Judith Farrés

Background: Adjunctive host-directed therapies (HDT) may improve treatment outcomes in tuberculosis (TB). Affordable repurposed drugs can be quickly implemented in clinical practice; however, predictive biomarkers are essential for determining their potential effectiveness. Methods: 72 patients (35.2% people with HIV-1) from South Africa with drug-sensitive pulmonary TB, recruited to the SMA-TB clinical trial of adjunctive acetylsalicylic acid (ASA) and ibuprofen (IBU), were included. CD4+ T-cell subsets and Mtb-specific CD4+ T-cell responses were analyzed by flow cytometry at baseline, week 2, week 8 and week 24 and tested as predictors for microbiological, clinical and radiological outcomes. Results: Most TB patients experienced a fast sputum culture conversion and good clinical and radiological outcomes by week 24, regardless of intervention or HIV coinfection. During TB therapy, fractions of Mtb-specific polyfunctional CD4+ T cells, Th1 and Th1/Th17 subsets, and CD153 expression increased, whereas Ki67+ HLA-DR + CD4+ T cells declined. No statistically significant differences were identified between the ASA or IBU groups and placebo for any defined outcome. Still, higher baseline fractions of polyfunctional and CD153-expressing CD4+ T cells were associated with fast sputum culture conversion in the ASA and placebo arms. Conclusions: CD4+ T-cell subsets show promise as markers of disease severity and potential predictors of microbiological, clinical, and radiological outcomes in treated TB. However, the present findings are insufficient to support the routine use of ASA or IBU in adjunctive HDT regimens, and larger, targeted studies are warranted.

Drug-resistant tuberculosis remains a major global health challenge, and excessive inflammation may contribute to tissue damage and poor outcomes. We conducted a phase IIA prospective open-label pilot trial (ClinicalTrials.gov: NCT02781909) evaluating adjunctive ibuprofen in adults with pulmonary pre-extensively drug-resistant (pre-XDR) or extensively drug-resistant (XDR) tuberculosis in Georgia. Twenty-eight participants received individualized background anti-tuberculosis regimens alone ( n = 14) or with ibuprofen 400 mg daily for 2 months ( n = 14) and were followed for 6 months. The primary efficacy outcome was the proportion of participants showing clinical and/or microbiological benefit, assessed by sputum culture conversion, radiological evolution, and WHO-defined treatment outcomes. Secondary outcomes were safety and tolerability, health-related quality of life, and inflammatory and transcriptomic responses. Adding adjunctive ibuprofen did not improve month-2 sputum culture negativity, time to stable culture conversion, radiological evolution, or final treatment outcomes. Safety and tolerability were similar between groups. Adverse events were recorded and reviewed, but not formally graded for severity. Ibuprofen treatment was associated with numerically greater reductions in several blood-based inflammatory measures and in transcriptomic signature scores associated with poor tuberculosis outcomes. These findings are exploratory and do not demonstrate clinical benefit but indicate biological activity and support evaluation of anti-inflammatory host-directed therapies in larger controlled trials.

Background: In extensively drug-resistant and pre–extensively drug-resistant TB, bacteriology-based monitoring often fails to capture structural lung recovery and patient-reported functional health. We aimed to characterize multidomain treatment response and examine host inflammatory and transcriptional features associated with incomplete recovery. Methods: We conducted an ancillary analysis of a prospective, open-label, pilot study evaluating adjunctive ibuprofen in XDR-TB ( NCT02781909 ). Participants were assessed at baseline and during treatment using TBS, chest radiography, sputum culture, SGRQ, blood cell indices, plasma cytokines, and whole-blood transcriptomic profiling. Clinical and laboratory measures were compared across outcome groups, and blood transcriptional profiles were analyzed in relation to treatment outcomes. Results: Here we show that microbiological and symptomatic improvement occurred earlier than radiological and functional recovery. Higher baseline systemic inflammation, including elevated NLR, SII, and IL-6, as well as increased expression of interferon-related genes such as CD274 and GBP5 , were associated with poorer radiological and SGRQ outcomes at 6 months. In contrast, transient elevations of IL-8 and IL-4 were associated with early bacteriological clearance. IL-8 was the only plasma biomarker consistently correlated with symptom severity, radiological findings, and functional health. Conclusions: Treatment response in drug-resistant TB is asynchronous across biological domains. Integrated host profiling identifies inflammatory and transcriptional features associated with incomplete structural and functional recovery, supporting the use of multidimensional endpoints to better capture long-term outcomes and inform individualized patient management. Plain Language Summary: People with highly drug-resistant tuberculosis can clear the infection but still experience lung damage and reduced quality of life after treatment. In this study, we examined recovery using several measures, including symptoms, chest X-rays, blood markers of inflammation, and gene activity, in addition to tests for tuberculosis bacteria. We analyzed data and stored samples from a small clinical trial to see how these measures changed over time. We found that lung structure and quality of life improved more slowly than bacterial clearance. People with higher levels of inflammation before treatment were more likely to have ongoing lung changes and poorer quality of life later. These results suggest that tuberculosis care should look beyond bacterial clearance and include monitoring inflammation to better support long-term recovery.

Background: As novel strategies are needed to improve tuberculosis (TB) outcomes and shorten treatment; we evaluated whether host-directed therapy with non-steroidal anti-inflammatory drugs (NSAIDs) could enhance treatment response when added to standard therapy. Methods: We conducted a phase 2b, double-blind, placebo-controlled, randomized trial in South Africa and Georgia. Adults with microbiologically confirmed pulmonary TB were randomized to receive standard therapy plus acetylsalicylic acid (ASA) (300 mg), ibuprofen (IBU) (400 mg), or placebo twice daily for 4 weeks and once daily for 4 weeks. Primary end points were time to a 67% reduction in the clinical symptom/sign-based TB score (TBS) and time to stable sputum culture conversion (SCC). Safety and clinical, radiological and microbiological assessments were performed up to 24 weeks after treatment completion. Results: Of 221 randomized participants, 204 were included in the analysis. No significant differences were observed in the primary end points; median time to 67% TBS reduction was 4.5 weeks (ASA) and 5.0 weeks (IBU and placebo), and median time to stable SCC was 8 weeks in all groups. Both NSAIDs were associated with earlier cavity resolution at week 8, sustained at week 24 for ASA. IBU was associated with greater clinical improvement in multidrug-resistant-TB. Adverse event rates were similar across arms. Conclusions: Adjunctive ASA and IBU did not shorten the time to clinical or microbiologic response but were associated with earlier cavity resolution and improved TBS in specific subgroups, with similar safety to standard therapy alone. Funded by the European Union’s Horizon 2020; ClinicalTrials.gov number, NCT04575519 .

Background: Drug-resistant tuberculosis (TB) remains a formidable global health challenge. Host-directed therapies (HDTs) offer the potential to mitigate tissue damage, reduce treatment duration, and improve clinical outcomes by modulating immune responses. We assessed the safety and potential efficacy of adjunctive ibuprofen—an inexpensive, well-tolerated non-steroidal anti-inflammatory drug—in patients with pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) TB. Methods: In this prospective, open-label, randomized pilot study ( NCT02781909 ) conducted in Georgia, 28 adults with bacteriologically confirmed pulmonary pre-XDR or XDR-TB were randomized 1:1 to receive either standard-of-care (SoC) TB treatment alone (n=14) or SoC plus 400 mg ibuprofen daily during the first 2 months (n=14). Participants were followed for 6 months. The primary endpoints were early sputum culture conversion and radiological improvement. Secondary endpoints included WHO-defined final treatment outcomes, safety, health-related quality of life (HQoL), and changes in inflammatory markers. Findings: By week 2, culture negativity was achieved in 27% of control participants versus 9% in the ibuprofen group (risk difference 18%, 95% CI −13 to 50). The median time to culture conversion was 4 months in both groups. At month 2, favourable X-ray evolution was observed in 64% of controls compared with 54% of the ibuprofen group (risk difference 9%, 95% CI −32 to 50), with 90% of participants in each group showing improvement by month 6. Final treatment outcomes were comparable (≈71% cured) and the incidence of safety-related events did not differ significantly. Notably, the ibuprofen group exhibited greater proportional reductions in inflammatory markers—including a statistically significant decrease in the monocyte-to-lymphocyte ratio at months 2 and 5, along with reductions in interferon gamma levels and the enrichment score for Thompson_FAIL_13 gene signature at month 6. Interpretation: Although adjunctive ibuprofen did not improve primary microbiological or radiological endpoints, its excellent safety profile and significant anti-inflammatory effects support its potential role as an immune-modulating adjunct in the treatment of drug-resistant TB. These findings warrant further investigation in larger studies to optimize dosing and evaluate clinical benefits. Funding: Catalan Government (2021 SGR 00920), Spanish Government-FEDER Funds (CPII18/00031, PI20/01424 and CB06/06/0031, and European Union’s Horizon 2020 research and innovation program under grant agreement No. 847762 (SMA-TB project). Research in context: Evidence before this study: Drug-resistant tuberculosis (TB) remains a major global health challenge. Host-directed therapies (HDTs) have emerged as a means to shorten treatment, improve outcomes and limit tissue damage from excessive inflammation. In preclinical models of active TB, non-steroidal anti-inflammatory drugs (NSAIDs) enhanced bacterial control and reduced lung pathology. Clinical data on NSAIDs as HDTs are scarce, confined to small studies in tuberculous meningitis and TB patients with diabetes, which reported encouraging but preliminary benefits. Added value of this study: This is the first randomized trial of adjunctive ibuprofen in patients with pre-XDR and XDR-TB. Whilst ibuprofen did not confer microbiological or clinical benefit at two and six months, it was safe, well tolerated and significantly lowered systemic inflammatory markers. Baseline imbalances in disease severity and high inter-patient variability likely obscured any clinical effect despite reduced inflammation. Implications of all the available evidence: Our findings demonstrate that ibuprofen is a safe adjunct in drug-resistant TB and can mitigate harmful inflammation. Future work should explore optimised dosing regimens, alternative HDT candidates and more sensitive or tailored endpoints—potentially focusing on patient subgroups most likely to benefit. Such refinements will be essential to reveal the true clinical value of HDTs across diverse TB populations.

Prostate cancer is a significant global health issue with considerable mortality rates, emphasising the urgent need for advanced treatment options and improved diagnostic methods. Current diagnostic standards for prostate cancer, including PSA testing and digital rectal examination, often produce false positives, resulting in unnecessary biopsies for patients. This limitation highlights the critical requirement to incorporate more precise biomarkers to enhance diagnostic accuracy and reduce unnecessary procedures. This study aims to investigate biomarker candidates that can effectively determine prostate cancer aggressiveness. By integrating diverse prostate tissue expression datasets and employing machine-learning techniques, this approach seeks to refine diagnostics and provide insights into the molecular underpinnings of the disease, potentially transforming early detection and patient management strategies. Our proposed biomarkers achieve a minimum precision of 0.80, addressing the false positives limitations associated with classical prostate cancer biomarkers. Moreover, the ROC-AUC profiles of most of the candidates proposed in this study align with those exhibited by other innovative biomarkers recently proposed (ROC-AUC ≥ 0.70). We believe these biomarkers are promising candidates for further in vivo and in vitro investigation.

Oncology treatments require continuous individual adjustment based on the measurement of multiple clinical parameters. Prediction tools exploiting the patterns present in the clinical data could be used to assist decision making and ease the burden associated to the interpretation of all these parameters. The goal of this study was to predict the evolution of patients with pancreatic cancer at their next visit using information routinely recorded in health records, providing a decision‐support system for clinicians. We selected hematological variables as the visit's clinical outcomes, under the assumption that they can be predictive of the evolution of the patient. Multivariate models based on regression trees were generated to predict next‐visit values for each of the clinical outcomes selected, based on the longitudinal clinical data as well as on molecular data sets streaming from in silico simulations of individual patient status at each visit. The models predict, with a mean prediction score (balanced accuracy) of 0.79, the evolution trends of eosinophils, leukocytes, monocytes, and platelets. Time span between visits and neutropenia were among the most common factors contributing to the predicted evolution. The inclusion of molecular variables from the systems‐biology in silico simulations provided a molecular background for the observed variations in the selected outcome variables, mostly in relation to the regulation of hematopoiesis. In spite of its limitations, this study serves as a proof of concept for the application of next‐visit prediction tools in real‐world settings, even when available data sets are small.

Introduction Randomized clinical trials (RCT) are limited in reflecting observable results out of controlled settings, which requires the execution of further lengthy observational studies. The usage of real-world data (RWD) has been recently considered to be a viable alternative to overcome these issues and complement certain clinical conclusions. Transcriptomics and other high-throughput data contain a molecular description of medical conditions and disease states. When linked to RWD, including demographical information, transcriptomics data is capable of elucidating nuances in disease pathways in specific patient populations. This work focuses on the construction of a patient repository database with clinical information resulting from the integration of publicly available transcriptomics datasets. Results Samples from patient data were integrated into the patient repository by using a new post-processing technique allowing for the combined usage of samples originating from Gene Expression Omnibus (GEO) datasets. RWD was mined from GEO samples’ metadata, and a clinical and demographical characterization of the database was obtained. Our post-processing technique, that we’ve called MACAROON, aims to uniformize, and integrate transcriptomics data (considering batch effects and possible processing-originated artefacts). This process was able to better reproduce the down streaming biological conclusions in a 10% enhancement (compared to other methods available). RWD mining was done through a manually curated synonym dictionary allowing for the correct assignment (95.33% median accuracy) of medical conditions. Conclusion Our strategy produced a RWD repository, including molecular information and clinical and demographical RWD. The exploration of these data facilitates shedding light on clinical outcomes and pathways specific to predetermined populations of patients by integrating multiple public datasets.

This animated movie presents the mechanism of macroautophagy, hereafter autophagy, by showing the molecular features of the formation of autophagosomes, the hallmark organelle of this intracellular catabolic pathway. It is based on our current knowledge and it also illustrates how autophagosomes can recognize and eliminate selected cargoes.

Design and objectives A cross-sectional study to evaluate the impact of COVID-19 on the psychosocial sphere in both the general population and healthcare workers (HCWs). Methods The study was conducted in Catalonia (Spain) during the first wave of the COVID-19 pandemic when strict lockdown was in force. The study population included all people aged over 16 years who consented to participate in the study and completed the survey, in this case a 74-question questionnaire shared via social media using snowball sampling. A total of 56 656 completed survey questionnaires were obtained between 3 and 19 April 2020. The primary and secondary outcome measures included descriptive statistics for the non-psychological questions and the psychological impact of the pandemic, such as depression, anxiety, stress and post-traumatic stress disorder question scores. Results A n early and markedly negative impact on family finances, fear of working with COVID-19 patients and ethical issues related to COVID-19 care among HCWs was observed. A total of seven target groups at higher risk of impaired mental health and which may therefore benefit from an intervention were identified, namely women, subjects aged less than 42 years, people with a care burden, socioeconomically deprived groups, people with unskilled or unqualified jobs, patients with COVID-19 and HCWs working with patients with COVID-19. Conclusions Active implementation of specific strategies to increase resilience and to prepare an adequate organisational response should be encouraged for the seven groups identified as high risk and susceptible to benefit from an intervention. Trial registration number NCT04378452.