Lack of Detectable HIV-1 Molecular Evolution during Suppressive Antiretroviral Therapy

A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1-15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Impact of HIV on Cell Survival and Antiviral Activity of Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) are important mediators of innate immunity that act mainly through secretion of interferon (IFN)-α. Previous studies have found that these cells can suppress HIV in vitro; additionally, pDCs have been shown to be severely reduced in the peripheral blood of HIV-infected individuals. In the present study, we sought to determine the ability of pDCs to directly suppress viral replication ex vivo and to delineate the potential mechanisms whereby pDCs are depleted in HIV-infected individuals. We demonstrate that activated pDCs strongly suppress HIV replication in autologous CD4(+) T cells via a mechanism involving IFN-α as well as other antiviral factors. Of note, unstimulated pDCs from infected individuals who maintain low levels of plasma viremia without antiretroviral therapy were able to suppress HIV ex vivo via a mechanism requiring cell-to-cell contact. Our data also demonstrate that death of pDCs by both apoptosis and necrosis is induced by fusion of HIV with pDCs. Taken together, our data suggest that pDCs play an important role in the control of HIV replication and that high levels of viral replication in vivo are associated with pDC cell death via apoptosis and necrosis. Elucidation of the mechanism by which pDCs suppress HIV replication in vivo may have clinically relevant implications for future therapeutic strategies

Characterization of CD56(–)/CD16(+) natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals

Natural killer (NK) cells are an important component of the innate immune response against viral infections. NK cell-mediated cytolytic activity is defective in HIV-infected individuals with high levels of viral replication. In the present study, we examined the phenotypic and functional characteristics of an unusual CD56(–)/CD16(+) (CD56(–)) NK subset that is greatly expanded in HIV-viremic individuals. The higher level of expression of inhibitory NK receptors and the lower level of expression of natural cytotoxicity receptors observed in the CD56(–) NK fraction compared with that of CD56(+) NK cells was associated with extremely poor in vitro cytotoxic function of this subset. In addition, the secretion of certain cytokines known to be important in initiating antiviral immune responses was markedly reduced in the CD56(–), as compared with the CD56(+) NK cell subset. These data suggest that the expansion of this highly dysfunctional CD56(–) NK cell subset in HIV-viremic individuals largely accounts for the impaired function of the total NK cell population

Association Between Childhood Adversity and Functional Outcomes in People With Psychosis:A Meta-analysis

Background and Hypothesis: Despite the accepted link between childhood adversity (CA) and psychotic disorders, evidence on the relationship between CA and poor functional outcome remains less consistent and has never been reviewed quantitatively. The aim of this meta-analysis was to systematically examine the association between CA and functional outcomes in people with psychotic disorders. Study Design: The study protocol was registered on the International Prospective Register of Systematic Reviews (CRD42021254201). A search was conducted across EMBASE, MEDLINE, PsycINFO, and Cochrane Libraries (CENTRAL) using search terms related to psychosis; CA (general, sexual abuse, physical abuse, emotional abuse, physical neglect, and emotional neglect); and functional outcomes (social, occupational, and general functioning [GF]). We conducted random-effects models, sensitivity and heterogeneity analyses, meta-regressions, and we assessed quality. Study Results: Our meta-analysis comprised 35 studies, including 10 568 cases with psychosis. General CA was negatively associated with GF (28 studies; r = −0.109, 95%CI = −0.161 to −0.05, P &lt; .001), with greater effects in prospective data (10 studies; r = −0.151, 95% CI = −0.236 to −0.063, P = .001). General CA was also associated with social functioning (r = −0.062, 95% CI = −0.120 to −0.004, P = .018) but not occupational outcomes. All CA subtypes except sexual abuse were significantly associated with GF, with emotional and physical neglect showing the largest magnitudes of effect (ranging from r = −0.199 to r = −0.250). Conclusions: This meta-analysis provides evidence for a negative association between general CA, specific subtypes, and general and social functional outcomes in people with psychosis.</p

Measurements of HIV-1 diversity calculated as APD before, during and/or after cART in all patients in (A) Group 1 - short-term cART (B) Group 2 - long-term cART (C) Group 3 - cART with treatment interruptions and (D) the average of all groups.

<p>Duration of treatment is shown in years in parentheses above the bar with the diversity measurement. Overall, HIV-1 plasma diversity did not change with initiation of therapy.</p

Allele frequency during cART.

a<p>Analysis includes only patients who had sampling during viral RNA decay on cART.</p

Measurements of the probability of panmixia before and after cART in (A) Group 1 - short-term cART (B) Group 2 - long-term cART (C) Group 3 - cART with treatment interruptions.

<p>We considered a panmixia p value of <0.001 to be statistically significant according to the original publication of the method (1). Significance reveals a shift in population over time on cART and was found primarily in patients on long-term cART.</p