Effects of Probiotics on Colitis-Induced Exacerbation of Alzheimer's Disease in AppNL-G-F Mice.

Alzheimer's disease (AD) is characterized by progressive cognitive decline and is a leading cause of death in the United States. Neuroinflammation has been implicated in the progression of AD, and several recent studies suggest that peripheral immune dysfunction may influence the disease. Continuing evidence indicates that intestinal dysbiosis is an attribute of AD, and inflammatory bowel disease (IBD) has been shown to aggravate cognitive impairment. Previously, we separately demonstrated that an IBD-like condition exacerbates AD-related changes in the brains of the AppNL-G-F mouse model of AD, while probiotic intervention has an attenuating effect. In this study, we investigated the combination of a dietary probiotic and an IBD-like condition for effects on the brains of mice. Male C57BL/6 wild type (WT) and AppNL-G-F mice were randomly divided into four groups: vehicle control, oral probiotic, dextran sulfate sodium (DSS), and DSS given with probiotics. As anticipated, probiotic treatment attenuated the DSS-induced colitis disease activity index in WT and AppNL-G-F mice. Although probiotic feeding significantly attenuated the DSS-mediated increase in WT colonic lipocalin levels, it was less protective in the AppNL-G-F DSS-treated group. In parallel with the intestinal changes, combined probiotic and DSS treatment increased microglial, neutrophil elastase, and 5hmC immunoreactivity while decreasing c-Fos staining compared to DSS treatment alone in the brains of WT mice. Although less abundant, probiotic combined with DSS treatment demonstrated a few similar changes in AppNL-G-F brains with increased microglial and decreased c-Fos immunoreactivity in addition to a slight increase in Aß plaque staining. Both probiotic and DSS treatment also altered the levels of several cytokines in WT and AppNL-G-F brains, with a unique increase in the levels of TNFα and IL-2 being observed in only AppNL-G-F mice following combined DSS and probiotic treatment. Our data indicate that, while dietary probiotic intervention provides protection against the colitis-like condition, it also influences numerous glial, cytokine, and neuronal changes in the brain that may regulate brain function and the progression of AD.

IL-1ß stimulates a novel, IKKα -dependent, NIK -independent activation of non-canonical NFκB signalling.

In this study, we examined the activation of non-canonical nuclear factor Kappa B (NFκB) signalling in U2OS cells, a cellular metastatic bone cancer model. Whilst Lymphotoxin α1ß2 (LTα1ß2) stimulated the expected slow, delayed, sustained activation of serine 866/870 p100 phosphorylation and increased cellular expression of p52 NFκB, we found that canonical agonists, Interleukin-1ß (IL-1ß) and also Tumour necrosis factor-α (TNFα) generated a rapid transient increase in pp100, which was maximal by 15-30 min. This rapid phosphorylation was also observed in other cells types, such as DU145 and HCAECs suggesting the phenomenon is universal. IKKα deletion using CRISPR/Cas9 revealed an IKKα-dependent mechanism for serine 866/870 and additionally serine 872 p100 phosphorylation for both IL-1ß and LTα1ß2. In contrast, knockdown of IKKß using siRNA or pharmacological inhibition of IKKß activity was without effect on p100 phosphorylation. Pre-incubation of cells with the NFκB inducing-kinase (NIK) inhibitor, CW15337, had no effect on IL-1ß induced phosphorylation of p100 however, the response to LTα1ß2 was virtually abolished. Surprisingly IL-1ß also stimulated p52 nuclear translocation as early as 60 min, this response and the concomitant p65 translocation was partially reduced by IKKα deletion. Furthermore, p52 nuclear translocation was unaffected by CW15337. In contrast, the response to LTα1ß2 was essentially abolished by both IKKα deletion and CW15337. Taken together, these finding reveal novel forms of NFκB non-canonical signalling stimulated by ligands that activate the canonical NFκB pathway strongly such as IL-1ß.

Do screening tools assess palliative care needs and 12-month mortality in patients admitted to hepatology in-patient wards?

Background: Many liver patients have unmet palliative care needs, but liver clinicians are unclear whom to refer to specialist palliative care (SPC). The Supportive and Palliative Care Indicator Tool (SPICT) and the Bristol Prognostic Screening Tool (BPST) could help identify suitable patients, but neither has been tested for this role. This study evaluated their role as screening tools for palliative care needs and for predicting 12-month mortality. Methods: A case note review of hepatology in-patients, who were not peritransplant and post-transplant status, was conducted in one tertiary unit. Main outcomes were clinical judgement of need for SPC referral, BPST scores, SPICT attribution of caseness and 12-month survival status. Discriminatory ability of tools was assessed using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic (AUROC) curve. Results: 117 medical notes were reviewed for survival analysis, 47 of which were additionally assessed for suitability for SPC referral, using clinical judgement. SPICT (sensitivity=93%; PPV=93%; AUROC=0.933) and BPST (sensitivity=59%, PPV=79%, AUROC=0.693) demonstrated excellent and good performance, respectively, in predicting patients' need for SPC referral. SPICT and BPST only had moderate ability at predicting death at 12 months (PPV: 54% and 56%, respectively). Conclusion: SPICT and BPST show potential as screening tools for identifying patients for referral to SPC. Further work is needed to determine how to implement these tools in a clinical setting.

Palliative Care for Patients with End-Stage Liver Disease on the Liver Transplant Waiting List: An International Systematic Review.

People with end-stage liver disease on the liver transplant waiting list have high symptom burden, which can successfully be addressed by specialist palliative care. Potential tensions with the perceived curative nature of liver transplant make delivering specialist palliative care challenging. This systematic review seeks to establish what is known on the impact of specialist palliative care for patients on liver transplant waiting lists, healthcare professionals' perspectives of providing specialist palliative care for this population, and uptake of advance care planning (ACP). Medline, Embase, and CINAHL were searched to May 5, 2020. Qualitative and quantitative findings were grouped together according to main relevant themes. Eight studies of mixed quality and mainly quantitative, were identified. Findings suggest early palliative care intervention improve patients' symptoms and prompt ACP conversations, but patients on the waiting list receive limited palliative care input. Liver physicians' lack of clarity on referral criteria and liver transplant patients' concerns of being abandoned, were reasons for reluctance to refer to specialist palliative care. They felt referral to specialist palliative care is appropriate only for patients receiving hospice or end of life care. Uptake and understanding of ACP and goals of care designation by patients is poor. This review found evidence of benefit of specialist palliative care for patients on liver transplant waiting lists, but found in a limited understanding of their role. Evidence is limited to studies from North America. Future research is needed to understand better how palliative care could be provided into this clinical environment.

Use of non-sterile gloves in the ward environment: an evaluation of healthcare workers' perception of risk and decision making.

BACKGROUND: Studies have found that inappropriate use of non-sterile gloves (NSG) can affect hand hygiene compliance; the main risks are missing opportunities for hand hygiene and gloves being a vector for microbial transmission. AIM: The aims of this study were to explore the accuracy of healthcare worker (HCW) risk assessment and decision making regarding the use of NSG. METHODS: The study was conducted in two acute NHS Trusts and a community social enterprise. A cross-sectional survey was carried out, followed by qualitative semi-structured interviews. FINDINGS: There were highly significant differences at the 95% probability level between staff groups, unqualified staff being significantly more likely than qualified staff to report NSG use when not indicated (P < 0.0001). The primary motivating factor for staff to wear NSG was for personal protection; the secondary factor being the protection of patients. Staff were also motivated by a desire to create an image of professionalism. Respondents were more likely to follow the lead of seniors in their own profession. DISCUSSION: The results suggest a necessity for change interventions aimed at unqualified staff such as healthcare assistants (HCAs). It would be beneficial to review the indications for glove use and amend organisational policies accordingly. Leaders in each professional staff group would be required to influence practice across organisations, taking into account motivating factors, and in association with multi-modal interventions to improve practice.

Improving Communication in Outpatient Consultations in People With Cirrhosis: The Development of a Question Prompt List (QPL).

BACKGROUND AND AIMS: Liver health professionals have difficulty discussing liver cirrhosis and its prognosis with patients and families. Question Prompt Lists (QPLs), which are evidence-based lists of "recommended questions," may improve communication but need to be designed specifically for the target population. This study aimed to develop and pilot a QPL for patients with cirrhosis. METHODS: A mixed-methods design in 3 phases. In phase 1 (item generation), potential questions for inclusion in the QPL were identified from 3 sources-a scoping literature review; an online survey; and interviews with patients, family members, and health professionals. In phase 2 (QPL construction), a multidisciplinary expert panel finalized the selection of questions and the format of the QPL. In phase 3 (pilot study), the QPL was assessed for acceptability and feasibility in a hepatology outpatient clinic population. RESULTS: From 258 topics initially identified, 30 questions were included in the first draft of the QPL. After review by a multidisciplinary expert panel including patients, the QPL was reduced to 22 questions. In the pilot study, 133/215 eligible patients consented to participate, although only 67/133 used the QPL in their clinic appointment. Among those who used the QPL, all questions were asked at least once. The most commonly asked question related to life expectancy. Most participants expressed support for the content of the QPL. CONCLUSIONS: A QPL, suitable for use in patients with liver cirrhosis attending hepatology outpatient clinics, has been developed and piloted. The QPL seems to be feasible to use and acceptable to patients and clinicians. Further work is needed to evaluate its effectiveness and to determine optimum delivery in clinical practice.

The influence of mental fatigue on brain activity: Evidence from a systematic review with meta-analyses.

The occurrence of mental fatigue during tasks like driving a vehicle increases risk of injury or death. Changes in electroencephalographic (EEG) activity associated with mental fatigue has been frequently studied and considered a promising biomarker of mental fatigue. This is despite differences in methodologies and outcomes in prior research. A systematic review with meta-analyses was conducted to establish the influence of mental fatigue on EEG activity spectral bands, and to determine in which regions fatigue-related EEG spectral changes are likely to occur. A high-yield search strategy identified 21 studies meeting inclusion criteria for investigating the change in EEG spectral activity in non-diseased adults engaged in mentally fatiguing tasks. A medium effect size (using Cohen's g) of 0.68 (95%CI: 0.24-1.13) was found for increase in overall EEG activity following mental fatigue. Further examination of individual EEG spectral bands and regions using network meta-analyses indicated large increases in theta (g = 1.03; 95%CI: 0.79-1.60) and alpha bands (g = 0.85; 95%CI: 0.47-1.43), with small to moderate changes found in delta and beta bands. Central regions of the scalp showed largest change (g = 0.80; 95%CI: 0.46-1.21). Sub-group analyses indicated large increases in theta activity in frontal, central and posterior sites (all g > 1), with moderate changes in alpha activity in central and posterior sites. Findings have implications for fatigue monitoring and countermeasures with support for change in theta activity in frontal, central and posterior sites as a robust biomarker of mental fatigue and change in alpha wave activity considered a second line biomarker to account for individual variability.

Chlamydia trachomatis Pgp3 Antibody Population Seroprevalence before and during an Era of Widespread Opportunistic Chlamydia Screening in England (1994-2012).

BACKGROUND: Opportunistic chlamydia screening of <25 year-olds was nationally-implemented in England in 2008 but its impact on chlamydia transmission is poorly understood. We undertook a population-based seroprevalence study to explore the impact of screening on cumulative incidence of chlamydia, as measured by C.trachomatis-specific antibody. METHODS: Anonymised sera from participants in the nationally-representative Health Surveys for England (HSE) were tested for C.trachomatis antibodies using two novel Pgp3 enzyme-linked immunosorbent assays (ELISAs) as a marker of past infection. Determinants of being seropositive were explored using logistic regression among 16-44 year-old women and men in 2010 and 2012 (years when sexual behaviour questions were included in the survey) (n = 1,402 women; 1,119 men). Seroprevalence trends among 16-24 year-old women (n = 3,361) were investigated over ten time points from 1994-2012. RESULTS: In HSE2010/2012, Pgp3 seroprevalence among 16-44 year-olds was 24.4% (95%CI 22.0-27.1) in women and 13.9% (11.8-16.2) in men. Seroprevalence increased with age (up to 33.5% [27.5-40.2] in 30-34 year-old women, 18.7% [13.4-25.6] in 35-39 year-old men); years since first sex; number of lifetime sexual partners; and younger age at first sex. 76.7% of seropositive 16-24 year-olds had never been diagnosed with chlamydia. Among 16-24 year-old women, a non-significant decline in seroprevalence was observed from 2008-2012 (prevalence ratio per year: 0.94 [0.84-1.05]). CONCLUSION: Our application of Pgp3 ELISAs demonstrates a high lifetime risk of chlamydia infection among women and a large proportion of undiagnosed infections. A decrease in age-specific cumulative incidence following national implementation of opportunistic chlamydia screening has not yet been demonstrated. We propose these assays be used to assess impact of chlamydia control programmes.

Asking about Sex in General Health Surveys: Comparing the Methods and Findings of the 2010 Health Survey for England with Those of the Third National Survey of Sexual Attitudes and Lifestyles.

OBJECTIVES: Including questions about sexual health in the annual Health Survey for England (HSE) provides opportunities for regular measurement of key public health indicators, augmenting Britain's decennial National Survey of Sexual Attitudes and Lifestyles (Natsal). However, contextual and methodological differences may limit comparability of the findings. We examine the extent of these differences between HSE 2010 and Natsal-3 and investigate their impact on parameter estimates. METHODS: Complex survey analyses of data from men and women in the 2010 HSE (n = 2,782 men and 3,588 women) and Natsal-3 undertaken 2010-2012 (n = 4,882 men and 6,869 women) aged 16-69y and resident in England, both using probability sampling, compared their characteristics, the amount of non-response to, and estimates from, sexual health questions. Both surveys used self-completion for the sexual behaviour questions but this was via computer-assisted self-interview (CASI) in Natsal-3 and a pen-and-paper questionnaire in HSE 2010. RESULTS: The surveys achieved similar response rates, both around 60%, and demographic profiles largely consistent with the census, although HSE participants tended to be less educated, and reported worse general health, than Natsal-3 participants. Item non-response to the sexual health questions was typically higher in HSE 2010 (range: 9-18%) relative to Natsal-3 (all <5%). Prevalence estimates for sexual risk behaviours and STI-related indicators were generally slightly lower in HSE 2010 than Natsal-3. CONCLUSIONS: While a relatively high response to sexual health questions in HSE 2010 demonstrates the feasibility of asking such questions in a general health survey, differences with Natsal-3 do exist. These are likely due to the HSE's context as a general health survey and methodological limitations such as its current use of pen-and-paper questionnaires. Methodological developments to the HSE should be considered so that its data can be interpreted in combination with those from dedicated sexual health surveys, thus improving our ability to monitor trends in sexual health.

Cohort profile: the health survey for England.

To monitor the health of the public in England, UK, the Central Health Monitoring Unit within the UK Department of Health commissioned an annual health examination survey, which became known as the Health Survey for England (HSE). The first survey was completed in 1991. The HSE covers all of England and is a nationally representative sample of those residing at private residential addresses. Each survey year consists of a new sample of private residential addresses and people. The HSE collects detailed information on mental and physical health, health-related behaviour, and objective physical and biological measures in relation to demographic and socio-economic characteristics of people aged 16 years and over at private residential addresses. There are two parts to the HSE; an interviewer visit, to conduct an interview and measure height and weight, then a nurse visit, to carry out further measurements and take biological samples. Since 1994, survey participants aged 16 years and over have been asked for consent to follow-up through linkage to mortality and cancer registration data, and from 2003, to the Hospital Episode Statistics database, thus converting annual cross-sectional survey data into a longitudinal study. Annual survey data (1994-2009) are available through the UK Data Archive.