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Because cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships. One hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine. Five patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity <1.3 U/mg), and only one among them experienced early severe hematological toxicity. There was no statistically significant difference in CDA activity between patients experiencing hematological severe toxicities (28.44%) and patients who tolerated the treatment (71.56%). CDA genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity. Regarding pharmacokinetics, a wide inter-individual variability has been observed in patients. This study, which included only 4.6% of CDA-deficient patients, failed in identifying CDA status as a predictive marker of toxicities with gemcitabine. A lack of statistical power because of smoothing effect of CDA variability as compared with real life conditions could explain this absence of impact. ClinicalTrials.gov NCT01416662.

Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. EPIdemiology GIST, is an observational multicenter longitudinal follow-up cohort study reporting the prescribing patterns of imatinib in patients with GIST and the impact of the treatment in a real-world (standard clinical) setting. Eligible patients had a confirmed diagnosis of unresectable or metastatic KIT-positive GIST and started treatment with imatinib for the first time between May 24, 2002, and June 30, 2010. During routine visits, annual collection of clinical characteristics was requested, i.e., age, GIST stage at diagnosis, history, imatinib treatment duration and dosage, adherence, and concomitant medications. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analyzed using descriptive statistics. Of 151 patients enrolled, imatinib was initiated for 126 patients before enrollment and for 25 patients on the day of enrollment or soon after. The patient characteristics were similar to those in published prospective trials. The estimated 1-, 2-, 3-, and 4-year overall survival rates were 90.4% (95% confidence interval [CI; 84.8%-94.0%]), 84.7% (95% CI [78.1%-89.4%]), 73.0% (95% CI [65.0%-79.4%]), and 60.7% (95% CI [51.4%-68.8%]), respectively. The most common adverse events (AEs) were diarrhea (39%), asthenia (39%), eyelid or periorbital edema (32%), abdominal pain (23%), and anemia (21%). Eight of 126 serious AEs were possibly related to the treatment as assessed by investigators. Study results showed that patients in real-life populations are generally treated in accordance with national and international clinical recommendations and have outcomes comparable to those of patients in clinical trials.

The move towards reducing environmental and health risks related to pesticide application in smallholder agriculture requires a more detailed understanding of farmers’ awareness and pesticide use practices. Drawing on field observations and interviews with 90 randomly selected farmers, this study assesses the choice of pesticide, use patterns and the level of awareness of pesticide risks among male and female farmers growing vegetables on Idjwi Island, eastern Democratic Republic of Congo. The main crops grown are tomatoes, eggplants, and cabbages, which are vulnerable to pest attacks, leading to fruit rot (70%), leaf holes, and spots (17%), resulting in significant economic losses. To protect crops, farmers use various pesticides, including fungicides (e.g., Metalaxyl, Mancozeb) and insecticides (e.g., profenofos, Cypermethrin), based on their availability on local market, perceived effectiveness, and relatively affordable prices. Although the results did not reveal significant differences in pesticide use patterns between male and female farmers, men (41%) make decisions about pesticide purchase and use within households either alone or jointly with their spouses (31%). Regrettably, farmers disregard safety instructions and hygiene practices following pesticide application, leading to concerns about public health and the environmental impact of using these products. While we highlight the factors influencing farmers’ willingness to wear protective equipment, findings also show that 75% of the participants are willing to pay $US 5 for any alternative method to pesticide use. This study emphasizes the need for improving awareness and recommends field farmers’ schools to train farmers on pesticides’ proper usage and management. The results suggest further research on farmers’ exposure to pesticide and the exploration of existing alternative methods based on integrated pest management to advance sustainable agriculture. Plain Language Summary Pesticide Choice and Use Practices Among smallholder farmers on Idjwi Island, Democratic Republic of Congo Pesticide-based crop protection has become prevalent among farmers seeking to increase crop yields and minimize losses in market-oriented vegetable farms. While the risk of pesticides for human health and the environment are still minimized and poorly understood by farmers, the choice of pesticides is essentially based on their availability on markets, perceived effectiveness, and affordable prices. In 41% of cases, men generally decide on the purchase and pesticide application. Regrettably, farmers disregard safety instructions and hygiene practices following pesticide application, leading to concerns about public health and the environmental impact of using these products. The results of this study can inform recommendations for the safety of agricultural workers, farmers and the protection of the environment.

Mesenchymal stromal cells (MSCs) are multipotent adult cells with relevant biological properties making them interesting tools for cell-based therapy. These cells have the ability to home to sites of injury and secrete bioactive factors as part of their therapeutic functions. However, depending on the local environment, diverse functions of MSCs can be modulated and thus can influence their therapeutic value. The specific cytokine milieu within the site of inflammation is vital in determining the fate and cell behaviors of MSCs. Indeed, inflammatory signals (called as inflammatory priming), may induce critical changes on the phenotype, multilineage potential, hematopoietic support and immunomodulatory capacity of MSCs. Thus, for appropriate clinical application of MSCs, it is important to well know and understand these effects. In summary, investigating MSC interactions with the inflammatory environment is necessary to empower the therapeutic value of MSCs.

The integration of a viral genome into the host genome has a major impact on the trajectory of the infected cell. Integration location and variation within the associated viral genome can influence both clonal expansion and persistence of infected cells. Methods based on short-read sequencing can identify viral insertion sites, but the sequence of the viral genomes within remains unobserved. We develop PCIP-seq, a method that leverages long reads to identify insertion sites and sequence their associated viral genome. We apply the technique to exogenous retroviruses HTLV-1, BLV, and HIV-1, endogenous retroviruses, and human papillomavirus.

The tomato sector in the Democratic Republic of the Congo faces significant post-harvest losses and poor market hygiene. This study, conducted in Bukavu with 360 tomato sellers, assessed perceptions of post-harvest losses, preservation methods, and hygiene practices.The results reveal that post-harvest losses are very high and that sellers’ hygiene practices are inadequate along the tomato supply chain, from production to marketing. Preservation methods included cassava flour coating (52.8%), open-air storage (37.5%), and chemical pesticides (6.1%). The use of pesticides, particularly mancozeb, poses serious food safety risks due to toxic residues. Post-harvest losses of 5–10% were reported by 45% of sellers, mainly caused by microbial contamination (37.2%), physical damage (35.3%), and inadequate preservation (17.5%). Hygiene conditions were critically inadequate: 92.2% of sellers do not wash tomatoes, 67.2% display them on unhygienic surfaces, 93.1% have no dust protection, and 66.9% of stalls are infested with flies. Tomatoes are often transported in unwashed containers, increasing contamination risks. Improved hygiene training, better storage, and stricter pesticide regulation are urgently needed to enhance food safety in Bukavu.

ObjectiveTo assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).MethodsRandomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).ResultsIntention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12).ConclusionsThe primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.Trial registration numberNCT01295736.

The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus eradication. Activation of HIV-1 gene expression in these cells together with an efficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viral reservoirs. Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, we here demonstrated a strong synergistic activation of HIV-1 production by clinically used histone deacetylase inhibitors (HDACIs) combined with prostratin, a non-tumor-promoting nuclear factor (NF)- kappaB inducer. In J-Lat cells, we showed that this synergism was due, at least partially, to the synergistic recruitment of unresponsive cells into the expressing cell population. A combination of prostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR) from HIV-1 Major group subtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporter assays. Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaB and degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha . Moreover, the combined treatment prostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter region than the treatments with the compounds alone. This more pronounced remodeling correlated with a synergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, as demonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated and elongated transcripts. The physiological relevance of the prostratin+HDACI synergism was shown in CD8(+)-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viral load. Moreover, this combined treatment reactivated viral replication in resting CD4(+) T cells isolated from similar patients. Our results suggest that combinations of different kinds of proviral activators may have important implications for reducing the size of latent HIV-1 reservoirs in HAART-treated patients.

Patients with interstitial lung disease have been considered at high risk of complications of COVID-19 because of their underlying lung disease and use of immunosuppressive agents.1 However, data on COVID-19 in patients with sarcoidosis are scarce.2–4 Several reasons for an increased risk of severe forms of COVID-19 among sarcoidosis patients have been hypothesised: the involvement of the lung in almost 90% of patients with COVID-19, some of whom have reduced pulmonary function and comorbidities such as diabetes or hypertension, which are largely associated with the use of glucocorticosteroids for treating sarcoidosis; and the use of immunosuppressive agents in a subset of these patients.5 Recently, Gyorfi et al6 described the case of a patient with sarcoidosis who experienced a symptomatic SARS-CoV-2 infection with spontaneous clinical improvement, and a virological relapse after steroids treatment. This case illustrated the fact that immunosuppression with glucocorticoids may induce relapse of COVID-19 in patients with sarcoidosis. However, we lack data on the outcomes of patients with sarcoidosis affected by COVID-19. We retrospectively collected data for all patients with sarcoidosis and SARS-CoV-2 infection seen among 15 French centres between 1 March and 20 May 2020. The inclusion criteria were a sarcoidosis diagnosis based on the American Thoracic Society/European Respiratory Society/World Association for Sarcoidosis and other granulomatous diseases criteria7 and SARS-CoV-2 infection based on at least one of the following: nasopharyngeal or tracheal swab reverse transcription (RT)-PCR positive for SARS-CoV-2; SARS-CoV-2-positive serology; or typical clinical and radiological findings.

Autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a promising treatment option in severely affected and refractory patients with autoimmune diseases. This is a retrospective survey of patients reported to the EBMT registry between 1998 and 2019, who received AHSCT for TAK. Data from six patients treated with AHSCT for refractory TAK have been identified, five were female (83%), median age 25 (9–39) years. All patients were pretreated with a median of 6 (4–8) lines of therapy, including steroids (six patients), methotrexate (five patients), cyclophosphamide, mycophenolate mofetil or infliximab (four patients), tocilizumab or etanercept (two patients). Conditioning included cyclophosphamide and rabbit anti-thymocyte globulin in all patients. At 6 months post transplantation, remission was obtained in all cases, which persisted at 12 months in five cases. Four patients reactivated TAK at a median time of 27 (7–52) months after AHSCT, and three resumed disease-modifying therapy. At last follow-up, all patients were alive, two patients were in remission (off-therapy), two patients improved compared with baseline, and two patients were in complete and partial remission, respectively, under immunosuppressive treatment. This retrospective case-series demonstrates that AHSCT has the potential to provide significant clinical responses in TAK patients, but large prospective trials are necessary to confirm these preliminary data.