Reply to Lu et al.
Bibliographic record
Abstract
To the Editor—We thank Lu et al. for their interesting report [1] and for highlighting the complex treatment-related issues for patients coinfected with HIV and Mycobacterium tuberculosis who commence highly active antiretroviral therapy (HAART). The challenge is to reduce treatment-related complications, including paradoxical reactions, while at the same time maximizing the benefit of HAART, to improve survival and prevent opportunistic infections [2]. However, as Lu et al. point out, prospective studies are needed to determine the optimum timing of the initiation of HAART in patients coinfected with HIV and mycobacteria. This is particularly important, because tuberculosis (TB) is the most common serious opportunistic infection worldwide, and HAART is now being used in developing countries. Sentinel studies, at multiple sites in the developing world, are urgently needed, so that this information can be ascertained As was recently shown in HIV-positive patients with TB in both Africa [3] and the United Kingdom [4], HAART may also unmask subclinical disease in HIV-positive patients with leprosy [1]. Furthermore, the treatment of leprosy itself [1] or the initiation of HAART [5] may result in immune reconstitution inflammatory syndrome (IRIS) or leprosy reversal reactions. Nevertheless, given the number of subjects we see from areas in which leprosy is endemic, in our experience, these presentations are uncommon. The putative immunological mechanisms that underpin these reactions remain unclear. It is intriguing that progressive HIV disease, unlike the scenario in TB, is not thought to substantially alter the clinical course of leprosy [6], but that treatment with HAART may precipitate IRIS in patients with leprosy. This suggests that HIV itself attenuates the inflammatory response but not the disease-limiting immunity to leprosy; the situation may be reversed during treatment with HAART, which markedly reduces plasma viral load. We have recently shown that Th2 profiles (interleukin [IL]–4 mRNA levels) are up-regulated in patients with HIV and M. tuberculosis coinfection, even in those with low CD4+ cell counts, but are not up-regulated in matched, otherwise healthy HIV-positive control subjects [7]. Furthermore, IL-4d2, the natural antagonist and splice variant of IL-4, was up-regulated in the lung but not in the periphery. Further studies are required to determine if similar mechanisms operate in leprosy; we speculate that mycobacterial coinfection up-regulates Th2 responses, and the IL-4:IL-4d2 ratio may modulate the clinical presentation of leprosy and IRIS. Alternatively, abnormalities in antigen-specific Treg (driven by HIV and/or mycobacteria) may support these observations and may explain why leprosy does not worsen in the presence of progressive HIV disease; the role of Treg in mycobacterial disease has not yet been elucidated
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.035 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.003 | 0.003 |
| Scholarly communication | 0.004 | 0.007 |
| Open science | 0.005 | 0.003 |
| Research integrity | 0.032 | 0.043 |
| Insufficient payload (model declined to judge) | 0.009 | 0.009 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".