Age-associated Senescent - T Cell Signaling Promotes Type 3 Immunity that Inhibits the Biomaterial Regenerative Response.

Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and can potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and regenerative medicine therapies remain unknown. Here, it is characterized how aging induces changes in immunological signatures that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix. Signatures of inflammation and interleukin (IL)-17 signaling increased with injury and treatment both locally and regionally in aged animals, and computational analysis uncovered age-associated senescent-T cell communication that promotes type 3 immunity in T cells. Local inhibition of type 3 immune activation using IL17-neutralizing antibodies improves healing and restores therapeutic response to the regenerative biomaterial, promoting muscle repair in older animals. These results provide insights into tissue immune dysregulation that occurs with aging that can be targeted to rejuvenate repair.

Senolytic treatment reduces oxidative protein stress in an aging male murine model of post-traumatic osteoarthritis.

Senolytic drugs are designed to selectively clear senescent cells (SnCs) that accumulate with injury or aging. In a mouse model of osteoarthritis (OA), senolysis yields a pro-regenerative response, but the therapeutic benefit is reduced in aged mice. Increased oxidative stress is a hallmark of advanced age. Therefore, here we investigate whether senolytic treatment differentially affects joint oxidative load in young and aged animals. We find that senolysis by a p53/MDM2 interaction inhibitor, UBX0101, reduces protein oxidative modification in the aged arthritic knee joint. Mass spectrometry coupled with protein interaction network analysis and biophysical stability prediction of extracted joint proteins revealed divergent responses to senolysis between young and aged animals, broadly suggesting that knee regeneration and cellular stress programs are contrarily poised to respond as a function of age. These opposing responses include differing signatures of protein-by-protein oxidative modification and abundance change, disparate quantitative trends in modified protein network centrality, and contrasting patterns of oxidation-induced folding free energy perturbation between young and old. We develop a composite sensitivity score to identify specific key proteins in the proteomes of aged osteoarthritic joints, thereby nominating prospective therapeutic targets to complement senolytics.

The Importance of the Nephrologist in the Treatment of the Diuretic-Resistant Heart Failure.

Heart failure is not only a global problem but also significantly limits the life prospects of these patients. The epidemiology and presentation of heart failure are intensively researched topics in cardiology. The risk factors leading to heart failure are well known; however, the real challenge is to provide effective treatments. A vicious cycle develops in heart failure of all etiologies, sooner or later compromising both cardiac and kidney functions simultaneously. This can explain the repeated hospital admissions due to decompensation and the significantly reduced quality of life. Moreover, diuretic-refractory heart failure represents a distinct challenge due to repeated hospital admissions and increased mortality. In our narrative review, we wanted to draw attention to nephrology treatment options for severe diuretic-resistant heart failure. The incremental value of peritoneal dialysis in severe heart failure and the feasibility of percutaneous peritoneal dialysis catheter insertion have been well known for many years. In contrast, the science and narrative of acute peritoneal dialysis in diuretic-resistant heart failure remains underrepresented. We believe that nephrologists are uniquely positioned to help these patients by providing acute peritoneal dialysis to reduce hospitalization dependency and increase their quality of life.

Hypomagnesemia as a Risk Factor and Accelerator for Vascular Aging in Diabetes Mellitus and Chronic Kidney Disease.

The age-old axiom that one is as old as his or her vessels are, calls for ongoing critical re-examination of modifiable risk factors of accelerated vascular ageing in chronic kidney diseases. Attempts to modulate vascular risk with cholesterol-lowering agents have largely failed in advanced chronic kidney disease (CKD). In addition to nitrogen waste products, many pathological biochemical processes also play a role in vascular calcification in chronic kidney damage. Magnesium, a cation vital for the body, may substantially reduce cardiovascular diseases' risk and progression. This narrative review aimed to address the relationship between hypomagnesemia and vascular calcification, which promotes further cardiovascular complications in diabetes, aging, and CKD. Articles with predefined keywords were searched for in the PubMed and Google Scholar databases with specific inclusion and exclusion criteria. We hypothesized that a decrease in serum magnesium levels contributes to increased vascular calcification and thereby increases cardiovascular mortality. In summary, based on existing evidence in the literature, it appears that simple and inexpensive oral magnesium supplementation may reduce the cardiovascular mortality of patients who are already severely affected by such diseases; in this context, the concept of 'normal' vs. 'ideal' serum magnesium levels should be carefully re-examined.

The value of active follow up of a newly acquired hepatitis B infection - lessons for current approaches.

Abstract: The standard practice of blood borne virus (BBV) follow-up in New South Wales is a passive approach of general-practitioner-led testing. The value of this approach is unknown. We undertook an active contact tracing method with the aims of investigating a potential hepatitis B source, along with accurately measuring the participation rate, to consider the value of this and other follow-up methods for future BBV investigations. Investigation of a newly-acquired hepatitis B infection was undertaken at a dental practice identified as a possible exposure site. To screen for hepatitis B infection among potential source or co-exposed clients, we actively followed up with staff and clients of the practice to request they undertake hepatitis B serology. Eligible staff and clients received up to four phone calls and were provided with a pathology request form by the public health unit (PHU). Access to free serology was offered to people who did not have access to Medicare. Reminder calls were made if serology results were not received by the PHU. As the ordering doctor, the public health physician was responsible for providing results and referring for follow-up care. Of 160 clients, 63 (39%) undertook hepatitis B serology. Of these 63, none were found to have hepatitis B infection. It was estimated the active investigation involved an extra 430 hours of PHU staff time at a cost in Australian dollars of $30,000. Active follow-up allows an accurate participation rate to be documented. Despite intense active follow-up, only 39% of clients undertook testing, bringing into question the yield of the usual approach in which active follow-up of potential mass BBV exposures is not undertaken. While active follow-up is resource intensive, it should be considered where the risks and consequences from the BBV infection are high.

Bondi and beyond. Lessons from three waves of COVID-19 from 2020.

OBJECTIVES: To describe local operational aspects of the coronavirus disease 2019 (COVID-19) response during the first three waves of outbreaks in New South Wales (NSW), Australia, which began in January, July and December 2020. Type of program or service: Public health outbreak response. METHODS: Narrative with epidemiological linking and genomic testing. RESULTS: Epidemiological linking and genomic testing found that during the first wave of COVID-19 in NSW, a large number of community transmissions went undetected because of limited testing for the virus and limited contact tracing of cases. The second wave of COVID-19 in NSW emerged following reintroduction from the second wave in Victoria, Australia in July 2020, and the third wave followed undetected introduction from overseas. By the second and third waves, cases could be more effectively detected and isolated through an increased ability to test and contact trace, and to rapidly genomic sequence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolates, allowing most cases to be identified and epidemiologically linked. This greater certainty in understanding chains of transmission resulted in control of the outbreaks despite less stringent restrictions on the community, by using a refined strategy of targeted shutdown, restrictions on cases, their close contacts, identified hotspots and venues of concern rather than a whole of community lockdown. Risk assessments of potential transmission sites were constantly updated through our evolving experience with transmission events. However, this refined strategy did leave the potential for large point source outbreaks should any cases go undetected. [Addendum] A fourth wave that began in Sydney in June 2021 challenged this strategy due to the more transmissible nature of the Delta variant of SARS-CoV-2. LESSONS LEARNT: A wave of COVID-19 infections can develop quickly from one infected person. The community needs to remain vigilant, adhering to physical distancing measures, signing in to venues they visit, and getting tested if they have any symptoms. Signing out of venues on exit allows public health resources to be used more efficiently to respond to outbreaks.