The characteristics of patients currently abusing controlled-release (CR) oxycodone admitted for inpatient detoxification were ascertained from medical record review of 48 inpatients with CR ...oxycodone dependence. Patients were categorized according to the manner in which they initially received the drug: illicitly or by prescription for legitimate medical use. Fifteen of the 48 patients (31%) initially obtained a CR oxycodone prescription legitimately for a medical condition. While none of these 15 patients had a history of prior opioid misuse, they were more likely than illicit CR oxycodone users to report prior detoxifications (
P < 0.03) as well as a lower mean age of first alcohol use (legitimate = 11.7 versus illicit = 14.7,
P < 0.05) and first illicit drug use (legitimate = 12.8 versus illicit = 15.8,
P < 0.05). These findings suggest that a history of substance abuse is common among patients abusing CR oxycodone, including individuals for whom CR oxycodone was initially legitimately prescribed for pain.
Study 10, a four-part Phase 1/2 study, evaluated oral rucaparib monotherapy in patients with advanced solid tumours. Here we report the final efficacy and safety results in heavily pretreated ...patients with ovarian cancer who received rucaparib in Study 10 Parts 2A and 2B.
Parts 2A and 2B (Phase 2 portions) enrolled patients with relapsed, high-grade, platinum-sensitive or platinum-resistant, BRCA-mutated ovarian cancer who had received 2-4 (Part 2A) or 3-4 (Part 2B) prior chemotherapies. Patients received oral rucaparib 600 mg twice daily (starting dose). The primary endpoint was the investigator-assessed objective response rate (ORR) by RECIST v1.1.
Fifty-four patients were enrolled: 42 in Part 2A (all had platinum-sensitive disease) and 12 in Part 2B (4 with platinum-sensitive disease; 8 with platinum-resistant disease). ORR was 59.3% (95% CI 45.0-72.4%). The median time to onset of the most common nonhaematological treatment-emergent adverse events (TEAEs) was typically early (<56 days) and was later for haematological TEAEs (53-84 days). The median duration of grade ≥3 TEAEs was ≤13 days.
In patients with relapsed, platinum-sensitive or platinum-resistant germline BRCA-mutant high-grade ovarian cancer who had received ≥2 prior chemotherapies, rucaparib had robust antitumour activity with a safety profile consistent with prior reports.
NCT01482715.
This article reviews the use of opioid antagonists in the pharmacologic treatment of alcohol dependence. The rationale for using the opioid antagonists naltrexone and nalmefene to prevent relapse in ...alcohol-dependent subjects is discussed by reviewing past and current clinical trials. The role of psychotherapies, particularly coping skills therapy, in combination with opioid antagonists is highlighted in the presentations of the clinical data. Finally, future research directions for opioid antagonists are discussed.
Phenotypic properties of transmitted founder HIV-1 Parrish, Nicholas F.; Gao, Feng; Li, Hui ...
Proceedings of the National Academy of Sciences - PNAS,
04/2013, Letnik:
110, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Defining the virus–host interactions responsible for HIV-1 transmission, including the phenotypic requirements of viruses capable of establishing de novo infections, could be important for AIDS ...vaccine development. Previous analyses have failed to identify phenotypic properties other than chemokine receptor 5 (CCR5) and CD4+ T-cell tropism that are preferentially associated with viral transmission. However, most of these studies were limited to examining envelope (Env) function in the context of pseudoviruses. Here, we generated infectious molecular clones of transmitted founder (TF; n = 27) and chronic control (CC; n = 14) viruses of subtypes B (n = 18) and C (n = 23) and compared their phenotypic properties in assays specifically designed to probe the earliest stages of HIV-1 infection. We found that TF virions were 1.7-fold more infectious (P = 0.049) and contained 1.9-fold more Env per particle (P = 0.048) compared with CC viruses. TF viruses were also captured by monocyte-derived dendritic cells 1.7-fold more efficiently (P = 0.035) and more readily transferred to CD4+ T cells (P = 0.025). In primary CD4+ T cells, TF and CC viruses replicated with comparable kinetics; however, when propagated in the presence of IFN-α, TF viruses replicated to higher titers than CC viruses. This difference was significant for subtype B (P = 0.000013) but not subtype C (P = 0.53) viruses, possibly reflecting demographic differences of the respective patient cohorts. Together, these data indicate that TF viruses are enriched for higher Env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative IFN-α resistance. These viral properties, which likely act in concert, should be considered in the development and testing of AIDS vaccines.
Serogroup W and Y invasive meningococcal disease increased globally from 2000 onwards. Responding to a rapid increase in serogroup W clonal complex 11 (W:cc11) invasive meningococcal disease, the UK ...replaced an adolescent booster dose of meningococcal C conjugate vaccine with quadrivalent MenACWY conjugate vaccine in 2015. By 2018, the vaccine coverage in the eligible school cohorts aged 14 to 19 years was 84%. We assessed the impact of the MenACWY vaccination programme on meningococcal carriage.
An observational study of culture-defined oropharyngeal meningococcal carriage prevalence before and after the start of the MenACWY vaccination programme in UK school students, aged 15 to 19 years, using two cross-sectional studies: 2014 to 2015 “UKMenCar4” and 2018 “Be on the TEAM” (ISRCTN75858406).
A total of 10 625 participants preimplementation and 13 438 postimplementation were included. Carriage of genogroups C, W, and Y (combined) decreased from 2.03 to 0.71% (OR 0.34 95% CI 0.27–0.44, p < 0.001). Carriage of genogroup B meningococci did not change (1.26% vs 1.23% 95% CI 0.77–1.22, p = 0.80) and genogroup C remained rare (n = 7/10 625 vs 17/13 438, p = 0.135). The proportion of serogroup positive isolates (i.e. those expressing capsule) decreased for genogroup W by 53.8% (95% CI -5.0 – 79.8, p = 0.016) and for genogroup Y by 30.1% (95% CI 8.946·3, p = 0.0025).
The UK MenACWY vaccination programme reduced carriage acquisition of genogroup and serogroup Y and W meningococci and sustained low levels of genogroup C carriage. These data support the use of quadrivalent MenACWY conjugate vaccine for indirect (herd) protection.
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•Immunity to N. meningitidis serogroup X identified in 52.3 % of study participants.•Immunity to N. meningitidis serogroup X highest in 5–14-year age group.•SBA assay for N. meningitidis ...serogroup X was successfully validated.•SBA assay for N. meningitidis serogroup X suitable for use in future clinical trials.
Invasive meningococcal disease (IMD) affects approximately 1.2 million people worldwide annually. Prevention of IMD is mostly provided through vaccination; however, no licensed vaccine is currently available to protect against meningococcal serogroup X associated infection. Limited data are available on the natural immunity to Neisseria meningitidis serogroup X within the African sub-Saharan meningitis belt.
The objective of the study was to provide an overview of natural immunity to serogroup X within a community in the African meningitis belt prior to the introduction of a pentavalent conjugate vaccine (NmCV-5). Prior to its introduction, a validated assay to assess vaccine efficacy was also required. This study therefore incorporated two objectives: a seroprevalence study to assess natural immunity in serum samples (n = 377) collected from Niger, West Africa in 2012, and the validation of a serogroup X serum bactericidal antibody (SBA) assay.
Seroprevalence data obtained found that natural immunity to N. meningitidis serogroup X were present in 52.3% of study participants. The highest putative protective titres (≥8) to serogroup X were seen in age group 5–14 years-old (73.9%) and lowest in ages < 1 year old (0%). The SBA assay was successfully validated for selectivity/specificity, precision/reproducibility, linearity, and stability. This study demonstrated the suitability of the serogroup X SBA assay in clinical trials for future meningococcal conjugate vaccines containing serogroup X polysaccharides.
To assess the accuracy of the AbC-19 Rapid Test lateral flow immunoassay for the detection of previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Test accuracy study.
...Laboratory based evaluation.
2847 key workers (healthcare staff, fire and rescue officers, and police officers) in England in June 2020 (268 with a previous polymerase chain reaction (PCR) positive result (median 63 days previously), 2579 with unknown previous infection status); and 1995 pre-pandemic blood donors.
AbC-19 sensitivity and specificity, estimated using known negative (pre-pandemic) and known positive (PCR confirmed) samples as reference standards and secondly using the Roche Elecsys anti-nucleoprotein assay, a highly sensitive laboratory immunoassay, as a reference standard in samples from key workers.
Test result bands were often weak, with positive/negative discordance by three trained laboratory staff for 3.9% of devices. Using consensus readings, for known positive and negative samples sensitivity was 92.5% (95% confidence interval 88.8% to 95.1%) and specificity was 97.9% (97.2% to 98.4%). Using an immunoassay reference standard, sensitivity was 94.2% (90.7% to 96.5%) among PCR confirmed cases but 84.7% (80.6% to 88.1%) among other people with antibodies. This is consistent with AbC-19 being more sensitive when antibody concentrations are higher, as people with PCR confirmation tended to have more severe disease whereas only 62% (218/354) of seropositive participants had had symptoms. If 1 million key workers were tested with AbC-19 and 10% had actually been previously infected, 84 700 true positive and 18 900 false positive results would be projected. The probability that a positive result was correct would be 81.7% (76.8% to 85.8%).
AbC-19 sensitivity was lower among unselected populations than among PCR confirmed cases of SARS-CoV-2, highlighting the scope for overestimation of assay performance in studies involving only PCR confirmed cases, owing to "spectrum bias." Assuming that 10% of the tested population have had SARS-CoV-2 infection, around one in five key workers testing positive with AbC-19 would be false positives.
ISRCTN 56609224.
•4CMenB reduces disease due to strains with cross-reactive antigen variants.•No increase in absolute numbers of cases due to poorly covered strains was observed.•Further evidence of the importance of ...a booster for NadA-mediated protection.•Further evidence for waning of pora-mediated immunity pre-booster.
In 2015 the UK became the first country to implement the meningococcal B (MenB) vaccine, 4CMenB, into the national infant program. 4CMenB is expected to cover meningococci expressing sufficient levels of cross-reactive proteins. This study presents clonal complex, 4CMenB antigen genotyping, and 4CMenB coverage data for all English invasive MenB isolates from 2014/15 (1 year pre-vaccine) through 2017/18 and compares data from vaccinated and unvaccinated ≤3 year olds.
Vaccine coverage of all invasive MenB isolates from 2014/15 to 2017/18 (n = 784) was analysed using the Meningococcal Antigen Typing System. Genotyping utilised the Meningococcus Genome Library.
Among ≤3 year olds, proportionally fewer cases in vaccinees (1, 2 or 3 doses) were associated with well-covered strains e.g. cc41/44 (20.5% versus 36.4%; P<0.01) and antigens e.g. PorA P1.4 (7.2% versus 17.3%; P = 0.02) or fHbp variant 1 peptides (44.6% vs 69.1%; P<0.01). Conversely, proportionally more cases in vaccinees were associated with poorly-covered strains e.g. cc213 (22.9% versus 9.6%; P<0.01) and antigens e.g. variant 2 or 3 fHbp peptides (54.2% versus 30.9%; P<0.01).
4CMenB reduces disease due to strains with cross-reactive antigen variants. No increase in absolute numbers of cases due to poorly covered strains was observed in the study period.
•DTaP5-HB-IPV-Hib is a vaccine against diseases caused by 6 infectious agents.•DTaP5-HB-IPV-Hib was given with 1 of 2 meningococcus group C conjugate vaccines.•Satisfactory seroprotection rates were ...achieved against all vaccine antigens.•High rates of seroprotection against meningococcus group C were observed.
Concomitant administration of vaccines simplifies delivery. DTaP5-HB-IPV-Hib is a fully liquid, combination vaccine against 6 diseases. This study evaluated the compatibility of DTaP5-HB-IPV-Hib with 2 different meningococcus group C conjugate (MCC) vaccines in infants.
In a phase 3, open-label study, 284 healthy infants from 11 UK centres received DTaP5-HB-IPV-Hib at age 2, 3, and 4 months; 13-valent pneumococcal conjugate vaccine (PCV13) at 2 and 4 months; a Haemophilus influenzae type b (Hib)-MCC vaccine and a measles/mumps/rubella vaccine at 12 months. Participants were randomised 1:1 to receive either an MCC-detoxified tetanus toxin vaccine (MCC-TT; n = 141) or an MCC-Corynebacterium diphtheriae CRM197 protein vaccine (MCC-CRM; n = 143) at 3 and 4 months. The primary outcome was seroprotection rate (SPR) to MCC (percent with rabbit complement serum bactericidal antibody titer ≥8).
Per protocol analysis, MCC SPRs were 100 and 96.4 one month after the first dose, 100 and 99.1 after the second dose, and 100 and 97.3 after the third (booster) dose of MCC in the MCC-TT and MCC-CRM groups, respectively. One month after all 3 doses of DTaP5-HB-IPV-Hib, immunoglobulin G anti-polyribosylribitol phosphate SPRs (% ≥0.15 µg/mL) were 97.8 in the MCC-TT group and 100 in the MCC-CRM group; anti-hepatitis B antigen SPRs (% ≥10 mIU/mL) were 96.8 and 96.3 in the MCC-TT and MCC-CRM groups, respectively. All participants were seroprotected against diphtheria and tetanus (≥0.01 IU/mL) and poliovirus types 1, 2, and 3 (≥8 dilution), and seroresponse rates to all pertussis antigens were ≥90.4%. Two vaccine-related serious adverse events (transient severe abdominal pain and crying) occurred concomitantly in 1 participant in the MCC-CRM group. Adverse event rates were similar to other studies of DTaP5-HB-IPV-Hib, with pyrexia ≥38 °C in 10.9% of participants following any dose.
DTaP5-HB-IPV-Hib can be effectively used in a 2-, 3-, and 4-month infant priming schedule when given with 2 doses of MCC.
Background
People living with HIV have an increased risk of meningococcal disease. The Propositive trial evaluated co‐administration of two doses of a four‐component recombinant protein‐based MenB ...vaccine (4CMenB) and a quadrivalent conjugate polysaccharide MenACWY vaccine (MenACWY‐CRM197) given 1 month apart in people with HIV. The follow‐up trial assessed the immunogenicity of these vaccines at 1.5 and 2.5 years after primary vaccination.
Methods
Participants who completed the parent Propositive trial were invited to the follow‐up study. Immunogenicity analysis was performed at 18 and 30 months after primary vaccination. Primary outcome measures were serum bactericidal antibody (SBA) geometric mean titres (GMTs) against three MenB reference strains and the proportion of participants maintaining a protective SBA titre of ≥4 at 18 and 30 months. Secondary outcome measures were SBA GMTs against MenA, C, W, and Y serogroups and the proportion of participants maintaining a protective SBA titre of ≥8 at 18 and 30 months. The trial is registered with Clinicaltrials.gov (NCT042394300).
Results
A total of 40 participants aged 22–47 years were enrolled. Geometric mean titres waned by 18 and 30 months but remained higher than pre‐vaccination for all MenB strains and MenA, C, W, and Y. In total, 75%–85% of participants retained protective SBA titres by 30 months against individual MenB strains, whereas 68.8% of patients retained protective antibody titres against all three MenB strains. Antibodies against MenC waned more rapidly than did those against MenA, W, and Y. The proportion of participants with protective titres against MenC at 30 months was also lower (46.9%) than that with protective titres against MenA (87.5%), W (78.1%), and Y (87.5%).
Conclusions
Immune responses against MenB in our cohort of people living with HIV at 2.5 years of follow‐up were reassuring, with 68.8% of participants retaining protection against all three reference strains. However, responses against MenC were lower than those against MenA, W, and Y serogroups.
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