Natural IgM Prevents Autoimmunity by Enforcing B Cell Central Tolerance Induction

It is unclear why selective deficiency in secreted (s)IgM causes Ab-mediated autoimmunity. We demonstrate that sIgM is required for normal B cell development and selection. The CD5(+) B cells that were previously shown to accumulate in body cavities of sIgM(-/-) mice are not B-1a cells, but CD19(int), CD43(-), short-lived, BCR signaling-unresponsive anergic B-2 cells. Body cavity B-1 cells were >10-fold reduced, including VH11(+) and phosphotidylcholine-specific B-1a cells, whereas splenic B-1 cells were unaffected and marginal zone B cells increased. Follicular B cells had higher turnover rates, survived poorly after adoptive transfer, and were unresponsiveness to BCR stimulation in vitro. sIgM bound to B cell precursors and provided a positive signal to overcome a block at the pro/pre-B stage and during IgVH repertoire selection. Polyclonal IgM rescued B cell development and returned autoantibody levels to near normal. Thus, natural IgM deficiency causes primary autoimmune disease by altering B cell development, selection, and central tolerance induction

Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

The positive transcription elongation factor b (P-TEFb) is a critical coactivator for transcription of most cellular and viral genes, including those of HIV. While P-TEFb is regulated by 7SK snRNA in proliferating cells, P-TEFb is absent due to diminished levels of CycT1 in quiescent and terminally differentiated cells, which has remained unexplored. In these cells, we found that CycT1 not bound to CDK9 is rapidly degraded. Moreover, productive CycT1:CDK9 interactions are increased by PKC-mediated phosphorylation of CycT1 in human cells. Conversely, dephosphorylation of CycT1 by PP1 reverses this process. Thus, PKC inhibitors or removal of PKC by chronic activation results in P-TEFb disassembly and CycT1 degradation. This finding not only recapitulates P-TEFb depletion in resting CD4+ T cells but also in anergic T cells. Importantly, our studies reveal mechanisms of P-TEFb inactivation underlying T cell quiescence, anergy, and exhaustion as well as proviral latency and terminally differentiated cells

Interactions between climate change, urban infrastructure and mobility are driving dengue emergence in Vietnam

Dengue is expanding globally, but how dengue emergence is shaped locally by interactions between climatic and socio-environmental factors is not well understood. Here, we investigate the drivers of dengue incidence and emergence in Vietnam, through analysing 23 years of district-level case data spanning a period of significant socioeconomic change (1998-2020). We show that urban infrastructure factors (sanitation, water supply, long-term urban growth) predict local spatial patterns of dengue incidence, while human mobility is a more influential driver in subtropical northern regions than the endemic south. Temperature is the dominant factor shaping dengue’s distribution and dynamics, and using long-term reanalysis temperature data we show that warming since 1950 has expanded transmission risk throughout Vietnam, and most strongly in current dengue emergence hotspots (e.g., southern central regions, Ha Noi). In contrast, effects of hydrometeorology are complex, multi-scalar and dependent on local context: risk increases under either short-term precipitation excess or long-term drought, but improvements in water supply mitigate drought-associated risks except under extreme conditions. Our findings challenge the assumption that dengue is an urban disease, instead suggesting that incidence peaks in transitional landscapes with intermediate infrastructure provision, and provide evidence that interactions between recent climate change and mobility are contributing to dengue’s expansion throughout Vietnam

Risk factors associated with mechanical ventilation, autonomic nervous dysfunction and physical outcome in Vietnamese adults with tetanus.

BACKGROUND: Tetanus remains common in many low- and middle-income countries, but as critical care services improve, mortality from tetanus is improving. Nevertheless, patients develop severe syndromes associated with autonomic nervous system disturbance (ANSD) and the requirement for mechanical ventilation (MV). Understanding factors associated with worse outcome in such settings is important to direct interventions. In this study, we investigate risk factors for disease severity and long-term physical outcome in adults with tetanus admitted to a Vietnamese intensive care unit. METHODS: Clinical and demographic variables were collected prospectively from 180 adults with tetanus. Physical function component scores (PCS), calculated from Short Form Health Survey (SF-36), were assessed in 79 patients at hospital discharge, 3 and 6 months post discharge. RESULTS: Age, temperature, heart rate, lower peripheral oxygen saturation (SpO2) and shorter time from first symptom to admission were associated with MV (OR 1.03 [ 95% confidence interval (CI) 1.00, 1.05], p = 0.04; OR 2.10 [95% CI 1.03, 4.60], p = 0.04; OR 1.04 [ 95% CI 1.01, 1.07], p = 0.02); OR 0.80 [95% CI 0.66, 0.94], p = 0.02 and OR 0.65 [95% CI 0.52, 0.79, p < 0.001, respectively). Heart rate, SpO2 and time from first symptom to admission were associated with ANSD (OR 1.03 [95% CI 1.01, 1.06], p < 0.01; OR 0.95 [95% CI 0.9, 1.00], p = 0.04 and OR 0.64 [95% CI 0.48, 0.80], p < 0.01, respectively). Median [interquartile range] PCS at hospital discharge, 3 and 6 months were 32.37 [24.95-41.57, 53.0 [41.6-56.3] and 54.8 [51.6-57.3], respectively. Age, female sex, admission systolic blood pressure, admission SpO2, MV, ANSD, midazolam requirement, hospital-acquired infection, pressure ulcer and duration of ICU and hospital stay were associated with reduced 0.25 quantile PCS at 6 months after hospital discharge. CONCLUSIONS: MV and ANSD may be suitable endpoints for future research. Risk factors for reduced physical function at 3 months and 6 months post discharge suggest that modifiable features during hospital management are important determinants of long-term outcome

Laboratory prediction of the requirement for renal replacement in acute falciparum malaria

BACKGROUND: Acute renal failure is a common complication of severe malaria in adults, and without renal replacement therapy (RRT), it carries a poor prognosis. Even when RRT is available, delaying its initiation may increase mortality. Earlier identification of patients who will need RRT may improve outcomes. METHOD: Prospectively collected data from two intervention studies in adults with severe malaria were analysed focusing on laboratory features on presentation and their association with a later requirement for RRT. In particular, laboratory indices of acute tubular necrosis (ATN) and acute kidney injury (AKI) that are used in other settings were examined. RESULTS: Data from 163 patients were available for analysis. Whether or not the patients should have received RRT (a retrospective assessment determined by three independent reviewers) was used as the reference. Forty-three (26.4%) patients met criteria for dialysis, but only 19 (44.2%) were able to receive this intervention due to the limited availability of RRT. Patients with impaired renal function on admission (creatinine clearance < 60 ml/min) (n = 84) had their laboratory indices of ATN/AKI analysed. The plasma creatinine level had the greatest area under the ROC curve (AUC): 0.83 (95% confidence interval 0.74-0.92), significantly better than the AUCs for, urinary sodium level, the urea to creatinine ratio (UCR), the fractional excretion of urea (FeUN) and the urinary neutrophil gelatinase-associated lipocalcin (NGAL) level. The AUC for plasma creatinine was also greater than the AUC for blood urea nitrogen level, the fractional excretion of sodium (FeNa), the renal failure index (RFI), the urinary osmolality, the urine to plasma creatinine ratio (UPCR) and the creatinine clearance, although the difference for these variables did not reach statistical significance. CONCLUSIONS: In adult patients with severe malaria and impaired renal function on admission, none of the evaluated laboratory indices was superior to the plasma creatinine level when used to predict a later requirement for renal replacement therapy

A hidden HIV epidemic among women in Vietnam

<p>Abstract</p> <p>Background</p> <p>The HIV epidemic in Vietnam is still concentrated among high risk populations, including IDU and FSW. The response of the government has focused on the recognized high risk populations, mainly young male drug users. This concentration on one high risk population may leave other populations under-protected or unprepared for the risk and the consequences of HIV infection. In particular, attention to women's risks of exposure and needs for care may not receive sufficient attention as long as the perception persists that the epidemic is predominantly among young males. Without more knowledge of the epidemic among women, policy makers and planners cannot ensure that programs will also serve women's needs.</p> <p>Methods</p> <p>More than 300 documents appearing in the period 1990 to 2005 were gathered and reviewed to build an understanding of HIV infection and related risk behaviors among women and of the changes over time that may suggest needed policy changes.</p> <p>Results</p> <p>It appears that the risk of HIV transmission among women in Vietnam has been underestimated; the reported data may represent as little as 16% of the real number. Although modeling predicted that there would be 98,500 cases of HIV-infected women in 2005, only 15,633 were accounted for in reports from the health system. That could mean that in 2005, up to 83,000 women infected with HIV have not been detected by the health care system, for a number of possible reasons. For both detection and prevention, these women can be divided into sub-groups with different risk characteristics. They can be infected by sharing needles and syringes with IDU partners, or by having unsafe sex with clients, husbands or lovers. However, most new infections among women can be traced to sexual relations with young male injecting drug users engaged in extramarital sex. Each of these groups may need different interventions to increase the detection rate and thus ensure that the women receive the care they need.</p> <p>Conclusion</p> <p>Women in Vietnam are increasingly at risk of HIV transmission but that risk is under-reported and under-recognized. The reasons are that women are not getting tested, are not aware of risks, do not protect themselves and are not being protected by men. Based on this information, policy-makers and planners can develop better prevention and care programs that not only address women's needs but also reduce further spread of the infection among the general population.</p

Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial [version 1; referees: 2 approved]

Background: Tuberculosis kills more people than any other bacterial infection worldwide. In tuberculous meningitis (TBM), a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), predicts pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected individuals. The primary aim of this study is to determine whether LTA4H genotype determines benefit or harm from adjunctive dexamethasone in HIV-uninfected Vietnamese adults with TBM. The secondary aim is to investigate alternative management strategies in individuals who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy.  Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled,  multi-centre Phase III non-inferiority trial, comparing dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype. The primary endpoint will be death or new neurological event. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. 640 participants with CC or CT- LTA4H genotype will be randomised to either dexamethasone or placebo, and the remaining TT- genotype participants will be treated with standard-of-care dexamethasone. We will also perform a randomised comparison of three management strategies for anti-tuberculosis DILI. An identical ancillary study will also be perfomed in the linked randomised controlled trial of dexamethasone in HIV-infected adults with TBM (ACT HIV).  Discussion: Previous data have shown that LTA4H genotype may be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response in TBM. We will stratify dexamethasone therapy according to LTA4H genotype in HIV-uninfected adults, which may indicate a role for targeted anti-inflammatory therapy according to variation in LTA4H C/T transition. A comparison of DILI management strategies may allow the safe continuation of rifampicin and isoniazid

Burden of cancer in the Eastern Mediterranean Region, 2005–2015: findings from the Global Burden of Disease 2015 Study

Objectives: To estimate incidence, mortality, and disability-adjusted life years (DALYs) caused by cancer in the Eastern Mediterranean Region (EMR) between 2005 and 2015. Methods: Vital registration system and cancer registry data from the EMR region were analyzed for 29 cancer groups in 22 EMR countries using the Global Burden of Disease Study 2015 methodology. Results: In 2015, cancer was responsible for 9.4% of all deaths and 5.1% of all DALYs. It accounted for 722,646 new cases, 379,093 deaths, and 11.7 million DALYs. Between 2005 and 2015, incident cases increased by 46%, deaths by 33%, and DALYs by 31%. The increase in cancer incidence was largely driven by population growth and population aging. Breast cancer, lung cancer, and leukemia were the most common cancers, while lung, breast, and stomach cancers caused most cancer deaths. Conclusions: Cancer is responsible for a substantial disease burden in the EMR, which is increasing. There is an urgent need to expand cancer prevention, screening, and awareness programs in EMR countries as well as to improve diagnosis, treatment, and palliative care services.The funding source played no role in the design of thestudy, the analysis and interpretation of data, and the writing of thepaper. GBD 2015 is funded by Bill & Melinda Gates Foundation