Acutely ill nursing home residents with advanced dementia are frequently transferred to acute-care hospitals. However, some people would argue that a palliative approach, without transfer to the hospital, is appropriate for many such patients.

Using a national dataset with information from most U.S. nursing homes, researchers examined the prevalence of do-not-hospitalize (DNH) orders among more than 91,000 nursing home residents aged 65 and older with advanced dementia (defined as "very severe impairment with eating problems"). Of these residents, 7.1% had DNH orders, with prevalences ranging from 1% in Oklahoma to 26% in Rhode Island. In multivariate analysis, the following characteristics were associated with increased likelihood of DNH orders: white race, age over 84, having a living will or durable power of attorney, lower percentage of black residents in the nursing home, urban location, facility not part of a corporate chain, presence of a special dementia unit, lower proportion of Medicaid beds, more direct staffing hours per resident, and having a nurse practitioner or physician assistant on staff.

Comment: This study demonstrates that DNH orders are uncommon among nursing home residents with advanced dementia. However, the prevalence of DNH orders varies substantially by region, and numerous patient and facility characteristics correlate with these orders. The findings suggest interventions — for example, better staffing ratios — that might increase DNH orders. The racial differences associated with DNH orders deserve further study.

— Allan S. Brett, MD

Like several other major neurodegenerative diseases, Parkinson disease (PD) is associated with aging. In PD, the protein -synuclein causes aggregates called Lewy bodies and leads to the death of dopamine-containing cells in the substantia nigra. The human sirtuin genes play a role in aging. Therefore, a multi-institutional team asked whether the sirtuin genes might directly affect the pathogenesis of PD.

The team discovered two molecules that inhibit sirtuin 2 (SIRT2). They used those inhibitors, as well as the technique of RNA interference, to inhibit the activity of SIRT2 in human glioma cells that make -synuclein, in rat neuronal cells that make -synuclein, and in a fruit fly that develops loss of dopamine-containing neurons, which causes a Parkinson-like disease. Inhibiting SIRT2 protected against -synuclein–induced cell toxicity in the first two experiments and against dopaminergic cell death and Parkinson-like disease in the fruit fly.

Comment: This study suggests a molecular link between aging and the pathogenesis of PD. It also suggests a new approach to treating PD, by inhibiting the action of the molecule SIRT2, thereby reducing the toxicity to dopamine-containing neurons by -synuclein.

— Anthony L.Komaroff, MD

Individuals with diabetes are known to be at high risk for cardiovascular events. However, it remains unclear whether diabetic patients fare worse than nondiabetic patients across the full spectrum of acute coronary syndromes and with the benefit of contemporary treatment strategies. To compare differences in outcomes between diabetic and nondiabetic patients, investigators pooled data from 11 Thrombolysis in Myocardial Infarction (TIMI) clinical ACS trials conducted between 1997 and 2006. The primary outcomes of interest were mortality at 30 days and at 1 year.

Of the 62,036 patients included in the analysis, 10,613 had diabetes. At 30 days and 1 year, mortality rates were significantly higher for diabetic patients than for nondiabetic patients, irrespective of the type of ACS (unstable angina, non–ST-segment-elevation MI, or ST-segment-elevation MI [STEMI]). Patients with diabetes were significantly more likely than those without diabetes to receive aspirin and ACE inhibitors or angiotensin receptor blockers, and to undergo revascularization.

Comment: Although it is generally accepted that diabetic patients have worse outcomes from STEMI than nondiabetic patients do, this large, pooled analysis of patients receiving high-quality ACS care demonstrates that outcomes for diabetics remain worse across the full spectrum of ACS. Indeed, although diabetic patients were more likely to receive guideline-based therapies than nondiabetic patients, they still had worse outcomes. These findings suggest that novel strategies and approaches may be necessary to improve outcomes in diabetic patients with ACS; whether such strategies would (or should) differ from general strategies to reduce the elevated risk for death in diabetic patients without ACS is an important question to address.

—JoAnne M. Foody, MD

We are well acquainted with the worst outcomes of HIV infection but have surprisingly little descriptive information on the best outcomes among patients who respond optimally to treatment. European researchers evaluated long-term CD4-cell response among patients with consistently suppressed viral loads on initial treatment regimens.

Among 1835 such patients (most were white and male) enrolled in a large, multinational, prospective cohort study, median CD4 count at start of treatment was 204 cells/mm³. After more than 5 years of follow-up, mean CD4 count was 497 cells/mm³ among those who started treatment with 200, 676 for those who started with 201¨C350, and 794 for those who started with >350. As CD4-cell counts rose, the yearly rate of rise slowed, but did not stop. Demographic variables, coexisting hepatitis B or C, and even age did not influence CD4 response in multivariate analysis.

Comment: Other data suggest that only 50% to 75% of all HIV-infected patients beginning treatment will achieve complete and persistent virologic suppression on a first regimen, without drug side effects or evolving resistance complicating their course. But for these lucky individuals, the news is all good: This study now suggests that, eventually, their CD4-cell counts are likely to rise into the normal range, while other studies suggest that the functionality of their new CD4 populations will eventually normalize as well.

¡ªAbigail Zuger, MD

Prepregnancy obesity has been associated with birth defects, particularly spina bifida, but data are limited. To further examine this association, researchers analyzed data from the National Birth Defects Prevention Study, an ongoing multisite case-control study. Sixteen categories of birth defects were analyzed, and self-reported height and prepregnancy weight were used to calculate body-mass index.

In analysis adjusted for potential confounders including maternal age, parity, smoking, and folic acid supplement intake, maternal obesity (BMI 30 kg/m²) was associated with significantly increased risks among infants for spina bifida, heart defects, anorectal atresia, hypospadias, limb reduction defects, diaphragmatic hernia, and omphalocele (adjusted odds ratios ranging from 1.33 to 2.10). Excluding mothers with gestational diabetes decreased the associations slightly between each of the seven birth defects and maternal obesity. Maternal obesity was associated with significantly decreased risk for gastroschisis (AOR, 0.19). Maternal overweight (BMI 25 and <30) posed a similarly increased risk for heart defects, hypospadias, and omphalocele.

Comment: Maternal obesity is a significant risk factor for many types of birth defects. In this study, the positive associations were not strong, unlike the protective effect of maternal obesity on gastroschisis. Although the reasons for the associations have not been determined, the authors believe that undiagnosed gestational diabetes or insulin resistance may be involved.

¡ª Robert A. Dershewitz, MD, MSc

Summary

The incidence of pigmented lesions and diffuse hyperpigmentation involving the genitalia is difficult to ascertain, but such lesions can be found in about 10% of white women. Approximately 2% of these are nevocellular nevi (other benign pigmented lesions found here include seborrheic keratoses, melanoses, lentigines, warts, and postinflammatory hyperpigmentation). In general, nevi on the vulva are identical in morphology and histopathology to nevi elsewhere on the body, except for a small subset of nevi in younger women that have the unusual feature of enlarged junctional nests varying in size, shape, and position. Their long-term biologic behavior has not been determined. The histologic and clinical features of these "atypical melanocytic nevi of the genital type" or "atypical genital nevi" (AGN) are the subject of this study.

The authors reviewed hematoxylin- and eosin-stained sections and medical records from 56 cases of AGN. Mean patient age was 26, but four patients were younger than 10 years. Nearly half the lesions were atypical on clinical exam (mean diameter, 6 mm). More than half arose in hair-bearing skin, the rest in glabrous skin or mucosa. In the pediatric group, juxtamucosal or glabrous surfaces (clitoris and labium minus) were the most frequently affected.

The mean follow-up period was 3.5 years. Ten of 17 cases with positive margins had follow-up data available; only 1 of these persisted or recurred, with no further recurrence after complete excision. About 80% of lesions were compound; more than two thirds showed moderate-to-severe cytologic atypia. Ten cases were focal but had pagetoid spread. Adnexal spread and nuclear atypia of the melanocytes situated in the superficial dermis were relatively common. Rare mitoses were identified (maximum, 2 per section). Dermal fibrosis was seen in 45%.

Comment: Melanocytic lesions in the genitalia and along the milk line (axillae, breasts, periumbilical region, and groin) have a tendency to be overdiagnosed as malignant melanomas, a pitfall ascribable to the presence of histologic features usually associated with aggressive biologic behavior. Awareness of this distinct subgroup of pigmented lesions affecting women of reproductive age is essential to avoid unnecessary surgery and patient distress. Although follow-up data on these lesions are limited, among 63 cases in the literature, no metastases have been reported to date.

Small single-hospital studies show lower rates of survival from in-hospital cardiac arrest at night than during the day. In the current study, researchers analyzed data from the 507 hospitals in the National Registry of Cardiopulmonary Resuscitation to compare outcomes of in-hospital cardiac arrest between 07:00 and 22:59 (day/evening) and between 23:00 and 06:59 (night).

From 2000 to 2007, about 59,000 arrests occurred at night and 28,000 occurred during the day/evening. Rates of survival to discharge were significantly lower at night than during the day/evening (15% vs. 20%), as were rates of return of spontaneous circulation for >20 minutes (45% vs. 51%), survival at 24 hours (29% vs. 35%), and favorable neurologic outcome based on cerebral performance category scoring (11% vs. 15%). Among day/evening cases, survival rates were significantly higher on weekdays than on weekends (21% vs. 17%; odds ratio, 1.15), but, among night cases, survival rates were similar on weekdays and weekends (about 15%; OR, 1.02). The first documented rhythm was significantly more likely to be asystole at night than during day/evening hours (40% vs. 34%) and less likely to be ventricular fibrillation (20% vs. 23%).

Comment: The results of this multivariate regression analysis that was adjusted for patient, event, and hospital characteristics are no surprise. Factors during nights and weekends that might explain the worse outcomes include diminished physician psychomotor skills, lighter staffing, less physician familiarity with cross-covered patients, and fewer visitor "witnesses." Of note, survival rates did not vary by time of day or day of the week only in the emergency department and on the trauma service, which typically are staffed with attending physicians and senior residents 24/7.

In patients with acute pancreatitis — particularly those who develop pancreatic necrosis — infectious complications are a major cause of morbidity and mortality. Two recent randomized studies and two meta-analyses failed to demonstrate a benefit of prophylactic antibiotics in preventing infection among such patients. Now, researchers in the Netherlands have conducted a multicenter, double-blind trial involving 296 adults with acute pancreatitis and a predicted severe course of disease to determine whether probiotics might be useful.

Participants were randomized to receive a multispecies probiotic preparation or placebo, administered enterally (by nasojejunal feeding tube) twice daily for up to 28 days, beginning within 72 hours after symptom onset. A contrast-enhanced computed tomography scan was performed 7 days after admission to detect pancreatic necrosis.

Incidence of infectious complications (i.e., infected pancreatic necrosis, bacteremia, pneumonia, urosepsis, or infected ascites, detected within 90 days of admission) was similar between the probiotics group and the placebo group (30% vs. 28%; relative risk, 1.06; 95% CI, 0.75–1.51). The 90-day mortality rate was higher in the probiotics group (16% vs. 6%; P=0.01), with most of the deaths (82% overall) due to multiorgan failure. Bowel ischemia developed in nine probiotics-group patients (8 of whom died) but no placebo-group patients (P=0.004). Among individuals with pancreatic necrosis (46 in the probiotics group and 34 in the placebo group), probiotics recipients appeared to have a higher rate of infectious complications than did placebo recipients, but the difference was not statistically significant (70% vs. 53%; P=0.16); in any case, probiotics recipients did have a significantly higher mortality rate (41% vs. 15%; P=0.01).

Comment: This randomized, double-blind, placebo-controlled trial involving patients with predicted severe acute pancreatitis showed no beneficial effect of probiotic prophylaxis on the occurrence of infectious complications. In fact, probiotics were associated with higher rates of multiorgan failure, bowel ischemia, and mortality. Thus, probiotics (at least the combination of strains used in this study) should not be used in patients with acute pancreatitis.