Self-Collected Anterior Nasal and Saliva Specimens versus Health Care Worker-Collected Nasopharyngeal Swabs for the Molecular Detection of SARS-CoV-2.

We prospectively compared health care worker-collected nasopharyngeal swabs (NPS) to self-collected anterior nasal swabs (ANS) and straight saliva for the diagnosis of coronavirus disease 2019 (COVID-19) in 354 patients. The percent positive agreement between NPS and ANS or saliva was 86.3% (95% confidence interval [CI], 76.7 to 92.9%) and 93.8% (95% CI, 86.0 to 97.9%), respectively. The percent negative agreement was 99.6% (95% CI, 98.0 to 100.0%) for NPS versus ANS and 97.8% (95% CI, 95.3 to 99.2%) for NPS versus saliva. More cases were detected by the use of NPS (n = 80) and saliva (n = 81) than by the use of ANS (n = 70), but no single specimen type detected all severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts.

BACKGROUND: CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time. METHODS: Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years. RESULTS: At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group. CONCLUSIONS: ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation.

Assessment of chloroquine as a modulator of immune activation to improve CD4 recovery in immune nonresponding HIV-infected patients receiving antiretroviral therapy.

OBJECTIVES: Chloroquine (CQ), an anti-inflammatory drug, inhibits Toll-like receptor (TLR) signalling in plasmacytoid dendritic cells (pDCs) and may be beneficial for HIV-infected patients in whom immune activation persists despite effective antiretroviral therapy (ART). The effect of CQ on CD4 T-cell recovery and immune activation in immune nonresponding patients receiving successful ART was therefore studied. METHODS: Nineteen adults on ART with CD4 counts ≤ 350 cells/µL and undetectable viral load (VL) orally received CQ at 250 mg/day for 24 weeks. Side effects, CD4 and CD8 T-cell counts, VL, T-cell activation, pDC proportion and plasma inflammatory markers were assessed at baseline, at 24 weeks, and at 12 weeks after CQ discontinuation (clinicaltrial.org registration #NCT02004314). RESULTS: CQ was well tolerated and all patients maintained an undetectable VL. The absolute CD4 and CD8 T-cell counts and their percentages, the pDC proportion, T-cell activation, D-dimer and C-reactive protein (CRP) plasma levels and the kynurenine/tryptophan ratio did not change with CQ treatment. Among nine cytokines/chemokines measured, only levels of interferon (IFN)-α2 were significantly increased by CQ treatment. CONCLUSIONS: CQ was well tolerated in patients with low CD4 T-cell counts despite long-term effective ART; however, 24 weeks of CQ treatment did not improved CD4 T-cell recovery, lymphoid and myeloid immune activation or inflammatory markers.

Soluble CD40-ligand (sCD40L, sCD154) plays an immunosuppressive role via regulatory T cell expansion in HIV infection.

CD40/CD40-ligand (CD40L) signalling is a key stimulatory pathway which triggers the tryptophan (Trp) catabolizing enzyme IDO in dendritic cells and is immunosuppressive in cancer. We reported IDO-induced Trp catabolism results in a T helper type 17 (Th17)/regulatory T cell (Treg ) imbalance, and favours microbial translocation in HIV chronic infection. Here we assessed the link between sCD40L, Tregs and IDO activity in HIV-infected patients with different clinical outcomes. Plasmatic sCD40L and inflammatory cytokines were assessed in anti-retroviral therapy (ART)-naive, ART-successfully treated (ST), elite controllers (EC) and healthy subjects (HS). Plasma levels of Trp and its metabolite Kynurenine (Kyn) were measured by isotope dilution tandem mass spectrometry and sCD14 was assessed by enzyme-linked immunosorbent assay (ELISA). IDO-mRNA expression was quantified by reverse transcription-polymerase chain reaction (RT-PCR). The in-vitro functional assay of sCD40L on Treg induction and T cell activation were assessed on peripheral blood mononuclear cells (PBMCs) from HS. sCD40L levels in ART-naive subjects were significantly higher compared to ST and HS, whereas EC showed only a minor increase. In ART-naive alone, sCD40L was correlated with T cell activation, IDO-mRNA expression and CD4 T cell depletion but not with viral load. sCD40L was correlated positively with IDO enzymatic activity (Kyn/Trp ratio), Treg frequency, plasma sCD14 and inflammatory soluble factors in all HIV-infected patients. In-vitro functional sCD40L stimulation induced Treg expansion and favoured Treg differentiation by reducing central memory and increasing terminal effector Treg proportion. sCD40L also increased T cell activation measured by co-expression of CD38/human leucocyte antigen D-related (HLA-DR). These results indicate that elevated sCD40L induces immunosuppression in HIV infection by mediating IDO-induced Trp catabolism and Treg expansion.

Effect of BG-12 on contrast-enhanced lesions in patients with relapsing--remitting multiple sclerosis: subgroup analyses from the phase 2b study.

BACKGROUND: In a phase 2b study in patients with relapsing-remitting MS (RRMS), BG-12 240 mg three times daily significantly reduced the number of new gadolinium-enhanced (Gd+) lesions from weeks 12 to 24 (primary end point) by 69% compared with placebo. OBJECTIVE: In this analysis, the effect of BG-12 240 mg three times daily on the number of Gd+ lesions from weeks 12 to 24 was evaluated in subgroups based on baseline disease characteristics and demographics. METHODS: Two hundred and fifty-seven patients were randomized equally to receive BG-12 (120 mg once daily or three times daily or 240 mg three times daily) or placebo. RESULTS: BG-12 240 mg three times daily significantly reduced the number of new Gd+ lesions compared with placebo in the following subgroups: Expanded Disability Status Scale (EDSS) score ≤ 2.5 (74%), EDSS score > 2.5 (63%), no Gd+ lesions (80%), ≥ 1 Gd+ lesion (55%), age < 40 years (49%), age ≥ 40 years (89%), female patients (81%), disease duration ≤ 6 years (81%) and disease duration > 6 years (54%) (all comparisons p < 0.05). CONCLUSION: BG-12 demonstrated efficacy in patients with RRMS by decreasing new Gd+ lesion development across a range of subgroups defined by baseline disease characteristics or demographics.

Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study.

BACKGROUND: Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis. METHODS: 257 patients, aged 18-55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4-24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701. FINDINGS: Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1.4 vs 4.5, p<0.0001). It also reduced number of new or enlarging T2-hyperintense (p=0.0006) and new T1-hypointense (p=0.014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0.44 vs 0.65 for placebo; p=0.272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot. INTERPRETATION: The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups.

Influence of RANTES, SDF-1 and TGF-beta levels on the value of interleukin-7 as a predictor of virological response in HIV-1-infected patients receiving double boosted protease inhibitor-based therapy.

OBJECTIVES: Interleukin-7 (IL-7), RANTES (regulated on activation, normal T cell expressed and secreted), stromal cell-derived factor-1 (SDF-1) and transforming growth factor-beta (TGF-beta) appear to share certain biological properties in vitro and all are involved in HIV-1 disease progression. Our earlier observations indicated that IL-7 levels decrease upon CD4 T-cell recovery and represent a new, independent predictor of virological response. Here, we examine associations among circulating levels of IL-7, RANTES, SDF-1 and TGF-beta in hopes of gaining insight into their contribution to the predictive value of IL-7. METHODS: Levels of IL-7, RANTES, SDF-1 and TGF-beta, and immune and viral parameters were assessed in HIV-1-infected patients. RESULTS: Cross-sectional (n=148) and longitudinal (n=36) analyses showed that levels of IL-7, but not RANTES, SDF-1 or TGF-beta, were increased in HIV-1-infected adults compared with those of healthy controls. In the cross-sectional study, levels of IL-7 were correlated with RANTES (r=0.31, P=0.002) and TGF-beta (r=0.53, P<0.001) but not with SDF-1 (r=0.12, P=0.22), and these associations were more pronounced in patients with CD4 T-cell counts >200 cells/microL. In contrast to IL-7, levels of RANTES, SDF-1 and TGF-beta were not correlated with CD4 T-cell counts. Longitudinal analysis revealed a marked decline in IL-7 levels accompanied by an increase in CD4 T-cell count following antiretroviral therapy (ART), but no changes in RANTES, SDF-1 or TGF-beta levels. Multivariate regression analysis showed no influence of baseline RANTES, SDF-1 or TGF-beta levels on the value of IL-7 as a predictor of virological response at 48 weeks. CONCLUSIONS: Collectively, these results indicate that changes in IL-7 levels did not induce changes in RANTES, SDF-1 or TGF-beta. Furthermore, they indicate that RANTES, SDF-1 or TGF-beta levels do not explain the predictor value of IL-7 in patients receiving ART.

Interleukin-7 levels may predict virological response in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy.

OBJECTIVES: To examine the relationship between levels of the T-cell regulatory cytokine interleukin-7 (IL-7) and CD4 cell counts during immune reconstitution and to assess its prognostic value in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy. METHODS: Thirty-six HIV-1-infected adults who completed 48 weeks of follow-up visits were included in this prospective study. Patients having failed two or more antiretroviral therapy regimens were treated with lopinavir/ritonavir-based therapy. An enzyme-linked immunosorbent assay was used to determine IL-7 plasma levels, flow cytometry was used to analyse cell surface antigens, and polymerase chain reaction was used to quantify plasma HIV-1. RESULTS: Pretreatment IL-7 levels were elevated in all patients (mean 11.0 pg/mL) and were negatively correlated with CD4 cell counts and age (r=-0.59, P<0.001 and r=-0.57, P<0.001, respectively). During the course of treatment, IL-7 levels decreased by 34% while CD4 cell numbers progressively increased by 88%. Multivariate regression analysis showed that only pretreatment IL-7 levels predicted viral load at 48 weeks when controlling for baseline CD4 cell counts, viral load and patient demographics. CONCLUSIONS: These findings are consistent with regulation of T-cell recovery by IL-7, and suggest that IL-7 measurements might be used to predict virological response.

Drug use and human rights: privacy, vulnerability, disability, and human rights infringements.

Drug use is a complex social phenomenon involving the drugs which are used, the people using them, the context in which they are acquired and used, and the social construction of drug use by society and by governments. It is a popular yet controversial behavior which elicits extreme public opinion. Discourse about drug use is often polarized, emotional, and divisive. This is most evident in the approaches used or proposed to control drug use and the risks and harms associated with its use and control. Despite this, there is almost no discourse about the human rights of drug users. This Article addresses this issue by examining the privacy rights of drug users, their vulnerability to use drugs and to be harmed by using them, and the deprivation of opportunities for drug users to exercise their rights. This Article will also analyze disabilities attributable to drug use, as well as situations in which the human rights of drug users are likely to be infringed.

Asplenism and systemic lupus erythematosus.

Although functional hyposplenism, secondary to Fc-receptor blockage by circulating immune complexes saturation, has been described in systemic lupus erythematosus (SLE), only few cases of complete asplenism have been reported. We observed a 60-year-old woman with congenital asplenism who presented with active SLE. The course and the clinical characteristics of such patients are reviewed and the relationship between the asplenic state and initiation and severity of SLE are discussed. These patients are at high risk for fatal pneumococcemia and pneumococcal vaccine is recommended even if long term results are still conflicting.

Stigmatization, scapegoating and discrimination in sexually transmitted diseases: overcoming 'them' and 'us'.

It is recognized that AIDS involves multiple epidemics. As well as an epidemic of HIV, we are experiencing epidemics of fear and of stigmatization, scapegoating and discrimination associated with AIDS. In this paper, we investigate the nature of these reactions and the links between them. In doing so, we identify some of their causes. We likewise investigate counter-reactions, pre-eminent among which is the promotion of concepts of respect for persons and for human rights. We also examine the 'tools' used to elicit and manifest both these reactions and counter-reactions. In all cases, these 'tools' include choice of language--especially in the form of metaphor and rhetoric--and the use of symbolism. We conclude that in order to deal humanely and compassionately with AIDS and persons with AIDS, and, ultimately, to protect society (including, the fundamental principles and rules on which it is based), a primary requirement is to recognize that we are all living with AIDS, whether infected or affected by it; that is, in the context of AIDS, it is imperative that we overcome any divisions into 'them' and 'us'.

Discontinuation of total parenteral nutrition in a patient with acquired immunodeficiency syndrome: a Canadian perspective.

Provision of nourishment to terminally ill patients has been a controversial topic in clinical medicine. Determination of the limits of palliative care requires an understanding of the disease process, as well as the boundaries of patient self-determination. With the advent of living wills, the determination of the patient to limit care, including nutrition support, has become socially acceptable. Difficulties arise when there are differences of opinion between the caregiver and the patient. The solutions to these conflicts are often decided in the courtroom, as demonstrated by the Cruzan and Quinlan cases. Living wills are often written to prevent unnecessary financial burdens in hopeless situations. As well, financial considerations influence the decisions made by caregivers in providing care to terminally ill patients. The following case report illustrates the conflict between patient self-determination and limitation of care for financial reasons. The use of substituted judgment within the Canadian health care system and the role of team meetings to resolve ethical decisions are discussed.

Economic impact of HIV infection and coronary heart disease in immigrants to Canada.

OBJECTIVE: To compare the direct health care costs of illnesses associated with the human immunodeficiency virus (HIV) and of coronary heart disease (CHD) in immigrants to Canada. DESIGN: Comparative cost analysis. PARTICIPANTS: All people who immigrated to Canada in 1988. The numbers with HIV infection and CHD were estimated from country-specific HIV seroprevalence data and national CHD mortality statistics and data from the Framingham study. Health care costs, projected over the 10 years after immigration, were calculated on the basis of data from the Hospital Medical Records Institute and provincial fee schedules. RESULTS: Of the 161,929 immigrants in 1988, 484 were estimated to be HIV positive. The total cost of treatment of HIV-related illnesses from 1989 to 1998 (discounted at 3%) would be $18.5 million: $17.1 million would be spent on the outpatient and inpatient care of the HIV-positive immigrants, $1.0 million on care of the subsequently infected sexual partners and $0.4 million on care of the HIV-positive children born to seropositive immigrant women. In comparison, CHD would develop in 2558 immigrants during the same 10-year period. The total CHD costs would be $21.6 million: $8.4 million would be spent on treating myocardial infarction, $3.2 million on coronary artery bypass grafting, $1.6 million on pacemaker insertion and $8.4 million on treating other CHD events. CONCLUSIONS: The economic impact of HIV infection in immigrants to Canada is similar to that of CHD. This comparison identifies an important shortcoming in current immigration policy: economic considerations can be arbitrarily applied to certain diseases, thereby discriminating against specific groups of immigrants.

The clinical utility of serum lactate dehydrogenase in diagnosing pneumocystis carinii pneumonia among hospitalized AIDS patients.

It has been previously demonstrated that serum lactate dehydrogenase is elevated among HIV patients with pneumocystis carinii pneumonia (PCP). To evaluate the clinical utility of this test we analyzed the admission LDH levels of patients hospitalized for the first time due to the secondary complications of AIDS. Among 76 patients without a prior history of PCP, 41 (54%) had PCP diagnosed during their hospitalization while 35 (46%) did not have PCP. Serum LDH was significantly higher among PCP patients than in patients without PCP (mean = 423 IU/L vs 234 IU/L). Receiver operating characteristic curve analysis demonstrated that at an optimal cutoff point of LDH greater than or equal to 240 IU/L, the test sensitivity and specificity were 0.78 and 0.74 respectively among all hospitalized patients. However, when only patients with dyspnea were considered, the optimal test sensitivity and specificity improved to 0.94 and 0.78 at a cutoff point of LDH greater than or equal to 220 IU/L. Comparing the areas under fitted ROC curves, serum LDH was a significantly better discriminator among patients with dyspnea than among those who were not short of breath. We conclude that while serum LDH is strongly associated with the presence of PCP among AIDS patients, it is a poor screening test for PCP when applied to all hospitalized AIDS patients with and without respiratory complaints. Serum LDH is no substitute for appropriate microbiological studies. However, with further evaluation, it may prove to be a useful test in guiding the clinical management of dyspneic patients in whom sputum or bronchial examinations are negative or not immediately available.

HIV disease: present status and future directions.

This review of the human immunodeficiency virus (HIV) epidemic shows that HIV has had and will have a major impact on dentistry, just as it has had on so many other aspects of medical practice and society. These areas include the prevention of HIV transmission in the dental care workplace, the early and safe care and treatment of those who are infected, and the protection of those who are vulnerable or made more vulnerable because of HIV infection. To do this, the dental professional must be educated about HIV and its diseases, their treatment, and what must be done to prevent HIV transmission. Early recognition and treatment of HIV-related oral diseases have become the norms of practice today. Although more and more dentists face potential exposure to HIV, excellent dental care can be provided while minimizing this risk.