Publications

Rising use of advance directives has made surrogate decision making both easier and harder. In many cases, these directives help guide decision making for patients who have lost decision-making capacity. In some cases, however, directives may conflict with what physicians or surrogates view as what is in the patient's best interest. These conflicts can place substantial emotional and moral burdens on physicians and surrogates, and there is little practical guidance for how to address them. We propose a 5-question framework for untangling the conflict between advance directives and best interests of a patient with a surrogate decision maker: (1) Is the clinical situation an emergency? (2) In view of the patient's values and goals, how likely is it that the benefits of the intervention will outweigh the burdens? (3) How well does the advance directive fit the situation at hand? (4) How much leeway did the patient provide the surrogate for overriding the advance directive? (5) How well does the surrogate represent the patient's best interests? We use 2 clinical cases with contrasting outcomes to demonstrate how this framework can help resolve common dilemmas.

BACKGROUND

Methadone maintenance treatment (MMT) has been successfully scaled up nationally in China. However, the program faces problems of poor attendance and high rates of continued drug use. We assessed whether a contingency management (CM) intervention implemented by MMT clinic staff could improve treatment attendance and drug abstinence.

METHODS

Eight MMT clinics in Guangdong province were randomly selected and divided into two groups. A total of 126 participants (55 in urban clinics and 71 in rural clinics) received CM during a 12-week trial, 120 participants (83 in urban clinics and 37 in rural clinics) received usual treatment (UT). Participants in the CM group had the opportunity to draw for prizes contingent on attending treatment daily and testing negative for morphine. Clinic- and individual-level outcomes were compared between the intervention and control groups.

RESULTS

The retention rate and negative urine testing rate were 14.2% (P=0.010) and 10.7% (P<0.001) higher in the CM group compared to the UT group, respectively. Compared with participants who received UT, CM participants missed on average 7.3 fewer (P=0.008) visits and were 1.91 (95% CI: 1.53-2.39) times more likely to submit a negative urine sample. All clinic- and individual- level effects of the intervention were observed at rural clinics, but the difference in retention rate between urban CM and UT clinics was not significant.

CONCLUSION

Although the frequency of monitoring and value of the incentives in this study was lower than in previous studies, the CM intervention significantly improved attendance and reduced drug use in China.

We have modeled the transition from acute to chronic pain in the rat. In this model (termed hyperalgesic priming) a chronic state develops after a prior inflammatory process or exposure to an inflammatory mediator, in which response to subsequent exposure to prostaglandin E2 (PGE2) is characterized by a protein kinase Cε-dependent marked prolongation of mechanical hyperalgesia. To assess the effect of priming on the function of the nociceptor, we have performed in vitro patch clamp and in vivo single-fiber electrophysiology studies using tumor necrosis factor α to induce priming. In vitro, the only change observed in nociceptors cultured from primed animals was a marked hyperpolarization in resting membrane potential (RMP); prolonged sensitization, measured at 60 minutes, could not be tested in vitro. However, complimentary with behavioral findings, in vivo baseline mechanical nociceptive threshold was significantly elevated compared to controls. Thirty minutes after injection of PGE2 into the peripheral receptive field, both primed and control nociceptors showed enhanced response to mechanical stimulation. However, 60 minutes after PGE2 administration, the response to mechanical stimulation was further increased in primed but not in control nociceptors. Thus, at the level of the primary afferent nociceptor, it is possible to demonstrate both altered function at baseline and prolonged PGE2-induced sensitization. Intrathecal antisense (AS) to Kv7.2, which contributes to RMP in sensory neurons, reversibly prevented the expression of priming in both behavioral and single-fiber electrophysiology experiments, implicating these channels in the expression of hyperalgesic priming.

BACKGROUND

Proton pump inhibitors (PPIs) are gastric acid-suppressing agents widely prescribed for the treatment of gastroesophageal reflux disease. Recently, several studies in patients with acute coronary syndrome have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events. The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed.

METHODS AND RESULTS

Plasma asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely because of its attenuation of the vasoprotective effects of endothelial nitric oxide synthase. We find that PPIs elevate plasma ADMA levels and reduce nitric oxide levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to and inhibit dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA.

CONCLUSIONS

We present a plausible biological mechanism to explain the association of PPIs with increased major adverse cardiovascular events in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with the use of the PPIs in the general population.