Continuum’s Reader’s Guides are clear, concise and accessible introductions to classic works of philosophy. Each book explores the major themes, historical and philosophical context and key passages ...of a major philosophical text, guiding the reader toward a thorough understanding of often demanding material. Ideal for undergraduate students, the guides provide an essential resource for anyone who needs to get to grips with a philosophical text. Heidegger’s Being and Time is one of the most influential and controversial philosophical treatises of the 20th century. It had a profound impact on Sartre and Merleau-Ponty in their further development of phenomenology and existentialism, hugely influenced Gadamer’s hermeneutics, and paved the way, partly directly and partly indirectly through Heidegger'’s later thought, for the emergence of deconstructionism. In addition to being a very important text, it is also a very difficult one. Heidegger presents a number of challenges to the the reader, asking them to abandon many assumptions fundamental to traditional philosophy, such as the mind/body distinction and the concept of substance. The text also introduces a whole host of new concepts and terms and as such is a hugely challenging, yet fascinating, piece of philosophical writing. In Heidegger’s ‘Being and Time’: A Reader’s Guide William Blattner explains the philosophical background against which the book was written and provides a clear and concise overview of the key themes and motifs. The book then examines this challenging text in details, guiding the reader to a clear understanding of Heidegger’s work as a whole. Finally Blattner explores the reception and influence of the work and offers the student guidance on further reading. This is the ideal companion to study of this most influential and challenging of texts.
The potential role of gender in the occurrence of HIV-related neurocognitive impairment (NCI) and associations with markers of HIV-related immune activity has not been previously examined. In this ...study 149 antiretroviral-naïve seropositive subjects in Nigeria (SP, 92 women and 57 men) and 58 seronegative (SN, 38 women and 20 men) were administered neuropsychological testing that assessed 7 ability domains. From the neuropsychological test scores was calculated a global deficit score (GDS), a measure of overall NCI. Percentages of circulating monocytes and plasma HIV RNA, soluble CD163 and soluble CD14 levels were also assessed. HIV SP women were found to be younger, more educated and had higher CD4+ T cell counts and borderline higher viral load measures than SP men. On the neuropsychological testing, SP women were more impaired in speed of information processing and verbal fluency and had a higher mean GDS than SN women. Compared to SP men, SP women were also more impaired in speed of information processing and verbal fluency as well as on tests of learning and memory. Numbers of circulating monocytes and plasma sCD14 and sCD163 levels were significantly higher for all SP versus all SN individuals and were also higher for SP women and for SP men versus their SN counterparts. Among SP women, soluble CD14 levels were slightly higher than for SP men, and SP women had higher viral load measurements and were more likely to have detectable virus than SP men. Higher sCD14 levels among SP women correlated with more severe global impairment, and higher viral load measurements correlated with higher monocyte numbers and sCD14 and sCD14 levels, associations that were not observed for SP men. These studies suggest that the risk of developing NCI differ for HIV infected women and men in Nigeria and, for women, may be linked to effects from higher plasma levels of HIV driving activation of circulating monocytes.
DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small ...animals and in macaques.
We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response.
This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity.
Clinicaltrials.gov NCT00115960 NCT00111605.
Untreated advanced HIV infection alters the gut microbiota, but it is unclear whether antiretroviral therapy (ART) reverses these changes. We compared the composition of the rectal microbiota among ...three groups of men who have sex with men (MSM): HIV-uninfected, untreated HIV, and ART-treated HIV-infected.
A cross-sectional study was conducted among 130 MSM (55 HIV-uninfected, 41 untreated HIV, and 34 ART-treated HIV) in Abuja, Nigeria.
Bacterial 16S rRNA genes were amplified from rectal swabs, sequenced and clustered into Genera-level operational taxonomic units. Alpha diversity was quantified using the Shannon index and compared among groups using the Kruskal-Wallis test; associations with other scale variables were quantified using Spearman's rank correlation (Rs). The relative abundance of the top 15 taxa was compared according to HIV infection/treatment status using the Wilcoxon rank sum test.
HIV-treated MSM had a decrease in a commensal phylum, Bacteroidetes (P < 0.01). Alpha diversity was positively correlated with viral loads (Rs = 0.32, P < 0.01). Statistically significant shifts in relative abundance of rectal microbiota for the HIV-treated group included a decrease in the most abundant bacteria, Prevotella (P = 0.02) and an increase in pathogenic bacteria, Peptoniphilus (P = 0.04), Finegoldia (P = 0.01), Anaerococcus (P = 0.03), and Campylobacter (P = 0.03) compared with the other groups.
Untreated HIV infection does not significantly alter the rectal microbiota, whereas prior treatment is associated with a shift toward a more pathogenic pattern of microbiota. Treatment with an antibiotic, co-trimoxazole, in conjunction with ART may have contributed to this shift.
Although in decline after successful anti-HIV therapy, B-cell lymphomas are still elevated in HIV-1-seropositive (HIV+) persons, and the mechanisms are obscure. The HIV-1 matrix protein p17 persists ...in germinal centers long after HIV-1 drug suppression, and some p17 variants (vp17s) activate Akt signaling and promote growth of transformed B cells. Here we show that vp17s derived from four of five non-Hodgkin lymphoma (NHL) tissues from HIV+ subjects display potent B-cell growth-promoting activity. They are characterized by amino acid insertions at position 117–118 (Ala–Ala) or 125–126 (Gly–Asn or Gly–Gln–Ala–Asn–Gln–Asn) among some other mutations throughout the sequence. Identical dominant vp17s are found in both tumor and plasma. Three of seven plasma samples from an independent set of NHL cases manifested multiple Ala insertions at position 117–118, and one with the Ala–Ala profile also promoted B-cell growth and activated Akt signaling. Ultradeep pyrosequencing showed that vp17s with C-terminal insertions are more frequently detected in plasma of HIV+ subjects with than without NHL. Insertion of Ala–Ala at position 117–118 into reference p17 (refp17) was sufficient to confer B-cell growth-promoting activity. In contrast, refp17 bearing the Gly–Asn insertion at position 125–126 did not, suggesting that mutations not restricted to the C terminus can also account for this activity. Biophysical analysis revealed that the Ala–Ala insertion mutant is destabilized compared with refp17, whereas the Gly–Asn form is stabilized. This finding provides an avenue for further exploration of structure function relationships and new treatment strategies in combating HIV-1–related NHL.
In January, 2014, the Same-Sex Marriage Prohibition Act was signed into law in Nigeria, further criminalising same-sex sexual relationships. We aimed to assess the immediate effect of this ...prohibition act on stigma, discrimination, and engagement in HIV prevention and treatment services in men who have sex with men (MSM) in Nigeria.
The TRUST cohort study uses respondent-driven sampling to assess the feasibility and effectiveness of engagement of MSM in HIV prevention and treatment services at a clinical site located with a community-based organisation trusted by the MSM community. TRUST is a prospective implementation research cohort of MSM (≥16 years) in Abuja, Nigeria. We compared HIV clinical outcomes and stigma, including fear and avoidance of health care, across baseline and quarterly visits before and after implementation of the the Same-Sex Marriage Prohibition Act. Outcomes assessed were measures of stigma and discrimination, loss to follow-up, antiretroviral therapy status, and viral load. We compared outcomes before and after the legislation with χ2 statistics, and estimated incident stigma-related events and loss to follow-up with Poisson regression.
Between March 19, 2013, and Aug 7, 2014, 707 MSM participated in baseline study procedures, contributing to 756 before legislation (prelaw) and 420 after legislation (postlaw) visits. Reported history of fear of seeking health care was significantly higher in postlaw visits than in prelaw visits (n=161 38% vs n=187 25%; p<0・0001), as was avoidance of health care (n=118 28% vs n=151 20%; p=0・001). In incidence analyses, of 192 MSM with follow-up data and no history of an event at baseline, reported fear of seeking health care was higher in the postlaw than the prelaw period (n=144; incidence rate ratio 2・57, 95% CI 1・29–5・10; p=0・007); loss to follow-up and incident healthcare avoidance were similar across periods. Of the 161 (89%) of 181 HIV-infected MSM with HIV viral loads available, those who had disclosed sexual behaviour with a health-care provider were more often virally suppressed at baseline than those with no previous disclosure (18 29% of 62 vs 13 13% of 99 men; p=0・013).
These analyses represent individual-level, quantitative, real-time prospective data for the health-related effects resulting from the enactment of legislation further criminalising same-sex practices. The negative effects of HIV treatment and care in MSM reinforce the unintended consequences of such legislation on global goals of HIV eradication. Strategies to reach MSM less likely to engage in HIV testing and care in highly stigmatised environments are needed to reduce time to HIV diagnosis and treatment.
National Institutes of Health.
Mononuclear cells play key roles in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Limited studies have looked at the association of markers of monocyte activation with HAND in ...Africa. We examined this association among HIV-1-infected patients in Nigeria.
A total of 190 HIV-infected treatment-naive participants with immune marker data were included in this cross-sectional study. Plasma levels of soluble CD14 (sCD14), soluble CD163, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and neopterin were measured. Demographically adjusted T scores obtained from a 7-domain neuropsychological test battery were generated, and functional status was assessed using activities of daily living questionnaire. Participants were classified as unimpaired, having asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD) in line with the "Frascati" criteria.
Thirty-two participants (16.8%) had ANI, 14 (7.4%) had MND, whereas none had HAD. In multivariable linear regression analyses, after adjusting for age, gender, education, CD4 count, and viral load, mean levels of sCD14 were higher among those with ANI and MND as compared with the unimpaired (P = 0.033 and 0.023, respectively). Similarly, the mean level of MCP-1 was greater among those with HAND as compared with the unimpaired (P = 0.047). There were also trends for higher levels of sCD163 and TNF-α among females with MND in univariable analyses.
Levels of monocyte activation markers correlate with the severity of impairment among individuals with HAND. The mechanisms that underlie these effects and the potential role of gender require further study.
To date, HIV incidence studies among men who have sex with men (MSM) across sub-Saharan Africa have focused on studying sexual risk practices with less focus on sexual networks.
TRUST/RV368 conducted ...in Abuja and Lagos, Nigeria, recruited MSM using respondent-driven sampling and followed HIV-negative men for incident infection over 4 years.
Four-hundred forty-one HIV-uninfected MSM underwent a parallel rapid HIV testing algorithm every 3 months for up to 18 months. HIV incidence per 100 person-years (PY) and 95% confidence intervals (CIs) were estimated using Poisson regression. Individual and network characteristics were examined using multivariable Cox-proportional hazards regression adjusted and unadjusted for respondent-driven sampling weights.
Among cohort members with a median age of 23 years interquartile range (IQR): 20-27, 81 HIV infections occurred over 527 PY (incidence 15.4/100 PY; 95% CI: 12.3 to 19.0). The incidence rate was highest among 16-19 year olds as compared to those 25 years or older (30.9/100 PY; 95% CI: 22.1 to 45.3 vs. 6.9/100 PY; 95% CI: 4.2 to 10.9, respectively). Individual determinants included receptive partnerships, condomless sex, no history of testing for HIV, and rectal gonorrhea. Sexual networks were larger and consisted of an older sexual partner, although there was no clustering by recruitment networks.
These HIV incidence data reinforce the unmet HIV prevention needs among young MSM in Nigeria. Even in the context of emerging HIV diagnostic and prevention strategies, structural challenges including stigma and criminalization of same-sex practices highlight the need for novel implementation approaches in the context of MSM-friendly services.
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