Improvements in physical function and pain sustained for up to 10 years after knee or hip arthroplasty irrespective of mental health status before surgery

Background and purpose — There are concerns that mental health (MH) may influence outcomes of total knee arthroplasty (TKA) or total hip arthroplasty (THA). We examined effects of poor MH before surgery on long-term outcomes of osteoarthritis-related TKA or THA in women.

Patients and methods — The data were from 9,737 middle-aged participants (47–52 years) and 9,292 older participants (73–78 years) in the Australian Longitudinal Study on Women’s Health who completed surveys between 1998 and 2013. Dates of arthroplasties were obtained from the Australian Orthopaedics Association National Joint Replacement Registry. Participants without procedures were matched with participants with procedures. Trajectories of the Short-Form 36 scores for physical functioning, bodily pain, social functioning, and mental health based on mixed modeling were plotted for participants with and without surgery (stratified according to mental health, separately for TKA and THA, and for middle-aged and older participants).

Results — In middle-aged women with poor and good MH, TKA improved physical function and reduced bodily pain, with improvements sustained up to 10 years after surgery. TKA contributed to restoration of social function in women with good MH, but this was less clear in women with poor MH. In both MH groups, mental health appeared to be unaffected by TKA. Similar patterns were observed after THA, and in older women.

Interpretation — Recovery of physical and social function and reductions in pain were sustained for up to 10 years after surgery. Improvements in physical function and pain were also observed in women with poor mental health. Thus, in our view poor mental health should not be a contraindication for arthroplasty.     

Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer’s disease

There are currently no disease-modifying treatments for Alzheimer’s disease (AD), and an understanding of preclinical causal biomarkers to help target disease pathogenesis in the earliest phases remains elusive. Here, we investigated whether 19 metabolites previously associated with midlife cognition—a preclinical predictor of AD—translate to later clinical risk, using Mendelian randomization (MR) to tease out AD-specific causal relationships. Summary statistics from the largest genome-wide association studies (GWASs) for AD and metabolites were used to perform bidirectional univariable MR. Bayesian model averaging (BMA) was additionally performed to address high correlation between metabolites and identify metabolite combinations that may be on the AD causal pathway. Univariable MR indicated four extra-large high-density lipoproteins (XL.HDL) on the causal pathway to AD: free cholesterol (XL.HDL.FC: 95% CI = 0.78 to 0.94), total lipids (XL.HDL.L: 95% CI = 0.80 to 0.97), phospholipids (XL.HDL.PL: 95% CI = 0.81 to 0.97), and concentration of XL.HDL particles (95% CI = 0.79 to 0.96), significant at an adjusted P < 0.009. MR–BMA corroborated XL.HDL.FC to be among the top three causal metabolites, in addition to total cholesterol in XL.HDL (XL.HDL.C) and glycoprotein acetyls (GP). Both XL.HDL.C and GP demonstrated suggestive univariable evidence of causality (P < 0.05), and GP successfully replicated within an independent dataset. This study offers insight into the causal relationship between metabolites demonstrating association with midlife cognition and AD. It highlights GP in addition to several XL.HDLs—particularly XL.HDL.FC—as causal candidates warranting further investigation. As AD pathology is thought to develop decades prior to symptom onset, expanding on these findings could inform risk reduction strategies.

More than 50 million people worldwide currently live with dementia, and with an aging world population, this figure is expected to increase to more than 152 million by 2050 (World Alzheimer Report 2018). The most common dementia type is Alzheimer’s disease (AD), characterized by impaired everyday function, severe cognitive decline—particularly working, episodic, and declarative memory (1)—and a range of neuropsychiatric symptoms (2). It represents a major source of global morbidity and mortality and poses significant human and economic costs (3).Disappointingly, AD drug development has proven difficult, with a 99.6% failure rate in the decade of 2002 to 2012, and this rate continues at the same low level today (4). Numerous reasons have been proposed as to why such clinical trials have failed, including incomplete understanding of true causal mechanisms and a failure to intervene early enough in the pathological cascade. It is therefore necessary to discover biomarkers that can identify individuals at high risk of developing AD and at the earliest possible stages of pathology onset. Moreover, it is important for these to be potentially modifiable so as to offer targets for preventative or therapeutic strategies.Metabolomics represents one avenue that may give a deeper insight into AD etiology. Metabolites are small molecules (<1,500 atomic mass units) with a role in metabolism (5). As the products of many biological processes, they sit at the end of the systems biology pathway and therefore represent effective intermediate phenotypes to a given disease because of their proximity to the clinical endpoint (6, 7). Due to 1) their noninvasive nature of measurement, 2) the fact that they are potentially modifiable through diet and lifestyle, and 3) the ability of many to cross the blood brain barrier, blood metabolites are both practical and valuable markers of biological processes and disease states in dementia (8).Markers of lipid metabolism have received particular attention in this context, as the impairment of lipid metabolism has been associated with AD (5, 8–11) and beta-amyloid (Aβ) burden (12, 13). Relevant to early intervention, they have also been associated with cognitive performance and brain function during normal aging (14, 15). Recently, using a large British population-based birth cohort, we investigated associations between 233 blood metabolites and both memory and processing speed at 60 to 64 y of age as well as changes in these cognitive domains from 60 to 64 to 69 y old. Associations with several metabolite classes were observed, including fatty acids (FAs), various compositions of high-density lipoproteins (HDLs), and glycoprotein acetyls (GP) (16).However, it is not yet established whether these metabolites are causally associated with dementia and AD. Using knowledge from these preclinical associations to investigate translatability to later AD risk could hold special utility in informing early treatment intervention, particularly if a causal relationship can be shown. This study therefore aims to expand our observational findings and assess whether 19 blood metabolites previously associated with late midlife cognition causally associate with later clinical AD status. Both univariable and Bayesian multivariable Mendelian randomization (MR) approaches are harnessed to interrogate independent as well as group associations, and a range of sensitivity analyses are performed to further scrutinize results. Identifying candidate blood metabolites, which are detectable preclinically and on the causal pathway to later AD diagnosis, will aid in facilitating further research into early intervention strategies and more targeted therapeutics.     

Cell adhesion molecules in oesophageal epithelium.

The distribution of a range of integrins, E-cadherin, and carcino-embryonic antigen (CEA) like molecules in normal human oesophageal epithelium was investigated immunohistochemically on frozen sections of endoscopic biopsy specimens. The integrin subunits alpha 2, alpha 3, alpha 6, alpha v, beta 1, and beta 5 were expressed throughout the epithelium. There was strong expression of alpha 2, alpha 3, and beta 1 subunits in the basal cell layer and for all the subunits studied the intensity of the staining decreased as cells moved towards the lumen. The heterodimer alpha v beta 3 was expressed weakly in the basal aspect of the basal cell layer only. The CEA molecules were not present in the basal cells layer but there was weak expression in the prickle cell layer and strong positivity in the mature functional layer. E-cadherin was found throughout the epithelium but was weakly expressed at the basal aspect of the basal cells layer and showed strong positivity in the prickle cell and squamous cell layers. These results indicate that cell-cell (E-cadherin, CEA) and cell-matrix (integrins) adhesion molecules show a well defined spatial pattern of immunoreactivity in the oesophageal mucosa and may play a part in the maintenance of normal tissue architecture and physiological homeostasis.