We Are All in This Together-Whole of Community Pain Science Education Campaigns to Promote Better Management of Persistent Pain.

Persistent pain is a major public health issue-estimated to affect a quarter of the world's population. Public understanding of persistent pain is based on outdated biomedical models, laden with misconceptions that are contrary to best evidence. This understanding is a barrier to effective pain management. Thus, there have been calls for public health-based interventions to address these misconceptions. Previous pain-focussed public education campaigns have targeted pain beliefs and behaviours that are thought to promote recovery, such as staying active. However, prevailing pain-related misconceptions render many of these approaches counter-intuitive, at best. Pain Science Education improves understanding of 'how pain works' and has been demonstrated to improve pain and disability outcomes. Extending Pain Science Education beyond the clinic to the wider community seems warranted. Learning from previous back pain-focussed and other public health educational campaigns could optimise the potential benefit of such a Pain Science Education campaign. Pain Science Education-grounded campaigns have been delivered in Australia and the UK and show promise, but robust evaluations are needed before any firm conclusions on their population impact can be made. Several challenges exist going forward. Not least is the need to ensure all stakeholders are involved in the development and implementation of Pain Science Education public messaging campaigns. Furthermore, it is crucial that campaigns are undertaken through a health equity lens, incorporating underrepresented communities to ensure that any intervention does not widen existing health inequalities associated with persistent pain. PERSPECTIVE: Public misconceptions about pain are a significant public health challenge and a viable intervention target to reduce the personal, social, and economic burden of persistent pain. Adaptation of Pain Science Education, which improves misconceptions in a clinical setting, into the public health setting seems a promising approach to explore.

Effect of high dose vitamin D3 on the HIV-1 reservoir: A pilot randomised controlled trial.

Introduction: Antiretroviral therapy for people living with HIV-1 must be taken lifelong due to the persistence of latent virus in long-lived and proliferating CD4+ T cells. Vitamin D3 is a steroidal gene transcription regulator which exerts diverse effects on immune and epithelial cells including reductions in CD4+ T cell proliferation and improvement in gut barrier integrity. We hypothesised that a high dose of vitamin D3 would reduce the size of the HIV-1 reservoir by reducing CD4+ T cell proliferation. Methods: We performed a randomised placebo-controlled trial evaluating the effect of 24 weeks of vitamin D3 (10,000 international units per day) on the HIV-1 reservoir and immunologic parameters in 30 adults on antiretroviral therapy; participants were followed for 12 weeks post-treatment. The primary endpoint was the effect on total HIV-1 DNA at week 24. Parameters were assessed using mixed-effects models. Results: We found no effect of vitamin D3 on the change in total HIV-1 DNA from week 0 to week 24 relative to placebo. There were also no changes in integrated HIV-1 DNA, 2-long-terminal repeat (2-LTR) circles or cell-associated HIV-1 RNA. Vitamin D3 induced a significant increase in the proportion of central memory CD4+ and CD8+ T cells, a reduction in the proportion of senescent CD8+ T cells and a reduction in the natural killer cell frequency at all time points including week 36, 12 weeks after the study drug cessation. At week 36, there was a significant reduction in total HIV-1 DNA relative to placebo and persistently elevated 25-hydroxyvitamin D levels. No significant safety issues were identified. Conclusions: Vitamin D3 administration had a significant impact on the T cell differentiation but overall effects on the HIV-1 reservoir were limited and a reduction in HIV-1 DNA was only seen following cessation of the study drug. Additional studies are required to determine whether the dose and duration of vitamin D3 can be optimised to promote a continued depletion of the HIV-1 reservoir over time. Trial registration: ClinicalTrials.gov NCT03426592.

Cross-sectional study examining the epidemiology of chronic pain in Nepal.

Introduction: The World Health Organization recognizes chronic pain as a global public health concern; however, there is a bias towards research conducted in relatively affluent nations. There is a dearth of large-scale epidemiological studies in Nepal using rigorously validated, cross-culturally adapted instruments. Objectives: The aim of this study was to examine the prevalence of both chronic pain and chronic pain of predominantly neuropathic origin and their associations with a range of sociodemographic and psychosocial characteristics. Methods: We conducted a cross-sectional study of adults (≥18 years) in all households in Ranipani, Baluwa Village Development Committee, Nepal. All adults (n = 887) were approached, and those consenting, who met the inclusion criteria (n = 520, 58.6%), participated. Questionnaires validated in Nepali were used to examine several constructs: demographics; chronic pain; neuropathic pain; pain catastrophizing; resilience, pain intensity; pain interference; sleep disturbance; and depression. Results: The point prevalence of chronic pain was 53.3% (n = 277). The point prevalence of chronic pain of predominantly neuropathic origin was 12.7% (n = 66). Chronic pain was associated with female gender, older age, and manual labour occupations. Using standardized scoring techniques, compared with available population estimates from other countries, those with chronic pain were associated with lower pain intensity and resilience scores and higher pain catastrophizing, pain interference, and depression scores. Conclusion: These findings are broadly comparable to epidemiological studies from other countries, and these indicate areas for targeting interventions (eg, occupational and mental health). For comparison, more data are needed, from larger population samples in this region.

The core minimum dataset for measuring pain outcomes in pain services across Scotland. Developing and testing a brief multi-dimensional questionnaire.

Background: There is currently no agreed minimum dataset to inform specialist chronic pain service provision. We aimed to develop a Core Minimum Dataset (CMD) for pain services in Scotland and perform preliminary analysis to evaluate its psychometric properties in adults with chronic pain. Methods: The questionnaire was developed following a review of existing relevant data collection instruments and national consultation. The CMD questionnaire was completed alongside a routine pre-clinic questionnaire by patients attending two pain services over 3 months. Concurrent validity was tested by comparing scores between the CMD and pre-existing questionnaires. Reliability was assessed by test-retest and discriminative validity via receiver operating characteristic (ROC) curves. Results: The final CMD questionnaire consisted of five questions on four domains: pain severity (Chronic Pain Grade [CPG] Q1); pain interference (CPG Q5); emotional impact (Patient Health Questionnaire-2 [PHQ-2], two questions); and quality of life (Short Form Health Survey-36 [SF-36] Q1). 530 patients completed the questionnaire. Strong correlation was found with the Hospital Anxiety and Depression Scale (rs = 0.753, p < 0.001). Moderate correlations were found with the Brief Pain Inventory for pain interference (rs = 0.585, p < 0.001) and pain severity (rs = 0.644, p < 0.001). Moderate to good reliability was demonstrated (Intra-class Correlation Coefficient = 0.572-0.845). All items indicated good discrimination for relevant health states. Conclusions: The findings represent initial steps towards developing an accurate questionnaire that is feasible for assessing chronic pain in adults attending specialist pain clinics and measuring service improvements in Scotland. Further validation testing, in clinical settings, is now required.

Memory CD4+ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency.

Programmed cell death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) suppress CD4+ T cell activation and may promote latent HIV infection. By performing leukapheresis (n = 21) and lymph node biopsies (n = 8) in people with HIV on antiretroviral therapy (ART) and sorting memory CD4+ T cells into subsets based on PD1/CTLA4 expression, we investigate the role of PD1 and CTLA 4 in HIV persistence. We show that double-positive (PD1+CTLA4+) cells in blood contain more HIV DNA compared with double-negative (PD1-CTLA4-) cells but still have a lower proportion of cells producing multiply spliced HIV RNA after stimulation as well as reduced upregulation of T cell activation and proliferation markers. Transcriptomics analyses identify differential expression of key genes regulating T cell activation and proliferation with MAF, KLRB1, and TIGIT being upregulated in double-positive compared with double-negative cells, whereas FOS is downregulated. We conclude that, in addition to being enriched for HIV DNA, double-positive cells are characterized by negative signaling and a reduced capacity to respond to stimulation, favoring HIV latency.

Pediatric Prediction Model for Low Immunoglobulin G Level Based on Serum Globulin and Illness Status.

Hypogammaglobulinemia is a condition that requires prompt diagnosis and treatment. Unfortunately, serum immunoglobulin (Ig) measurements are not widely accessible in numerous developing countries. Serum globulin is potentially the best candidate for screening of low IgG level (IgGLo) due to its high availability, low cost, and rapid turnover time. However, multiple factors may influence the probability of prediction. Our study aimed to establish a simple prediction model using serum globulin to predict the likelihood of IgGLo in children. For retrospective data of patients who were suspected of having IgGLo, both serum IgG and globulin were simultaneously collected and measured. Potential factors interfering with serum globulin and IgG levels were investigated for their impact using bivariate binary logistic regression. A multivariate binary logistic regression was used to generate a formula and score to predict IgGLo. We obtained 953 samples from 143 pediatric patients. A strong positive correlation between serum globulin and IgG levels was observed (r=0.83, p < 0.001). A screening test model using serum globulin and illness status was constructed to predict IgGLo. The formula for predicting IgGLo was generated as follows; Predicted score = (2 x globulin (g/dl)) - illness condition score (well=0, sick=1). When the score was <4, the patient has the probability of having IgGLo with a sensitivity of 0.78 (0.71, 0.84), a specificity of 0.71 (0.68, 0.74), PPV of 0.34 (0.29, 0.40) and NPV of 0.94 (0.92, 0.96). This formula will be useful as rapid and inexpensive screening tool for early IgGLo detection, particularly in countries/locations where serum IgG measurement is inaccessible.

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy.

In people with HIV (PWH) on antiretroviral therapy (ART), immune dysfunction persists, including elevated expression of immune checkpoint (IC) proteins on total and HIV-specific T cells. Reversing immune exhaustion is one strategy to enhance the elimination of HIV-infected cells that persist in PWH on ART. We aimed to evaluate whether blocking CTL-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell Ig domain and mucin domain 3 (TIM-3), T cell Ig and ITIM domain (TIGIT) and lymphocyte activation gene-3 (LAG-3) alone or in combination would enhance HIV-specific CD4+ and CD8+ T cell function ex vivo. Intracellular cytokine staining was performed using human PBMCs from PWH on ART (n = 11) and expression of CD107a, IFN-γ, TNF-α, and IL-2 was quantified with HIV peptides and Abs to IC. We found the following: 1) IC blockade enhanced the induction of CD107a and IL-2 but not IFN-γ and TNF-α in response to Gag and Nef peptides; 2) the induction of CD107a and IL-2 was greatest with multiple combinations of two Abs; and 3) Abs to LAG-3, CTLA-4, and TIGIT in combinations showed synergistic induction of IL-2 in HIV-specific CD8+ and CD107a and IL-2 production in HIV-specific CD4+ and CD8+ T cells. These results demonstrate that the combination of Abs to LAG-3, CTLA-4, or TIGIT can increase the frequency of cells expressing CD107a and IL-2 that associated with cytotoxicity and survival of HIV-specific CD4+ and CD8+ T cells in PWH on ART. These combinations should be further explored for an HIV cure.

Multiparameter immunohistochemistry analysis of HIV DNA, RNA and immune checkpoints in lymph node tissue.

The main barrier to a cure for HIV is the persistence of long-lived and proliferating latently infected CD4+ T-cells despite antiretroviral therapy (ART). Latency is well characterized in multiple CD4+ T-cell subsets, however, the contribution of regulatory T-cells (Tregs) expressing FoxP3 as well as immune checkpoints (ICs) PD-1 and CTLA-4 as targets for productive and latent HIV infection in people living with HIV on suppressive ART is less well defined. We used multiplex detection of HIV DNA and RNA with immunohistochemistry (mIHC) on formalin-fixed paraffin embedded (FFPE) cells to simultaneously detect HIV RNA and DNA and cellular markers. HIV DNA and RNA were detected by in situ hybridization (ISH) (RNA/DNAscope) and IHC was used to detect cellular markers (CD4, PD-1, FoxP3, and CTLA-4) by incorporating the tyramide system amplification (TSA) system. We evaluated latently infected cell lines, a primary cell model of HIV latency and excisional lymph node (LN) biopsies collected from people living with HIV (PLWH) on and off ART. We clearly detected infected cells that coexpressed HIV RNA and DNA (active replication) and DNA only (latently infected cells) in combination with IHC markers in the in vitro infection model as well as LN tissue from PLWH both on and off ART. Combining ISH targeting HIV RNA and DNA with IHC provides a platform to detect and quantify HIV persistence within cells identified by multiple markers in tissue samples from PLWH on ART or to study HIV latency.

Validation of the Nepali Version of the Self-reported Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) in Adults With Chronic Pain and Predominantly Low-literacy Levels.

Neuropathic pain research and clinical care is limited in low- and middle-income countries with high prevalence of chronic pain such as Nepal. We translated and cross-culturally adapted the Self-report version of the Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS)-a commonly used, reliable and valid instrument to screen for pain of predominantly neuropathic origin (POPNO)-into Nepali (S-LANSS-NP) and validated it using recommended guidelines. We recruited 30 patients with chronic pain in an outpatient setting for cognitive debriefing and recruited 287 individuals with chronic pain via door-to-door interviews for validation. For known-group validity, we hypothesized that the POPNO group would report significantly more pain intensity and pain interference than the chronic pain group without POPNO using a cut-off score of ≥10/24. The S-LANSS-NP was comprehensible based on the ease of understanding the questionnaire and lack of missing responses. The validation sample consisted of predominantly low-levels of literacy (81% had 5 years or less education); 23% were classified as having POPNO. Internal consistency was good (alpha = .80). Known-group validity was supported (chronic pain with POPNO reported significantly greater pain intensity than those without). The S-LANSS-NP is a comprehensible, unidimensional, internally consistent, and valid instrument to screen POPNO in individuals with chronic pain with predominantly low-levels of literacy for clinical and research use. PERSPECTIVE: This paper shows that the Nepali version of the S-LANSS is comprehensible, reliable and valid in adults with chronic pain and predominantly low-levels of literacy in rural Nepal. The study could potentially develop research and clinical care of neuropathic pain in this resource-limited setting where chronic pain is a significant problem.

Massive acetaminophen overdose with metabolic acidosis refractory to N-acetylcysteine, fomepizole, and renal replacement therapy.

Massive Acetaminophen (N-acetyl-p-aminophenol; APAP) overdose is a common presentation to emergency departments around the world. While N-acetylcysteine (NAC) remains the cornerstone of treatment for APAP overdose, extracorporeal treatment, in the form of renal replacement therapy with intermittent hemodialysis (IHD) or continuous renal replacement therapy (CRRT) may provide benefit in cases associated with altered mental status and metabolic acidosis. One treatment with IHD is typically sufficient for resolution of acidosis and global improvement clinically. We describe a case of massive APAP overdose presenting with altered mental status and lactic acidosis, refractory to multiple treatments of IHD as well as CRRT and high-dose NAC along with fomepizole. Despite these interventions, fulminant liver failure progressed with cerebral edema, coagulopathy and death. This is the first description of a fatal acetaminophen ingestion refractory to both IHD and prolonged CRRT. This case highlights the need for further investigation in the management of massive APAP overdose, including optimal method and timing of renal replacement therapy.

Frugal Innovation: Enabling Mechanical Ventilation During Coronavirus Disease 2019 Pandemic in Resource-Limited Settings.

ICUs worldwide are facing resource shortages including increased need for provision of invasive mechanical ventilation during the current coronavirus disease 2019 pandemic. Fearing shortage of ventilators, many private companies and public institutions have focused on building new inexpensive, open-source ventilators. However, designing and building new ventilators is not sufficient for addressing invasive mechanical ventilation needs in resource-limited settings. In this commentary, we highlight additional interdependent constraints that should be considered and provide a framework for addressing these constraints to ensure that the increasing stockpile of open-source ventilators are easily deployable and sustainable for use in resource-limited settings.

Knowledge translation tools to guide care of non-intubated patients with acute respiratory illness during the COVID-19 Pandemic.

Providing optimal care to patients with acute respiratory illness while preventing hospital transmission of COVID-19 is of paramount importance during the pandemic; the challenge lies in achieving both goals simultaneously. Controversy exists regarding the role of early intubation versus use of non-invasive respiratory support measures to avoid intubation. This review summarizes available evidence and provides a clinical decision algorithm with risk mitigation techniques to guide clinicians in care of the hypoxemic, non-intubated, patient during the COVID-19 pandemic. Although aerosolization of droplets may occur with aerosol-generating medical procedures (AGMP), including high flow nasal oxygen and non-invasive ventilation, the risk of using these AGMP is outweighed by the benefit in carefully selected patients, particularly if care is taken to mitigate risk of viral transmission. Non-invasive support measures should not be denied for conditions where previously proven effective and may be used even while there is suspicion of COVID-19 infection. Patients with de novo acute respiratory illness with suspected/confirmed COVID-19 may also benefit. These techniques may improve oxygenation sufficiently to allow some patients to avoid intubation; however, patients must be carefully monitored for signs of increased work of breathing. Patients showing signs of clinical deterioration or high work of breathing not alleviated by non-invasive support should proceed promptly to intubation and invasive lung protective ventilation strategy. With adherence to these principles, risk of viral spread can be minimized.

Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART.

The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p<0.001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.

Management of anteromedial coronoid fractures according to a protocol focused on instability assessment provides good outcomes with infrequent need for coronoid fixation.

BACKGROUND: Anteromedial coronoid fractures (AMCFs) are associated with persistent elbow instability and post-traumatic arthritis if managed incorrectly. It is unclear exactly which AMCFs require surgical intervention and how to make this decision. The aims of this study were to report outcomes of AMCFs managed using a protocol based on reproduction of instability using radiographic and clinical testing and to ascertain a threshold size of AMCF associated with instability. METHODS: Forty-three AMCFs were studied. Thirty-two patients formed the primary study group (group A). All were treated using a protocol in which the decision to perform coronoid fixation was based on the presence of radiographic or clinical evidence of instability. Functional outcomes (Oxford Elbow Score), radiographic outcomes, complications, and reoperations were collected, and a receiver operating characteristic curve analysis was performed to assess the optimal coronoid fracture height to recommend coronoid fixation. The results were compared with a historical group of 11 patients with AMCFs not treated according to the protocol (group B). RESULTS: Of the patients, 23 had an isolated AMCF and 20 had a concurrent radial head injury. Complete nonoperative treatment of the elbow was performed in 16 patients (37%) (11 of 32 [34%] in group A vs. 5 of 11 [45%] in group B, P = .46). In 10 patients (23%), only repair of the lateral collateral ligament was performed (9 in group A and 1 in group B), whereas 8 patients (19%) underwent repair of the lateral collateral ligament and radial head fixation or replacement (6 in group A and 2 in group B). Acute coronoid fixation was performed in 9 patients (21%) (6 in group A and 3 in group B). At a mean follow-up of 20 months (range, 12-56 months), group A showed a significantly better Oxford Elbow Score (42 vs. 31, P = .02), lower complication rate (3 of 32 [9%] vs. 8 of 11 [72%], P < .001), and lower reoperation rate (1 of 32 [3%] vs. 6 of 11 [54%], P < .001) than group B. Persistent instability was found in 6 patients in group B and none in group A. The receiver operating characteristic curve analysis demonstrated 6.5 mm to be the optimal AMCF size for surgery to prevent persistent instability. CONCLUSION: Patients treated according to a protocol in which preoperative reproduction of instability determined the degree of surgical intervention had good clinical and radiographic outcomes. Our study demonstrated that AMCFs > 6.5 mm are likely to be more unstable and require intervention. If these principles are followed, a specifically defined subset of AMCFs can be treated nonsurgically without adverse outcomes.

Influenza-specific IgG1+ memory B-cell numbers increase upon booster vaccination in healthy adults but not in patients with predominantly antibody deficiency.

BACKGROUND: Annual influenza vaccination is recommended to all individuals over 6 months of age, including predominantly antibody deficiency (PAD) patients. Vaccination responses are typically evaluated by serology, and because PAD patients are by definition impaired in generating IgG and receive immunoglobulin replacement therapy (IgRT), it remains unclear whether they can mount an antigen-specific response. OBJECTIVE: To quantify and characterise the antigen-specific memory B (Bmem) cell compartment in healthy controls and PAD patients following an influenza booster vaccination. METHODS: Recombinant hemagglutinin (HA) from the A/Michigan/2015 H1N1 (AM15) strain with an AviTag was generated in a mammalian cell line, and following targeted biotinylation, was tetramerised with BUV395 or BUV737 streptavidin conjugates. Multicolour flow cytometry was applied on blood samples before and 28 days after booster influenza vaccination in 16 healthy controls and five PAD patients with circulating Bmem cells. RESULTS: Recombinant HA tetramers were specifically recognised by 0.5-1% of B cells in previously vaccinated healthy adults. HA-specific Bmem cell numbers were significantly increased following booster vaccination and predominantly expressed IgG1. Similarly, PAD patients carried HA-specific Bmem cells, predominantly expressing IgG1. However, these numbers were lower than in controls and did not increase following booster vaccination. CONCLUSION: We have successfully identified AM15-specific Bmem cells in healthy controls and PAD patients. The presence of antigen-specific Bmem cells could offer an additional diagnostic tool to aid in the clinical diagnosis of PAD. Furthermore, alterations in the number or immunophenotype of HA-specific Bmem cells post-booster vaccination could assist in the evaluation of immune responses in individuals receiving IgRT.

C-reactive protein as a potential biomarker for disease progression in dengue: a multi-country observational study.

BACKGROUND: Dengue infection can cause a wide spectrum of clinical outcomes. The severe clinical manifestations occur sufficiently late in the disease course, during day 4-6 of illness, to allow a window of opportunity for risk stratification. Markers of inflammation may be useful biomarkers. We investigated the value of C-reactive protein (CRP) measured early on illness days 1-3 to predict dengue disease outcome and the difference in CRP levels between dengue and other febrile illnesses (OFI). METHOD: We performed a nested case-control study using the clinical data and samples collected from the IDAMS-consortium multi-country study. This was a prospective multi-center observational study that enrolled almost 8000 participants presenting with a dengue-like illness to outpatient facilities in 8 countries across Asia and Latin America. Predefined severity definitions of severe and intermediate dengue were used as the primary outcomes. A total of 281 cases with severe/intermediate dengue were compared to 836 uncomplicated dengue patients as controls (ratio 1:3), and also 394 patients with OFI. RESULTS: In patients with confirmed dengue, median (interquartile range) of CRP level within the first 3 days was 30.2 mg/L (12.4-61.2 mg/L) (uncomplicated dengue, 28.6 (10.5-58.9); severe or intermediate dengue, 34.0 (17.4-71.8)). Higher CRP levels in the first 3 days of illness were associated with a higher risk of severe or intermediate outcome (OR 1.17, 95% CI 1.07-1.29), especially in children. Higher CRP levels, exceeding 30 mg/L, also associated with hospitalization (OR 1.37, 95% CI 1.14-1.64) and longer fever clearance time (HR 0.84, 95% CI 0.76-0.93), especially in adults. CRP levels in patients with dengue were higher than patients with potential viral infection but lower than patients with potential bacterial infection, resulting in a quadratic association between dengue diagnosis and CRP, with levels of approximately 30 mg/L associated with the highest risk of having dengue. CRP had a positive correlation with total white cell count and neutrophils and negative correlation with lymphocytes, but did not correlate with liver transaminases, albumin, or platelet nadir. CONCLUSIONS: In summary, CRP measured in the first 3 days of illness could be a useful biomarker for early dengue risk prediction and may assist differentiating dengue from other febrile illnesses.

Diverse effects of interferon alpha on the establishment and reversal of HIV latency.

HIV latency is the major barrier to a cure for people living with HIV (PLWH) on antiretroviral therapy (ART) because the virus persists in long-lived non-proliferating and proliferating latently infected CD4+ T cells. Latently infected CD4+ T cells do not express viral proteins and are therefore not visible to immune mediated clearance. Therefore, identifying interventions that can reverse latency and also enhance immune mediated clearance is of high interest. Interferons (IFNs) have multiple immune enhancing effects and can inhibit HIV replication in activated CD4+ T cells. However, the effects of IFNs on the establishment and reversal of HIV latency is not understood. Using an in vitro model of latency, we demonstrated that plasmacytoid dendritic cells (pDC) inhibit the establishment of HIV latency through secretion of type I IFNα, IFNß and IFNω but not IFNε or type III IFNλ1 and IFNλ3. However, once latency was established, IFNα but no other IFNs were able to efficiently reverse latency in both an in vitro model of latency and CD4+ T cells collected from PLWH on suppressive ART. Binding of IFNα to its receptor expressed on primary CD4+ T cells did not induce activation of the canonical or non-canonical NFκB pathway but did induce phosphorylation of STAT1, 3 and 5 proteins. STAT5 has been previously demonstrated to bind to the HIV long terminal repeat and activate HIV transcription. We demonstrate diverse effects of interferons on HIV latency with type I IFNα; inhibiting the establishment of latency but also reversing HIV latency once latency is established.