Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine.

BACKGROUND: NVX-CoV2373 is a recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. METHODS: We initiated a randomized, placebo-controlled, phase 1-2 trial to evaluate the safety and immunogenicity of the rSARS-CoV-2 vaccine (in 5-µg and 25-µg doses, with or without Matrix-M1 adjuvant, and with observers unaware of trial-group assignments) in 131 healthy adults. In phase 1, vaccination comprised two intramuscular injections, 21 days apart. The primary outcomes were reactogenicity; laboratory values (serum chemistry and hematology), according to Food and Drug Administration toxicity scoring, to assess safety; and IgG anti-spike protein response (in enzyme-linked immunosorbent assay [ELISA] units). Secondary outcomes included unsolicited adverse events, wild-type virus neutralization (microneutralization assay), and T-cell responses (cytokine staining). IgG and microneutralization assay results were compared with 32 (IgG) and 29 (neutralization) convalescent serum samples from patients with Covid-19, most of whom were symptomatic. We performed a primary analysis at day 35. RESULTS: After randomization, 83 participants were assigned to receive the vaccine with adjuvant and 25 without adjuvant, and 23 participants were assigned to receive placebo. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean, ≤2 days). One participant had mild fever that lasted 1 day. Unsolicited adverse events were mild in most participants; there were no severe adverse events. The addition of adjuvant resulted in enhanced immune responses, was antigen dose-sparing, and induced a T helper 1 (Th1) response. The two-dose 5-µg adjuvanted regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic Covid-19 patients (8344 and 983, respectively). CONCLUSIONS: At 35 days, NVX-CoV2373 appeared to be safe, and it elicited immune responses that exceeded levels in Covid-19 convalescent serum. The Matrix-M1 adjuvant induced CD4+ T-cell responses that were biased toward a Th1 phenotype. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04368988).

Peripheral effects of vagus nerve stimulation on anxiety and extinction of conditioned fear in rats.

Vagus nerve stimulation (VNS) enhances extinction of conditioned fear in rats. Previous findings support the hypothesis that VNS effects on extinction are due to enhanced consolidation of extinction memories through promotion of plasticity in extinction-related brain pathways however, alternative explanations are plausible. According to one hypothesis, VNS may produce a hedonic effect and enhance extinction through counter-conditioning. According to another hypothesis, VNS reduces anxiety during exposure and this weakens the association of conditioned stimuli with aversive conditioned responses. The present set of experiments (1) used conditioned place preference (CPP) to identify potential rewarding effects associated with VNS and (2) examined the peripheral effects of VNS on anxiety and extinction enhancement. Male Sprague-Dawley rats were surgically implanted with cuff electrodes around the vagus nerve and subjected to a CPP task in which VNS and sham stimulation were each paired with one of two distinct contexts over the course of 5 d. Following this procedure, rats did not show a place preference, suggesting that VNS is not rewarding or aversive. The role of the peripheral parasympathetic system in the anxiolytic effect of VNS on the elevated plus maze was examined by blocking peripheral muscarinic receptors with intraperitoneal administration of methyl scopolamine prior to VNS. Methyl scopolamine blocked the VNS-induced reduction in anxiety but did not interfere with VNS enhancement of extinction of conditioned fear, indicating that the anxiety-reducing effect of VNS is not necessary for the extinction enhancement.

Physician report cards and rankings yield long-lasting hand hygiene compliance exceeding 90%.

INTRODUCTION: Hand hygiene is an effective, low-cost intervention that prevents the spread of multidrug-resistant bacteria. Despite mandatory education and reminders, compliance by physicians in our hospital remained stubbornly low. Our objective was to study whether surveillance by our unit coordinator (secretary) paired with regular feedback to chiefs of service would increase physician hand hygiene compliance in the ICU. METHOD: The ICU unit coordinator was trained to observe and measure hand hygiene compliance. Data were collected on hand hygiene compliance at room entry and exit for 9 months. Percentage compliance for each medical and surgical subspecialty was reported to chiefs of service at the end of each month. Comparative rankings by service were widely distributed throughout the physician organization and the medical center. RESULTS: The hand hygiene compliance rate among physicians increased from 65.1% to 91.6% during the study period (p < 0.0001). More importantly in the succeeding 24 months after study completion, physician hand hygiene compliance remained >90% in every month. CONCLUSIONS: Physician hand hygiene compliance increased as a consequence of the surveillance conducted by a full-time ICU team member, leading to a highly significant increase in the number of observations. In turn, this allowed for specific comparative monthly feedback to individual chiefs of service. Over the next 2 years after the study ended, these gains were sustained, suggesting an enduring culture change in physician behavior.

Comparison of physiological response to cardiopulmonary exercise testing among cancer survivors and healthy controls.

Selected physiological responses, including lactate kinetics, to cardiopulmonary exercise testing (CPET) were evaluated among a group of cancer survivors (CS, n = 55) and healthy controls (HC, n = 213). It was uncertain if lactate testing in a group of cancer survivors could provide useful information about training intensity. It was hypothesized that chemotherapy, radiation, surgery, physical inactivity or some combination thereof would alter the normal lactate kinetics (curvilinearity) in the relationship of lactate concentration versus power. Physiologic responses of CS (heart rate, blood pressure, O(2) saturation, RPE, lactate, VO(2peak), and peak power) during cycle ergometry were compared to HC. Comparisons (t tests and Chi-square) were made between the groups and shape of lactate plots were analyzed for determination of a breakpoint. Multiple logistical regressions were then utilized to identify factors related to the inability to determine lactate breakpoints. Lactate breakpoints were common to all but one HC whereas among the CS there was a small subset of subjects (n = 5) who did not show a lactate breakpoint. Group differences indicated that female CS were significantly older, had greater BMI's, and lower work capacity than HC. Males CS had significantly lower work capacity than HC. Multiple logistical regression analyses, in all instances, yielded no statistically significant models predictive of the inability to determine a lactate breakpoint. In this sample of CS and HC, physiological responses and lactate kinetics during CPET were similar while work capacity among the CS was lower. Because lactate breakpoints were found, lactate threshold could be determined for all but a few individuals. For those working with CS, CPET with ECG monitoring and lactate threshold measures should be considered for those wishing for precise and safe training intensities.

Individualized 12-week exercise training programs enhance aerobic capacity of cancer survivors.

Changes in aerobic capacity were evaluated after 12 weeks of training among a motivated heterogeneous group of cancer survivors (N = 54 [41 women and 13 men]), living at moderate altitude. Changes in power at lactate threshold (PT(lact)), peak power (P(peak)), and peak oxygen uptake (VO(2) peak) were evaluated in this group (average age, 53.8 + or - 10.8 years) that completed a minimum of 12 weeks of an individualized exercise program (on average 5 days x week(-1) for 47.5 + or - 17.2 min x session(-1)). Daily exercise duration was based on the goals and functional capacity of each individual. Training intensity for each subject was based on heart rate (HR) value at lactate threshold (T(lact)) obtained during a symptom-limited cardiopulmonary exercise test. Intensity was categorized into 5 ranges: recovery (60%-80% HR T(lact)); endurance (80%-100% HR T(lact)); threshold (100%-105% HR T(lact)); intervals (105%-115% HR T(lact)); and maximal efforts (> or = 115% HR T(lact)). Overall compliance with the exercise prescription was approximately 72% and subjects reported exercising within the 5 training ranges, 12.1%, 63.9%, 18.6%, 4.2%, and 1.2% of the time, respectively. After training, PT(lact) increased 9.5% (121.8 + or - 43.5 vs 133.2 + or - 34.1 W; P < 0.05), P(peak) increased 12.6% (175.5 + or - 55.6 vs 195.6 + or - 54.2 W; P < 0.05) and VO(2) peak increased 11.4% (33.4 + or - 12.5 vs 37.2 + or - 10.4 mL x kg(-1) x min(-1); P < 0.05). The results of this research indicate that: 1) cardiopulmonary exercise testing with lactate threshold determination was safe and effective in the evaluation and exercise prescription phase for a group of cancer survivors and 2) a training program based on 2 higher intensity workouts per week can elicit significant changes in aerobic capacity of a diverse group of cancer survivors.

Connecting Student Employment and Leadership Development.

This chapter will provide an understanding of the concepts of leadership development and student employment used in the volume. Current data and research is explained to establish the need for dialogue and support of leadership development through student employment on and off campus.

Evaluation of vacuum and wet-wipe methods for removal of World Trade Center dust from indoor environments.

The destruction of the buildings at the World Trade Center (WTC) complex dispersed dust and debris into the surrounding area. Pulverized building material made up most of the fallout and was intermixed with combustion byproducts of the aircraft and building contents. A study was conducted to confirm the effectiveness of several cleaning procedures in removing WTC-related contamination from lower Manhattan residences. The contaminants included asbestos, lead, dioxin/furans, synthetic vitreous fibers (fibrous glass), and crystalline silica. All cleaning procedures included the common elements of vacuuming and wet wiping with soap and water. This cleaning procedure combination is effective in reducing WTC-related contamination to below health-based benchmarks. Post-cleaning environmental test results suggested that airborne asbestos measurements can be used as a surrogate parameter in clearance determinations.

Exercise capacity of a breast cancer survivor: a case study.

PURPOSE: The processes by which we assess, create an individualized exercise program, and monitor training of a breast cancer survivor who was participating in a fitness plan during and after surgery, chemotherapy, and radiation treatments were examined over a 391-d period. CASE STUDY: A 57-yr-old female was diagnosed with stage I breast cancer (approximately 1.2 cm diameter, estrogen positive, HER2/neu negative) with no lymph node involvement. After lumpectomy and axillary node dissection, the client completed chemotherapy treatment (cyclophosphamide, methotrexate, 5-fluorouracil (CMF)) followed by 33 bouts of radiation therapy. Assessment (body composition, VO2max, lactate threshold, pulmonary function testing) was measured 4 d postdiagnosis and 2 months after treatments had ended. The client kept a daily log of exercise, average heart rate, and rating of perceived exertion in each exercise session. RESULTS: Over 391 calendar days, the client exercised 343 days (88%) and completed 424 exercise sessions. The client's body composition (15.1%) and body weight (41.4 kg) remained stable for the entire period. There was a significant decrease in VO2max (-7.8%) before and after treatment (56.4 to 52.0 mL x kg(-1) x min(-1), respectively). During the treatment phase (6.8 months), the client averaged 1.19 exercise sessions per day, with an average duration of 48.1 +/- 25.2 min at approximately 57% of VO2max (approximately 32 mL x kg(-1) x min(-1)). Posttreatment (approximately 6.2 months), the client averaged 1.32 exercise sessions per day, with an average duration of 69.3 +/- 38.5 min at approximately 59.6% VO2max (approximately 31.2 mL x kg(-1) x min(-1)). Pre- and posttreatment exercise durations were significantly different (P < 0.01). CONCLUSIONS: A cancer survivor who engaged in a medically supervised and proactive fitness plan starting from the day of diagnosis maintained a realistic level of physiologic function during and after cancer treatment.

Characterization of background concentrations in upper Manhattan, New York apartments for select contaminants identified in World Trade Center dust.

Residential indoor concentration of asbestos, lead, synthetic vitreous fiber (SVF), crystalline silica, calcite, gypsum, dioxin, and polycyclic aromatic hydrocarbons (PAHs) were measured in 25 residences and 9 building-interior common areas in upper Manhattan, NY. This was done to characterize the background levels of contaminants, identified in dust related to the collapse of the World Trade Center towers, at locations that were minimally impacted by the dust fallout. The study was initiated due to the paucity of background concentrations on building-related materials and combustion byproducts in urban residential dwellings. Asbestos, lead, SVF, crystalline silica, and dioxin were detected at very low concentration at some locations, and many samples tested below their respective analysis detection limits. Almost all of the environmental samples for PAHs, calcite, gypsum, and certain other building materials tested below their respective analysis detection limits. A comparative analysis to the limited literature data showed general agreement with the values found in this study. This study provides insight into the levels of these contaminants in lower Manhattan residential buildings prior to the attack, and these data will serve to enhance the available database for characterizing indoor environments for these contaminants.