and from the Secure Anonymised Information Linkage (SAIL) databank (n = 852,055 from Wales, age 40 to 70, mean age 54.2, 50.0% women, baseline January 2011). Multimorbidity (n = 40 long-term conditions [LTCs]) was identified from primary care Read codes and quantified using a simple count and a weighted score. Individual LTCs and LTC combinations were also assessed. Associations with all-cause mortality, unscheduled hospitalisation, and major adverse cardiovascular events (MACEs) were assessed using Weibull or negative binomial models adjusted for age, sex, and socioeconomic status, over 7.5 years follow-up for both datasets. Multimorbidity was less common in UK Biobank than SAIL (26.9% and 33.0% with ≥2 LTCs in UK Biobank and SAIL, respectively). This difference was attenuated, but persisted, after standardising by age, sex, and socioeconomic status. The association between increasing multimorbidity count and mortality, hospitalisation, and MACE was similar between both datasets at LTC counts of ≤3; however, above this level, UK Biobank underestimated the risk associated with multimorbidity (e.g., mortality hazard ratio for 2 LTCs 1.62 (95% confidence interval 1.57 to 1.68) in SAIL and 1.51 (1.43 to 1.59) in UK Biobank, hazard ratio for 5 LTCs was 3.46 (3.31 to 3.61) in SAIL and 2.88 (2.63 to 3.15) in UK Biobank). Absolute risk of mortality, hospitalisation, and MACE, at all levels of multimorbidity, was lower in UK Biobank than SAIL (adjusting for age, sex, and socioeconomic status). Both cohorts produced similar hazard ratios for some LTCs (e.g., hypertension and coronary heart disease), but UK Biobank underestimated the risk for others (e.g., alcohol-related disorders or mental health conditions). Hazard ratios for some LTC combinations were similar between the cohorts (e.g., cardiovascular conditions); however, UK Biobank underestimated the risk for combinations including other conditions (e.g., mental health conditions). The main limitations are that SAIL databank represents only part of the UK (Wales only) and that in both cohorts we lacked data on severity of the LTCs included. Conclusions In this study, we observed that UK Biobank accurately estimates relative risk of mortality, unscheduled hospitalisation, and MACE associated with LTC counts ≤3. However, for counts ≥4, and for some LTC combinations, estimates of magnitude of association from UK Biobank are likely to be conservative. Researchers should be mindful of these limitations of UK Biobank when conducting and interpreting analyses of multimorbidity. Nonetheless, the richness of data available in UK Biobank does offers opportunities to better understand multimorbidity, particularly where complementary data sources less susceptible to selection bias can be used to inform and qualify analyses of UK Biobank. Peter Hanlon and colleagues compare the associations between multimorbidity and adverse health outcomes in UK Biobank and the SAIL Databank. Author summary Why was this study done? Multimorbidity, the presence of multiple long-term conditions (LTCs), is associated with a range of adverse health outcomes. The UK Biobank cohort study has gathered and linked genetic, physical, and clinical information on a population scale providing unique opportunities to study the impact of multimorbidity. However, participants in UK Biobank appear on average to be healthier than the general population (“healthy volunteer bias”) and it is not clear if this selection bias affects estimates of the impact of multimorbidity using UK Biobank. What did the researchers do and find? We compared the prevalence of multimorbidity, and the impact of multimorbidity on adverse health outcomes, in UK Biobank and in a representative sample of people from Wales, UK (SAIL databank). While multimorbidity was less common in UK Biobank, the relationship between number of LTCs and mortality, hospital admissions, and major adverse cardiovascular events (MACEs) was similar between UK Biobank and SAIL at lower levels of multimorbidity (e.g., 2 or 3 LTCs) and for many common LTCs (e.g., hypertension, coronary artery disease, and chronic obstructive pulmonary disease). However, for people with higher LTC counts (e.g., 4 or more), or with specific LTCs such as mental health conditions, UK Biobank underestimates the risk of mortality, hospitalisation, and MACEs. What do these findings mean? The wide range of measures gathered by UK Biobank make it a valuable resource for studying multimorbidity, and our study suggests that analyses of modest levels of multimorbidity (such as people with 2 or 3 LTCs) are likely to yield reliable estimates. However, for people with a higher number of LTCs or with LTCs such as mental health conditions, alcohol-related disorders, or addiction, estimates based on UK Biobank data are likely to be conservative compared to a representative sample. Ideally, future LTC and multimorbidity research should combine insights from both representative routine data and information rich research cohorts such as UK Biobank. These analyses are limited by a lack of data on the severity of LTCs.

BackgroundDespite current resuscitation strategies, circulatory shock and organ injury after cardiac surgery occur in 25-40% of patients. Goal-directed resuscitation after cardiac surgery has generated significant interest, but clinical practice to normalize hemodynamic variables including mean arterial pressure, cardiac filling pressures, and cardiac output may not reverse microcirculation abnormalities and do not address cellular dysoxia. Recent advances in technology have made it possible to measure critical components of oxygen delivery and oxygen utilization systems in live human tissues and blood cells. The MicroRESUS study will be the first study to measure microcirculatory and mitochondrial function in patients with circulatory shock and link these findings with clinical outcomes.Methods and analysisThis will be a prospective, observational study that includes patients undergoing elective cardiovascular surgery with cardiopulmonary bypass (CPB). Microcirculation will be quantified with sublingual incident dark field videomicroscopy. Mitochondrial respiration will be measured by performing a substrate-uncoupler-inhibitor titration protocol with high resolution respirometry on peripheral blood mononuclear cells at baseline and serial timepoints during resuscitation and at recovery as a possible liquid biomarker. Plasma samples will be preserved for future analysis to examine endothelial injury and other mechanisms of microcirculatory dysfunction. Thirty-day ventilator and vasopressor-free days (VVFDs) will be measured as a primary outcome, along with sequential organ failure assessment scores, and other clinical parameters to determine if changes in microcirculation and mitochondrial respiration are more strongly associated with clinical outcomes compared to traditional resuscitation targets.DiscussionThis will be the first prospective study to examine both microcirculatory and mitochondrial function in human patients with circulatory shock undergoing cardiac bypass and address a key mechanistic knowledge gap in the cardiovascular literature. The results of this study will direct future research efforts and therapeutic development for patients with shock.

Multimorbidity (presence of ≥2 long term conditions (LTCs)) is a growing global health challenge, yet we know little about the experiences of those living with multimorbidity in low- and middle-income countries (LMICs). We therefore explore: 1) experiences of men and women living with multimorbidity in urban and rural Malawi including their experiences of burden of treatment and 2) examine the utility of Normalization Process Theory (NPT) and Burden of Treatment Theory (BOTT) for structuring analytical accounts of these experiences. We conducted in depth, semi-structured interviews with 32 people in rural (n = 16) and urban settings (n = 16); 16 males, 16 females; 15 under 50 years; and 17 over 50 years. Data were analysed thematically and then conceptualised through the lens of NPT and BOTT. Key elements of burden of treatment identified included: coming to terms with and gaining an understanding of life with multimorbidity; dealing with resulting disruptions to family life; the work of seeking family and community support; navigating healthcare systems; coping with lack of continuity of care; enacting self-management advice; negotiating medical advice; appraising treatments; and importantly, dealing with the burden of lack of treatments/services. Poverty and inadequate healthcare provision constrained capacity to deal with treatment burden while supportive social and community networks were important enabling features. Greater access to health information/education would lessen treatment burden as would better resourced healthcare systems and improved standards of living. Our work demonstrates the utility of NPT and BOTT for aiding conceptualisation of treatment burden issues in LMICs but our findings highlight that 'lack' of access to treatments or services is an important additional burden which must be integrated in accounts of treatment burden in LMICs.

Background: Understanding the mental health consequences of child maltreatment at different life stages is important in accurately quantifying the burden of maltreatment. This study investigated the association between child maltreatment and incident mental disorders in middle and older age as well as the potential mediators and moderators. Methods: This is a retrospective cohort study of 56,082 participants from UK Biobank. Child maltreatment was recalled using the Childhood Trauma Screener. Incident mental disorders, including depressive, anxiety and affective disorders, behavioural syndromes, post-traumatic stress disorder (PTSD), schizophrenia, substance abuse, and dementia, after baseline assessment were ascertained through linkage to primary care records. Findings: There was a dose-response relationship between child maltreatment and mental disorder. Those who experienced three or more maltreatment types had the highest risk of all mental disorders (HR 1.85, 95% CI: 1.67-2.06) followed by those who experienced two (HR 1.48, 95% CI: 1.35-1.63) and then one (HR 1.26, 95% CI: 1.19-2.35). Child maltreatment was most strongly associated with PTSD (HR 1.59, 95% CI: 1.20-2.10 P=0.001). The excess risk was largely unexplained by the included mediators. The association between child maltreatment and all mental disorders were stronger among participants who binge drank (Pinteraction=0.003) or had few social visits (Pinteraction=0.003). Interpretation: The mental health consequence of child maltreatment could last decades, even among those who had no recorded mental disorders in early adulthood. In the absence of strong mediators, prevention of child maltreatment remains the priority. Funding: Wellcome Trust Institutional Strategic Support Fund

The Ediacaran fossils of the Mistaken Point E surface have provided crucial insight into early animal communities, including how they reproduced, the importance of Ediacaran height and what the most important factors were to their community dynamics. Here, we use this iconic community to investigate how morphological variation between eight taxa affected their ability to withstand different flow conditions. For each of Beothukis, Bradgatia, Charniodiscus procerus, Charniodiscus spinosus, Plumeropriscum, Primocandelabrum, Thectardis and Fractofusus we measured the orientation and length of their stems (if present) and their fronds. We statistically tested each taxon’s stem and frond orientation distributions to see whether they displayed a uniform or multimodal distribution. Where multimodal distributions were identified, the stem/frond length of each cohort was tested to identify if there were differences in size between different orientation groups. We find that Bradgatia and Thectardis show a bimodal felling direction, and infer that they were felled by the turbulent head of the felling flow. In contrast, the frondose rangeomorphs including Beothukis, Plumeropriscum, Primocandelabrum, and the arboreomorphs were felled in a single direction, indicating that they were upright in the water column, and were likely felled by the laminar tail of the felling flow. These differences in directionality suggests that an elongate habit, and particularly possession of a stem, lent greater resilience to frondose taxa against turbulent flows, suggesting that such taxa would have had improved survivability in conditions with higher background turbulence than taxa like Bradgatia and Thectardis, that lacked a stem and had a higher centre of mass, which may have fared better in quieter water conditions.

Objectives: Chronic pain is often experienced alongside other long-term conditions (LTCs), yet our understanding of this, particularly in relation to multimorbidity (≥2 LTCs) is poor. We aimed to examine associations between the presence/extent of chronic pain with type/number of LTCs experienced. Methods: We examined the relationship between number/type of LTCs (N = 45) in UK Biobank participants (n = 500,295) who self-reported chronic pain lasting ≥3 months in seven body sites or widespread. Relative risk ratios (RRR) for presence/extent of chronic pain sites were compared using logistic regression adjusted for sociodemographic (sex/age/socioeconomic status) and lifestyle factors (smoking/alcohol intake/BMI/physical activity). Results: 218,648 participants self-reported chronic pain. Of these, 69.1% reported ≥1 LTC and 36.2% reported ≥2 LTCs. In 31/45 LTCs examined, >50% of participants experienced chronic pain. Chronic pain was common with migraine/headache and irritable bowel syndrome where pain is a primary symptom, but also with mental health conditions and diseases of the digestive system. Participants with >4 LTCs were over three times as likely to have chronic pain (RRR 3.56, 95% confidence intervals (CIs) 3.44–3.68) and 20 times as likely to have widespread chronic pain (RRR 20.13, 95% CI 18.26–22.19) as those with no LTCs. Conclusions: Chronic pain is extremely common across a wide range of LTCs. People with multimorbidity were at higher risk of having a greater extent of chronic pain. These results show that chronic pain is a key factor for consideration in the management of patients with LTCs or multimorbidity.

BackgroundThe use of graphic narratives, defined as stories that use images for narration, is growing in health communication. ObjectiveThe aim of this study was to describe the design and implementation of a graphic narrative screensaver (GNS) to communicate a guideline recommendation (ie, avoiding low-value acid suppressive therapy [AST] use in hospital inpatients) and examine the comparative effectiveness of the GNS versus a text-based screensaver (TBS) on clinical practice (ie, low-value AST prescriptions) and clinician recall. MethodsDuring a 2-year period, the GNS and the TBS were displayed on inpatient clinical workstations. The numbers of new AST prescriptions were examined in the four quarters before, the three quarters during, and the one quarter after screensavers were implemented. Additionally, an electronic survey was sent to resident physicians 1 year after the intervention to assess screensaver recall. ResultsDesigning an aesthetically engaging graphic that could be rapidly understood was critical in the development of the GNS. The odds of receiving an AST prescription on medicine and medicine subspecialty services after the screensavers were implemented were lower for all four quarters (ie, GNS and TBS broadcast together, only TBS broadcast, only GNS broadcast, and no AST screensavers broadcast) compared to the quarter prior to implementation (odds ratio [OR] 0.85, 95% CI 0.78-0.92; OR 0.89, 95% CI 0.82-0.97; OR 0.87, 95% CI 0.80-0.95; and OR 0.81, 95% CI 0.75-0.89, respectively; P

Abstract Dispersal of ground‐dwelling arthropods is understudied in forest ecosystems, which hinders understanding of effects of disturbances on population dynamics. The objective of the study was to quantify movement of ground‐dwelling arthropods in response to a factorial combination of canopy gap formation via girdling and understory vegetation removal, which was shown in a companion study to alter arthropod abundance and species richness. Arthropod movement was quantified using a self‐mark–capture technique where arthropods were marked as they crossed three concentric bands of different colored fluorescent powders located 3, 8, and 15 m from the center of 30 × 30 m experimental quadrats. The number of colors found on an individual was considered representative of dispersal such that the more colors detected, the more an individual moved. The likelihood that arthropods were marked with fluorescent powder and the number of colors detected differed among taxonomic groups. Most taxa were marked with one color and a high proportion of those individuals were collected adjacent to the band in which they were marked, suggesting limited dispersal. Canopy gaps and understory vegetation removal influenced movement of three taxa of highly mobile arthropods: Parajulidae and Paradoxosomatidae (detritivores), and Opiliones (scavengers). Opiliones were less likely to be marked with fluorescent powder in canopy gaps than under closed canopy in July, but more likely to be marked in August. Paradoxosomatidae were less likely to be marked in canopy gaps than under closed canopy in August, but their movement was unaffected in July. Parajulidae were more likely to be marked with fluorescent powders when understory vegetation was removed in July and August. Limited dispersal of most other ground‐dwelling arthropods suggests that these more sessile taxa may experience decreased survival and reproduction if they are unable to cope with environmental change in response to natural and anthropogenic disturbances. Understanding how disturbances mediate arthropod movement can inform biodiversity conservation strategies and sustainable forest management.

Background: Anticholinergic burden (ACB), is defined as the cumulative effect of anticholinergic medication which are widely prescribed to older adults despite increasing ACB being associated with adverse effects such as: falls, dementia and increased mortality. This research explores the views of health care professionals (HCPs) and patients on a planned trial to reduce ACB by stopping or switching anticholinergic medications. The objectives were to explore the views of key stakeholders (patients, the public, and HCPs) regarding the potential acceptability, design and conduct of an ACB reduction trial.Materials and Methods: We conducted qualitative interviews and focus groups with 25 HCPs involved in prescribing medication with anticholinergic properties and with 22 members of the public and patients who were prescribed with the medication. Topic guides for the interviews and focus groups explored aspects of feasibility including: 1) views of a trial of de-prescribing/medication switching; 2) how to best communicate information about such a trial; 3) views on who would be best placed and preferred to undertake such medication changes, e.g., pharmacists or General Practitioners (GPs)? 4) perceived barriers and facilitators to trial participation and the smooth conduct of such a trial; 5) HCP views on the future implementability of this approach to reducing ACB and 6) patients’ willingness to be contacted for participation in a future trial. Qualitative data analysis was underpinned by Normalization Process Theory.Results: The public, patients and HCPs were supportive of an ACB reduction trial. There was consensus among the different groups that key points to consider with such a trial included: 1) ensuring patient engagement throughout to enable concerns/potential pitfalls to be addressed from the beginning; 2) ensuring clear communication to minimise potential misconceptions about the reasons for ACB reduction; and 3) provision of access to a point of contact for patients throughout the life of a trial to address concerns; The HCPs in particular suggested two more key points: 4) minimise the workload implications of any trial; and 5) pharmacists may be best placed to carry out ACB reviews, though overall responsibility for patient medication should remain with GPs.Conclusion: Patients, the public and HCPs are supportive of trials to reduce ACB. Good communication and patient engagement during design and delivery of a trial are essential as well as safety netting and minimising workload.

Background/Aims Upper gastrointestinal cancers (oesophageal/stomach) have high mortality rates and are often diagnosed after the disease has progressed, making it important to identify populations at greater risk of upper gastrointestinal (UGI) cancer to promote earlier diagnosis. This study aims to determine if there is an association between a broad range of long-term conditions (LTCs) and incidence of UGI cancers. Method A prospective-based cohort of 487,798 UK Biobank participants (age 37–73 years) after excluding previous UGI cancer. Least Absolute Shrinkage and Selection Operator (LASSO) regression used to identify candidate LTCs as predictors for UGI cancer. Strength of association was studied using Cox’s regression adjusting for demographics and lifestyle factors. Results After median follow-up period of 86 months, 598 participants developed oesophageal cancer; 397 developed stomach cancer. In fully adjusted models, participants with alcohol addiction (Hazard Ratio-HR 4.11, 95% Confidence Interval-CI 2.01–8.43), Barrett’s oesophagus (HR 5.68, 95% CI 3.36–9.58), bronchiectasis (HR 2.72, 95% CI 1.01–7.31), diabetes (HR 1.38, 95% CI 1.06–1.81), hiatus hernia (HR 1.69, 95% CI 1.16–2.45), Parkinson’s disease (HR 3.86, 95% CI 1.60–9.37) and psoriasis/eczema (HR 1.53, 95% 1.08–2.17) were observed to have a higher risk of oesophageal cancer. Stomach cancer incidence was higher among participants with anorexia/bulimia (HR 8.86, 95% CI 1.20–65.14), Barrett’s oesophagus (HR 3.37, 95% 1.39–8.14), chronic fatigue syndrome (HR 3.36, 95% CI 1.25–9.03), glaucoma (HR 2.06, 95% CI 1.16–3.67), multiple sclerosis (HR 4.60, 95% CI 1.71–12.34), oesophageal stricture (HR 1.04, 95% CI 1.46–74.46) and pernicious anaemia (HR 6.93, 95% CI 3.42–14.03). Conclusion Previously unrecognised LTCs may have a role in symptom appraisal and risk assessment of UGI cancer in primary care. Further research should explore mechanisms underpinning these findings and determine whether they are replicable in other populations.

AbstractIntroductionThe aim of this study was to determine risk of being SARS‐CoV‐2 positive and severe infection (associated with hospitalization/mortality) in those with family history of diabetes. MethodsWe used UK Biobank, an observational cohort recruited between 2006 and 2010. We compared the risk of being SARS‐CoV‐2 positive and severe infection for those with family history of diabetes (mother/father/sibling) against those without.ResultsOf 401,268 participants in total, 13,331 tested positive for SARS‐CoV‐2 and 2282 had severe infection by end of January 2021. In unadjusted models, participants with ≥2 family members with diabetes were more likely to be SARS‐CoV‐2 positive (risk ratio‐RR 1.35; 95% confidence interval‐CI 1.24–1.47) and severe infection (RR 1.30; 95% CI 1.04–1.59), compared to those without. The excess risk of being tested positive for SARS‐CoV‐2 was attenuated but significant after adjusting for demographics, lifestyle factors, multimorbidity and presence of cardiometabolic conditions. The excess risk for severe infection was no longer significant after adjusting for demographics, lifestyle factors, multimorbidity and presence of cardiometabolic conditions, and was absent when excluding incident diabetes.ConclusionThe totality of the results suggests that good lifestyle and not developing incident diabetes may lessen risks of severe infections in people with a strong family of diabetes.

Introduction: People living with type 2 diabetes undertake a range of tasks to manage their condition, collectively referred to as self-management. Interventions designed to support self-management vary in their content, and efficacy. This systematic review will analyse self-management interventions for type 2 diabetes drawing on theoretical models of patient workload and capacity. Methods and analysis: Five electronic databases (Medline, Embase, CENTRAL, CINAHL and PsycINFO) will be searched from inception to 27th April 2021, supplemented by citation searching and hand-searching of reference lists. Two reviewers will independently review titles, abstracts and full texts. Inclusion criteria include Population: Adults with type 2 diabetes mellitus; Intervention: Randomised controlled trials of self-management support interventions; Comparison: Usual care; Outcomes: HbA1c (primary outcome) health-related quality of life (QOL), medication adherence, self-efficacy, treatment burden, healthcare utilization (e.g. number of appointment, hospital admissions), complications of type 2 diabetes (e.g. nephropathy, retinopathy, neuropathy, macrovascular disease) and mortality; Setting: Community. Study quality will be assessed using the Effective Practice and Organisation of Care (EPOC) risk of bias tool. Interventions will be classified according to the EPOC taxonomy and the PRISMS self-management taxonomy and grouped into similar interventions for analysis. Clinical and methodological heterogeneity will be assessed within subgroups, and random effects meta-analyses performed if appropriate. Otherwise, a narrative synthesis will be performed. Interventions will be graded on their likely impact on patient workload and support for patient capacity. The impact of these theoretical constructs on study outcomes will be explored using meta-regression. Conclusion This review will provide a broad overview of self-management interventions, analysed within the cumulative complexity model theoretical framework. Analyses will explore how the workload associated with self-management, and support for patient capacity, impact on outcomes of self-management interventions. Registration number: PROSPERO CRD42021236980.

Abstract Background Clinicians are less likely to prescribe guideline-recommended treatments to people with multimorbidity than to people with a single condition. Doubts as to the applicability of clinical trials of drug treatments (the gold standard for evidence-based medicine) when people have co-existing diseases (comorbidity) may underlie this apparent reluctance. Therefore, for a range of index conditions, we measured the comorbidity among participants in clinical trials of novel drug therapies and compared this to the comorbidity among patients in the community. Methods Data from industry-sponsored phase 3/4 multicentre trials of novel drug therapies for chronic medical conditions were identified from two repositories: Clinical Study Data Request and the Yale University Open Data Access project. We identified 116 trials (n = 122,969 participants) for 22 index conditions. Community patients were identified from a nationally representative sample of 2.3 million patients in Wales, UK. Twenty-one comorbidities were identified from medication use based on pre-specified definitions. We assessed the prevalence of each comorbidity and the total number of comorbidities (level of multimorbidity), for each trial and in community patients. Results In the trials, the commonest comorbidities in order of declining prevalence were chronic pain, cardiovascular disease, arthritis, affective disorders, acid-related disorders, asthma/COPD and diabetes. These conditions were also common in community-based patients. Mean comorbidity count for trial participants was approximately half that seen in community-based patients. Nonetheless, a substantial proportion of trial participants had a high degree of multimorbidity. For example, in asthma and psoriasis trials, 10–15% of participants had ≥ 3 conditions overall, while in osteoporosis and chronic obstructive pulmonary disease trials 40–60% of participants had ≥ 3 conditions overall. Conclusions Comorbidity and multimorbidity are less common in trials than in community populations with the same index condition. Comorbidity and multimorbidity are, nevertheless, common in trials. This suggests that standard, industry-funded clinical trials are an underused resource for investigating treatment effects in people with comorbidity and multimorbidity.

Abstract Background Multimorbidity is associated with higher mortality, but the relationship with cancer and cardiovascular mortality is unclear. The influence of demographics and type of condition on the relationship of multimorbidity with mortality remains unknown. We examine the relationship between multimorbidity (number/type) and cause of mortality and the impact of demographic factors on this relationship. Methods Data source: the UK Biobank; 500,769 participants; 37-73 years; 53.7% female. Exposure variables: number and type of long-term conditions (LTCs) (N = 43) at baseline, modelled separately. Cox regression models were used to study the impact of LTCs on all-cause/vascular/cancer mortality during median 7-year follow-up. All-cause mortality regression models were stratified by age/sex/socioeconomic status. Results All-cause mortality is 2.9% (14,348 participants). Of all deaths, 8350 (58.2%) were cancer deaths and 2985 (20.8%) vascular deaths. Dose-response relationship is observed between the increasing number of LTCs and all-cause/cancer/vascular mortality. A strong association is observed between cardiometabolic multimorbidity and all three clinical outcomes; non-cardiometabolic multimorbidity (excluding cancer) is associated with all-cause/vascular mortality. All-cause mortality risk for those with ≥ 4 LTCs was nearly 3 times higher than those with no LTCs (HR 2.79, CI 2.61–2.98); for ≥ 4 cardiometabolic conditions, it was > 3 times higher (HR 3.20, CI 2.56–4.00); and for ≥ 4 non-cardiometabolic conditions (excluding cancer), it was 50% more (HR 1.50, CI 1.36–1.67). For those with ≥ 4 LTCs, morbidity combinations that included cardiometabolic conditions, chronic kidney disease, cancer, epilepsy, chronic obstructive pulmonary disease, depression, osteoporosis and connective tissue disorders had the greatest impact on all-cause mortality. In the stratified model by age/sex, absolute all-cause mortality was higher among the 60–73 age group with an increasing number of LTCs; however, the relative effect size of the increasing number of LTCs on higher mortality risk was larger among those 37–49 years, especially men. While socioeconomic status was a significant predictor of all-cause mortality, mortality risk with increasing number of LTCs remained constant across different socioeconomic gradients. Conclusions Multimorbidity is associated with higher all-cause/cancer/vascular mortality. Type, as opposed to number, of LTCs may have an important role in understanding the relationship between multimorbidity and mortality. Multimorbidity had a greater relative impact on all-cause mortality in middle-aged as opposed to older populations, particularly males, which deserves exploration.

Background Echocardiography is considered the cornerstone of the diagnostic workup of heart failure with preserved ejection fraction. Thus far, validation of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) echo‐algorithm for evaluation of diastolic (dys)function in a patient suspected of heart failure with preserved ejection fraction has been limited. Methods and Results The diagnostic performance of the 2016 ASE/EACVI algorithm was assessed in 204 patients evaluated for unexplained dyspnea or pulmonary hypertension with echocardiogram and right heart catheterization. Invasively measured pulmonary capillary wedge pressure (PCWP) was used as the gold standard. In addition, the diagnostic performance of H2FPEF score and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) were evaluated. There was a poor correlation between indexed left atrial volume, E/e′ (septal and average) or early mitral inflow (E), and PCWP (r=0.25–0.30, P values all

Aim: Pseudo-pulseless electrical activity (pseudo-PEA) is a global hypotensive ischemic state with retained coordinated myocardial contractile activity and an organized ECG with no clinically detectable pulses. The role of standard external chest compressions (CPR) and its associated intrinsic hemodynamics remains unclear in the setting of pseudo-PEA. We undertook an experimental trial to compare epinephrine alone versus epinephrine with CPR in the treatment of pseudo-PEA. Methods: Using a porcine model of hypoxic pseudo-PEA, we randomized 12 Yorkshire male swine to resuscitation with epinephrine only (control) (0.0015 mg/kg) versus epinephrine plus standard CPR (intervention). Animals who achieved return of spontaneous circulation (ROSC) were stabilized, fully recovered to hemodynamic and respiratory baseline, and rearrested up to 6 times. Primary outcome was ROSC defined as a sustained systolic blood pressure (SBP) of 60 mmHg for 2 min. Secondary outcomes included time to ROSC, coronary perfusion pressure (CoPP), and end-tidal carbon dioxide (ETCO2). Results: Among 47 events of pseudo-PEA in 12 animals, we observed significantly higher proportion of ROSC when treatment included CPR (14/21 – 67%) compared to epinephrine alone (4/26 – 15%) (p = 0.0007). CoPP, aortic pressures and ETCO2 were significantly higher, and right atrial pressures were lower in the intervention group. Conclusions: In a swine model of hypoxia-induced pseudo-PEA, epinephrine plus CPR was associated with improved intra-arrest hemodynamics and higher probability of ROSC. Thus, epinephrine plus CPR may be superior to epinephrine alone in the treatment of patients with pseudo-PEA.

Pulmonary arterial hypertension is a heterogeneous group of diseases characterized by vascular cell proliferation leading to pulmonary vascular remodelling and ultimately right heart failure. Previous data indicated that 3′-deoxy-3′-[18F]-fluorothymidine ( 18 FLT) positron emission tomography (PET) scanning was increased in pulmonary arterial hypertension patients, hence providing a possible biomarker for pulmonary arterial hypertension as it reflects vascular cell hyperproliferation in the lung. This study sought to validate 18 FLT-PET in an expanded cohort of pulmonary arterial hypertension patients in comparison to matched healthy controls and unaffected bone morphogenetic protein receptor type 2 mutation carriers. 18 FLT-PET scanning was performed in 21 pulmonary arterial hypertension patients (15 hereditary pulmonary arterial hypertension and 6 idiopathic pulmonary arterial hypertension), 11 unaffected mutation carriers and 9 healthy control subjects. In-depth kinetic analysis indicated that there were no differences in lung 18 FLT k3 phosphorylation among pulmonary arterial hypertension patients, unaffected bone morphogenetic protein receptor type 2 mutation carriers and healthy controls. Lung 18 FLT uptake did not correlate with haemodynamic or clinical parameters in pulmonary arterial hypertension patients. Sequential 18 FLT-PET scanning in three patients demonstrated uneven regional distribution in 18 FLT uptake by 3D parametric mapping of the lung, although this did not follow the clinical course of the patient. We did not detect significantly increased lung 18 FLT uptake in pulmonary arterial hypertension patients, nor in the unaffected bone morphogenetic protein receptor type 2 mutation carriers, as compared to healthy subjects. The conflicting results with our preliminary human 18 FLT report may be explained by a small sample size previously and we observed large variation of lung 18 FLT signals between patients, challenging the application of 18 FLT-PET as a biomarker in the pulmonary arterial hypertension clinic.

Visual perception in natural environments depends on the ability to focus on salient stimuli while ignoring distractions. This kind of selective visual attention is associated with gamma activity in the visual cortex. While the nucleus reticularis thalami (nRT) has been implicated in selective attention, its role in modulating gamma activity in the visual cortex remains unknown. Here, we show that somatostatin- (SST) but not parvalbumin-expressing (PV) neurons in the visual sector of the nRT preferentially project to the dorsal lateral geniculate nucleus (dLGN), and modulate visual information transmission and gamma activity in primary visual cortex (V1). These findings pinpoint the SST neurons in nRT as powerful modulators of the visual information encoding accuracy in V1 and represent a novel circuit through which the nRT can influence representation of visual information.

Background: The Zanzibar Ministry of Health identified access to ultrasound (US) as a system priority due to limited diagnostic imaging capacity and consequent impact on patient care and requested a needs assessment in this regard. As a result, the objective of this study was to assess diagnostic imaging capacity focusing on ultrasound in Zanzibar, including health care providers’ (HCPs) current training, use, and barriers to implementation. Methods: A previously published ultrasound needs assessment survey was modified and administered on-site at the eight public hospitals in Zanzibar among a convenience sample of HCPs. Demographics, perceived US needs, current training and practice, and availability of specialty support were assessed. HCPs also completed focused personal interviews (FPIs) to explore experience with training, interests, and barriers to ultrasound. On-site diagnostic imaging modalities were assessed. Results: There were nine ultrasound machines present at six of the eight public hospitals assessed. All had x-ray, but only one had a CT scanner and a radiologist. There was no MRI capacity at the hospitals assessed at the time of the study. Survey data among 40 participants revealed that prior experience with POCUS was limited with only 10% reporting any prior ultrasound training or experience. The majority of those surveyed (72%), indicated a ‘high’ interest in learning ultrasound. Of those reporting interest in POCUS applications, obstetrics was the most often cited (70%). Lack of ultrasound machines (40%) and educators (28%) were identified as the greatest barriers. Conclusion: HCPs in Zanzibar have limited access to diagnostic imaging, including ultrasound, and expressed a high level of interest in learning point-of-care ultrasound. A shortage of machines and educators are the main barriers to widespread use. Obstetrics is the application for which ultrasound is currently most used and is the application HCPs are most interested in learning. Equipment and educational support for a POCUS program could improve care by increasing access to diagnostic imaging.

Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets. Objectives: Examine neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia patients (CAP). Methods: Isolated neutrophils underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NETosis and receptor expression. Circulating DNAse 1 activity, levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI were measured and correlated to clinical outcome. Serial sampling on day three to five post hospitalization were also measured. The effect of ex vivo PI3K inhibition was measured in a further cohort of 18 COVID-19 patients. Results: Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p = 0.0397) and NETosis (p = 0.0332), and impaired phagocytosis (p = 0.0036) associated with impaired ROS generation (p < 0.0001). The percentage of CD54+ neutrophils (p < 0.001) was significantly increased, while surface expression of CD11b (p = 0.0014) and PD-L1 (p = 0.006) were significantly decreased in COVID-19. COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p = 0.0396) and impaired DNAse activity (p < 0.0001). The ex vivo inhibition of PI3K γ and δ reduced NET release by COVID-19 neutrophils (p = 0.0129). Conclusions: COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration and NETosis, and impaired antimicrobial responses. These changes highlight that targeting neutrophil function may help modulate COVID-19 severity.

Background: COVID-19 is responsible for increasing deaths globally. As most people dying with COVID-19 are older with underlying long-term conditions (LTCs), some speculate that YLL are low. We aim to estimate YLL attributable to COVID-19, before and after adjustment for number/type of LTCs, using the limited data available early in the pandemic. Methods: We first estimated YLL from COVID-19 using WHO life tables, based on published age/sex data from COVID-19 deaths in Italy. We then used aggregate data on number/type of LTCs in a Bayesian model to estimate likely combinations of LTCs among people dying with COVID-19. We used routine UK healthcare data from Scotland and Wales to estimate life expectancy based on age/sex/these combinations of LTCs using Gompertz models from which we then estimate YLL. Results: Using the standard WHO life tables, YLL per COVID-19 death was 14 for men and 12 for women. After adjustment for number and type of LTCs, the mean YLL was slightly lower, but remained high (11.6 and 9.4 years for men and women, respectively). The number and type of LTCs led to wide variability in the estimated YLL at a given age (e.g. at ≥80 years, YLL was >10 years for people with 0 LTCs, and

[This corrects the article DOI: 10.1371/journal.pone.0238091.].

Summary: Background: Frailty, a state of increased vulnerability to adverse health outcomes, is important in diabetes management. We aimed to quantify the prevalence of frailty in people with diabetes, and to summarise the association between frailty and generic outcomes (eg, mortality) and diabetes-specific outcomes (eg, hypoglycaemia). Methods: In this systematic review and study-level meta-analysis, we searched MEDLINE, Embase, and Web of Science for observational studies published between Jan 1, 2001 (the year of the original publication of the Fried frailty phenotype), to Nov 26, 2019. We included studies that assessed and quantified frailty in adults with diabetes, aged 18 years and older; and excluded conference abstracts, grey literature, and studies not published in English. Data from eligible studies were extracted using a piloted data extraction form. Our primary outcome was the prevalence of frailty in people with diabetes. Secondary outcomes were incidence of frailty and generic and diabetes-specific outcomes. Data were assessed by random-effects meta-analysis where possible and by narrative synthesis where populations were too heterogeneous to allow meta-analysis. This study is registered with PROSPERO, CRD42020163109. Findings: Of the 3038 studies we identified, 118 studies using 20 different frailty measures were eligible for inclusion (n=1 375 373). The most commonly used measures of frailty were the frailty phenotype (69 [58%] of 118 studies), frailty (16 [14%]), and FRAIL scale (10 [8%]). Studies were heterogenous in setting (88 studies were community-based, 18 were outpatient-based, ten were inpatient-based, and two were based in residential care facilities), demographics, and inclusion criteria; therefore, we could not do a meta-analysis for the primary outcome and instead summarised prevalence data using a narrative synthesis. Median community frailty prevalence using frailty phenotype was 13% (IQR 9–21). Frailty was consistently associated with mortality in 13 (93%) of 14 studies assessing this outcome (pooled hazard ratio 1·51 [95% CI 1·30–1·76]), with hospital admission in seven (100%) of seven, and with disability in five (100%) of five studies. Frailty was associated with hypoglycaemia events in one study (

Objectives Low back pain (LBP) is a leading contributor to disability globally. Self-management is a core component of LBP management. We aimed to synthesise published qualitative literature concerning digital health interventions (DHIs) to support LBP self-management to: (1) determine engagement strategies, (2) identify barriers and facilitators affecting patient uptake/utilisation and (3) develop a preliminary conceptual model of barriers and facilitators to uptake/utilisation.Design Systematic review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.Data sources MEDLINE, Embase, CINAHL, PsycINFO, Cochrane Library, DoPHER, TRoPHI, Web of Science and OT Seeker, from January 2000 to December 2018, using the concepts: LBP, DHI and self-management.Eligibility criteria Peer-reviewed qualitative study (or component) examining engagement with, or barriers and/or facilitators to the uptake/utilisation of an interactive DHI for self-management of LBP in adults (community, primary or secondary care settings).Data extraction and synthesis Standardised data extraction form was completed. COREQ (Consolidated criteria for Reporting Qualitative research) checklist was used to assess methodology. Data was synthesised narratively for engagement strategies, thematically for barriers/facilitators to uptake/utilisation and normalisation process theory was applied to produce a conceptual model.Results We identified 14 191 citations, of which 105 full-text articles were screened, and five full-text articles from four studies included. These were from community and primary care contexts in Europe and the USA, and involved 56 adults with LBP and 19 healthcare professionals. There was a lack of consideration on how to sustain engagement with DHIs. Examination of barriers and facilitators for uptake/utilisation identified four major themes: IT (information technology) usability–accessibility; quality–quantity of content; tailoring–personalisation; and motivation–support. These themes informed the development of a preliminary conceptual model for uptake/utilisation of a DHI for LBP self-management.Conclusions We highlight key barriers and facilitators that should be considered when designing DHIs for LBP self-management. Our findings are in keeping with reviews of DHIs for other long-term conditions, implying these findings may not be condition specific.Systematic review registration A protocol for this systematic review was registered with https://www.crd.york.ac.uk/PROSPERO/ (CRD42016051182) on 10 November 2016. https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42016051182

Objective To investigate how the type and number of long-term conditions (LTCs) impact on all-cause mortality and major adverse cardiovascular events (MACE) in people with rheumatoid arthritis (RA).Design Population-based longitudinal cohort study.Setting UK Biobank.Participants UK Biobank participants (n=502 533) aged between 37 and 73 years old.Primary outcome measures Primary outcome measures were risk of all-cause mortality and MACE.Methods We examined the relationship between LTC count and individual comorbid LTCs (n=42) on adverse clinical outcomes in participants with self-reported RA (n=5658). Risk of all-cause mortality and MACE were compared using Cox’s proportional hazard models adjusted for lifestyle factors (smoking, alcohol intake, physical activity), demographic factors (sex, age, socioeconomic status) and rheumatoid factor.Results 75.7% of participants with RA had multimorbidity and these individuals were at increased risk of all-cause mortality and MACE. RA and >4 LTCs showed a threefold increased risk of all-cause mortality (HR 3.30, 95% CI 2.61 to 4.16), and MACE (HR 3.45, 95% CI 2.66 to 4.49) compared with those without LTCs. Of the comorbid LTCs studied, osteoporosis was most strongly associated with adverse outcomes in participants with RA compared with those without RA or LTCs: twofold increased risk of all-cause mortality (HR 2.20, 95% CI 1.55 to 3.12) and threefold increased risk of MACE (HR 3.17, 95% CI 2.27 to 4.64). These findings remained in a subset (n=3683) with RA diagnosis validated from clinical records or medication reports.Conclusion Those with RA and other LTCs, particularly comorbid osteoporosis, are at increased risk of adverse outcomes, although the role of corticosteroids could not be evaluated in this study. These results are clinically relevant for the monitoring and management of RA across the healthcare system, and future clinical guidelines for RA should acknowledge the importance of multimorbidity.

Introduction Diabetes mellitus is common and growing in prevalence, and an increasing proportion of people with diabetes are living to older age. Frailty is, therefore, becoming an important concept in diabetes. Frailty is associated with older age and describes a state of increased susceptibility to decompensation in response to physiological stress. A range of measures have been used to quantify frailty. This systematic review aims to identify measures used to quantify frailty in people with diabetes (any type); to summarise the prevalence of frailty in diabetes; and to describe the relationship between frailty and adverse clinical outcomes in people with diabetes.Methods and analysis Three electronic databases (Medline, Embase and Web of Science) will be searched from 2000 to November 2019 and supplemented by citation searching of relevant articles and hand searching of reference lists. Two reviewers will independently review titles, abstracts and full texts. Inclusion criteria include: (1) adults with any type of diabetes mellitus; (2) quantify frailty using any validated frailty measure; (3) report the prevalence of frailty and/or the association between frailty and clinical outcomes in people with diabetes; (4) studies that assess generic (eg, mortality, hospital admission and falls) or diabetes-specific outcomes (eg, hypoglycaemic episodes, cardiovascular events, diabetic nephropathy and diabetic retinopathy); (5) cross-sectional and longitudinal observational studies. Study quality will be assessed using the Newcastle–Ottawa Scale for observational studies. Clinical and methodological heterogeneity will be assessed, and a random effects meta-analysis performed if appropriate. Otherwise, a narrative synthesis will be performed.Ethics and dissemination This manuscript describes the protocol for a systematic review of observational studies and does not require ethical approval.PROSPERO registration number CRD42020163109.

The International Multimorbidity Symposium was held in November 2019 at Western University to achieve three main objectives: to discuss progress and findings from various jurisdictions; to facilitate collaboration through group discussion to identify strategies to move multimorbidity research forward; and to create concrete plans to ensure advances in multimorbidity research and knowledge can be achieved through cross-national partnership. This event included keynote presentations, elevator pitch presentations and breakout sessions and there was a total of 35 attendees from eight countries, representing diverse disciplines and training levels. The overall themes arising from the event were: the importance of integrating the study and management of multimorbidity from both the primary care and public health perspectives; meaningful engagement and collaboration with patients and caregivers to understand key dimensions of multimorbidity; the considerable benefit of collaborative international partnerships; and the need to spread and scale innovations for health care systems that can better respond to the complex needs of patients and caregivers who are living with multimorbidity. Finally, it was well-acknowledged among the attendees that expanding the collaboration and discussion among international colleagues via in-person and virtual events will be important to move multimorbidity research forward.

Background Although most newly presenting patients with pulmonary hypertension (PH) have elevated pulmonary artery wedge pressure, identification of so‐called postcapillary PH can be challenging. A noninvasive tool predicting elevated pulmonary artery wedge pressure in patients with incident PH may help avoid unnecessary invasive diagnostic procedures. Methods and Results A combination of clinical data, ECG, and echocardiographic parameters was used to refine a previously developed left heart failure risk score in a retrospective cohort of pre‐ and postcapillary PH patients. This updated score (renamed the OPTICS risk score) was externally validated in a prospective cohort of patients from 12 Dutch nonreferral centers the OPTICS network. Using the updated OPTICS risk score, the presence of postcapillary PH could be predicted on the basis of body mass index ≥30, diabetes mellitus, atrial fibrillation, dyslipidemia, history of valvular surgery, sum of SV1 (deflection in V1 in millimeters) and RV6 (deflection in V6 in millimeters) on ECG, and left atrial dilation. The external validation cohort included 81 postcapillary PH patients and 66 precapillary PH patients. Using a predefined cutoff of >104, the OPTICS score had 100% specificity for postcapillary PH (sensitivity, 22%). In addition, we investigated whether a high probability of heart failure with preserved ejection fraction, assessed by the H2FPEF score (obesity, atrial fibrillation, age >60 yrs, ≥2 antihypertensives, E/e' >9, and pulmonary artery systolic pressure by echo >35 mmHg), similarly predicted the presence of elevated pulmonary artery wedge pressure. High probability of heart failure with preserved ejection fraction (H2FPEF score ≥6) was less specific for postcapillary PH. Conclusions In a community setting, the OPTICS risk score can predict elevated pulmonary artery wedge pressure in PH patients without clear signs of left‐sided heart disease. The OPTICS risk score may be used to tailor the decision to perform invasive diagnostic testing.

Background: There is an urgent need for epidemiological research in primary care to develop risk assessment processes for patients presenting with COVID-19, but lack of a standardised approach to data collection is a significant barrier to implementation. Aim: To collate a list of relevant symptoms, assessment items, demographics, and lifestyle and health conditions associated with COVID-19, and match these data items with corresponding SNOMED CT clinical terms to support the development and implementation of consultation templates. Design & setting: Published and preprint literature for systematic reviews, meta-analyses, and clinical guidelines describing the symptoms, assessment items, demographics, and/or lifestyle and health conditions associated with COVID-19 and its complications were reviewed. Corresponding clinical concepts from SNOMED CT, a widely used structured clinical vocabulary for electronic primary care health records, were identified. Method: Guidelines and published and unpublished reviews (N = 61) were utilised to collate a list of relevant data items for COVID-19 consultations. The NHS Digital SNOMED CT Browser was used to identify concept and descriptive identifiers. Key implementation challenges were conceptualised through a Normalisation Process Theory (NPT) lens. Results: In total, 32 symptoms, eight demographic and lifestyle features, 25 health conditions, and 20 assessment items relevant to COVID-19 were identified, with proposed corresponding SNOMED CT concepts. These data items can be adapted into a consultation template for COVID-19. Key implementation challenges include: 1) engaging with key stakeholders to achieve ’buy in’; and 2) ensuring any template is usable within practice settings. Conclusion: Consultation templates for COVID-19 are needed to standardise data collection, facilitate research and learning, and potentially improve quality of care for COVID-19.

Background: Child maltreatment is associated with long-term conditions (LTCs) in adulthood. Its relationship to multimorbidity (≥2 LTCs) is less clear. We explore the relationship between child maltreatment, multimorbidity and factors complicating management. Methods: Cross-sectional analysis of 157,357 UK Biobank participants. Experience of four maltreatment types (physical/sexual/emotional/neglect) was identified. We explored the relationship between type, number and frequency of maltreatment and LTC count (0, 1, 2, 3, ≥4) using multinomial logistic regression. Binary logistic regression assessed the relationship between maltreatment and self-rated health, loneliness, social isolation, frailty and widespread pain in those with multimorbidity, adjusting for sociodemographics and lifestyle factors. Results: 52,675 participants (33%) experienced ≥1 type of maltreatment; 983 (0.6%) experienced all four. Type, frequency and number of types of maltreatment were associated with higher LTC count. People experiencing four types of maltreatment were 5 times as likely to have a LTC count of ≥4 as those experiencing none (odds ratio (OR): 5.16; 99% confidence interval (CI): 3.77-7.07). Greater number of types of maltreatment was associated with higher prevalence of combined physical/mental health LTCs (OR: 2.99; 99% CI: 2.54–3.51 for four types of maltreatment). Compared to people who reported no maltreatment, people experiencing all four types of maltreatment were more likely to have poor self-rated health (OR: 3.56; 99% CI: 2.58–4.90), loneliness (OR: 3.16; 99% CI: 2.17–4.60), social isolation (OR: 1.45; 99% CI: 1.03–2.05), widespread pain (OR: 3.19; 99% CI: 1.87–5.44) and frailty (OR: 3.21; 99% CI: 2.04–5.05). Conclusion: Peoplewith a history of maltreatment have higher LTC counts and potentially more complicated management needs reinforcing calls for early intervention.

Objective To systematically review the literature exploring the associations between multimorbidity (the presence of two or more long-term conditions (LTCs)) and adverse clinical outcomes in patients with chronic kidney disease (CKD).Design Systematic review and meta-analysis.Data sources MEDLINE, EMBASE, CINAHL, Cochrane Library and SCOPUS (1946–2019). The main search terms were ‘Chronic Kidney Failure’ and ‘Multimorbid*’.Eligibility criteria Observational studies of adults over the age of 18 with CKD stages 3–5, that is, estimated glomerular filtration rate less than 60 mL/min/1.73 m2. The exposure was multimorbidity quantified by measures and the outcomes were all-cause mortality, renal progression, hospitalisation and cardiovascular events. We did not consider CKD as a comorbid LTC.Data extraction and synthesis Newcastle-Ottawa Scale for quality appraisal and risk of bias assessment and fixed effects meta-analysis for data synthesis.Results Of 1852 papers identified, 26 met the inclusion criteria. 21 papers involved patients with advanced CKD and no studies were from low or middle-income countries. All-cause mortality was an outcome in all studies. Patients with multimorbidity were at higher risk of mortality compared with patients without multimorbidity (total risk ratio 2.28 (95% CI 1.81 to 2.88)). The risk of mortality was higher with increasing multimorbidity (total HR 1.31 (95% CI 1.27 to 1.36)) and both concordant and discordant LTCs were associated with heightened risk. Multimorbidity was associated with renal progression in four studies, hospitalisation in five studies and cardiovascular events in two studies.Limitations Meta-analysis could only include 10 of 26 papers as the methodologies of studies were heterogeneous.Conclusions There are associations between multimorbidity and adverse clinical outcomes in patients with CKD. However, most data relate to mortality risk in patients with advanced CKD. There is limited evidence regarding patients with mild to moderate CKD, outcomes such as cardiovascular events, types of LTCs and regarding patients from low or middle-income countries.PROSPERO registration number CRD42019147424.

Abstract Introduction The TNF‐α‐induced protein‐8 (TNFAIP8, also known as TIPE) family of molecules comprises four members: TNFAIP8 and TIPEs1‐3. Since the first description of these proteins, their roles in fine‐tuning inflammation and in directing leukocyte migration have been described in several organ systems. However, their relationship with intervertebral disc (IVD) is unknown. Materials and methods Here, we describe the expression of TNFAIP8 family genes in the nucleus pulposus (NP) and annulus fibrosus (AF) of the normal adult murine IVD. We further describe the expression of these genes in the injured male and female murine IVD. Results Tnfaip8 gene expression was decreased, and Tipe1 gene expression was essentially unchanged, in response to injury. Tipe2 and Tipe3 gene expression was markedly elevated in response to IVD injury, along with those encoding known inflammatory markers (ie, Tnfa, Il6, Cxcl1, and Adam8). Additionally, sex‐related differences were also observed for some of these genes in intact and injured mouse IVDs. Future studies include examining tissue distribution of TNFAIP8 family proteins and identifying cells that produce them. In addition, examining mice that are deficient in TNFAIP8 molecules, in relation to gene expression, tissue morphology and mouse behavior, may further delineate the roles of these molecules in IVD inflammation and degeneration.

Historically, neuroscience principles have heavily influenced artificial intelligence (AI), for example the influence of the perceptron model, essentially a simple model of a biological neuron, on artificial neural networks. More recently, notable recent AI advances, for example the growing popularity of reinforcement learning, often appear more aligned with cognitive neuroscience or psychology, focusing on function at a relatively abstract level. At the same time, neuroscience stands poised to enter a new era of large-scale high-resolution data and appears more focused on underlying neural mechanisms or architectures that can, at times, seem rather removed from functional descriptions. While this might seem to foretell a new generation of AI approaches arising from a deeper exploration of neuroscience specifically for AI, the most direct path for achieving this is unclear. Here we discuss cultural differences between the two fields, including divergent priorities that should be considered when leveraging modern-day neuroscience for AI. For example, the two fields feed two very different applications that at times require potentially conflicting perspectives. We highlight small but significant cultural shifts that we feel would greatly facilitate increased synergy between the two fields.

​Maf (c-Maf) and Mafb transcription factors (TFs) have compensatory roles in repressing somatostatin (SST+) interneuron (IN) production in medial ganglionic eminence (MGE) secondary progenitors in mice. Maf and Mafb conditional deletion (cDKO) decreases the survival of MGE-derived cortical interneurons (CINs) and changes their physiological properties. Herein, we show that (1) Mef2c and Snap25 are positively regulated by Maf and Mafb to drive IN morphological maturation; (2) Maf and Mafb promote Mef2c expression which specifies parvalbumin (PV+) INs; (3) Elmo1, Igfbp4 and Mef2c are candidate markers of immature PV+ hippocampal INs (HIN). Furthermore, Maf/Mafb neonatal cDKOs have decreased CINs and increased HINs, that express Pnoc, an HIN specific marker. Our findings not only elucidate key gene targets of Maf and Mafb that control IN development, but also identify for the first time TFs that differentially regulate CIN vs. HIN production.

BackgroundThere is emerging interest in multimorbidity in type 2 diabetes (T2D), which can be either concordant (T2D related) or discordant (unrelated), as a way of understanding the burden of disease in T2D. Current diabetes guidelines acknowledge the complex nature of multimorbidity, the management of which should be based on the patient's individual clinical needs and comorbidities. However, although associations between multimorbidity, glycated haemoglobin (HbA1c), and mortality in people with T2D have been studied to some extent, significant gaps remain, particularly regarding different patterns of multimorbidity, including concordant and discordant conditions. This study explores associations between multimorbidity (total condition counts/concordant/discordant/different combinations of conditions), baseline HbA1c, and all-cause mortality in T2D.Methods and findingsWe studied two longitudinal cohorts of people with T2D using the UK Biobank (n = 20,569) and the Taiwan National Diabetes Care Management Program (NDCMP) (n = 59,657). The number of conditions in addition to T2D was used to quantify total multimorbidity, concordant, and discordant counts, and the effects of different combinations of conditions were also studied. Outcomes of interest were baseline HbA1c and all-cause mortality. For the UK Biobank and Taiwan NDCMP, mean (SD) ages were 60.2 (6.8) years and 60.8 (11.3) years; 7,579 (36.8%) and 31,339 (52.5%) were female; body mass index (BMI) medians (IQR) were 30.8 (27.7, 34.8) kg/m2 and 25.6 (23.5, 28.7) kg/m2; and 2,197 (10.8%) and 9,423 (15.8) were current smokers, respectively. Increasing total and discordant multimorbidity counts were associated with lower HbA1c and increased mortality in both datasets. In Taiwan NDCMP, for those with four or more additional conditions compared with T2D only, the mean difference (95% CI) in HbA1c was -0.82% (-0.88, -0.76) p < 0.001. In UK Biobank, hazard ratios (HRs) (95% CI) for all-cause mortality in people with T2D and one, two, three, and four or more additional conditions compared with those without comorbidity were 1.20 (0.91-1.56) p < 0.001, 1.75 (1.35-2.27) p < 0.001, 2.17 (1.67-2.81) p < 0.001, and 3.14 (2.43-4.03) p < 0.001, respectively. Both concordant/discordant conditions were significantly associated with mortality; however, HRs were largest for concordant conditions. Those with four or more concordant conditions had >5 times the mortality (5.83 [4.28-7.93] p ConclusionsMultimorbidity patterns associated with the highest mortality differed between UK Biobank (a population predominantly comprising people of European descent) and the Taiwan NDCMP, a predominantly ethnic Chinese population. Future research should explore the mechanisms underpinning the observed relationship between increasing multimorbidity count and reduced HbA1c alongside increased mortality in people with T2D and further examine the implications of different patterns of multimorbidity across different ethnic groups. Better understanding of these issues, especially effects of condition type, will enable more effective personalisation of care.

Our thoughts, feelings, and behaviors are shaped in critical ways by our beliefs about how we compare to other people. Prior research has predominately focused on the consequences of believing oneself to be better than average (BTA). Research on the consequences of worse-than-average (WTA) beliefs has been far more limited, focusing mostly on the downsides of WTA beliefs. In this paper, we argue for the systematic investigation of the possible long-term benefits of WTA beliefs in domains including motivation, task performance, and subjective well-being. We develop a conceptual framework for examining these possible benefits, we explore the usefulness of this framework to generate novel insights in an important psychological domain (skill learning), and we conclude with broader recommendations for research in other domains such as friendship formation, moral, and political decision making.

Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta-blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta-blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [ 11 C]-hydroxyephedrine positron emission tomography ([ 11 C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity. [ 11 C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [ 11 C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [ 11 C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [ 11 C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [ 11 C]HED retention index was lower compared to LV tracer uptake (p

Objective: Patient satisfaction is emerging as a new health-care metric. We hypothesized that an emergency department (ED) informational pamphlet would significantly improve patient understanding of ED operations and ultimately improve patient satisfaction. Methods: We performed a prospective study of patients presenting to a single tertiary care center ED from April to July 2017. All patients were given a pamphlet on alternating weeks with regular care on opposite weeks and were surveyed upon ED discharge. The primary outcome was patient satisfaction with ED care. Secondary outcomes included patient understanding of various wait times (test results, consultants), discharge process, who was on the care team and what to expect during the ED visit. Results: Four hundred ninety-four patients were included in this study and 266 (54%) were in the control group. Of 228 (46%) patients who were given the pamphlet, 116 (51%) were unaware they received it. Of the remaining 112 (49%) patients who remembered receiving the pamphlet, 43 (38%) stated they read it. Among those reading the pamphlet, only two statements were significant: knowing what to expect during the ED visit (88% vs 71%; P = 0.012) and waiting time for test results (95% vs 75%; P = 0.003) when compared to those who did not receive or read the pamphlet. Conclusion: An ED informational pamphlet, when utilized by patients, does improve patient understanding of some aspects of the ED visit but does not appear to be the best tool to convey all information. Ultimately, sustained improvement in patient satisfaction is a complex and dynamic issue necessitating a multifactorial approach and other methods should be explored.

Background: Oxidative stress and inflammation are considered to be important pathways leading to particulate matter (PM)-associated disease. In this exploratory study, we examined the effects of metals and oxidative potential (OP) in urban PM on biomarkers of systemic inflammation, oxidative stress and neural function. Methods: Fifty-three healthy non-smoking volunteers (mean age 28 years, twenty-eight females) were exposed to coarse (2.5–10 μm, mean 213 μg/m3), fine (0.15–2.5 μm, 238 μg/m3), and/or ultrafine concentrated ambient PM (

Abstract Background Understanding and measuring implementation processes is a key challenge for implementation researchers. This study draws on Normalization Process Theory (NPT) to develop an instrument that can be applied to assess, monitor or measure factors likely to affect normalization from the perspective of implementation participants. Methods An iterative process of instrument development was undertaken using the following methods: theoretical elaboration, item generation and item reduction (team workshops); item appraisal (QAS-99); cognitive testing with complex intervention teams; theory re-validation with NPT experts; and pilot testing of instrument. Results We initially generated 112 potential questionnaire items; these were then reduced to 47 through team workshops and item appraisal. No concerns about item wording and construction were raised through the item appraisal process. We undertook three rounds of cognitive interviews with professionals (n = 30) involved in the development, evaluation, delivery or reception of complex interventions. We identified minor issues around wording of some items; universal issues around how to engage with people at different time points in an intervention; and conceptual issues around the types of people for whom the instrument should be designed. We managed these by adding extra items (n = 6) and including a new set of option responses: ‘not relevant at this stage’, ‘not relevant to my role’ and ‘not relevant to this intervention’ and decided to design an instrument explicitly for those people either delivering or receiving an intervention. This version of the instrument had 53 items. Twenty-three people with a good working knowledge of NPT reviewed the items for theoretical drift. Items that displayed a poor alignment with NPT sub-constructs were removed (n = 8) and others revised or combined (n = 6). The final instrument, with 43 items, was successfully piloted with five people, with a 100% completion rate of items. Conclusion The process of moving through cycles of theoretical translation, item generation, cognitive testing, and theoretical (re)validation was essential for maintaining a balance between the theoretical integrity of the NPT concepts and the ease with which intended respondents could answer the questions. The final instrument could be easily understood and completed, while retaining theoretical validity. NoMAD represents a measure that can be used to understand implementation participants’ experiences. It is intended as a measure that can be used alongside instruments that measure other dimensions of implementation activity, such as implementation fidelity, adoption, and readiness.

Abstract Introduction Successful implementation and embedding of new health care practices relies on co-ordinated, collective behaviour of individuals working within the constraints of health care settings. Normalization Process Theory (NPT) provides a theory of implementation that emphasises collective action in explaining, and shaping, the embedding of new practices. To extend the practical utility of NPT for improving implementation success, an instrument (NoMAD) was developed and validated. Methods Descriptive analysis and psychometric testing of an instrument developed by the authors, through an iterative process that included item generation, consensus methods, item appraisal, and cognitive testing. A 46 item questionnaire was tested in 6 sites implementing health related interventions, using paper and online completion. Participants were staff directly involved in working with the interventions. Descriptive analysis and consensus methods were used to remove redundancy, reducing the final tool to 23 items. Data were subject to confirmatory factor analysis which sought to confirm the theoretical structure within the sample. Results We obtained 831 completed questionnaires, an average response rate of 39% (range: 22–77%). Full completion of items was 50% (n = 413). The confirmatory factor analysis showed the model achieved acceptable fit (CFI = 0.95, TLI = 0.93, RMSEA = 0.08, SRMR = 0.03). Construct validity of the four theoretical constructs of NPT was supported, and internal consistency (Cronbach’s alpha) were as follows: Coherence (4 items, α = 0.71); Collective Action (7 items, α = 0.78); Cognitive Participation (4 items, α = 0.81); Reflexive Monitoring (5 items, α = 0.65). The normalisation scale overall, was highly reliable (20 items, α = 0.89). Conclusions The NoMAD instrument has good face validity, construct validity and internal consistency, for assessing staff perceptions of factors relevant to embedding interventions that change their work practices. Uses in evaluating and guiding implementation are proposed.

Abstract Background Normalization Process Theory (NPT) identifies, characterises and explains key mechanisms that promote and inhibit the implementation, embedding and integration of new health techniques, technologies and other complex interventions. A large body of literature that employs NPT to inform feasibility studies and process evaluations of complex healthcare interventions has now emerged. The aims of this review were to review this literature; to identify and characterise the uses and limits of NPT in research on the implementation and integration of healthcare interventions; and to explore NPT’s contribution to understanding the dynamics of these processes. Methods A qualitative systematic review was conducted. We searched Web of Science, Scopus and Google Scholar for articles with empirical data in peer-reviewed journals that cited either key papers presenting and developing NPT, or the NPT Online Toolkit (www.normalizationprocess.org). We included in the review only articles that used NPT as the primary approach to collection, analysis or reporting of data in studies of the implementation of healthcare techniques, technologies or other interventions. A structured data extraction instrument was used, and data were analysed qualitatively. Results Searches revealed 3322 citations. We show that after eliminating 2337 duplicates and broken or junk URLs, 985 were screened as titles and abstracts. Of these, 101 were excluded because they did not fit the inclusion criteria for the review. This left 884 articles for full-text screening. Of these, 754 did not fit the inclusion criteria for the review. This left 130 papers presenting results from 108 identifiable studies to be included in the review. NPT appears to provide researchers and practitioners with a conceptual vocabulary for rigorous studies of implementation processes. It identifies, characterises and explains empirically identifiable mechanisms that motivate and shape implementation processes. Taken together, these mean that analyses using NPT can effectively assist in the explanation of the success or failure of specific implementation projects. Ten percent of papers included critiques of some aspect of NPT, with those that did mainly focusing on its terminology. However, two studies critiqued NPT emphasis on agency, and one study critiqued NPT for its normative focus. Conclusions This review demonstrates that researchers found NPT useful and applied it across a wide range of interventions. It has been effectively used to aid intervention development and implementation planning as well as evaluating and understanding implementation processes themselves. In particular, NPT appears to have offered a valuable set of conceptual tools to aid understanding of implementation as a dynamic process.

Biomedical engineering (BME) spans a wide range of research fields and professional activities. Most BME departments use a seminar series to introduce graduate students to exciting research conducted outside their own university, learn about professional opportunities, and enhance their understanding of related topics (e.g., ethics in BME, engineering education, entrepreneurship). However, even a stellar lineup of expert seminar speakers cannot appeal to all graduate students--even though the information presented may be very important to that student in the future. Can we initiate active learning assignments to increase student engagement with all speakers? Our BME department developed a strategy to scaffold active learning activities to enhance student engagement in the graduate seminars. All speakers supplied three papers for advance reading and students were required to generate questions based on reading the papers. The questions were provided to the speakers in advance of the seminar. Both students and speakers submitted short reflection surveys after the seminar. With increasing graduate experience, students were also required to critique the articles, evaluate presentation styles, and answer the questions of other students. The requirement to read the papers and generate questions definitely increased student engagement with the speakers. The increased personal engagement was evident in the critical thinking by the students as they subsequently discussed trends in different fields, evaluated presentation styles, and learned about different career opportunities. The increase in student engagement had the added benefit of creating a positive impression of our students with the speakers visiting from other institutions.

Abstract Background Recognition of the difficult airway is a critical element of emergency practice. Mallampati score and body mass index (BMI) are not always predictive and they may be unavailable in critically ill patients. Ultrasonography provides high-resolution images that are rapidly obtainable, mobile, and non-invasive. Studies have shown correlation of ultrasound measurements with difficult laryngoscopy; however, none have been performed in the Emergency Department (ED) using a consistent scanning protocol. Objectives This study seeks to determine the feasibility of ultrasound measurements of the upper airway performed in the ED by emergency physicians, the inter-rater reliability of such measurements, and their relationship with Mallampati score and BMI. Methods A convenience sample of volunteer ED patients and healthy volunteers with no known airway issues, aged > 18 years, had images taken of their airway using a standardized ultrasound scanning protocol by two EM ultrasound fellowship trained physicians. Measurements consisted of tongue base, tongue base-to-skin, epiglottic width and thickness, and pre-epiglottic space. Mean and standard deviation (SD) were used to summarize measurements. Inter-rater reliability was assessed by intraclass correlation coefficients (ICCs). Analysis of variance with linear contrasts was used to compare measurements with Mallampati scores and linear regression with BMI. Results Of 39 participants, 50% were female, 50% white, 42% black, with median age 32.5 years (range 19–90), and BMI 26.0 (range 19–47). Mean ± SD for each measurement (mm) was as follows: tongue base (44.6 ± 5.1), tongue base-to-skin (60.9 ± 5.3), epiglottic width (15.0 ± 2.8) and thickness (2.0 ± 0.37), and pre-epiglottic space (11.4 ± 2.4). ICCs ranged from 0.76 to 0.88 for all measurements except epiglottis thickness (ICC = 0.57). Tongue base and tongue base-to-skin thickness were found to increase with increasing Mallampati score (p = .04, .01), whereas only tongue-to-skin thickness was loosely correlated with BMI (r = .38). Conclusions A standardized ultrasound scanning protocol demonstrates that the airway can be measured by emergency sonologists with good inter-operator reliability in all but epiglottic thickness. The measurements correlate with Mallampati score but not with BMI. Future investigation might focus on ultrasound evaluation of the airway in patients receiving airway management to determine whether ultrasound can predict challenging or abnormal airway anatomy prior to laryngoscopy.

Abstract Background Treatment burden is the workload of healthcare experienced by those with long-term conditions and the impact that this has on well-being. Treatment burden can negatively impact on quality of life and adherence to treatments. Individuals are likely to differ in their ability to manage health problems and follow treatments, defined as patient capacity. This has been under investigated in stroke. The aim of this paper is to create a conceptual model of treatment burden and patient capacity for people who have had a stroke through exploration of their experiences of healthcare. Methods Interviews were conducted at home with 29 individuals who have had a stroke. These were recorded and transcribed verbatim. Fifteen explored treatment burden and were analysed by framework analysis underpinned by Normalisation Process Theory (NPT). Fourteen explored patient capacity and were analysed by thematic analysis. Taxonomies of treatment burden and patient capacity were created and a conceptual model produced. Results Mean age was 68 years. Sixteen were men and 13 women. The following broad areas of treatment burden were identified: making sense of stroke management and planning care; interacting with others including health professionals, family and other stroke patients; enacting management strategies; and reflecting on management. Treatment burdens were identified as arising from either: the workload of healthcare; or the endurance of care deficiencies. Six factors were identified that influence patient capacity: personal attributes and skills; physical and cognitive abilities; support network; financial status; life workload, and environment. Conclusions Healthcare workload and the presence of care deficiencies can influence and be influenced by patient capacity. The quality and configuration of health and social care services has considerable influence on treatment burden and patient capacity. Findings have important implications for the design of clinical guidelines and healthcare delivery, highlighting issues such as the importance of good care co-ordination.