Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.     

Guardianship: A medicolegal review for clinicians

Guardianship may pose an ethical dilemma for physicians, who must balance protecting vulnerable patients from potential safety concerns with respecting their autonomy. Older adults with dementia are particularly susceptible to loss of independence and the ability to participate in medical decision making. To have the capacity for medical decision making, individuals must understand relevant information, appreciate their circumstances, demonstrate reasoning, and express a consistent choice free from coercion. Although capacity assessments are usually task-specific, geriatricians and other specialists may be asked to comment on capacity more globally. These determinations may be used to support a Petition for the Appointment of a Guardian of a Legally Incapacitated Adult, the legal process of pursuing guardianship in probate court. Assigned guardians may be known to the incapacitated individual (e.g., a family member or friend) or may be professional guardians with no prior relationship to the ward. Guardians are encouraged to use substituted decision-making, taking into account the ward's previously expressed values and preferences. Although a number of viable alternatives to guardianship exist, numerous systemic barriers may prevent these from being fully explored. The ongoing need for guardianship should be periodically revisited and reassessed. Data about guardians and wards is shockingly sparse, as there are no centralized databases. Laws and regulations for guardianships vary significantly between states. Physicians can serve as important allies and advocates for patients with cognitive impairment at risk of incapacity, can help preserve their autonomy for as long as possible, and ensure appropriate protections are in place if the patient does lose their decision-making ability.     

“I do like the activities which I can do…” Leisure participation experiences of children with movement impairments

Aim: To explore in depth the leisure participation experiences of children with movement impairments.

Methods: We used Interpretative Phenomenological Analysis approach to interpret and understand the experiences of 22 children with movement impairments, aged between 6 and 12?years. Children expressed their views through flexible child-centred methods of data collection that allowed the children to draw, paint, use stickers, and demonstrate their leisure activities and equipment while communicating about their experiences.

Results: Children participated in leisure activities of their choice, and expressed positive experience of fun, challenge, independence and achievement. The choice of activities depended on a combination of the motor functioning of the individual child, inspiration and support from families, friends and health professionals, as well as the possibility of adaptations and availability of community programmes. At times children felt disappointed and avoided some activities due to associated negative experience such as injury, fear, non-inclusion and the difficulty they had experienced in adapting and performing certain activities.

Conclusion: Families, therapists and community service providers such as disability organisations could enhance leisure participation experiences by suggesting and creating opportunities that could increase children’s choices of leisure activities.

• Implications for rehabilitation

• Children’s choice of activities, places and friends is important for positive experiences of fun, achievement, challenge, independence and motivation in leisure participation.

• Families and health professionals could assist children make appropriate choices for leisure activities that depends on factors such as motor abilities, adaptations and availability of activities in the community.

• In the community, widening the options for leisure activities such as non-competitive adaptive sports and indoor sports for children with variable levels of movement impairment could improve leisure participation experiences.

     

Paucity of antigen-specific IgA responses in sera and external secretions of HIV-type 1-infected individuals

This study was undertaken to resolve existing controversies with respect to the detection of IgA HIV-1-specific mucosal antibodies in infected individuals. External secretions, including tears, nasal, rectal, and vaginal washes, saliva, semen, urine, and sera were obtained from 50 HIV-1-infected individuals and 20 controls using collection procedures that minimize the irritation of mucosal surfaces. Levels of total and antigen (gp120 and gp160)-specific antibodies of the IgG and IgA isotypes were measured by assays that proved reliable in a large multicenter study: quantitative ELISA and chemiluminescence-enhanced Western blot analyses. Although the levels of total IgG and IgA were increased or remained unchanged in body fluids of HIV-1-infected individuals as compared to the controls, HIV-1-specific IgA antibodies were either absent or present at low levels even in secretions with characteristically high relative contents of total IgA vs. IgG (saliva, tears, and rectal and nasal washes). In these secretions, HIV-1-specific IgG antibodies dominated. In assessing levels and frequency of detection of IgG antibodies, both female and male genital tract secretions, urine, and nasal wash were preferable to parotid saliva and especially to rectal wash. External secretions contained IgG antibodies to gp160> gp120> gp41 and p24; when present, IgA antibodies were predominantly directed at gp160. Analyses of peripheral blood antibody-secreting cells (ASC) isolated from the same individuals paralleled these serological findings: gp160-specific IgG-secreting ASC were dominant. Therefore, in striking contrast to other mucosally encountered microbial infections, HIV-1 does not induce vigorous specific IgA responses in any body fluid examined or in ASC in peripheral blood.     

Interactions of CRH, AVP and cortisol in the secretion of ACTH from perifused equine anterior pituitary cells: "permissive" roles for cortisol and CRH

To further elucidate the interaction of CRH, AVP and cortisol in the control of ACTH secretion, we used an in vitro perifusion model with dispersed equine anterior pituitary cells. To approximate the in vivo milieu in the horse, CRH was perifused continuously (at 0, 2 and 20 pmol/L) and 5-min pulses of AVP (0, 1, 3 and 10 nmol/L) were given every 30 min in the presence of 0 or 100 nmol/L cortisol. Total (baseline + incremental) ACTH secretion increased as both the CRH (p<0.001) and the AVP (p<0.001) concentration increased and interaction between CRH and AVP was significant (p=0.042). Cortisol reduced total ACTH secretion in the presence of 2 pmol CRH/L (p=0.001) but not 0 or 20 pmol CRH/L. For incremental ACTH there was interaction between CRH and AVP (p<0.0001), with increased secretion at higher concentrations, and no significant main effect of cortisol. There was significant (p=0.001) interaction between cortisol and CRH, with cortisol attenuating ACTH release at 0 pmol CRH/L (p=0.008), having no effect at 2 pmol CRH/L and potentiating it at 20 pmol CRH/L (p=0.026). We conclude that (1) CRH at high physiological levels has a "permissive" role in preventing the cortisol inhibition of the ACTH response to AVP, and (2) basal cortisol levels have a "permissive" action in priming the HPA axis for maximal responsiveness to stimulated levels of CRH and AVP.