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Discusses the issues surrounding the large-scale application of complex-mixture proteomic analysis for drug target discovery. Identification of disease-specific biomarkers that could be used for diagnostics or prognostic test; Characterization of the frequency of a differential expression across a range of samples taken from many individuals with the disease.

Background The magnitude of an individual’s serotype-specific immunoglobulin G (IgG) response to a pneumococcal conjugate vaccine (PCV) has been associated with the vaccine’s protective efficacy against carriage of pneumococci of that serotype, though the relationship with other serotypes needs to be understood. Methods Using immunogenicity data collected during a trial comparing the 7-valent (PCV7) and 13-valent (PCV13) vaccines, we measured associations between serotype-specific IgG levels, and used multiple regressions to identify demographic predictors of response. Results Vaccine-induced IgG levels were moderately positively correlated with one another, with pairwise correlation coefficients of 0.40–0.70. Principal component analysis of vaccine-serotype responses yielded one principal component indicating general immune responsiveness, and a second principal component mainly describing responses to serotype 14, which was the least correlated with the other responses. Overall, demographic variables explained only 17.0 and 20.4% of the geometric mean PCV7 and PCV13 responses, respectively. In both groups, older age at the first vaccine dose and shorter time from vaccination to antibody measurement were independently associated with stronger geometric mean responses. Discussion Improved understanding of the nature and causes of variation in immune response may aid in optimizing vaccination schedules and identifying robust correlates of protection. [ABSTRACT FROM AUTHOR]

Unproductive patient-provider communication, marked by low patient communication self-efficacy and lack of participation in treatment decision-making, is a key driver of healthcare disparities for racial and ethnic minority groups. PARTNER-MH, a 6-month peer support and patient navigation intervention, was designed to improve minority patients' communication self-efficacy. We examined feasibility, acceptability, and preliminary effects of PARTNER-MH with minority patients in a pilot randomized controlled trial, at a large Veterans Affairs Medical Center outpatient mental health clinic. Feasibility was assessed by evaluating recruitment, retention, acceptability, and adherence to study protocol. Communication self-efficacy was assessed at baseline, 3 months, and 6 months using the PEPPI-5. Additional questions evaluated participants' involvement in shared decision-making (SDM), visit goals accomplished, feeling heard by provider, and perceived barriers to SDM. We also conducted qualitative interviews with participants from the intervention arm. Participants (N=50) were mostly male (62%), non-Hispanic Black (70%) veterans, with a median age that falls in the 45-54 range. We recruited 45% of the target sample and enrolled 68% of eligible participants. Retention was 72% and peers' fidelity to the study protocol consistently improved. 89% of participants reported satisfaction with PARTNER-MH. We saw a positive trend in PEPPI-5 scores with the intervention group having larger increases than the control group at 3-months (3.61 vs. 1.22) and 6-months (6.53 vs. 1.88). Intervention participants reported increased participation in SDM and fewer barriers to SDM than did control participants. Scores for the item, "thinking about your goal for the visit, how much do you feel you accomplished," improved the most. Qualitative data corroborate these findings. Participants consistently reported that PARTNER-MH improved their communication self-efficacy and relationships with their mental health providers. PARTNER-MH is a feasible and acceptable mental healthcare disparity intervention that shows promise in improving patient-provider communication for minority veterans. [ABSTRACT FROM AUTHOR]

Biomarkers have the potential to accelerate drug development, as early indicators of improved clinical response, to improve patient safety, and for personalised medicine. However, few have been approved through the biomarker qualification pathways of the regulatory agencies. This paper outlines how biomarkers can accelerate drug development, and reviews the lessons learned by the EU IMI2-funded LITMUS consortium, which has had several interactions with regulatory agencies in both the US and EU regarding biomarker qualification in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Sharing knowledge of such interactions with the scientific community is of paramount importance to increase the chances of qualification of relevant biomarkers that may accelerate drug development, and thereby help patients, across disease indications. A qualified biomarker enables a decision to be made that all understand and support in a common framework. [ABSTRACT FROM AUTHOR]

Background The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) assessed vaccine-type community-acquired pneumonia (VT-CAP) and vaccine-type invasive pneumococcal disease (VT-IPD) prevention with 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ⩾65 years. We report vaccine efficacy (VE) of PCV13 for the remaining 23 exploratory endpoints and serotype distributions for pneumococcal CAP and IPD. Methods This was a parallel-group, randomised, placebo-controlled, double-blind trial comparing single-dose PCV13 with placebo. Exploratory CAP endpoints included first episode of confirmed non-VT (NVT) pneumococcal CAP; all confirmed episodes of NVT pneumococcal CAP, pneumococcal CAP, nonbacteraemic/noninvasive (NB/NI) VT pneumococcal CAP, and NB/NI pneumococcal CAP; and first and all episodes of culture-confirmed VT pneumococcal CAP, culture-confirmed pneumococcal CAP, culture-confirmed NVT pneumococcal CAP, probable VT pneumococcal CAP, probable NVT pneumococcal CAP, and probable and possible pneumococcal CAP. Exploratory IPD endpoints included all episodes of VT-IPD and IPD, and first and all episodes of NVT-IPD. The per-protocol and modified intent-to-treat (mITT) populations were evaluated. Results In total, 84,496 participants were enrolled. Eight of 23 exploratory CAP and IPD endpoints were statistically significant in both populations. In the per-protocol population, these included VE of 29% for all episodes of confirmed pneumococcal CAP, 43% for all NB/NI episodes of VT pneumococcal CAP, 52% for all episodes of culture-confirmed pneumococcal CAP, and 53% for all episodes of IPD. Comparable VE estimates were observed in the mITT population. The most common VT serotypes were 1 (10 first episodes of confirmed pneumococcal CAP; 2 first episodes of IPD) and 7F (22; 7) among PCV13 and placebo recipients, respectively. Conclusions The results of this analysis yielded statistically significant PCV13 VE for all episodes of confirmed pneumococcal CAP (including NB/NI and culture-confirmed episodes) and for all episodes of IPD in adults aged ⩾65 years. These findings are consistent with the primary efficacy analysis. ClinicalTrials.gov identifier: NCT00744263 . [ABSTRACT FROM AUTHOR]

Highlights: [•] Safety meta-analyses enable detection of rare safety events. [•] PCV7 has a well-known safety profile based on 10 years clinical experience. [•] Across 13 clinical trials PCV13 demonstrated a safety profile similar to PCV7. [Copyright &y& Elsevier]

Background: Upper airway injuries can be fatal in burn patients if not recognized, a scenario that causes a significant amount of anxiety for physicians providing initial assessment of burn patients. Early elective intubation is often performed; sometimes unnecessarily. However, some providers employ nasolaryngoscopy for patients presenting with facial burns or signs/symptoms of upper airway injury in order to assess the need for intubation, but this practice is not considered standard of care and may also be unnecessary. Evidence is currently lacking about the utility of nasolaryngoscopy as an adjuvant assessment during evaluation of potential upper airway burn injuries. The objective of this study was to determine if nasolaryngoscopy provides additional information to the history and physical in making the decision to electively intubate patients with facial burns.Methods: This study was a retrospective analysis of all patients who underwent fiberoptic nasolaryngoscopy after facial burn injury to evaluate for upper airway injury associated with burns over a 2 year period at a regional burn center. During this time period, all patients who presented with facial burns, soot, or carbonaceous sputum underwent nasolaryngoscopy to look for upper airway injury regardless of mechanism of injury. Patients intubated prior to arrival were excluded from the study. Patients were considered to have signs/symptoms of airway injury (symptomatic) if they presented with dyspnea, tachypnea, hypoxia, or significant burns to buccal mucosa. Procedure notes were used to determine if supraglottic/glottic injury (erythema or edema) was present on nasolaryngoscopy. Presence of pathologic changes and whether they led to intubation were evaluated in the asymptomatic and the symptomatic groups of patients. Select individual records were inspected further to help determine if the nasolaryngoscopy findings altered management plans and if intubation was ultimately necessary based upon the presence or absence of a cuff leak and the duration of intubation.Results: Twenty-two patients were symptomatic upon presentation, 14 of which had positive findings on laryngoscopy and 7 (50%) were intubated. One-hundred and eighty-eight patients were asymptomatic, 58 (31%) of which had either erythema or edema or carbonaceous debris on nasolaryngoscopy, and only 2 (1%) were intubated. These patients were both extubated within two days. None of the 130 asymptomatic patients with negative nasolaryngoscopy were intubated.Conclusions: This study showed disparity between signs and symptoms of airway injury and nasolaryngoscopy findings. Asymptomatic patients showed pathologic changes in 30% of scopes, but this finding only changed management 1% of the time. Furthermore, the two patients in this group were extubated quickly, suggesting they may have been suitable for observation without intubation. These results indicate that the presence of erythema or edema is of questionable clinical significance in asymptomatic patients and nasolaryngoscopy is of limited benefit in this group. Only 50% of the symptomatic patients with airway injury evident on nasolaryngoscopy were actually intubated, also bringing into question the significance of the pathologic changes in this group. However, negative nasolaryngoscopy may have had some benefit in preventing intubation in a few, select symptomatic patients. This study suggests that a thorough history and physical is the best tool to identify patients at higher risk of upper airway injury who need intubation, but this should be further studied in prospective trials to determine the definitive role of nasolaryngoscopy. [ABSTRACT FROM AUTHOR]

Background: Diagnosing the extremes of superficial burns and full-thickness burns is straightforward. It is in the middle ground of partial-thickness burns where the diagnostic difficulties emerge; it can take up to 3 to 5 days for signs of healing to appear. We hypothesize that cooling partial-thickness burns and tracking the rate of rewarming will immediately reflect the condition of the burn: shallow partial-thickness burns that retain cell health and blood flow will rewarm rapidly, and deeper burns with damaged microvessels will rewarm slowly.Study Design: We enrolled 16 patients with isolated, partial-thickness burns on their extremities who were diagnosed as indeterminate by our burn surgeon. Within 24 hours after presentation, room-temperature saline was poured over the burn as a cooling challenge. An infrared camera that was sensitive to body temperature produced false-color images showing pixel-by-pixel temperatures. A time-lapse recording from the infrared camera images taken as the burn rewarmed produced a time-temperature curve that reflected the kinetics of rewarming. The outcomes variable was whether or not the patient received a skin graft, which was determined 72 hours after presentation.Results: The method correctly predicted whether or not the patient required a skin graft.Conclusions: Here we report a new technique that permits determination of wound viability much earlier than clinical examination. Due to the simplicity of the method, non-experts can successfully perform the technique on the first day of the burn and make the correct diagnosis and decision to graft or not to graft. [ABSTRACT FROM AUTHOR]

Objective Prophylactic antipyretic use during pediatric vaccination is common. This study assessed whether paracetamol or ibuprofen prophylaxis interfere with immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13) given concomitantly with the combined DTaP/HBV/IPV/Hib vaccine. Methods Subjects received prophylactic paracetamol or ibuprofen at 0, 6–8, and 12–16 h after vaccination, or 6–8 and 12–16 h after vaccination at 2, 3, 4, and 12 months of age. At 5 and 13 months, immune responses were evaluated versus responses in controls who received no prophylaxis. Results After the infant series, paracetamol recipients had lower levels of circulating serotype-specific pneumococcal anticapsular immunoglobulin G than controls, reaching significance (P < 0.0125) for 5 serotypes (serotypes 3, 4, 5, 6B, and 23F) when paracetamol was started at vaccination. Opsonophagocytic activity assay (OPA) results were similar between groups. Ibuprofen did not affect pneumococcal responses, but significantly (P < 0.0125) reduced antibody responses to pertussis filamentous hemagglutinin and tetanus antigens after the infant series when started at vaccination. No differences were observed for any group after the toddler dose. Conclusions Prophylactic antipyretics affect immune responses to vaccines; these effects vary depending on the vaccine, antipyretic agent, and time of administration. In infants, paracetamol may interfere with immune responses to pneumococcal antigens, and ibuprofen may reduce responses to pertussis and tetanus antigens. The use of antipyretics for fever prophylaxis during infant vaccination merits careful consideration. ClinicalTrials.gov identifier: NCT01392378 https://clinicaltrials.gov/ct2/show/ NCT01392378 ?term=NCT01392378&rank=1 [ABSTRACT FROM AUTHOR]

Background In addition to reducing vaccine-type nasopharyngeal carriage rates, pneumococcal conjugate vaccines (PCVs) may decrease carriage density in vaccinated individuals still carrying vaccine serotypes. However, reduction of carriage density has not been systematically studied. This study compared the effect of PCV13 versus PCV7 on carriage density of the serotypes in PCV13 that are not included in PCV7. Methods This randomized, double-blind study was conducted in southern Israel and included Jewish and Bedouin subjects. Per protocol, 881 and 873 infants received PCV13 and PCV7, respectively, at ages 2, 4, 6, and 12 months. Nasopharyngeal cultures at ages 7, 12, 13, 18, and 24 months were plated using the 4-quadrant semiquantitative method and graded 0 (negative) to 4 (growth in all plate quadrants). In this post hoc analysis, the least squares means of cumulative colonization densities per serotype and serotype combination of the total population and each ethnic subpopulation in each vaccine group were calculated, and differences between vaccine groups derived from a linear model. Results PCV13-vaccinated children still carrying the 6 additional PCV13 serotypes unique to PCV13 showed no significant differences in carriage density compared with the PCV7-vaccinated control group. No differences in carriage density were shown between Jewish and Bedouin subpopulations despite higher carriage rates among Bedouin subjects. Conclusions Although PCV13 vaccination reduces vaccine-type carriage compared with PCV7 vaccination by reducing nasopharyngeal acquisition of the additional PCV13 serotypes as previously reported, the current study lacks evidence of a decrease in carriage density of these serotypes when acquired in vaccinated children. Despite the lack of effect on carriage density observed, surveillance data suggest a dramatic decrease in disease rates after PCV implementation. Thus, the current analysis suggests that PCV’s impact on carriage density has minimal or no impact on vaccine success. ( www.ClinicalTrials.gov : NCT00508742) [ABSTRACT FROM AUTHOR]

Background A prior 7- and 13-valent pneumococcal conjugate vaccine (PCV7 and PCV13) study provided sufficient data ( N = 1754; Jewish, n = 1154; Bedouin, n = 595; other, n = 5) to investigate the association between nasopharyngeal (NP) acquisition of common PCV7 serotypes and cross-reacting 6A (PCV7 + 6A) and IgG concentrations. Methods Using a logistic regression model, serotype specific association between postinfant series IgG concentration (age 7 months) and new NP acquisition between ages 7 and 24 months was assessed and adjusted for ethnicity. From a subset of subjects with new NP acquisition ( n = 9–152 across serotypes studied), new acquisition percentiles and associated IgG concentrations were calculated. Results For the serotypes studied , new NP acquisition rates decreased as IgG concentrations increased. Ethnicity did not influence these associations despite differences in carriage rates. From the subset with new acquisitions, 50% of the events occurred at IgG concentrations >0.61–5.58 μg/mL; and 10% of the acquisitions occurred at IgG concentrations >2.48–17.69 μg/mL. Conclusion Remarkably high IgG concentrations are required to reduce NP acquisition. These IgG concentrations differ between serotypes. Ethnicity did not influence the association between high IgG concentrations and prevention of carriage despite differences in carriage rates. Since carriage determines transmission, these results may have important implications for herd protection. Trial registration: ClinicalTrials.gov number, NCT00508742 ; http://clinicaltrials.gov/ct2/show/NCT00508742 [ABSTRACT FROM AUTHOR]

Background Herd protection from infant pneumococcal conjugate vaccination is well established for invasive pneumococcal disease (IPD) but not for non-IPD pneumococcal community-acquired pneumonia (PCAP). We assessed the contribution of vaccine-serotypes in non-IPD PCAP in adults 65 years and older in the period 2008–2013. Methods This is a post hoc analysis of two prospective studies from the Netherlands. Serotype specific urinary antigen detection and routine microbiological testing were used to categorize episodes as IPD or non-IPD PCAP caused by 7-valent pneumococcal conjugate vaccine (PCV7), PCV10-7 (three additional PCV10 serotypes), PCV13-10 (three additional PCV13 serotypes), and non-PCV13 serotypes. Proportions per vaccine-serotype group were assessed per year from June 1st to May 31st. Time trends were compared to national IPD data. Results Of 270 non-IPD PCAP episodes with known serotype, PCV7 serotypes decreased from 28% in 2008/2009 to 7% in 2012/2013 ( p -value for trend <0.001). No change in PCV10-7 (19% overall) and PCV13-10 (29% overall) serotypes was observed. Non-PCV13 serotypes increased from 30% in 2008/2009 to 37% in 2012/2013 ( p -value for trend 0.048). Trends corresponded with national IPD data. Conclusion PCV7 serotypes declined in non-IPD PCAP among elderly between 2008 and 2013, comparable to IPD data. No reduction in the additional PCV10 serotypes could be demonstrated within the first two years after PCV10 introduction. [ABSTRACT FROM AUTHOR]

Highlights: [•] In some routine immunization programs, PCV13 is administered in a 2+1 schedule. [•] Summarized immune responses from 2+1 and 3+1 studies of PCV13 with postdose 2 data. [•] Immune responses to the PCV7 serotypes postdose 2 were similar for PCV13 and PCV7. [•] All 13 serotypes showed boosting posttoddler dose in the 2+1 studies. [•] These results support transition from PCV7 to PCV13 in countries with 2+1 schedules. [ABSTRACT FROM AUTHOR]

Abstract: Background: The inclusion of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs in many countries has significantly decreased the incidence of disease caused by Streptococcus pneumoniae. However, a substantial portion of disease remained and, in some areas, there has been an increase in disease produced by serotypes not included in PCV7. A 13-valent pneumococcal conjugate vaccine (PCV13) was studied in healthy Brazilian infants in a phase 3, double-blind, randomized study. Methods: Infants were randomized to receive either PCV7 or PCV13 at 2, 4, 6, (doses 1–3), and 12 (toddler dose) months of age, along with routine pediatric vaccinations (diphtheria, tetanus, whole-cell pertussis, and Haemophilus influenzae type b vaccine). Pneumococcal anticapsular polysaccharide-binding immunoglobulin G (IgG) responses and antibody responses to pertussis antigens were measured 1 month after both dose 3 of the infant series and the toddler dose. Safety and tolerability were also assessed. Results: The proportion of subjects achieving a serotype-specific IgG concentration ≥0.35μg/mL measured 1 month after the infant series was comparable in the PCV13 (≥94.2%) and PCV7 (≥93.0%) groups for the 7 serotypes common to both vaccines. The percentage of responders for the 6 additional serotypes ranged from 87.1 to 100% for PCV13. The percentage of responders varied across the pertussis antigens studied, but was not different in PCV13 and PCV7 recipients. Overall, the safety profile of PCV13 was comparable with that of PCV7. Conclusions: PCV13 was comparable to PCV7 in safety and tolerability, elicited comparable immune responses to the common serotypes, and did not interfere with immune responses to concomitantly administered whole-cell pertussis vaccine. The robust immunogenicity exhibited by PCV13 for the additional serotypes suggests that it could provide significant protection against these serotypes. [Copyright &y& Elsevier]