Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults.

BACKGROUND: Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization. RESULTS: A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52). CONCLUSIONS: Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).

Handling missing disease information due to death in diseases that need two visits to diagnose.

In studies that assess disease status periodically, time of disease onset is interval censored between visits. Participants who die between two visits may have unknown disease status after their last visit. In this work, we consider an additional scenario where diagnosis requires two consecutive positive tests, such that disease status can also be unknown at the last visit preceding death. We show that this impacts the choice of censoring time for those who die without an observed disease diagnosis. We investigate two classes of models that quantify the effect of risk factors on disease outcome: a Cox proportional hazards model with death as a competing risk and an illness death model that treats disease as a possible intermediate state. We also consider four censoring strategies: participants without observed disease are censored at death (Cox model only), the last visit, the last visit with a negative test, or the second last visit. We evaluate the performance of model and censoring strategy combinations on simulated data with a binary risk factor and illustrate with a real data application. We find that the illness death model with censoring at the second last visit shows the best performance in all simulation settings. Other combinations show bias that varies in magnitude and direction depending on the differential mortality between diseased and disease-free subjects, the gap between visits, and the choice of the censoring time.

Two biases in incubation time estimation related to exposure.

BACKGROUND: Estimation of the SARS-CoV-2 incubation time distribution is hampered by incomplete data about infection. We discuss two biases that may result from incorrect handling of such data. Notified cases may recall recent exposures more precisely (differential recall). This creates bias if the analysis is restricted to observations with well-defined exposures, as longer incubation times are more likely to be excluded. Another bias occurred in the initial estimates based on data concerning travellers from Wuhan. Only individuals who developed symptoms after their departure were included, leading to under-representation of cases with shorter incubation times (left truncation). This issue was not addressed in the analyses performed in the literature. METHODS: We performed simulations and provide a literature review to investigate the amount of bias in estimated percentiles of the SARS-CoV-2 incubation time distribution. RESULTS: Depending on the rate of differential recall, restricting the analysis to a subset of narrow exposure windows resulted in underestimation in the median and even more in the 95th percentile. Failing to account for left truncation led to an overestimation of multiple days in both the median and the 95th percentile. CONCLUSION: We examined two overlooked sources of bias concerning exposure information that the researcher engaged in incubation time estimation needs to be aware of.

A novel diagnostic model for tuberculous meningitis using Bayesian latent class analysis.

BACKGROUND: Diagnosis of tuberculous meningitis (TBM) is hampered by the lack of a gold standard. Current microbiological tests lack sensitivity and clinical diagnostic approaches are subjective. We therefore built a diagnostic model that can be used before microbiological test results are known. METHODS: We included 659 individuals aged [Formula: see text] years with suspected brain infections from a prospective observational study conducted in Vietnam. We fitted a logistic regression diagnostic model for TBM status, with unknown values estimated via a latent class model on three mycobacterial tests: Ziehl-Neelsen smear, Mycobacterial culture, and GeneXpert. We additionally re-evaluated mycobacterial test performance, estimated individual mycobacillary burden, and quantified the reduction in TBM risk after confirmatory tests were negative. We also fitted a simplified model and developed a scoring table for early screening. All models were compared and validated internally. RESULTS: Participants with HIV, miliary TB, long symptom duration, and high cerebrospinal fluid (CSF) lymphocyte count were more likely to have TBM. HIV and higher CSF protein were associated with higher mycobacillary burden. In the simplified model, HIV infection, clinical symptoms with long duration, and clinical or radiological evidence of extra-neural TB were associated with TBM At the cutpoints based on Youden's Index, the sensitivity and specificity in diagnosing TBM for our full and simplified models were 86.0% and 79.0%, and 88.0% and 75.0% respectively. CONCLUSION: Our diagnostic model shows reliable performance and can be developed as a decision assistant for clinicians to detect patients at high risk of TBM. Diagnosis of tuberculous meningitis is hampered by the lack of gold standard. We developed a diagnostic model using latent class analysis, combining confirmatory test results and risk factors. Models were accurate, well-calibrated, and can support both clinical practice and research.

Incidence and Clearance of Anal Human Papillomavirus Infection in 16 164 Individuals, According to Human Immunodeficiency Virus Status, Sex, and Male Sexuality: An International Pooled Analysis of 34 Longitudinal Studies.

BACKGROUND: Understanding the natural history of anal high-risk human papillomavirus (hrHPV) infection is key for designing anal cancer prevention programs but has not been systematically characterized. METHODS: We reanalyzed data from 34 studies including 16 164 individuals in 6 risk groups defined by human immunodeficiency virus (HIV) status, sex, and male sexuality: men who have sex with men (MSM) and people with HIV (MSMWH), HIV-negative MSM, women with HIV (WWH), HIV-negative women, men who have sex with women (MSW) with HIV (MSWWH), and HIV-negative MSW. We used Markov models to estimate incidence and clearance of 13 hrHPV types and their determinants. RESULTS: Human papillomavirus (HPV) 16 had the highest incidence-clearance ratio of the hrHPV types. MSMWH had the highest hrHPV incidence (eg, 15.5% newly HPV-16 infected within 2 years), followed by HIV-negative MSM (7.5%), WWH (6.6%), HIV-negative women (2.9%), MSWWH (1.7%), and HIV-negative MSW (0.7%). Determinants of HPV-16 incidence included HIV status and number of sexual partners for MSM, women, and MSW, and anal sex behavior for MSM only. HPV-16 clearance was lower for people with HIV (PWH) and lower for prevalent than incident infection. Among MSM, increasing age was associated with lower clearance of prevalent, but not incident, HPV-16 infection. CONCLUSIONS: This robust and unifying analysis of anal hrHPV natural history is essential to designing and predicting the impact of HPV vaccination and HPV-based screening programs on anal cancer prevention, particularly in MSM and PWH. Importantly, it demonstrates the higher carcinogenic potential of longstanding anal prevalent hrHPV infection than more recent incident infection.

Towards robust and accurate estimates of the incubation time distribution, with focus on upper tail probabilities and SARS-CoV-2 infection.

Quarantine length for individuals who have been at risk for infection with SARS-CoV-2 has been based on estimates of the incubation time distribution. The time of infection is often not known exactly, yielding data with an interval censored time origin. We give a detailed account of the data structure, likelihood formulation and assumptions usually made in the literature: (i) the risk of infection is assumed constant on the exposure window and (ii) the incubation time follows a specific parametric distribution. The impact of these assumptions remains unclear, especially for the right tail of the distribution which informs quarantine policy. We quantified bias in percentiles by means of simulation studies that mimic reality as close as possible. If assumption (i) is not correct, then median and upper percentiles are affected similarly, whereas misspecification of the parametric approach (ii) mainly affects upper percentiles. The latter may yield considerable bias. We suggest a semiparametric method that provides more robust estimates without the need of a parametric choice. Additionally, we used a simulation study to evaluate a method that has been suggested if all infection times are left censored. It assumes that the width of the interval from infection to latest possible exposure follows a uniform distribution. This assumption gave biased results in the exponential phase of an outbreak. Our application to open source data suggests that focus should be on the level of information in the observations, as expressed by the width of exposure windows, rather than the number of observations.

Effectiveness of Continuous Endotracheal Cuff Pressure Control for the Prevention of Ventilator-Associated Respiratory Infections: An Open-Label Randomized, Controlled Trial.

BACKGROUND: An endotracheal tube cuff pressure between 20 and 30 cmH2O is recommended to prevent ventilator-associated respiratory infection (VARI). We aimed to evaluate whether continuous cuff pressure control (CPC) was associated with reduced VARI incidence compared with intermittent CPC. METHODS: We conducted a multicenter open-label randomized controlled trial in intensive care unit (ICU) patients within 24 hours of intubation in Vietnam. Patients were randomly assigned 1:1 to receive either continuous CPC using an automated electronic device or intermittent CPC using a manually hand-held manometer. The primary endpoint was the occurrence of VARI, evaluated by an independent reviewer blinded to the CPC allocation. RESULTS: We randomized 600 patients; 597 received the intervention or control and were included in the intention to treat analysis. Compared with intermittent CPC, continuous CPC did not reduce the proportion of patients with at least one episode of VARI (74/296 [25%] vs 69/301 [23%]; odds ratio [OR] 1.13; 95% confidence interval [CI] .77-1.67]. There were no significant differences between continuous and intermittent CPC concerning the proportion of microbiologically confirmed VARI (OR 1.40; 95% CI .94-2.10), the proportion of intubated days without antimicrobials (relative proportion [RP] 0.99; 95% CI .87-1.12), rate of ICU discharge (cause-specific hazard ratio [HR] 0.95; 95% CI .78-1.16), cost of ICU stay (difference in transformed mean [DTM] 0.02; 95% CI -.05 to .08], cost of ICU antimicrobials (DTM 0.02; 95% CI -.25 to .28), cost of hospital stay (DTM 0.02; 95% CI -.04 to .08), and ICU mortality risk (OR 0.96; 95% CI .67-1.38). CONCLUSIONS: Maintaining CPC through an automated electronic device did not reduce VARI incidence. CLINICAL TRIAL REGISTRATION: NCT02966392.

A modified Sequential Organ Failure Assessment score for dengue: development, evaluation and proposal for use in clinical trials.

BACKGROUND: Dengue is a neglected tropical disease, for which no therapeutic agents have shown clinical efficacy to date. Clinical trials have used strikingly variable clinical endpoints, which hampers reproducibility and comparability of findings. We investigated a delta modified Sequential Organ Failure Assessment (delta mSOFA) score as a uniform composite clinical endpoint for use in clinical trials investigating therapeutics for moderate and severe dengue. METHODS: We developed a modified SOFA score for dengue, measured and evaluated its performance at baseline and 48 h after enrolment in a prospective observational cohort of 124 adults admitted to a tertiary referral hospital in Vietnam with dengue shock. The modified SOFA score included pulse pressure in the cardiovascular component. Binary logistic regression, cox proportional hazard and linear regression models were used to estimate association between mSOFA, delta mSOFA and clinical outcomes. RESULTS: The analysis included 124 adults with dengue shock. 29 (23.4%) patients required ICU admission for organ support or due to persistent haemodynamic instability: 9/124 (7.3%) required mechanical ventilation, 8/124 (6.5%) required vasopressors, 6/124 (4.8%) required haemofiltration and 5/124 (4.0%) patients died. In univariate analyses, higher baseline and delta (48 h) mSOFA score for dengue were associated with admission to ICU, requirement for organ support and mortality, duration of ICU and hospital admission and IV fluid use. CONCLUSIONS: The baseline and delta mSOFA scores for dengue performed well to discriminate patients with dengue shock by clinical outcomes, including duration of ICU and hospital admission, requirement for organ support and death. We plan to use delta mSOFA as the primary endpoint in an upcoming host-directed therapeutic trial and investigate the performance of this score in other phenotypes of severe dengue in adults and children.

Higher Plasma Viremia in the Febrile Phase Is Associated With Adverse Dengue Outcomes Irrespective of Infecting Serotype or Host Immune Status: An Analysis of 5642 Vietnamese Cases.

BACKGROUND: One of the generally accepted constructs of dengue pathogenesis is that clinical disease severity is at least partially dependent upon plasma viremia, yet data on plasma viremia in primary versus secondary infections and in relation to clinically relevant endpoints remain limited and contradictory. METHODS: Using a large database comprising detailed clinical and laboratory characterization of Vietnamese participants enrolled in a series of research studies executed over a 15-year period, we explored relationships between plasma viremia measured by reverse transcription-polymerase chain reaction and 3 clinically relevant endpoints-severe dengue, plasma leakage, and hospitalization-in the dengue-confirmed cases. All 4 dengue serotypes and both primary and secondary infections were well represented. In our logistic regression models we allowed for a nonlinear effect of viremia and for associations between viremia and outcome to differ by age, serotype, host immune status, and illness day at study enrollment. RESULTS: Among 5642 dengue-confirmed cases we identified 259 (4.6%) severe dengue cases, 701 (12.4%) patients with plasma leakage, and 1441 of 4008 (40.0%) patients recruited in outpatient settings who were subsequently hospitalized. From the early febrile phase onwards, higher viremia increased the risk of developing all 3 endpoints, but effect sizes were modest (ORs ranging from 1.12-1.27 per 1-log increase) compared with the effects of a secondary immune response (ORs, 1.67-7.76). The associations were consistent across age, serotype, and immune status groups, and in the various sensitivity and subgroup analyses we undertook. CONCLUSIONS: Higher plasma viremia is associated with increased dengue severity, regardless of serotype or immune status.

Trimethoprim-sulfamethoxazole Versus Azithromycin for the Treatment of Undifferentiated Febrile Illness in Nepal: A Double-blind, Randomized, Placebo-controlled Trial.

BACKGROUND: Azithromycin and trimethoprim-sulfamethoxazole (SXT) are widely used to treat undifferentiated febrile illness (UFI). We hypothesized that azithromycin is superior to SXT for UFI treatment, but the drugs are noninferior to each other for culture-confirmed enteric fever treatment. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of azithromycin (20 mg/kg/day) or SXT (trimethoprim 10 mg/kg/day plus sulfamethoxazole 50 mg/kg/day) orally for 7 days for UFI treatment in Nepal. We enrolled patients >2 years and <65 years of age presenting to 2 Kathmandu hospitals with temperature ≥38.0°C for ≥4 days without localizing signs. The primary endpoint was fever clearance time (FCT); secondary endpoints were treatment failure and adverse events. RESULTS: From June 2016 to May 2019, we randomized 326 participants (163 in each arm); 87 (26.7%) had blood culture-confirmed enteric fever. In all participants, the median FCT was 2.7 days (95% confidence interval [CI], 2.6-3.3 days) in the SXT arm and 2.1 days (95% CI, 1.6-3.2 days) in the azithromycin arm (hazard ratio [HR], 1.25 [95% CI, .99-1.58]; P = .059). The HR of treatment failures by 28 days between azithromycin and SXT was 0.62 (95% CI, .37-1.05; P = .073). Planned subgroup analysis showed that azithromycin resulted in faster FCT in those with sterile blood cultures and fewer relapses in culture-confirmed enteric fever. Nausea, vomiting, constipation, and headache were more common in the SXT arm. CONCLUSIONS: Despite similar FCT and treatment failure in the 2 arms, significantly fewer complications and relapses make azithromycin a better choice for empirical treatment of UFI in Nepal. CLINICAL TRIALS REGISTRATION: NCT02773407.

A novel method for measuring phenotypic colistin resistance in Escherichia coli populations from chicken flocks.

Colistin is extensively used in animal production in many low- and middle-income countries. There is a need to develop methodologies to benchmark and monitor changes in resistance among mixed commensal bacterial populations in farms. We aimed to evaluate the performance of a broth microdilution method based on culturing a pooled Escherichia coli suspension (30-50 organisms) obtained from each sample. To confirm the biological basis and sensitivity of the method, we cultured 16 combinations of one colistin-susceptible and one mcr-1 encoded colistin-resistant E. coli in the presence of 2mg/L colistin. Optical density (OD600nm) readings over time were used to generate a growth curve, and these values were adjusted to the values obtained in the absence of colistin (adjusted Area Under the Curve, AUCadj). The median limit of detection was 1 resistant in 104 susceptible colonies [1st - 3rd quartile, 102:1 -105:1]. We applied this method to 108 pooled faecal samples from 36 chicken flocks from the Mekong Delta (Vietnam), and determined the correlation between this method and the prevalence of colistin resistance in individual colonies harvested from field samples, determined by the Minimum Inhibitory Concentration. The overall prevalence of colistin resistance at sample and isolate level (estimated from the AUCadj) was 38.9% [95%CI, 29.8-48.8%] and 19.4% (SD± 26.3%), respectively. Increased colistin resistance was associated with recent (2 weeks) use of colistin (OR=3.67) and other, non-colistin antimicrobials (OR=1.84). Our method is a sensitive and affordable approach to monitor changes in colistin resistance in E. coli populations from faecal samples over time.IMPORTANCE Colistin (polymyxin E) is an antimicrobial with poor solubility in agar-based media, and therefore broth microdilution is the only available method for phenotypic resistance. However, estimating colistin resistance in mixed Escherichia coli populations is laborious since it requires individual colony isolation, identification and susceptibility testing. We developed a growth-based microdilution method suitable for pooled faecal samples. We validated the method by comparing it with individual MIC of 909 E. coli isolates; we then tested 108 pooled faecal samples from 36 healthy chicken flocks collected over their production cycle. A higher level of resistance was seen in flocks recently treated with colistin in water, although the observed generated resistance was short-lived. Our method is affordable, and may potentially be integrated into surveillance systems aiming at estimating the prevalence of resistance at colony level in flocks/herds. Furthermore, it may also be adapted to other complex biological systems, such as farms and abattoirs.

Using the geometric average hazard ratio in sample size calculation for time-to-event data with composite endpoints.

BACKGROUND: Sample size calculation is a key point in the design of a randomized controlled trial. With time-to-event outcomes, it's often based on the logrank test. We provide a sample size calculation method for a composite endpoint (CE) based on the geometric average hazard ratio (gAHR) in case the proportional hazards assumption can be assumed to hold for the components, but not for the CE. METHODS: The required number of events, sample size and power formulae are based on the non-centrality parameter of the logrank test under the alternative hypothesis which is a function of the gAHR. We use the web platform, CompARE, for the sample size computations. A simulation study evaluates the empirical power of the logrank test for the CE based on the sample size in terms of the gAHR. We consider different values of the component hazard ratios, the probabilities of observing the events in the control group and the degrees of association between the components. We illustrate the sample size computations using two published randomized controlled trials. Their primary CEs are, respectively, progression-free survival (time to progression of disease or death) and the composite of bacteriologically confirmed treatment failure or Staphylococcus aureus related death by 12 weeks. RESULTS: For a target power of 0.80, the simulation study provided mean (± SE) empirical powers equal to 0.799 (±0.004) and 0.798 (±0.004) in the exponential and non-exponential settings, respectively. The power was attained in more than 95% of the simulated scenarios and was always above 0.78, regardless of compliance with the proportional-hazard assumption. CONCLUSIONS: The geometric average hazard ratio as an effect measure for a composite endpoint has a meaningful interpretation in the case of non-proportional hazards. Furthermore it is the natural effect measure when using the logrank test to compare the hazard rates of two groups and should be used instead of the standard hazard ratio.

Biphasic pattern in the effect of severe measles infection; the difference between additive and multiplicative scale.

BACKGROUND: Infection with measles virus (MeV) causes immunosuppression and increased susceptibility to other infectious diseases. Only few studies reported a duration of immunosuppression, with varying results. We investigated the effect of immunosuppression on the incidence of hospital admissions for infectious diseases in Vietnamese children. METHODS: We used retrospective data (2005 to 2015; N = 4419) from the two pediatric hospitals in Ho Chi Minh City, Vietnam. We compared the age-specific incidence of hospital admission for infectious diseases before and after hospitalization for measles. We fitted a Poisson regression model that included gender, current age, and time since measles to obtain a multiplicative effect measure. Estimates were transformed to the additive scale. RESULTS: We observed two phases in the incidence of hospital admission after measles. The first phase started with a fourfold increased rate of admissions during the first month after measles, dropping to a level quite comparable to children of the same age before measles. In the second phase, lasting until at least 6 years after measles, the admission rate decreased further, with values up to 20 times lower than in children of the same age before measles. However, on the additive scale the effect size in the second phase was much smaller than in the first phase. CONCLUSION: The first phase highlights the public health benefits of measles vaccination by preventing measles and immune amnesia. The beneficial second phase is interesting, but its strength strongly depends on the scale. It suggests a complicated interaction between MeV infection and the host immunity.

Dynamic Prediction of Death in Patients With Tuberculous Meningitis Using Time-updated Glasgow Coma Scale and Plasma Sodium Measurements.

BACKGROUND: Pretreatment predictors of death from tuberculous meningitis (TBM) are well established, but whether outcome can be predicted more accurately after the start of treatment by updated clinical variables is unknown. Hence, we developed and validated models that dynamically predict mortality using time-updated Glasgow Coma Scale (GCS) and plasma sodium measurements, together with patient baseline characteristics. METHODS: We included 1048 adults from 4 TBM studies conducted in southern Vietnam from 2004 to 2016. We used a landmarking approach to predict death within 120 days after treatment initiation using time-updated data during the first 30 days of treatment. Separate models were built for patients with and without human immunodeficiency virus (HIV) infection. We used the area under the receiver operating characteristic curve (AUC) to evaluate performance of the models at days 10, 20, and 30 of treatment to predict mortality by 60, 90, and 120 days. Our internal validation was corrected for overoptimism using bootstrap. We provide a web-based application that computes mortality risk within 120 days. RESULTS: Higher GCS indicated better prognosis in all patients. In HIV-infected patients, higher plasma sodium was uniformly associated with good prognosis, whereas in HIV-uninfected patients the association was heterogeneous over time. The bias-corrected AUC of the models ranged from 0.82 to 0.92 and 0.81 to 0.85 in HIV-uninfected and HIV-infected individuals, respectively. The models outperformed the previously published baseline models. CONCLUSIONS: Time-updated GCS and plasma sodium measurements improved predictions based solely on information obtained at diagnosis. Our models may be used in practice to define those with poor prognosis during treatment.

The Natural History and Transmission Potential of Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: Little is known about the natural history of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We conducted a prospective study at a quarantine center for coronavirus disease 2019 in Ho Chi Minh City, Vietnam. We enrolled quarantined people with reverse-transcription polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection, collecting clinical data, travel and contact history, and saliva at enrollment and daily nasopharyngeal/throat swabs (NTSs) for RT-PCR testing. We compared the natural history and transmission potential of asymptomatic and symptomatic individuals. RESULTS: Between 10 March and 4 April 2020, 14 000 quarantined people were tested for SARS-CoV-2; 49 were positive. Of these, 30 participated in the study: 13 (43%) never had symptoms and 17 (57%) were symptomatic. Seventeen (57%) participants imported cases. Compared with symptomatic individuals, asymptomatic people were less likely to have detectable SARS-CoV-2 in NTS collected at enrollment (8/13 [62%] vs 17/17 [100%]; P = .02). SARS-CoV-2 RNA was detected in 20 of 27 (74%) available saliva samples (7 of 11 [64%] in the asymptomatic group and 13 of 16 [81%] in the symptomatic group; P = .56). Analysis of RT-PCR positivity probability showed that asymptomatic participants had faster viral clearance than symptomatic participants (P < .001 for difference over the first 19 days). This difference was most pronounced during the first week of follow-up. Two of the asymptomatic individuals appeared to transmit SARS-CoV-2 to 4 contacts. CONCLUSIONS: Asymptomatic SARS-CoV-2 infection is common and can be detected by analysis of saliva or NTSs. The NTS viral loads fall faster in asymptomatic individuals, but these individuals appear able to transmit the virus to others.

Do Intracerebral Cytokine Responses Explain the Harmful Effects of Dexamethasone in Human Immunodeficiency Virus-associated Cryptococcal Meningitis?

BACKGROUND: The CryptoDex trial showed that dexamethasone caused poorer clinical outcomes and slowed fungal clearance in human immunodeficiency virus-associated cryptococcal meningitis. We analyzed cerebrospinal fluid (CSF) cytokine concentrations from participants over the first week of treatment to investigate mechanisms of harm and test 2 hypotheses: (1) dexamethasone reduced proinflammatory cytokine concentrations, leading to poorer outcomes and (2) leukotriene A4 hydrolase (LTA4H) genotype influenced the clinical impact of dexamethasone, as observed in tuberculous meningitis. METHODS: We included participants from Vietnam, Thailand, and Uganda. Using the Luminex system, we measured CSF concentrations of the following: interferon γ, tumor necrosis factor (TNF) α, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant 1, macrophage inflammatory protein 1α, and interleukin 6, 12p70, 8, 4, 10, and 17. We determined the LTA4H genotype based on the promoter region single-nucleotide polymorphism rs17525495. We assessed the impact of dexamethasone on cytokine concentration dynamics and the association between cytokine concentration dynamics and fungal clearance with mixed effect models. We measured the influence of LTA4H genotype on outcomes with Cox regression models. RESULTS: Dexamethasone increased the rate TNF-α concentration's decline in (-0.13 log2pg/mL/d (95% confidence interval, -.22 to -.06 log2pg/mL/d; P = .03), which was associated with slower fungal clearance (correlation, -0.62; 95% confidence interval, -.83 to -.26). LTA4H genotype had no statistically significant impact on outcome or response to dexamethasone therapy. Better clinical outcomes were associated with higher baseline concentrations of interferon γ. CONCLUSIONS: Dexamethasone may slow fungal clearance and worsen outcomes by increasing TNF-α concentration's rate of decline.

Risk of Parkinson's disease dementia related to level I MDS PD-MCI.

BACKGROUND: The International Parkinson and Movement Disorders Society criteria for mild cognitive impairment in PD need validation. The objectives of this present study were to evaluate prognostic validity of level I (abbreviated) International Parkinson and Movement Disorders Society mild cognitive impairment in PD criteria for development of PD dementia and compared them with level II (comprehensive) criteria. METHODS: We analyzed data from 8 international studies (1045 patients) from our consortium that included baseline data on demographics, motor signs, depression, detailed neuropsychological testing, and longitudinal follow-up for conversion to Parkinson's disease dementia. Survival analysis evaluated their contribution to the hazard of Parkinson's disease dementia. RESULTS: Level I mild cognitive impairment in PD, increasing age, male sex, and severity of PD motor signs independently increased the hazard of Parkinson's disease dementia. Level I and level II mild cognitive impairment in PD classification had similar discriminative ability with respect to the time to Parkinson's disease dementia. CONCLUSIONS: Level I mild cognitive impairment in PD classification independently contributes to the hazard of Parkinson's disease dementia. This finding supports the prognostic validity of the abbreviated mild cognitive impairment in PD criteria. © 2019 International Parkinson and Movement Disorder Society.

Assessing the efficacy and safety of magnesium sulfate for management of autonomic nervous system dysregulation in Vietnamese children with severe hand foot and mouth disease.

BACKGROUND: Brainstem encephalitis is a serious complication of hand foot and mouth disease (HFMD) in children. Autonomic nervous system (ANS) dysregulation and hypertension may occur, sometimes progressing to cardiopulmonary failure and death. Vietnamese national guidelines recommend use of milrinone if ANS dysregulation with Stage 2 hypertension develops. We wished to investigate whether magnesium sulfate (MgSO4) improved outcomes in children with HFMD if used earlier in the evolution of the ANS dysregulation (Stage 1 hypertension). METHODS: During a regional epidemic we conducted a randomized, double-blind, placebo-controlled trial of MgSO4 in children with HFMD, ANS dysregulation and Stage 1 hypertension, at the Hospital for Tropical Diseases in Ho Chi Minh city. Study participants received an infusion of MgSO4 or matched placebo for 72 h. We also reviewed data from non-trial HFMD patients in whom milrinone failed to control hypertension, some of whom received MgSO4 as second line therapy. The primary outcome for both analyses was a composite of disease progression within 72 h - addition of milrinone (trial participants only), need for ventilation, shock, or death. RESULTS: Between June 2014 and September 2016, 14 and 12 participants received MgSO4 or placebo respectively, before the trial was stopped due to futility. Among 45 non-trial cases with poorly controlled hypertension despite high-dose milrinone, 33 received MgSO4 while 12 did not. There were no statistically significant differences in the composite outcome between the MgSO4 and the placebo/control groups in either study (adjusted relative risk (95%CI) of [6/14 (43%) vs. 6/12 (50%)], 0.84 (0.37, 1.92), p = 0.682 in the trial and [1/33 (3%) vs. 2/12 (17%)], 0.16 (0.01, 1.79), p = 0.132 in the observational cohort). The incidence of adverse events was similar between the groups. Potentially toxic magnesium levels occurred very rarely with the infusion regime used. CONCLUSION: Although we could not demonstrate efficacy in these studies, there were no safety signals associated with use of 30-50 mg/kg/hr. MgSO4 in severe HFMD. Intermittent outbreaks of HFMD are likely to continue across the region, and an adequately powered trial is still needed to evaluate use of MgSO4 in controlling hypertension in severe HFMD, potentially involving a higher dose regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 AUG 2013). Trial sponsor: University of Oxford.

A comparison of model selection methods for prediction in the presence of multiply imputed data.

Many approaches for variable selection with multiply imputed data in the development of a prognostic model have been proposed. However, no method prevails as uniformly best. We conducted a simulation study with a binary outcome and a logistic regression model to compare two classes of variable selection methods in the presence of MI data: (I) Model selection on bootstrap data, using backward elimination based on AIC or lasso, and fit the final model based on the most frequently (e.g. ≥50% ) selected variables over all MI and bootstrap data sets; (II) Model selection on original MI data, using lasso. The final model is obtained by (i) averaging estimates of variables that were selected in any MI data set or (ii) in 50% of the MI data; (iii) performing lasso on the stacked MI data, and (iv) as in (iii) but using individual weights as determined by the fraction of missingness. In all lasso models, we used both the optimal penalty and the 1-se rule. We considered recalibrating models to correct for overshrinkage due to the suboptimal penalty by refitting the linear predictor or all individual variables. We applied the methods on a real dataset of 951 adult patients with tuberculous meningitis to predict mortality within nine months. Overall, applying lasso selection with the 1-se penalty shows the best performance, both in approach I and II. Stacking MI data is an attractive approach because it does not require choosing a selection threshold when combining results from separate MI data sets.

A novel prognostic model for transplant-free survival in primary sclerosing cholangitis.

OBJECTIVE: Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables. DESIGN: The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models' predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates. RESULTS: The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up. CONCLUSION: The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available.