Late-life shift in caloric intake affects fly metabolism and longevity.

The prevalence of obesity is increasing in older adults and contributes to age-related decline. Caloric restriction (CR) alleviates obesity phenotypes and delays the onset of age-related changes. However, how late in life organisms benefit from switching from a high-(H) to a low-calorie (L) diet is unclear. We transferred male flies from a H to a L (HL) diet or vice versa (LH) at different times during life. Both shifts immediately change fly rate of aging even when applied late in life. HL shift rapidly reduces fly mortality rate to briefly lower rate than in flies on a constant L diet, and extends lifespan. Transcriptomic analysis uncovers that flies aged on H diet have acquired increased stress response, which may have temporal advantage over flies aged on L diet and leads to rapid decrease in mortality rate after HL switch. Conversely, a LH shift increases mortality rate, which is temporarily higher than in flies aged on a H diet, and shortens lifespan. Unexpectedly, more abundant transcriptomic changes accompanied LH shift, including increase in ribosome biogenesis, stress response and growth. These changes reflect protection from sudden release of ROS, energy storage, and use of energy to growth, which all likely contribute to higher mortality rate. As the beneficial effects of CR on physiology and lifespan are conserved across many organisms, our study provides framework to study underlying mechanisms of CR interventions that counteract the detrimental effects of H diets and reduce rate of aging even when initiated later in life.

Targeting the hallmarks of aging to improve influenza vaccine responses in older adults.

Age-related declines in immune response pose a challenge in combating diseases later in life. Influenza (flu) infection remains a significant burden on older populations and often results in catastrophic disability in those who survive infection. Despite having vaccines designed specifically for older adults, the burden of flu remains high and overall flu vaccine efficacy remains inadequate in this population. Recent geroscience research has highlighted the utility in targeting biological aging to improve multiple age-related declines. Indeed, the response to vaccination is highly coordinated, and diminished responses in older adults are likely not due to a singular deficit, but rather a multitude of age-related declines. In this review we highlight deficits in the aged vaccine responses and potential geroscience guided approaches to overcome these deficits. More specifically, we propose that alternative vaccine platforms and interventions that target the hallmarks of aging, including inflammation, cellular senescence, microbiome disturbances, and mitochondrial dysfunction, may improve vaccine responses and overall immunological resilience in older adults. Elucidating novel interventions and approaches that enhance immunological protection from vaccination is crucial to minimize the disproportionate effect of flu and other infectious diseases on older adults.

The effect of metformin on influenza vaccine responses in nondiabetic older adults: a pilot trial.

BACKGROUND: Aging is associated with progressive declines in immune responses leading to increased risk of severe infection and diminished vaccination responses. Influenza (flu) is a leading killer of older adults despite availability of seasonal vaccines. Geroscience-guided interventions targeting biological aging could offer transformational approaches to reverse broad declines in immune responses with aging. Here, we evaluated effects of metformin, an FDA approved diabetes drug and candidate anti-aging drug, on flu vaccination responses and markers of immunological resilience in a pilot and feasibility double-blinded placebo-controlled study. RESULTS: Healthy older adults (non-diabetic/non-prediabetic, age: 74.4 ± 1.7 years) were randomized to metformin (n = 8, 1500 mg extended release/daily) or placebo (n = 7) treatment for 20 weeks and were vaccinated with high-dose flu vaccine after 10 weeks of treatment. Peripheral blood mononuclear cells (PBMCs), serum, and plasma were collected prior to treatment, immediately prior to vaccination, and 1, 5, and 10 weeks post vaccination. Increased serum antibody titers were observed post vaccination with no significant differences between groups. Metformin treatment led to trending increases in circulating T follicular helper cells post-vaccination. Furthermore, 20 weeks of metformin treatment reduced expression of exhaustion marker CD57 in circulating CD4 T cells. CONCLUSIONS: Pre-vaccination metformin treatment improved some components of flu vaccine responses and reduced some markers of T cell exhaustion without serious adverse events in nondiabetic older adults. Thus, our findings highlight the potential utility of metformin to improve flu vaccine responses and reduce age-related immune exhaustion in older adults, providing improved immunological resilience in nondiabetic older adults.

Missed opportunities: saving lives through organ donation following voluntary assisted dying.

Organ donation after voluntary assisted dying (VAD) in Australia may potentially increase organ transplant rates. Despite significant international experience with donation after VAD, there has been little discussion of this in Australia. We review potential ethical and practical concerns relating to donation after VAD and advocate action to establish programmes in Australia that ensure safe, ethical and effective donation after VAD.

First clinical-grade porcine kidney xenotransplant using a human decedent model.

A radical solution is needed for the organ supply crisis, and the domestic pig is a promising organ source. In preparation for a clinical trial of xenotransplantation, we developed an in vivo pre-clinical human model to test safety and feasibility tenets established in animal models. After performance of a novel, prospective compatible crossmatch, we performed bilateral native nephrectomies in a human brain-dead decedent and subsequently transplanted two kidneys from a pig genetically engineered for human xenotransplantation. The decedent was hemodynamically stable through reperfusion, and vascular integrity was maintained despite the exposure of the xenografts to human blood pressure. No hyperacute rejection was observed, and the kidneys remained viable until termination 74 h later. No chimerism or transmission of porcine retroviruses was detected. Longitudinal biopsies revealed thrombotic microangiopathy that did not progress in severity, without evidence of cellular rejection or deposition of antibody or complement proteins. Although the xenografts produced variable amounts of urine, creatinine clearance did not recover. Whether renal recovery was impacted by the milieu of brain death and/or microvascular injury remains unknown. In summary, our study suggests that major barriers to human xenotransplantation have been surmounted and identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans.

Transitions in decision-making authority at the end of life: a problem of law, ethics and practice in deceased donation.

Where a person is unable to make medical decisions for themselves, law and practice allows others to make decisions on their behalf. This is common at the end of a person's life where decision-making capacity is often lost. A further, and separate, decision that is often considered at the time of death (and often preceding death) is whether the person wanted to act as an organ or tissue donor. However, in some jurisdictions, the lawful decision-maker for the donation decision (the 'donation decision-maker') is different from the person who was granted decision-making authority for medical decisions during the person's life. To date, little attention has been given in the literature to the ethical concerns and practical problems that arise where this shift in legal authority occurs. Such a change in decision-making authority is particularly problematic where premortem measures are suggested to maximise the chances of a successful organ donation. This paper examines this shift in decision-making authority and discusses the legal, ethical and practical implications of such frameworks.

Better, Faster, Stronger: mRNA Vaccines Show Promise for Influenza Vaccination in Older Adults.

Older adults have diminished immune responses that lead to increased susceptibility and severity of infectious diseases. Influenza is a leading killer of older adults despite the availability of seasonal influenza vaccination. Influenza vaccines are strain specific, and their efficacy varies greatly year to year based on how well the vaccine virus matches the circulating strains. Additionally, older adults have reduced vaccination responses. The COVID-19 pandemic highlighted the increased mortality rate in older adults for infectious disease, and brought vaccine development to the forefront. The speed of vaccine development was met with an equally impressive vaccine efficacy. Interestingly, both mRNA-based COVID-19 vaccines currently available have shown similar efficacy in both young and older adults. mRNA vaccine production has significantly reduced the production timeline compared to current influenza vaccines, making them particularly attractive for influenza vaccine development. Faster production coupled with improved efficacy would be a tremendous advancement in protecting older adults from influenza morbidity and mortality.

Addressing ethical confusion in deceased donation and transplantation research: the need for dedicated guidance.

Innovative research in deceased donation and transplantation often presents ethical challenges for researchers and those responsible for ethical governance of research. These challenges have been recognized as potential barriers to the conduct of research. We review the literature to identify and describe ethical considerations that may cause confusion or uncertainty in the context of research involving potential deceased donors or deceased donor transplantation. We normatively examine these considerations and discuss their implications for the ethical conduct of research. In addition to the complexities of research involving critically ill, dying or recently deceased individuals, uncertainty may arise regarding the ethical status of various individuals who may be involved in research aimed at improving availability and outcomes of organ transplantation. Consequently, routine ethical guidelines for clinical research may fail to provide clear guidance with regards to the design, conduct and governance of some deceased donation or transplantation studies. Ethical uncertainty may result in delays or barriers to research, or neglect of important ethical considerations. Specific ethical guidance is needed to support research in deceased donation and transplantation as the ethical considerations that arise in the design and conduct of such research may not be addressed in the existing guidelines for human research.

[Total reconstruction of the lower lip: Lip suspension technique by double nasolabial rigging and review of the literature]. / Reconstruction totale de la lèvre inférieure : technique de suspension labiale par double haubanage nasogénien et revue de la littérature.

BACKGROUND: Total lower lip defect is rare and its reconstruction difficult. The challenges are both aesthetic and functional. Suspension of the lower lip is essential for restoring oral competence. We report an original and simple technique of suspension by double nasolabial rigging. METHOD: Two upper base orbitonasolabial flaps, extended over several centimeters below the lip commissures are raised. The epidermis is completely removed. Then, the flaps are tunneled under the skin and fixed to the reconstructed lower lip in order to provide it with effective suspension to the maxillary. RESULTS: In our experience, we used the nasolabial rigging associated with a total reconstruction of the lower lip for three patients. Lip continence is effective in the long term. The review of literature shows that the use of conventional locoregional flaps restores a good labial competence but is limited to subtotal lower lip defect. Distant pedicled flaps or free flaps made without suspension of the lower lip don't restore the labial competence. Several procedures to suspend the lower lip with strips of fascia lata or tendon of palmaris longus, associated or not with a free flap, seem to provide satisfactory oral competence. All these techniques are poorly standardized and technically difficult. CONCLUSION: The technique of the double nasolabial rigging that we describe seems to be an effective and interesting alternative by its simplicity, its reproducibility and its adaptability. It allows to obtain a perfectly fixed posterior plane, able to receive any reconstruction of the lower lip.

Ethics of kidney care in the era of COVID-19.

The coronavirus disease 2019 pandemic presents significant challenges for health systems globally, including substantive ethical dilemmas that may pose specific concerns in the context of care for people with kidney disease. Ethical concerns may arise as changes in policy and practice affect the ability of all health professionals to fulfill their ethical duties toward their patients in providing best practice care. In this article, we briefly describe such concerns and elaborate on issues of particular ethical complexity in kidney care: equitable access to dialysis during pandemic surges; balancing the risks and benefits of different kidney failure treatments, specifically with regard to suspending kidney transplantation programs and prioritizing home dialysis, and barriers to shared decision-making; and ensuring ethical practice when using unproven interventions. We present preliminary advice on how to approach these issues and recommend urgent efforts to develop resources that will support health professionals and patients in managing them.

Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals.

PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

Increasing access to integrated ESKD care as part of universal health coverage.

The global nephrology community recognizes the need for a cohesive strategy to address the growing problem of end-stage kidney disease (ESKD). In March 2018, the International Society of Nephrology hosted a summit on integrated ESKD care, including 92 individuals from around the globe with diverse expertise and professional backgrounds. The attendees were from 41 countries, including 16 participants from 11 low- and lower-middle-income countries. The purpose was to develop a strategic plan to improve worldwide access to integrated ESKD care, by identifying and prioritizing key activities across 8 themes: (i) estimates of ESKD burden and treatment coverage, (ii) advocacy, (iii) education and training/workforce, (iv) financing/funding models, (v) ethics, (vi) dialysis, (vii) transplantation, and (viii) conservative care. Action plans with prioritized lists of goals, activities, and key deliverables, and an overarching performance framework were developed for each theme. Examples of these key deliverables include improved data availability, integration of core registry measures and analysis to inform development of health care policy; a framework for advocacy; improved and continued stakeholder engagement; improved workforce training; equitable, efficient, and cost-effective funding models; greater understanding and greater application of ethical principles in practice and policy; definition and application of standards for safe and sustainable dialysis treatment and a set of measurable quality parameters; and integration of dialysis, transplantation, and comprehensive conservative care as ESKD treatment options within the context of overall health priorities. Intended users of the action plans include clinicians, patients and their families, scientists, industry partners, government decision makers, and advocacy organizations. Implementation of this integrated and comprehensive plan is intended to improve quality and access to care and thereby reduce serious health-related suffering of adults and children affected by ESKD worldwide.

Ethical issues in dialysis therapy.

Treatment for end-stage kidney disease is a major economic challenge and a public health concern worldwide. Renal-replacement therapy poses several practical and ethical dilemmas of global relevance for patients, clinicians, and policy makers. These include how to: promote patients' best interests; increase access to dialysis while maintaining procedural and distributive justice; minimise the influence of financial incentives and competing interests; ensure quality of care in service delivery and access to non-dialytic supportive care when needed; minimise the financial burden on patients and health-care system; and protect the interests of vulnerable groups during crisis situations. These issues have received comparatively little attention, and there is scant ethical analysis and guidance available to decision makers. In this Health Policy, we provide an overview of the major ethical issues related to dialysis provision worldwide, identify priorities for further investigation and management, and present preliminary recommendations to guide practice and policy.

Banking on Living Kidney Donors-A New Way to Facilitate Donation without Compromising on Ethical Values.

Public surveys conducted in many countries report widespread willingness of individuals to donate a kidney while alive to a family member or close friend, yet thousands suffer and many die each year while waiting for a kidney transplant. Advocates of financial incentive programs or "regulated markets" in kidneys present the problem of the kidney shortage as one of insufficient public motivation to donate, arguing that incentives will increase the number of donors. Others believe the solutions lie-at least in part-in facilitating so-called "altruistic donation;" harnessing the willingness of relatives and friends to donate by addressing the many barriers which serve as disincentives to living donation. Strategies designed to minimize financial barriers to donation and the use of paired kidney exchange programs are increasingly enabling donation, and now, an innovative program designed to address what has been termed "chronologically incompatible donation" is being piloted at the University of California, Los Angeles, and elsewhere in the United States. In this program, a person whose kidney is not currently required for transplantation in a specific recipient may instead donate to the paired exchange program; in return, a commitment is made to the specified recipient that priority access for a living-donor transplant in a paired exchange program will be offered when or if the need arises in the future. We address here potential ethical concerns related to this form of organ "banking" from living donors, and argue that it offers significant benefits without undermining the well-established ethical principles and values currently underpinning living donation programs.

Therapeutic appropriation: a new concept in the ethics of clinical research.

Ethical concerns about therapeutic misconception have been raised since the early 1980s. This concept was originally described as research participants' assumptions that decisions relating to research interventions are made on the basis of their individual therapeutic needs. The term has since been used to refer to a range of 'misunderstandings' that research participants may have. In this paper, we describe a new concept-therapeutic appropriation Therapeutic appropriation occurs when patients, or clinicians, actively reframe research participation as an opportunity to enhance patients' clinical care, while simultaneously acknowledging the generalised research aims. To illustrate the concept of therapeutic appropriation, we draw on data from an interview study which we conducted to investigate the experiences of patients and general practitioners involved in clinical trials in primary care. We argue that therapeutic appropriation has two key elements: comprehension that the research project is not necessarily aiming to benefit participants and the deliberate use of incidental features of the research for personal therapeutic benefit of various kinds. We conclude that therapeutic appropriation is a useful concept that refines understanding of potential ethical problems in clinical research, and points to strategies to address them.

Financial Incentives for Living Kidney Donors: Are They Necessary?

In the face of the perceived failure of altruistic organ donation programs to generate sufficient kidneys to meet demand, introducing financial incentives for living donors is sometimes argued as the only effective strategy by which lives currently lost while awaiting kidney transplantation might be saved. This argument from life-saving necessity is implicit in many incentive proposals, but rarely challenged by opponents. The core empirical claims on which it rests are thus rarely interrogated: that the gap between supply of and demand for donor kidneys is large and growing, the current system cannot meet demand, and financial incentives would increase the overall supply of kidneys and thus save lives. We consider these claims in the context of the United States. While we acknowledge the plausibility of claims that incentives, if sufficiently large, may successfully recruit greater numbers of living donors, we argue that strategies compatible with the existing altruistic system may also increase the supply of kidneys and save lives otherwise lost to kidney failure. We conclude that current appeals to the life-saving necessity argument have yet to establish sufficient grounds to justify trials of incentives.

Cellular senescence is a double-edged sword in regulating aged immune responses to influenza.

Clearance of senescent cells has demonstrated therapeutic potential in the context of chronic age-related diseases. Little is known, however, how clearing senescent cells affects the ability to respond to an acute infection and form quality immunological memory. We aimed to probe the effects of clearing senescent cells in aged mice on the immune response to influenza (flu) infection. We utilized a p16 trimodality reporter mouse model (p16-3MR) to allow for identification and selective clearance of p16-expressing cells upon administration of ganciclovir (GCV). While p16-expressing cells may exacerbate dysfunctional responses to a primary infection, our data suggest they may play a role in fostering memory cell generation. We demonstrate that although clearance of p16-expressing cells enhanced viral clearance, this also severely limited antibody production in the lungs of flu-infected aged mice. 30 days later, there were fewer flu-specific CD8 memory T cells and lower levels of flu-specific antibodies in the lungs of GCV-treated mice. Furthermore, GCV-treated mice were unable to mount an optimal memory response and demonstrated increased viral load following heterosubtypic challenge. These results suggest that targeting senescent cells may potentiate primary responses while limiting the ability to form durable and protective immune memory with age.