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Background: Chronic inflammation is recognised as an important component of Alzheimer's disease (AD), yet its relationship with cognitive decline, sex-differences, and age is not well understood. This study investigated the relationship between inflammatory markers, cognition, sex, and age in individuals with mild cognitive impairment (MCI) and AD. Methods: A systematic review was performed to identify case-control studies which measured cognitive function and inflammatory markers in serum, plasma, and cerebrospinal fluid in individuals with MCI or AD compared with healthy control (HC) participants. Meta-analysis was performed with Hedges’ g calculated in a random effects model. Meta-regression was conducted using age, sex, and mini-mental status exam (MMSE) values. Results: A total of 106 studies without a high risk of bias were included in the meta-analysis including 18,145 individuals: 5625 AD participants, 3907 MCI participants, and 8613 HC participants. Combined serum and plasma meta-analysis found that IL1β, IL6, IL8, IL18, CRP, and hsCRP were significantly raised in individuals with AD compared to HC. In CSF, YKL40, and MCP-1 were raised in AD compared to HC. YKL40 was also raised in MCI compared to HC. Meta-regression analysis highlighted several novel findings: MMSE was negatively correlated with IL6 and positively correlated with IL1α in AD, while in MCI studies, MMSE was negatively correlated with IL8 and TNFα. Meta-regression also revealed sex-specific differences in levels of IL1α, IL4, IL6, IL18, hsCRP, MCP-1, and YKL-40 across AD and MCI studies, and age was found to account for heterogeneity of CRP, MCP-1, and IL4 in MCI and AD. Conclusion: Elevated levels of IL6 and YKL40 may reflect microglial inflammatory activity in both MCI and AD. Systemic inflammation may interact with the central nervous system, as poor cognitive function in individuals with AD and MCI was associated with higher levels of serum and plasma proinflammatory cytokines IL6 and TNFα. Moreover, variations of systemic inflammation between males and females may be modulated by sex-specific hormonal changes, such as declining oestrogen levels in females throughout the menopause transition. Longitudinal studies sampling a range of biospecimen types are needed to elucidate the nuances of the relationship between inflammation and cognition in individuals with MCI and AD, and understand how systemic and central inflammation differentially impact cognitive function.

Abstract INTRODUCTION This study primarily aimed to evaluate the efficacy and safety of SaiLuoTong (SLT) on cognition in mild cognitive impairment (MCI). METHODS Community‐dwelling people with MCI aged ≥60 years were randomly assigned to 180 mg/day SLT or placebo for 12 weeks. RESULTS Thirty‐nine participants were randomized to each group (N = 78); 65 were included in the final analysis. After 12 weeks, the between‐groups difference in Logical Memory delayed recall scores was 1.40 (95% confidence interval [CI]: 0.22 to 2.58; P = 0.010); Delis–Kaplan Executive Function System Trail Making Test Condition 4 switching and contrast scaled scores were 1.42 (95% CI: –0.15 to 2.99; P = 0.038) and 1.56 (95% CI: –0.09 to 3.20; P = 0.032), respectively; Rey Auditory Verbal Learning Test delayed recall was 1.37 (95% CI: –0.10 to 2.84; P = 0.034); and Functional Activities Questionnaire was 1.21 (95% CI: –0.21 to 2.63; P = 0.047; P < 0.001 after controlling for baseline scores). DISCUSSION SLT is well tolerated and may be useful in supporting aspects of memory retrieval and executive function in people with MCI. Highlights SaiLuoTong (SLT) improves delayed memory retrieval and executive function in people with mild cognitive impairment (MCI). SLT is well tolerated in people ≥ 60 years. The sample of community dwellers with MCI was well characterized and homogeneous.

Abstract Japan has long embarked on the city transformation journey, from green city to eco city, ubiquitous city, sustainable city, and now zero‐emission city. A smart city is not considered smart if it is not green, not sustainable, and not environmentally friendly. The journey is long but progressive, and the Japanese government has been supportive in its city transformational efforts. Japanese cities are marked by distinctive local cultures, habitat, people, food, beliefs, history etc. From Tokyo to Osaka, Nagoya, Fukuoka, Kobe and Yokohama, cities in Japan have advanced into high levels of urbanisation. The increase in population and traffic utilisation have resulted in higher energy demands and pollution of the environment. These concerns have motivated Japan to strive for cities with zero‐emission and Tokyo, as the country's capital, will lead in this drive. The author outlines the current situation in Japan, the impact of global warming and climate change, presents the motivation behind the new strategy, and narrates and discusses Tokyo city’s zero‐emission strategy and execution plans and how it works towards achieving net zero by 2050.

Consumption of a Western-style diet (WS-diet), high in saturated fat and added sugar, is associated with increased depression risk. However, the physiological mechanisms underlying the relationship requires elucidation. Diet can alter tryptophan metabolism along the kynurenine pathway (KP), potentially linking inflammation and depression. This study aimed to examine whether urinary inflammatory markers and KP metabolites differed according to WS-diet consumption and depression severity. Depression symptoms and habitual WS-diet consumption were assessed in 169 healthy adults aged 17–35 recruited from two experimental studies. Targeted metabolomics profiling of seven KP metabolites, ELISA-based assays of interleukin-6 (IL-6) and C-reactive protein (CRP) were performed using urine samples collected from the participants. Parametric tests were performed for group comparison and associations analysis. Multilevel mixed-effect modelling was applied to control for biases. Higher intake of WS-diet was associated with lower levels of neuroprotective kynurenic acid (KA; R = −0.17, p = 0.0236). There were no differences in IL-6 or CRP across diet groups (p > 0.05). Physical activity had negative associations with most KP metabolites. Mixed-effects regression analysis showed the glutamatergic inhibitor, KA, was the only biomarker to have a significant association with depression symptoms in a model adjusted for demographic and lifestyle variables: a unit increase in KA was associated with 0.21 unit decrease in Depression Anxiety and Stress Scale-21 depression score (p = 0.009). These findings suggest that urinary KA is associated with both habitual WS-diet intake, and levels of depression symptoms, independent of inflammation. Findings support the role of neuroprotection and glutamatergic modulation in depression. We propose that KA may act as endogenous glutamatergic inhibition in regulating depression severity in the absence of inflammation. Further comparison with blood-based markers will assist in validating the utility of non-invasive urine samples for measuring KP metabolites.

Yalin Cheng, Ke Chai, Wanrong Zhu, Yuhao Wan, Yaodan Liang, Minghui Du, Yingying Li, Ning Sun, Jiefu Yang, Hua Wang Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Hua WangDepartment of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaTel/Fax +86-10-85133852Email wanghua2764@bjhmoh.cnPurpose: Elderly heart failure (HF) patients have different clinical characteristics and poorer prognosis compared with younger patients. Prognostic risk scores for HF have not been validated well in elderly patients. We aimed to validate the Seattle Heart Failure Model (SHFM) and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score in an elderly Chinese HF cohort.Patients and Methods: This retrospective study enrolled 675 elderly HF patients (age≥ 70 years) discharged from our hospital between 2012 and 2017. The performance of the two risk scores was evaluated in terms of discrimination, using receiver-operating characteristic analysis, and calibration using a calibration plot and Hosmer–Lemeshow (H-L) test. Absolute risk reclassification was used to compare the two scores.Results: During the mean follow-up time of 32.6 months, 193 patients (28.6%) died, and 1-year mortality was 10.5%. The predicted median 1-year mortality was 8% for the SHFM and 18% for the MAGGIC score. A Kaplan–Meier survival curve demonstrated that event rates of all-cause mortality significantly increased with increasing SHFM and MAGGIC scores. The discriminatory capacity of the SHFM was greater than that of the MAGGIC score (c-statistics were 0.72 and 0.67, respectively; P = 0.05). The calibration plot for the SHFM was better than that for MAGGIC score for 1-year mortality (SHFM: H-L χ2 =8.2, P = 0.41; MAGGIC: H-L χ2 =18.8, P =0.02). Compared with the MAGGIC score, the net reclassification index (NRI) of the SHFM was 2.96% (Z=5.88, P< 0.0001).Conclusion: The SHFM performs better than MAGGIC score, having good discrimination, calibration and risk classification for the prediction of 1-year mortality in elderly Chinese HF patients.Keywords: heart failure, risk score, prognosis, elderly patient

Abstract We examined the effect of total and afferent renal denervation (RDN) on hypertension and the renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic kidney disease (PKD). Lewis Polycystic Kidney (LPK) and control rats received total, afferent or sham RDN by periaxonal application of phenol, capsaicin or normal saline, respectively, and were monitored for 4-weeks. Afferent RDN did not affect systolic blood pressure (SBP) determined by radiotelemetry in either strain (n = 19) while total RDN significantly reduced SBP in Lewis rats 4-weeks post-denervation (total vs. sham, 122 ± 1 vs. 130 ± 2 mmHg, P = 0.002, n = 25). Plasma and kidney renin content determined by radioimmunoassay were significantly lower in LPK vs. Lewis (plasma: 278.2 ± 6.7 vs. 376.5 ± 11.9 ng Ang I/ml/h; kidney: 260.1 ± 6.3 vs. 753.2 ± 37.9 ng Ang I/mg/h, P

Abstract Background Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. Methods To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively. Results We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). Conclusions Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

Social-cognitive difficulties can negatively impact interpersonal communication, shared social experience, and meaningful relationships. This pilot investigation examined the relationship between social-cognitive functioning and inflammatory markers in people with multiple sclerosis (MS) and demographically-matched healthy individuals. Additionally, we compared the immune marker profile in serum and urine-matched samples. Social cognitive functioning was objectively assessed using The Awareness of Social Inference Test – Short (TASIT-S) and subjectively assessed using self-reports of abilities in emotion recognition, emotional empathy, and cognitive theory of mind. In people with MS and healthy individuals, there were moderate-to-large negative relationships between pro-inflammatory biomarkers (serum IL-1β, IL-17, TNF-α, IP-10, MIP-1α, and urine IP-10, MIP-1β) of the innate immune system and social-cognitive functioning. In MS, a higher serum concentration of the anti-inflammatory marker IL-1ra was associated with better social-cognitive functioning (i.e., self-reported emotional empathy and TASIT-S sarcasm detection performance). However, there were mixed findings for anti-inflammatory serum markers IL-4 and IL-10. Overall, our findings indicate a relationship between pro-inflammatory cytokines and social-cognitive abilities. Future studies may provide greater insight into biologically-derived inflammatory processes, sickness behaviour, and their connection with social cognition.

Traffic signs have come a long way since the first automobile was invented. They have long served the purpose of warning and guiding drivers and also enforcing the traffic laws governing speed, parking, turns, and stopping. In this study, the authors discuss the issues and challenges facing current traffic signs, and how it will evolve into a next‐generation traffic sign architecture using advanced wireless communications technologies. With technological advances in the areas of wireless communications and embedded electronics and software, we foresee that, in the future, digital traffic sign posts will be capable of transmitting the traffic sign information wirelessly to road users, and this will transform our roads into intelligent roads, where signs will appear promptly and automatically on in‐vehicle displays to alert the driver. There is no longer the need to watch out for traffic signs since the detection will be automatic and performed wirelessly. This transformation will lessen burden on the drivers, so that they can then focus more on the traffic ahead while driving. Also, this evolution into wireless digital sign posts will fit well with the vision of future smart cities, where smart transportation technologies will be present to transform how we drive and commute, yielding greater safety, ease, and assistance to drivers.

Summary: Dicer knockout mouse models demonstrated a key role for microRNAs in pancreatic β-cell function. Studies to identify specific microRNA(s) associated with human (pro-)endocrine gene expression are needed. We profiled microRNAs and key pancreatic genes in 353 human tissue samples. Machine learning workflows identified microRNAs associated with (pro-)insulin transcripts in a discovery set of islets (n = 30) and insulin-negative tissues (n = 62). This microRNA signature was validated in remaining 261 tissues that include nine islet samples from individuals with type 2 diabetes. Top eight microRNAs (miR-183-5p, -375-3p, 216b-5p, 183-3p, -7-5p, -217-5p, -7-2-3p, and -429-3p) were confirmed to be associated with and predictive of (pro-)insulin transcript levels. Use of doxycycline-inducible microRNA-overexpressing human pancreatic duct cell lines confirmed the regulatory roles of these microRNAs in (pro-)endocrine gene expression. Knockdown of these microRNAs in human islet cells reduced (pro-)insulin transcript abundance. Our data provide specific microRNAs to further study microRNA-mRNA interactions in regulating insulin transcription.

The metabolism of tryptophan through the kynurenine pathway (KP) has been increasingly recognised in contributing to disease progression in the autoimmune and inflammatory disease multiple sclerosis (MS). In this review, the roles of inflammation and the KP are recontextualised to better understand the aetiology of the neuropsychiatric symptoms (depression, postpartum depression, suicidality, fatigue and cognitive dysfunction) in MS. These symptoms will be discussed in the context of cytokine-induced sickness behaviours, KP activation and levels of neurotoxicity and neuroprotection in MS. In particular, there will be emphasis on how neuropsychiatric symptoms in MS occur against the shared background of inflammation and KP dysregulation. The discourse of this review aims to promote future research in elucidating KP mechanisms in MS that would inevitably lead to more targeted treatment options for neuropsychiatric symptoms and disease progression.

BackgroundMagnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and the McDonald’s clinical criteria are currently utilized tools in diagnosing multiple sclerosis. However, a more conclusive, consistent, and efficient way of diagnosing multiple sclerosis (MS) is yet to be discovered. A potential biomarker, discovered using advances in high-throughput sequencing such as nuclear magnetic resonance (NMR) spectroscopy and other “Omics”-based techniques, may make diagnosis and prognosis more reliable resulting in a more personalized and targeted treatment regime and improved outcomes. The aim of this review was to systematically search the literature for potential biomarkers from any bodily fluid that could consistently and accurately diagnose MS and/or indicate disease progression.MethodsA systematic literature review of EMBASE, PubMed (MEDLINE), The Cochrane Library, and CINAHL databases produced over a thousand potential studies. Inclusion criteria stated studies with potential biomarker outcomes for people with MS were to be included in the review. Studies were limited to those with human participants who had a clinically defined diagnosis of MS and published in English, with no limit placed on date of publication or the type of bodily fluid sampled.ResultsA total of 1,805 studies were recorded from the literature search. A total of 1,760 studies were removed based on their abstract, with a further 18 removed after considering the full text. A total of 30 studies were considered relevant and had their data retrieved and analyzed. Due to the heterogeneity of focus and results from the refined studies, a narrative synthesis was favored.ConclusionSeveral promising candidate biomarkers suitable for clinical application in MS have been studied. It is recommended follow-up studies with larger sample sizes be completed on several potential biomarkers.

There is strong epidemiological evidence that poor diet is associated with depression. The reverse has also been shown, namely that eating a healthy diet rich in fruit, vegetables, fish and lean meat, is associated with reduced risk of depression. To date, only one randomised controlled trial (RCT) has been conducted with elevated depression symptoms being an inclusion criterion, with results showing that a diet intervention can reduce clinical levels of depression. No such RCTs have been performed in young adults. Young adults with elevated levels of depression symptoms and who habitually consume a poor diet were randomly allocated to a brief 3-week diet intervention (Diet Group) or a habitual diet control group (Control Group). The primary and secondary outcome measures assessed at baseline and after the intervention included symptoms of depression (Centre for Epidemiological Studies Depression Scale; CESD-R; and Depression Anxiety and Stress Scale- 21 depression subscale; DASS-21-D), current mood (Profile of Mood States), self-efficacy (New General Self-Efficacy Scale) and memory (Hopkins Verbal Learning Test). Diet compliance was measured via self-report questionnaires and spectrophotometry. One-hundred-and-one individuals were enrolled in the study and randomly assigned to the Diet Group or the Control Group. Upon completion of the study, there was complete data for 38 individuals in each group. There was good compliance with the diet intervention recommendations assessed using self-report and spectrophotometry. The Diet group had significantly lower self-reported depression symptoms than the Control Group on the CESD-R (p = 0.007, Cohen's d = 0.65) and DASS-21 depression subscale (p = 0.002, Cohen's d = 0.75) controlling for baseline scores on these scales. Reduced DASS-21 depression subscale scores were maintained on follow up phone call 3 months later (p = .009). These results are the first to show that young adults with elevated depression symptoms can engage in and adhere to a diet intervention, and that this can reduce symptoms of depression. The findings provide justification for future research into the duration of these benefits, the impacts of varying diet composition, and their biological basis.