Induction of protective immunity against lethal anthrax challenge with a patch

BACKGROUND: Transcutaneous immunization (TCI) is a needle-free technique that delivers antigens and adjuvants to potent epidermal immune cells. To address critical unmet needs in biodefense against anthrax, we have designed a novel vaccine delivery system using a dry adhesive patch that simplifies administration and improves tolerability of a subunit anthrax vaccine. METHODS: Mice and rabbits were vaccinated with recombinant protective antigen of Bacillus anthracis and the heat-labile toxin of Escherichia coli. Serologic changes, levels of toxin-neutralizing antibodies (TNAs), and pulmonary and nodal responses were monitored in the mice. A lethal aerosolized B. anthracis challenge model was used in A/J mice, to demonstrate efficacy. RESULTS: The level of systemic immunity and protection induced by TCI was comparable to that induced by intramuscular vaccination, and peak immunity could be achieved with only 2 doses. The addition of adjuvant in the patch induced superior TNA levels, compared with injected vaccination. CONCLUSIONS: Anthrax vaccine patches stimulated robust and functional immune responses that protected against lethal challenge. Demonstration of responses in the lung suggests that a mechanism exists for protection against challenge with aerosolized anthrax spores. A formulated, pressure-sensitive, dry adhesive patch, which is stable and can be manufactured in large scale, elicited comparable immunoglobulin G and TNA responses, suggesting that an anthrax vaccine patch is feasible and should advance into clinical evaluation.     

The cross-clade neutralizing activity of a human monoclonal antibody is determined by the GPGR V3 motif of HIV type 1

Both polyclonal and monoclonal human antibodies (Abs) to the V3 domain of HIV-1 gp120 display cross-clade neutralizing activity against primary isolates and T cell-adapted virus strains. The most broadly neutralizing of the human anti-V3 monoclonal Abs (mAbs), 447-52D, recognizes 14 amino acids, including the GPxR core epitope at the tip of the V3 loop. Monoclonal Ab 447-52D neutralized 92% of 38 primary isolates carrying the GPGR V3 motif regardless of whether the viruses belonged to clades A, B, F, or H; in contrast, none of 19 viruses with the GPGQ and other non-GPGR/Q sequences at the tip of the V3 loop was sensitive to mAb 447-52D. These data are consistent with the crystallographic resolution of a complex of the Fab fragment of mAb 447-52D with a V3 peptide that shows that the binding specificity of the mAb is due to recognition of the GPGR motif at the tip of the loop. The critical role of the Arg residue in this motif was determined using viruses pseudotyped with the envelope of primary isolate CA1 containing the GPGR motif or with a mutated envelope with a Gln (Q) replacing the Arg (R) at the tip of the loop. While the wild-type pseudovirus was neutralized by mAb 447-52D, the pseudovirus carrying the point mutation was resistant to neutralization. These data illuminate the structural basis for both the breadth and specificity of a broadly neutralizing human mAb and contribute to our understanding of the epitopes recognized by Abs that protect against infection with HIV-1.     

Predictive Value of QT Dispersion for Ventricular Tachyarrhythmias in Patients with Implantable Cardioverter Defibrillator

Background: QT dispersion, measured as interlead variability of QT intervals in the surface electrocardiogram, has been demonstrated to provide an indirect measurement of the inhomogeneity of myocardial repolarization as a potential substrate for ventricular arrhythmias. Methods: QT dispersion was measured in the standard 12-lead ECG in 51 patients at the time of implantation of a third generation implantable cardioverter defibrillator (ICD) with automatic electrogram storage capability for electrical events triggering device therapy. In addition, QT dispersion was measured in 100 age- and sex-matched healthy controls. All 5 1 study patients with ICD were prospectively followed to determine possible associations between QT dispersion at implant and subsequent spontaneous ICD shocks for ventricular tachyarrhythmias (VT). Results: Rate-corrected QT dispersion and adjusted QTc dispersion, which takes account of the number of leads measured, were significantly greater in ICD patients compared to controls (76 ± 25 ms vs 46 ± 11 ms, and 24 ± 7 ms vs 14 ± 3 ms respectively, P < 0.0 1). During 15 ± 8 months follow-up, ventricular tachyarrhythmias occurred in 23 (45%) of 51 ICD patients. QTc dispersion and adjusted QTc dispersion were not significantly different between ICD patients with ventricular tachyarrhythmias and ICD patients without ventricular tachyarrhythmias during follow-up (74 ± 19 ms versus 77 ± 29 ms, and 23 ± 6 ms vs 25 ± 8 ms respectively). Conclusion: Increased QT dispersion measured in the 12-lead standard ECG does not appear to be a useful marker for future arrhythmic events in a mixed patient population with ICD.     

Inhibitory effect of intragastric glucose on gastric acid secretion and gastric emptying of liquids in man

Intragastric glucose inhibits gastric acid secretion and gastric emptying in man. To determine if these effects are mediated by somatostatin—a known inhibitor of gastric acid production, gastrin secretion, and gastric motility—the plasma somatostatin-like immunoreactivity (SLI) levels were determined in healthy human subjects after an intragastric load of 30% glucose solution. These findings were compared with results after an instillation of distilled water. Following the glucose load, the intragastric acid concentration, the acid output, and the fractional gastric emptying rate declined significantly (P<0.01) before either the plasma glucose or plasma insulin levels had increased. Neither the gastrin nor SLI plasma concentrations changed after the water or glucose load. These findings suggest that the suppression of gastric acid secretion and inhibition of the rate of gastric emptying that occur with intragastric glucose are mediated by factors other than changes in the peripheral circulating levels of SLI, gastrin, insulin, or glucose.     

Relationship between white blood cell count and incident hypertension

BACKGROUND: Elevated white blood cell (WBC) count is considered to be prospectively associated with cardiovascular disease. However, its relationship to hypertension, independent of smoking and other established cardiovascular risk factors, is not clear, especially among women. METHODS: We used data from a large population-based study in Wisconsin (Beaver Dam Eye study) to examine the prospective association between elevated WBC count and incident hypertension among 2459 hypertension-free women (48.6%) and men (51.4%) after adjusting for, and stratifying by smoking and several other potential confounding factors. RESULTS: In multivariable proportional hazards models, increasing tertiles of WBC count was associated with increased risk ratios (RR) of hypertension in the whole cohort (WBC count tertiles 1-3; RR 1, 1.2, 1.7; P <.01), and separately among women (WBC count tertiles 1-3; RR 1, 1.1, 1.4; P <.05) and men (WBC count tertiles 1-3; RR 1, 1.3, 1.9; P <.01). Results from subsequent analyses stratified by smoking and several other related factors were consistent with this finding. CONCLUSIONS: Elevated WBC count is associated with incident hypertension among women and men independent of smoking and most traditional cardiovascular risk factors in this predominantly white cohort. Further research is required to determine whether this association is true among racial minorities (eg, African Americans), and independent of C-reactive protein, a more specific marker of inflammation.     

Evaluation of Alternatives to Winter Closure of Black Sea Bass Pot Gear: Projected Impacts on Catch and Risk of Entanglement with North Atlantic Right Whales Eubalaena glacialis

Time–area closures have been widely used in fisheries management to prevent overfishing and reduce the bycatch of protected species. Due to quota overages and concerns about entanglement of federally protected North Atlantic right whales Eubalaena glacialis, the commercial harvest of Black Sea Bass Centropristis striata using pot gear has been prohibited in the southeastern United States in winter since 2009. Following the rebuilding of the Black Sea Bass stock and a change to the start date of the fishing year, the South Atlantic Fishery Management Council (SAFMC) increased the commercial annual catch limit (ACL) and is considering twelve alternatives to the pot gear closure that would revise the timing and/or spatial extent of the closure. Changes to this closure could affect the annual catch of Black Sea Bass and increase the risk of right whale entanglement in pot gear. Using historical fishing effort, landings, and right whale sightings data, we projected Black Sea Bass landings and the relative risk of right whale entanglement for each closure alternative, expressed in relative risk units (RRU). We predict that the ACL would be caught, resulting in an in-season closure for most of the proposed SAFMC closure alternatives. The relative risk of entanglement, estimated from the spatial and temporal overlap of Black Sea Bass pot gear fishing effort and right whale relative abundance, was lower for some alternatives than for others, and the relative differences between alternatives were consistent among uncertainty scenarios. The SAFMC’s preferred alternative is projected to result in a relatively low increase in risk to North Atlantic right whales (3–15 RRU off North Carolina and 1–12 RRU off Florida–South Carolina). This framework demonstrates the use of temporally dynamic spatial overlays in assessing the impacts of time–area closures with multiple objectives.

Received April 23, 2015; accepted January 15, 2016     

Case finding and referral model for emergency department elders: a randomized clinical trial

STUDY OBJECTIVE: Elderly emergency department patients have complex medical needs and limited social support. A transitional model of care adapted from hospitals was tested for its effectiveness in the ED in reducing subsequent service use. METHODS: A randomized clinical trial was conducted at 2 urban, academically affiliated hospitals. Participants were 650 community-residing individuals 65 years or older who were discharged home after an ED visit. Main outcomes were service use rates, defined as repeat ED visits, hospitalizations, or nursing home admissions, and health care costs at 30 and 120 days. Intervention consisted of comprehensive geriatric assessment in the ED by an advanced practice nurse and subsequent referral to a community or social agency, primary care provider, and/or geriatric clinic for unmet health, social, and medical needs. Control group participants received usual and customary ED care. RESULTS: The intervention had no effect on overall service use rates at 30 or 120 days. However, the intervention was effective in lowering nursing home admissions at 30 days (0.7% versus 3%; odds ratio 0.21; 95% confidence interval [CI] 0.05 to 0.99) and in increasing patient satisfaction with ED discharge care (3.41 versus 3.03; mean difference 0.37; 95% CI 0.13 to 0.62). The intervention was more effective for high-risk than low-risk elders. CONCLUSION: An ED-based transitional model of care reduced subsequent nursing home admissions but did not decrease overall service use for older ED patients. Further studies are needed to determine the best models of care for this setting and for at-risk patients.     

Automatic Activation of Alcohol Concepts in Response to Positive Outcomes of Alcohol Use

Seventy-one subjects with various levels of drinking experience completed a computerized semantic priming task. Prime phrases (describing positive outcomes of drinking alcohol or neutral phrases) were presented immediately before a target word (either alcohol-related or not). The results replicated earlier basic research examining the effects of semantically related primes on the processing of subsequent words. Furthermore, the results provided evidence that, for heavy drinking subjects, the presentation of phrases describing positive drinking outcomes significantly primed, or facilitated, responses to the alcohol-related words. These results are consistent with the view that for some individuals, thoughts about certain outcomes automatically prime, or make accessible, concepts related to alcohol use. An increase in the accessibility of these concepts has important implications for behavioral decisions about alcohol consumption.