Publications

Amongst the side effects of triptans, a substantial percentage of patients experience injection site pain and tenderness, the underlying mechanism of which is unknown. We found that the dose range from 10fg to 1000ng (intradermal) of sumatriptan induced a complex dose-dependent mechanical hyperalgesia in male rats, with distinct peaks, at 1pg and 10ng, but no hyperalgesia at 1ng. In contrast, in females, there was 1 broad peak. The highest dose (1000ng) did not produce hyperalgesia in either sex. We evaluated the receptors mediating sumatriptan hyperalgesia (1pg, 1 and 10ng). In males, the injection of an antagonist for the serotonin (5-HT) receptor subtype 1B (5-HT), but not 5-HT, markedly inhibited sumatriptan (1pg)-induced hyperalgesia, at 10ng a 5-HT receptor antagonist completely eliminated hyperalgesia. In contrast, in females, the 5-HT, but not 5-HT, receptor antagonist completely blocked sumatriptan (1pg and 10ng) hyperalgesia and both 5-HT and 5-HT receptor antagonists attenuated hyperalgesia (1ng) in females, which is GPR30 estrogen receptor dependent. While selective 5-HT or 5-HT, agonists produce robust hyperalgesia in female and male rats, respectively, when co-injected the hyperalgesia induced in both sexes was attenuated. Mechanical hyperalgesia induced by sumatriptan (1pg and 10ng) is dependent on the G-protein α subunit and protein kinase A (PKA), in IB4-positive and negative nociceptors. Understanding the mechanisms responsible for the complex dose dependence for triptan hyperalgesia may provide useful information for the design of anti-migraine drugs with improved therapeutic profiles.

CONTEXT

A validated 82-item Advance Care Planning (ACP) Engagement Survey measures a broad range of behaviors. However, concise surveys are needed.

OBJECTIVES

The objective of this study was to validate shorter versions of the survey.

METHODS

The survey included 57 process (e.g., readiness) and 25 action items (e.g., discussions). For item reduction, we systematically eliminated questions based on face validity, item nonresponse, redundancy, ceiling effects, and factor analysis. We assessed internal consistency (Cronbach's alpha) and construct validity with cross-sectional correlations and the ability of the progressively shorter survey versions to detect change one week after exposure to an ACP intervention (Pearson correlation coefficients).

RESULTS

Five hundred one participants (four Canadian and three US sites) were included in item reduction (mean age 69 years [±10], 41% nonwhite). Because of high correlations between readiness and action items, all action items were removed. Because of high correlations and ceiling effects, two process items were removed. Successive factor analysis then created 55-, 34-, 15-, nine-, and four-item versions; 664 participants (from three US ACP clinical trials) were included in validity analysis (age 65 years [±8], 72% nonwhite, 34% Spanish speaking). Cronbach's alphas were high for all versions (four items 0.84-55 items 0.97). Compared with the original survey, cross-sectional correlations were high (four items 0.85; 55 items 0.97) as were delta correlations (four items 0.68; 55 items 0.93).

CONCLUSION

Shorter versions of the ACP Engagement Survey are valid, internally consistent, and able to detect change across a broad range of ACP behaviors for English and Spanish speakers. Shorter ACP surveys can efficiently measure broad ACP behaviors in research and clinical settings.

Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens. Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. .

OBJECTIVES

To explore how older adults in the community with a limited life expectancy make healthcare decisions and the processes used when they are not in an acute crisis.

DESIGN

Grounded theory.

SETTING

Medical programs and geriatrics clinics at the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center.

PARTICIPANTS

Community-dwelling adults aged 67 to 98 with a life expectancy of less than 1 year (N = 20).

MEASUREMENTS

In-depth semistructured interviews in participants' homes. Constant comparative analysis was used to develop codes and identify themes.

RESULTS

Participants generally delegated decisions to others, expressing their wishes by describing desired end-of-life outcomes and highlighting meaningful aspects of their lives. They did this in the belief that the delegate would make appropriate decisions on their behalf. In this way, participants were able to achieve a sense of control without being in control of decisions. Four themes emerged from the analysis that reflect the various approaches participants used to articulate their goals and maintain a sense of control: direct communication, third-party analogies, adaptive denial, and engaged avoidance.

CONCLUSION

These findings challenge the prevailing view of personal autonomy. These older adults suggest a path to decision-making that focuses on priorities and goals, allowing them to take a more-passive approach to decision-making while still maintaining a sense of control.