Can metformin prevent cancer relative to sulfonylureas? A target trial emulation accounting for competing risks and poor overlap via double/debiased machine learning estimators.

There is mounting interest in the possibility that metformin, indicated for glycemic control in type 2 diabetes, has a range of additional beneficial effects. Randomized trials have shown that metformin prevents adverse cardiovascular events, and metformin use has also been associated with reduced cognitive decline and cancer incidence. In this paper, we dig more deeply into whether metformin prevents cancer by emulating target randomized trials comparing metformin to sulfonylureas as first line diabetes therapy using data from Clinical Practice Research Datalink, a U.K. primary care database (1987-2018). We included individuals with diabetes, no prior cancer diagnosis, no chronic kidney disease, and no prior diabetes therapy who initiated metformin (N=93353) or a sulfonylurea (N=13864). In our cohort, the estimated overlap weighted additive separable direct effect of metformin compared to sulfonylureas on cancer risk at 6 years was -1% (.95 CI=-2.2%, 0.1%), which is consistent with metformin providing no direct protection against cancer incidence or substantial protection. The analysis faced two methodological challenges-poor overlap, and pre-cancer death as a competing risk. To address these issues while minimizing nuisance model misspecification, we develop and apply double/debiased machine learning estimators of overlap weighted separable effects in addition to more traditional effect estimates.

A role of ROS-dependent defects in mitochondrial dynamic and autophagy in carbon black nanoparticle-mediated myocardial cell damage.

Carbon black nanoparticles (CBNPs) are widely distributed in the environment and are increasingly recognized as a contributor in the development of cardiovascular disease. A variety of cardiac injuries and diseases result from structural and functional damage to cardiomyocytes. This study explored the mechanisms of CBNPs-mediated myocardial toxicity. CBNPs were given to mice through intra-tracheal instillation and it was demonstrated that the particles can be taken up into the cardiac tissue. Exposure to CBNPs induced cardiomyocyte inflammation and apoptosis. In combination with in vitro experiments, we showed that CBNPs increased the ROS and induced mitochondria fragmentation. Functionally, CBNPs-exposed cardiomyocyte exhibited depolarization of the mitochondrial membrane potential, release of cytochrome c, and activation of pro-apoptotic BAX, thereby initiating programmed cell death. On the other hand, CBNPs impaired autophagy, leading to the inadequate removal of dysfunctional mitochondria. The excess accumulation of damaged mitochondria further stimulated NF-κB activation and triggered the NLRP3 inflammasome pathway. Both the antioxidant N-acetylcysteine and the autophagy activator rapamycin were effective to attenuate the damage of CBNPs on cardiomyocytes. Taken together, this study elucidated the potential mechanism underlying CBNPs-induced myocardial injury and provided a scientific reference for the evaluation and prevention of the CBNPs-related heart risk.

Population incidence and associated mortality of urinary tract infection in people living with dementia.

OBJECTIVES: Urinary tract infections (UTIs) frequently cause hospitalisation and death in people living with dementia (PLWD). We examine UTI incidence and associated mortality among PLWD relative to matched controls and people with diabetes and investigate whether delayed or withheld treatment further impacts mortality. METHODS: Data were extracted for n = 2,449,814 people aged ≥ 50 in Wales from 2000-2021, with groups matched by age, sex, and multimorbidity. Poisson regression was used to estimate incidences of UTI and mortality. Cox regression was used to study the effects of treatment timing. RESULTS: UTIs in dementia (HR=2.18, 95 %CI [1.88-2.53], p < .0) and diabetes (1.21[1.01-1.45], p = .035) were associated with high mortality, with the highest risk in individuals with diabetes and dementia (both) (2.83[2.40-3.34], p < .0) compared to matched individuals with neither dementia nor diabetes. 5.4 % of untreated PLWD died within 60 days of GP diagnosis-increasing to 5.9 % in PLWD with diabetes. CONCLUSIONS: Incidences of UTI and associated mortality are high in PLWD, especially in those with diabetes and dementia. Delayed treatment for UTI is further associated with high mortality.

Multiple long-term conditions in people with psoriasis: a latent class and bidirectional Mendelian randomization analysis.

BACKGROUND: Coexisting long-term conditions (LTCs) in psoriasis and their potential causal associations with the disease are not well -established. OBJECTIVES: To determine distinct clusters of LTCs in people with psoriasis and the potential bidirectional causal association between these LTCs and psoriasis. METHODS: Using latent class analysis, cross-sectional data from people with psoriasis from the UK Biobank were analysed to identify distinct psoriasis-related comorbidity profiles. Linkage disequilibrium score regression (LDSR) was applied to compute the genetic correlation between psoriasis and LTCs. Two-sample bidirectional Mendelian randomization (MR) analysis assessed the potential causal direction using independent genetic variants that reached genome-wide significance (P < 5 × 10-8). RESULTS: Five comorbidity clusters were identified in a population of 10 873 people with psoriasis. LDSR revealed that psoriasis was positively genetically correlated with heart failure [genetic correlation (rg) = 0.23, P = 8.8 × 10-8], depression (rg = 0.12, P = 2.7 × 10-5), coronary artery disease (CAD; rg = 0.15, P = 2 × 10-4) and type 2 diabetes (rg = 0.19, P = 3 × 10-3). Genetic liability to CAD was associated with an increased risk of psoriasis [inverse variance weighted (IVW) odds ratio (ORIVW) 1.159, 95% confidence interval (CI) 1.055-1.274; P = 2 × 10-3]. The MR pleiotropy residual sum and outlier (MR-PRESSO; ORMR-PRESSO 1.13, 95% CI 1.042-1.228; P = 6 × 10-3) and the MR-robust adjusted profile score (RAPS) (ORMR-RAPS 1.149, 95% CI 1.062-1.242; P = 5 × 10-4) approaches corroborate the IVW findings. The weighted median (WM) generated similar and consistent effect estimates but was not statistically significant (ORWM 1.076, 95% CI 0.949-1.221; P = 0.25). Evidence for a suggestive increased risk was detected for CAD (ORIVW 1.031, 95% CI 1.003-1.059; P = 0.03) and heart failure (ORIVW 1.019, 95% CI 1.005-1.033; P = 9 × 10-3) in those with a genetic liability to psoriasis; however, MR sensitivity analyses did not reach statistical significance. CONCLUSIONS: Five distinct clusters of psoriasis comorbidities were observed with these findings to offer opportunities for an integrated approach to comorbidity prevention and treatment. Coexisting LTCs share with psoriasis common genetic and nongenetic risk factors, and aggressive lifestyle modification in these people is anticipated to have an impact beyond psoriasis risk. Genetically predicted CAD is possibly associated with an increased risk of psoriasis, altering our prior knowledge.

Dementia risk in patients with type 2 diabetes: Comparing metformin with no pharmacological treatment.

INTRODUCTION: Metformin has been suggested as a therapeutic agent for dementia, but the relevant evidence has been partial and inconsistent. METHODS: We established a national cohort of 210,237 type 2 diabetes patients in the UK Clinical Practice Research Datalink. Risks of incident dementia were compared between metformin initiators and those who were not prescribed any anti-diabetes medication during follow-up. RESULTS: Compared with metformin initiators (n = 114,628), patients who received no anti-diabetes medication (n = 95,609) had lower HbA1c and better cardiovascular health at baseline. Both Cox regression and propensity score weighting analysis showed metformin initiators had lower risk of dementia compared to those non-users (adjusted hazard ratio = 0.88 [95% confidence interval: 0.84-0.92] and 0.90 [0.84-0.96]). Patients on long-term metformin treatment had an even lower risk of dementia. DISCUSSION: Metformin may act beyond its glycemic effect and reduce dementia risk to an even lower level than that of patients with milder diabetes and better health profiles. HIGHLIGHTS: Metformin initiators had a significantly lower risk of dementia compared with patients not receiving anti-diabetes medication. Compared with metformin initiators, diabetes patients not receiving pharmacological treatment had better glycemic profiles at baseline and during follow-up. Patients on long-term metformin treatment had an even lower risk of subsequent dementia incidence. Metformin may act beyond its effect on hyperglycemia and has the potential of being repurposed for dementia prevention.

Pairing with Enriched Sound Exposure Restores Auditory Processing Degraded by an Antidepressant.

Antidepressants, while effective in treating depression and anxiety disorders, also induce deficits in sensory (particularly auditory) processing, which in turn may exacerbate psychiatric symptoms. How antidepressants cause auditory signature deficits remains largely unknown. Here, we found that fluoxetine-treated adult female rats were significantly less accurate when performing a tone-frequency discrimination task compared with age-matched control rats. Their cortical neurons also responded less selectively to sound frequencies. The degraded behavioral and cortical processing was accompanied by decreased cortical perineuronal nets, particularly those wrapped around parvalbumin-expressing inhibitory interneurons. Furthermore, fluoxetine induced critical period-like plasticity in their already mature auditory cortices; therefore, a brief rearing of these drug-treated rats under an enriched acoustic environment renormalized auditory processing degraded by fluoxetine. The altered cortical expression of perineuronal nets was also reversed as a result of enriched sound exposure. These findings suggest that the adverse effects of antidepressants on auditory processing, possibly because of a reduction in intracortical inhibition, can be substantially alleviated by simply pairing drug treatment with passive, enriched sound exposure. They have important implications for understanding the neurobiological basis of antidepressant effects on hearing and for designing novel pharmacological treatment strategies for psychiatric disorders.SIGNIFICANCE STATEMENT Clinical experience suggests that antidepressants adversely affect sensory (particularly auditory) processing, which can exacerbate patients' psychiatric symptoms. Here, we show that the antidepressant fluoxetine reduces cortical inhibition in adult rats, leading to degraded behavioral and cortical spectral processing of sound. Importantly, fluoxetine induces a critical period-like state of plasticity in the mature cortex; therefore, a brief rearing under an enriched acoustic environment is sufficient to reverse the changes in auditory processing caused by the administration of fluoxetine. These results provide a putative neurobiological basis for the effects of antidepressants on hearing and indicate that antidepressant treatment combined with enriched sensory experiences could optimize clinical outcomes.

Inflammatory Diseases, Inflammatory Biomarkers, and Alzheimer Disease: An Observational Analysis and Mendelian Randomization.

BACKGROUND AND OBJECTIVES: Whether chronic autoimmune inflammatory diseases causally affect the risk of Alzheimer disease (AD) is controversial. We characterized the relationship between inflammatory diseases and risk of AD and explored the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. METHODS: We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large-scale genome-wide association study data sets, we performed 2-sample Mendelian randomizations (MRs) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. RESULTS: Cox regression models using CPRD data showed that the overall incidence of AD was higher among patients with inflammatory bowel disease (hazard ratio [HR] 1.17; 95% CI 1.15-1.19; p = 2.1 × 10-4), other inflammatory polyarthropathies and systematic connective tissue disorders (HR 1.13; 95% CI 1.12-1.14; p = 8.6 × 10-5), psoriasis (HR 1.13; 95% CI 1.10-1.16; p = 2.6 × 10-4), rheumatoid arthritis (HR 1.08; 95% CI 1.06-1.11; p = 4.0 × 10-4), and multiple sclerosis (HR 1.06; 95% CI 1.04-1.07; p = 2.8 × 10-4) compared with the age (±5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted [ORIVW] 1.23; 95% CI 1.06-1.42; p IVW = 0.007) and lower risk of Crohn disease (ORIVW 0.73; 95% CI -0.62 to 0.86; p IVW = 1.3 × 10-4). Colocalization supported a common causal single nucleotide polymorphism for MIG and Crohn disease (posterior probability = 0.74), but not AD (posterior probability = 0.03). Using a 2-sample MR approach, genetically predicted risks of inflammatory diseases were not associated with higher AD risk. DISCUSSION: Our data suggest that the association between inflammatory diseases and risk of AD is unlikely to be causal and may be a result of confounding. In support, although inflammatory biomarkers showed evidence for causal associations with inflammatory diseases, evidence was weak that they affected both inflammatory disease and AD.

Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia.

Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin's action in the brain.

Genetic Evidence for Protective Effects of Angiotensin-Converting Enzyme Against Alzheimer Disease But Not Other Neurodegenerative Diseases in European Populations.

Background and Objectives: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases. Methods: We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk in people of European ancestry. We further investigated whether any effect of ACE expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm. Results: There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk in people of European ancestry. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that ACE expression affected risk of other neurodegenerative traits. Discussion: Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease.

Structural Design and Preliminary Tests of a Novel Patient Transfer Apparatus for Medical Scenarios.

Patient transfer has always been a difficult problem, usually requiring multiple caregivers to work together, which is time consuming and can easily cause secondary injuries to the patient. In addition, with the crisis of COVID-19, the issue of patient transfer is even more critical, as caregivers are at a high risk of infection, causing significant damage to healthcare resources. In this paper, a patient transfer assist system named E-pat-plus (Easy Patient Transfer plus) has been proposed; it can assist caregivers in transferring patients, reduce direct contact between them, and avoid secondary injuries. In the mechanical structure of this apparatus, a novel five-gear assembly module and a synchronous belt pulley set are proposed; they are the key points to the basic functional realization of the device and can reduce the cost of the prototype. Furthermore, a fuzzy (proportion-integration-differentiation) PID-based cross-coupling control strategy is applied to the apparatus to ensure the stability and safety of the operation. Finally, some preliminary experiments, including current experiments and error experiments, are carried out to verify the reliability of the device and lay the foundation for clinical tests.

Glycemic Control, Diabetic Complications, and Risk of Dementia in Patients With Diabetes: Results From a Large U.K. Cohort Study.

OBJECTIVE: Type 2 diabetes is an established risk factor for dementia. However, the roles of glycemic control and diabetic complications in the development of dementia have been less well substantiated. This large-scale cohort study aims to examine associations of longitudinal HbA1c levels and diabetic complications with the risk of dementia incidence among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Data of eligible patients with diabetes, aged ≥50 years in the U.K. Clinical Practice Research Datalink from 1987 to 2018, were analyzed. Time-varying Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% CIs for dementia risk. RESULTS: Among 457,902 patients with diabetes, 28,627 (6.3%) incident dementia cases were observed during a median of 6 years' follow-up. Patients with recorded hypoglycemic events or microvascular complications were at higher risk of dementia incidence compared with those without such complications (HR 1.30 [95% CI 1.22-1.39] and 1.10 [1.06-1.14], respectively). The HbA1c level, modeled as a time-varying exposure, was associated with increased dementia risk (HR 1.08 [95% CI 1.07-1.09] per 1% HbA1c increment) among 372,287 patients with diabetes with postdiagnosis HbA1c records. Similarly, a higher coefficient of variation of HbA1c during the initial 3 years of follow-up was associated with higher subsequent dementia risk (HR 1.03 [95% CI 1.01-1.04] per 1-SD increment). CONCLUSIONS: Higher or unstable HbA1c levels and the presence of diabetic complications in patients with type 2 diabetes are associated with increased dementia risk. Effective management of glycemia might have a significant role in maintaining cognitive health among older adults with diabetes.

Prevalence of and factors associated with burnout in midwifery: A scoping review.

INTRODUCTION: Midwifery care meets the triple aims of health system improvement, i.e. good health outcomes, high client satisfaction, and low per capita costs. Scaling up access to midwifery care is a global priority yet the growth and sustainability of the profession is threatened by high levels of burnout and attrition. This scoping review provides a comprehensive review of the existing literature on burnout in midwifery, with a focus on prevalence, associated factors and potential solutions. METHODS: Four electronic databases were searched to locate relevant literature up to July 2019. A total of 1034 articles were identified and reduced to 27 articles that met inclusion criteria. We summarize sample sizes, settings, study designs, burnout measures, prevalence of burnout, associated factors and potential solutions, and recommendations. RESULTS: Prevalence of burnout was highest among Australian, Western Canadian and Senegalese midwives and lowest among Dutch and Norwegian midwives. Midwives working in caseload/continuity models reported significantly lower burnout compared to midwives working in other models. We identified 26 organizational and personal factors that were significantly associated with burnout, such as high workload, exposure to traumatic events, and fewer years in practices. Organizational support to improve work-life balance and emotional well-being, as well as more continuing education to raise awareness about burnout and how to cope with it, emerged as common strategies to prevent and address burnout. CONCLUSIONS: Burnout is a serious and complex occupational phenomenon. More qualitative research is needed in this area, to better understand the lived experience of burnout.

Cortisol, Amyloid-ß, and Reserve Predicts Alzheimer's Disease Progression for Cognitively Normal Older Adults.

Elevated cortisol as a measure of hypothalamic-pituitary-adrenal-axis hyperactivity has emerged as a predictor of clinical progression of Alzheimer's disease (AD), in conjunction with amyloid-ß (Aß) abnormalities. Yet factors exist which have the propensity to delay AD symptomatic expression in the face of an AD-type biomarker-based pathological profile. This study sought to determine whether abnormal cerebrospinal fluid (CSF) Aß and elevated cortisol levels are associated with clinical transition to mild cognitive impairment (MCI) and AD in cognitively normal (CN) individuals, and if this association is modified by reserve proxies. Data from 91 CN individuals participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available morning CSF cortisol and Aß42 were evaluated. Reserve was modelled as a latent composite score of standardized intracranial volume and lifetime experience proxies. Cox regressions were used to test associations between baseline CSF cortisol/Aß42, reserve score and AD progression; adjusting for age, sex, apolipoprotein E genotype, and depressive symptoms. Individuals with elevated cortisol + abnormal Aß42 levels at baseline showed highest risk of clinical progression. After a median of 84 months follow-up, significant cortisol/Aß/ reserve interaction for clinical progression was noted (adjusted HR = 0.15, p < 0.001), suggesting a moderating effect of reserve on the association between cortisol/Aß+ and clinical progression. Our findings indicate that cortisol hypersecretion accelerates clinical progression in CN individuals presenting with pathological Aß42. High reserve reduces the associated AD progression risk in these high-risk individuals.

Correction to: Associations between post-operative rehabilitation of hip fracture and outcomes: national database analysis.

Following publication of the original article [1], the author reported an error in the Title. The original article has been corrected.

Associations between post-operative rehabilitation of hip fracture and outcomes: national database analysis (90 characters).

BACKGROUND: Rehabilitation programmes are used to improve hip fracture outcomes. There is little published trial clinical trial or population-based data on the effects of the type or provider of rehabilitation treatments on hip fracture outcomes. We evaluated the associations of rehabilitation interventions with post-operative hip fracture outcomes. METHODS: Cross-sectional (2013-2015) analysis of data from the English National Hip Fracture Database (NHFD) from all 191 English hospitals treating hip fractures. Of 62,844 NHFD patients, we included 17,708 patients with rehabilitation treatment and 30-day mobility data, and 34,142 patients with rehabilitation treatment and discharge destination data. The intervention was early mobilisation rehabilitation treatments delivered by a physiotherapist (PT, physical therapist in North America) or other clinical staff as identifiable in NHFD. We used ordinal logistic and propensity scoring regression models to adjust for confounding variables including age, sex, pre-fracture mobility, operative delay, and cognitive function and peri-operative risk scores. RESULTS: In both the adjusted multivariate and propensity-weighted analyses, mobilisation on the day or the day following surgery is associated with better mobility function 30 days after discharge. However patients mobilised by a PT did not have better mobility compared to mobilisation by other professionals. Patients who received a PT assessment were not protected from poorer mobility 30 days after discharge, compared with those who did not receive an assessment. The discharge destination outcome is also better in mobilised than unmobilised patients, whether done by a PT or another health professional, and the difference persists, slightly attenuated, after propensity weighting. CONCLUSIONS: In addition to the type of health professional initiating mobilisation, data on rehabilitation treatment activity and post-operative gait speed is needed to determine optimum rehabilitation dosage and functional outcome. After adjustment patients mobilised by non-PTs did as well as patients mobilised by PTs, suggesting that PTs' current roles in very early rehabilitation should be reconsidered, with a view to redeploying them to more specialised later rehabilitation activity.

Characteristics of hand involvement in a comparative study of two early RA cohorts from the UK and China.

AIM: To compare the characteristics of early hand involvement in rheumatoid arthritis (RA) using two matched populations, from the UK and China. METHODS: A cohort comparison study was conducted. Sixty Chinese patients recruited from Shanghai, China were matched on gender and age with 60 patients from a prospective early RA cohort from the UK (SARAH trial). The procedures of data collection in China followed the standard operating procedures employed in the SARAH trial. Outcome measures including Michigan Hand Outcomes Questionnaire (MHQ), medication history and physical assessments were used to assess functional ability and hand impairment. RESULTS: UK patients reported significantly more hand pain (P = 0.015), less satisfaction with dominant hand performance (P  = 0.040), more swollen and tender joints (P = 0.016 and P = 0.001) and greater dexterity of both dominant and non-dominant hands (P < 0.001 and P < 0.001), while Chinese patients had higher disease activity indicated by erythrocyte sedimentation rate and C-reactive protein, more rheumatoid factor, less satisfaction in both dominant and non-dominant hand appearances (P < 0.001 and P < 0.001, respectively) and greater dominant hand deformity (P  = 0.003). No statistically significant differences were seen in range of movement and overall hand function as reported by the MHQ. CONCLUSION: The severity of RA is not milder in China than in the UK and the characteristics of hand involvement tend to be different. Clinicians should consider country-specific differences in managing pain and delivering treatment. It would be helpful for a future study to investigate the RA impact characteristics on a wider range of patients both from within China and from other populations.

Online survey data of public subjective well-being on high occupancy vehicle lane in China.

The data presented in this article are related to the research article entitled "Out-of-home activities, daily travel, and SWB" (Ettema et al., 2010) [1]. The paper provides an online survey questionnaire and data about the public subjective well-being of high occupancy vehicle lanes in China. The survey data are made publicly available to extended analysis.