Publications

Purpose The rapidly increasing number of older adults cycling through local criminal justice systems (jails, probation, and parole) suggests a need for greater collaboration among a diverse group of local stakeholders including professionals from healthcare delivery, public health, and criminal justice and directly affected individuals, their families, and advocates. The purpose of this paper is to develop a framework that local communities can use to understand and begin to address the needs of criminal justice-involved older adults. Design/methodology/approach The framework included solicit input from community stakeholders to identify pressing challenges facing criminal justice-involved older adults, conduct needs assessments of criminal justice-involved older adults and professionals working with them; implement quick-response interventions based on needs assessments; share findings with community stakeholders and generate public feedback; engage interdisciplinary group to develop an action plan to optimize services. Findings A five-step framework for creating an interdisciplinary community response is an effective approach to action planning and broad stakeholder engagement on behalf of older adults cycling through the criminal justice system. Originality/value This study proposes the Criminal Justice Involved Older Adults in Need of Treatment Initiative Framework for establishing an interdisciplinary community response to the growing population of medically and socially vulnerable criminal justice-involved older adults.

BACKGROUND

Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples.

METHODS

MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography-mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson's correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs).

RESULTS

Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26-44%), 74% (40-97%) and 46% (9-37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R = 0.657), but no PARPi-platinum interaction was observed in patients' PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60-1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21-0.66%, P < 0.0001).

CONCLUSIONS

PARPi/platinum tumor penetration can be measured by MALDI-MSI and ICP-MS in PBMCs and fresh frozen, OCT embedded core needle biopsies. Large variability in platinum adduct formation and spatial heterogeneity in veliparib distribution may lead to insufficient drug exposure in select cell populations.

OBJECTIVE

To investigate proteins associated with neuronal damage in plasma neuron-derived exosomes (NDE) of HIV-infected study participants as a liquid biomarker for cognitive impairment.

METHODS

Plasma NDE were isolated using precipitation and immunoadsorption with antibody to a cell surface-specific neuronal marker. Total exosomes and NDE were enumerated, characterized, and proteins extracted and targets quantified by ELISA.

RESULTS

Plasma NDE from 23 HIV seropositive individuals of which 11 had mild cognitive impairment, and 12 HIV seronegative controls of which three had cognitive impairment were isolated. NDE were enriched for the neuronal markers neurofilament light (NF-L) and synaptophysin (SYP). Neuropsychologically impaired individuals had fewer NDE compared with neuropsychologically normal study participants. NDE from neuropsychologically impaired study participants had significantly higher levels of high-mobility group box 1 (HMGB1), NF-L, and amyloid β proteins compared with neuropsychologically normal individuals. NDE HMGB1 protein significantly decreased with age in HIV-infected individuals.

CONCLUSION

Plasma NDE were altered in several ways in HIV infection. Elevated HMGB1, NF-L, and amyloid β proteins could distinguish cognitive impairment. NDE contents reflect neuronal health in 'real time' and may be useful for following cognitive impairment and response to therapy in HIV infection.

Sepsis remains a highly lethal entity resulting in more than 200 000 deaths in the USA each year. The in-hospital mortality approaches 30% despite advances in critical care during the last several decades. The direct health care costs in the USA exceed $24 billion dollars annually and continue to escalate each year especially as the population ages. The Surviving Sepsis Campaign published their initial clinical practice guidelines for the management of severe sepsis and septic shock in 2004. Updated versions were published in 2008, 2012 and most recently in 2016 following the convening of the Third International Consensus Definitions Task Force. This task force was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine to address prior criticisms of the multiple definitions used clinically for sepsis-related illnesses. In the 2016 guidelines, sepsis is redefined by the taskforce as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In addition to using the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score to more rapidly identify patients with sepsis, the task force also proposed a novel scoring system to rapidly screen for patients outside the ICU who are at risk of developing sepsis: the 'quickSOFA' (qSOFA) score. To date, the largest reductions in mortality have been associated with early identification of sepsis, initiation of a 3-hour care bundle and rapid administration of broad-spectrum antibiotics. The lack of progress in mortality reduction in sepsis treatment despite extraordinary investment of research resources underscores the variability in patients with sepsis. No single solution is likely to be universally beneficial, and sepsis continues to be an entity that should receive high priority for the development of precision health approaches for treatment.