The influence of aging and the microbiome in multiple sclerosis and other neurologic diseases.

The human gut microbiome is well-recognized as a key player in maintaining health. However, it is a dynamic entity that changes across the lifespan. How the microbial changes that occur in later decades of life shape host health or impact age-associated inflammatory neurological diseases such as multiple sclerosis (MS) is still unclear. Current understanding of the aging gut microbiome is largely limited to cross-sectional observational studies. Moreover, studies in humans are limited by confounding host-intrinsic and extrinsic factors that are not easily disentangled from aging. This review provides a comprehensive summary of existing literature on the aging gut microbiome and its known relationships with neurological diseases, with a specific focus on MS. We will also discuss preclinical animal models and human studies that shed light on the complex microbiota-host interactions that have the potential to influence disease pathology and progression in aging individuals. Lastly, we propose potential avenues of investigation to deconvolute features of an aging microbiota that contribute to disease, or alternatively promote health in advanced age.

Patient Perceptions of Surveillance of Small Abdominal Aortic Aneurysms in the Over 85s.

BACKGROUND: Recently instigated local practice for patients with small abdominal aortic aneurysms (AAAs) involves contacting all patients, aged ≥85 years, to discuss with them the advantages and disadvantages of removal from surveillance. However, reasons why patients opt to remain on, or come off, surveillance, are currently unknown. The present study's objective is to explore patient perception of surveillance decision-making. METHODS: A mixed-methods exploratory evaluation was undertaken using patient feedback obtained from a telephone survey. All patients aged ≥85 years, who had a consultation regarding ongoing surveillance of small AAAs (30-49 mm), and consented, were contacted by researchers, who conducted semi-structured interviews concerning factors influencing decision-making. RESULTS: A total of 24 patients (20 male; mean age = 86.9 years) were interviewed; 16 of 24 (66%) had opted to remain on surveillance, with no age difference between those opting in or out. Most felt surveillance was important (91%), and that it made them feel safer (73%). The majority (73%) thought they knew what happened when their AAA reached threshold (5.5 cm), what happened when a threshold AAA is not fixed (64%), and how major AAA surgery is (59%). However, actual knowledge was poor: most (91%) correctly understood surgery was major, but 56% thought that threshold AAA meant certain death or rupture; and 38% thought immediate surgery was required. Thematic analysis expounded patients' beliefs regarding surveillance, which were summarized in 3 distinct subgroups: reliance on professionals' opinions, needing peace of mind, and poor understanding. CONCLUSIONS: While most patients find surveillance reassuring, patient knowledge of AAA management at threshold is poor, potentially impacting surveillance decision-making. Elderly patients, with small AAAs contemplating ongoing surveillance, need to be better informed about AAA management at threshold to support shared decision-making.

T4 Bacteriophage and E. coli Interaction in the Murine Intestine: A Prototypical Model for Studying Host-Bacteriophage Dynamics In Vivo.

Bacteriophages (phages) are viruses that infect bacteria with species- and strain-level specificity and are the most abundant biological entities across all known ecosystems. Within bacterial communities, such as those found in the gut microbiota, phages are implicated in regulating microbiota population dynamics and driving bacterial evolution. There has been renewed interest in phage research in the last decade, in part due to the host-specific killing capabilities of lytic phages, which offer a promising tool to counter the increasing threat of antimicrobial resistant bacteria. Furthermore, recent studies demonstrating that phages adhere to intestinal mucus suggest they may have a protective role in preventing bacterial invasion into the underlying epithelium. Importantly, like bacterial microbiomes, disrupted phageomes have been associated with worsened outcomes in diseases such as inflammatory bowel disease. Previous studies have demonstrated that phages can modulate the microbiome of animals and humans through fecal filtrate transplants, benefiting the host's health. With this recent wave of research comes the necessity to establish and standardize protocols for studying phages in the context of the gut microbiome. This protocol provides a set of procedures to study isolated T4 phages and their bacterial host, Escherichia coli, in the context of the murine gastrointestinal tract. The methods described here outline how to start from a phage lysate, administer it to mice and assess effects on bacterial host and phage levels. This protocol can be modified and applied to other phage-bacterial pairs and provides a starting point for studying host-phage dynamics in vivo.

Relationship between depression, anxiety, and attendance at pelvic-floor muscle training sessions.

OBJECTIVES: Psychological comorbidities are associated with non-attendance for pelvic-floor muscle training (PFMT) appointments and non-engagement with ongoing treatment. However, little direct work has examined the precise relationship between these variables. DESIGN: A prospective observational study of consecutively referred women patients with Pelvic-floor Dysfunction. Patients were assessed at intake for age, BMI, pelvic symptoms (measured by the Queensland Pelvic Symptom Scale), and anxiety and depression (measured by the Hospital Anxiety and Depression Scales). SETTING: A women's health physiotherapy outpatient unit of a metropolitan hospital. PARTICIPANTS: 433 consecutively-referred women with pelvic-floor dysfunction (PFD). INTERVENTIONS: Six sessions of PFMT, lasting over a period of 6 months. MAIN OUTCOME MEASURES: Attendance at PFMT sessions was the outcome, and was related to intake patient age, BMI, pelvic symptoms, as well as anxiety and depression. RESULTS: Psychological symptoms of depression and anxiety predicted attendance at PFMT sessions, over and above physical symptoms. Depression was the key predictor of non-attendance, with anxiety having a more complex relationship with attendance. There were few differences between these psychological variables and the different types of PFD, or between type of PFD and PFMT attendance. CONCLUSIONS: The findings add to the literature suggesting that consideration of patients' psychological state is important when designing treatment-regimes. CONTRIBUTION OF THE PAPER.

Longitudinal relationship between problematic internet use with loneliness during and after COVID-19 social restrictions: Short title: Internet use and loneliness.

Two, three-month long longitudinal studies examined the temporal relationships between problematic internet use (PIU), internet usage, and loneliness ratings, during and after lockdown restrictions. Experiment 1 examined 32, 18-51 year old participants, over a three-month period of lockdown restrictions. Experiment 2 studied 41, 18-51 year old participants, over a three-month period following the lifting of lockdown restrictions. Participants completed the internet addiction test, UCLA loneliness scale, and answered questioned about their online usage, at two time points. All cross-sectional analyses revealed a positive relationship between PIU and loneliness. However, there was no association between online use and loneliness. Longitudinal relationships between PIU and loneliness differed during and after lockdown restrictions. During a period of lockdown, there were both positive associations between earlier PIU and subsequent loneliness, and between earlier loneliness and subsequent PIU. However, following the easing of lockdown restrictions, only the temporal relationship between earlier internet addiction and later loneliness was significant.

Virus induced dysbiosis promotes type 1 diabetes onset.

Autoimmune disorders are complex diseases of unclear etiology, although evidence suggests that the convergence of genetic susceptibility and environmental factors are critical. In type 1 diabetes (T1D), enterovirus infection and disruption of the intestinal microbiota are two environmental factors that have been independently associated with T1D onset in both humans and animal models. However, the possible interaction between viral infection and the intestinal microbiota remains unknown. Here, we demonstrate that Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice, induced restructuring of the intestinal microbiome prior to T1D onset. Microbiome restructuring was associated with an eroded mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased circulating and intestinal commensal-reactive antibodies. The CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, implying a mutual "diabetogenic" microbiome. Notably, members of the Bifidobacteria and Akkermansia genera emerged as conspicuous members of this diabetogenic microbiome, implicating these taxa, among others, in diabetes onset. Further, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice enhanced T1D susceptibility and led to diminished expression of the short chain fatty acid receptor GPR43 and fewer IL-10-expressing regulatory CD4+ T cells in the intestine of naïve NOD recipients. These findings support an overlap in known environmental risk factors of T1D, and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D.

Exploratory Study of Parenting Differences for Autism Spectrum Disorder and Attachment Disorder.

The current study explored similarities and differences in parenting stress (PSI) and behaviours in parent reports of autism spectrum disorder (ASD) and attachment disorder (AD). 155 parents whose children had developmental delays and disorders completed the social communication questionnaire, Randolph attachment questionnaire, strengths and difficulties questionnaire, PSI, and parent-child relationship inventory. Parents of children with AD reported greater levels of PSI than parents of children with ASD. Parents of children reaching criteria for both disorders reported the greatest levels of PSI. Limit setting was poorest in parents of children with both classifications, followed by parents of children with AD, and then ASD. Limit setting mediated the relationship between PSI and child behaviour problems for parents of children with ASD < but not for parents of children with AD. These findings suggest different areas of difficulty for parents of children with these conditions, which may be of help in designing interventions.

Change in depression predicts change in bladder symptoms for women with urinary incontinence undergoing pelvic-floor muscle training.

INTRODUCTION: To examine the relationship between depression and bladder symptoms, especially the impact of change in depression on changes in bladder symptoms, for women with urge and stress urinary incontinence undergoing a course of PFMT. METHOD: 106 adult females with pelvic-floor dysfunction (PFD), consecutively referred to an outpatient pelvic-floor muscle training (PFMT) programme for either urge, stress, or mixed incontinence, participated in a prospective observational study. Participants reported subjective views of their pelvic floor problems (Queensland), and their levels of depression (HADS_D), and data relating to age and BMI were collected. The trial was registered on clinicaltrials.gov (NCT02549157). RESULTS: There was a positive relationship between depression and bladder symptoms at intake. Levels of initial depression significantly predicted levels of bladder symptoms at completion of PFMT, and ability to complete the PFMT programme. Change in depression significantly predicted change in bladder symptoms, over and above intake patient characteristics and symptoms. DISCUSSION: These data imply a multidisciplinary focus, including psychological input, for PFD may be a highly effective strategy for its management.

Wolf-Hirschhorn Syndrome with Hyperparathyroidism: A Case Report and a Narrative Review of the Literature.

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion condition. The WHS core phenotype includes developmental delays, intellectual disabilities, seizures, and distinctive facial features. Various other comorbidities have also been reported, such as hearing loss, heart defects, as well as eye problems and kidney problems. In this report, we present a case of WHS accompanied by hyperparathyroidism and hypercalcemia, which has not been previously reported. A girl was born at 37 weeks of gestation by vaginal delivery. She was small for the gestational age (2,045 g) and admitted to neonatal intensive care unit. She had typical WHS facial features and was found to have bilateral small kidneys associated with transient metabolic acidosis and renal insufficiency. She had right-sided sensorineural hearing loss, a small atrial septal defect, and colpocephaly and hypoplasia of corpus callosum. She had a single seizure which was well controlled with an oral antiepileptic medication. Cytogenetic studies demonstrated a large terminal chromosome 4p deletion (21.4 Mb) and 4p duplication (2.1 Mb) adjacent to the deletion. A unique finding in this patient is her consistently elevated levels of parathyroid hormone and serum calcium, suggesting hyperparathyroidism. We present this rare case along with a review of the literature and hope to draw an attention to a potential relationship between WHS and hyperparathyroidism.

Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS.

While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Here, we directly compared CD11c+T-bet+ ABCs using models of Epstein-Barr virus (EBV), gammaherpesvirus 68 (γHV68), multiple sclerosis (MS), and experimental autoimmune encephalomyelitis (EAE), and found that each drives the ABC population to opposing phenotypes. EBV infection has long been implicated in MS, and we have previously shown that latent γHV68 infection exacerbates EAE. Here, we demonstrate that ABCs are required for γHV68-enhanced disease. We then show that the circulating ABC population is expanded and phenotypically altered in people with relapsing MS. In this study, we show that viral infection and autoimmunity differentially affect the phenotype of ABCs in humans and mice, and we identify ABCs as functional mediators of viral-enhanced autoimmunity.

Patient and economic benefits of psychological support for noncompliant patients.

The current paper provides an overview of treatment noncompliance at various points in the treatment pathway, especially with respect to treatment for Pelvic-floor Dysfunction (PFD). The effects of noncompliance on healthcare are considered, and examples of supporting patients psychologically to increase compliance are discussed. An outline of a method to identify costs of non-compliance, and where such costs most intensely impact the healthcare system, is provided. It is suggested that psychological support is effective in terms of increased compliance and improved healthcare economics. The model is presented for PFD, but the principles developed can be generalised to many aspects of healthcare.

Inhibition of Th1 activation and differentiation by dietary guar gum ameliorates experimental autoimmune encephalomyelitis.

Dietary fibers are potent modulators of immune responses that can restrain inflammation in multiple disease contexts. However, dietary fibers encompass a biochemically diverse family of carbohydrates, and it remains unknown how individual fiber sources influence immunity. In a direct comparison of four different high-fiber diets, we demonstrate a potent ability of guar gum to delay disease and neuroinflammation in experimental autoimmune encephalomyelitis, a T cell-mediated mouse model of multiple sclerosis. Guar gum-specific alterations to the microbiota are limited, and disease protection appears to be independent of fiber-induced increases in short-chain fatty acid levels or regulatory CD4+ T cells. Instead, CD4+ T cells of guar gum-supplemented mice are less encephalitogenic due to reduced activation, proliferation, Th1 differentiation, and altered migratory potential. These findings reveal specificity in the host response to fiber sources and define a pathway of fiber-induced immunomodulation that protects against pathologic neuroinflammation.

A gut-centric view of aging: Do intestinal epithelial cells contribute to age-associated microbiota changes, inflammaging, and immunosenescence?

Intestinal epithelial cells (IECs) serve as both a physical and an antimicrobial barrier against the microbiota, as well as a conduit for signaling between the microbiota and systemic host immunity. As individuals age, the balance between these systems undergoes a myriad of changes due to age-associated changes to the microbiota, IECs themselves, immunosenescence, and inflammaging. In this review, we discuss emerging data related to age-associated loss of intestinal barrier integrity and posit that IEC dysfunction may play a central role in propagating age-associated alterations in microbiota composition and immune homeostasis.

Eo, what are we doing here?

A plethora of studies have established the importance of eosinophils in protective immunity against infections and in allergy. In this issue of Immunity, Ignacio et al. (2022) define a vital for eosinophils in coordinating a microbiota-epithelial-immune axis that maintains intestinal homeostasis.

Patient Satisfaction with Tele- and Video-Consultation in the COVID-19 Era - A Survey of Vascular Surgical Patients.

BACKGROUND: The COVID 19 pandemic has resulted in the increasing use of telemedicine due to the advantages of avoiding viral transmission. Evidence suggests that telemedicine, for certain conditions, may be as effective as face-to-face consultations; however, there is no research to date regarding vascular patients' acceptance or satisfaction with telemedicine during and after the COVID-19 pandemic. METHODS: A patient satisfaction interview was designed to survey three aspects of the service: patient acceptability of teleconsultations as a replacement to physical clinics; their views of teleconsultation during the pandemic; and the future role of teleconsultations postpandemic. Patients undergoing remote teleconsultation (either by telephone or video software), between April and June 2020 were suitable for inclusion. Patients were contacted by telephone in August 2020 to undertake the survey. Local "Research and Development" approval was obtained. RESULTS: A total of 333 patients had a consultation with a vascular consultant between April and June 2020, of which 178 were teleconsultations. Successful contact was made with 72 patients, of whom 68 agreed to participate; 10 patients had undergone video consultations, while the remainder had telephone consultations. Teleconsultations were widely viewed as acceptable, and over 90% of patients felt they were beneficial. 91% felt that not needing to travel for appointments was advantageous to them. The option of teleconsultation during the COVID pandemic was valued by 94% of the cohort. While all interviewees felt teleclinics should continue during the pandemic, the majority (74%) also wanted to use teleconsultations for clinic appointments after the pandemic. CONCLUSIONS: Telemedicine is viewed by vascular patients as generally acceptable and beneficial for use during the pandemic. The majority of patients wanted future telemedicine appointments postpandemic. Telemedicine services started as a result of the COVID-19 pandemic, which may have been viewed as a temporary measure, should be planned to continue long term.

Age-dependent gray matter demyelination is associated with leptomeningeal neutrophil accumulation.

People living with multiple sclerosis (MS) experience episodic CNS white matter lesions instigated by autoreactive T cells. With age, patients with MS show evidence of gray matter demyelination and experience devastating nonremitting symptomology. What drives progression is unclear and studying this has been hampered by the lack of suitable animal models. Here, we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induced a nonremitting clinical phenotype that was associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young, SJL/J mice. Although the quantity and quality of T cells did not differ in the brains of old versus young EAE mice, an increase in neutrophils and a decrease in B cells were observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and gray matter pathology are dictated by age and associated with other immune cells, such as neutrophils.

Restriction of Viral Replication, Rather than T Cell Immunopathology, Drives Lethality in Murine Norovirus CR6-Infected STAT1-Deficient Mice.

Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that regulate the virome remain largely unknown. In this study, we used colonization with the model commensal murine norovirus (MNV; strain CR6) to interrogate host-directed mechanisms of viral regulation, and we show that STAT1 is a central coordinator of both viral replication and antiviral T cell responses. In addition to restricting CR6 replication to the intestinal tract, we show that STAT1 regulates antiviral CD4+ and CD8+ T cell responses and prevents systemic viral-induced tissue damage and disease. Despite altered T cell responses that resemble those that mediate lethal immunopathology in systemic viral infections in STAT1-deficient mice, depletion of adaptive immune cells and their associated effector functions had no effect on CR6-induced disease. However, therapeutic administration of an antiviral compound limited viral replication, preventing virus-induced tissue damage and death without impacting the generation of inflammatory antiviral T cell responses. Collectively, our data show that STAT1 restricts MNV CR6 replication within the intestinal mucosa and that uncontrolled viral replication mediates disease rather than the concomitant development of dysregulated antiviral T cell responses in STAT1-deficient mice. IMPORTANCE The intestinal microbiota is a collection of bacteria, archaea, fungi, and viruses that colonize the mammalian gut. Coevolution of the host and microbiota has required development of immunological tolerance to prevent ongoing inflammatory responses against intestinal microbes. Breakdown of tolerance to bacterial components of the microbiota can contribute to immune activation and inflammatory disease. However, the mechanisms that are necessary to maintain tolerance to viral components of the microbiome, and the consequences of loss of tolerance, are less well understood. Here, we show that STAT1 is integral for preventing escape of a commensal-like virus, murine norovirus CR6 (MNV CR6), from the gut and that in the absence of STAT1, mice succumb to infection-induced disease. In contrast to the case with other systemic viral infections, mortality of STAT1-deficient mice is not driven by immune-mediated pathology. Our data demonstrate the importance of host-mediated geographical restriction of commensal-like viruses.

Cluster randomised control trial of the effect on attendance and outcomes of multi-disciplinary teams involving psychologists during pelvic floor muscle training for pelvic floor dysfunction.

Pelvic floor muscle training (PFMT) is effective, acceptable to patients, and cost efficient as a treatment for Pelvic Floor Dysfunction (PFD). However, PFMT outcomes are mediated by patient variables, such as depression, anxiety, motivation, and health values. The current study examined whether multi-disciplinary provision of PFMT involving a psychologist would improve attendance and outcomes (Clinical Trial Registration: NCT02549157). 88 consecutively referred patients (age 28 - 85 years), with a variety of PFD, were randomised into two groups: PFMT treatment as usual (n = 47), and PFMT with a psychologist involved (n = 41). Patients received 6-month out-patient physiotherapy. More patients with the psychologist completed the course, and there were significantly greater improvements in subjective symptoms (Queensland scale), quality of life (EQ-5D), and anxiety (HADS), although not in objective measures (Oxford Grading) or depression (HADS). These results suggest that an MDT including a psychologist during PFMT intervention treatment may help some patients.IMPACT STATEMENTWhat is already known on this subject? Pelvic floor muscle training (PFMT) is effective, acceptable to patients, and cost efficient as a treatment for Pelvic Floor Dysfunction (PFD). However, PFMT outcomes are mediated by patient variables, such as depression, anxiety, motivation, and health values. The effectiveness of a multi-disciplinary team delivering both PFMT and psychological support simultaneously to women undergoing PFMT for PFD is unknown.What do the results of this study add? Psychological support delivered alongside PFMT increased patient attendance, improved subjective ratings of pelvic floor functioning, health-related quality of life, and reduced anxiety. This is one of the first demonstrations that this can be achieved through a multi-disciplinary team delivering their support simultaneously to the patients.What are the implications of these findings for clinical practice and/or further research? Improving subjective functioning and reducing attrition rates in PFD patients has cost implications in terms of reduced need for surgery, and making future surgery more effective. The inclusion of brief, easily delivered psychological support, integrated into the PFMT sessions in a multidisciplinary way may represent an extremely cost effective method of improving the service for these patients.