Signals were broadly positive for months, but never definitive: the tocilizumab story

BACKGROUND: Most COVID-19 treatment guidelines currently recommend tocilizumab in combination with dexamethasone in critically ill patients who are exhibiting rapid respiratory decompensation. OBJECTIVES: To produce a critical review and summary of the pathway which led to the repurposing of tocilizumab for COVID-19 treatment, from in vitro observations to guidelines recommendations. SOURCES: All studies evaluating the effectiveness of tocilizumab to treat COVID-19 disease published over July 2020-July 2021. CONTENT: Two large methodologically well conducted observational studies, the TESEO and the STOP COVID cohorts, showed a reduction in the risk of invasive mechanical ventilation or death in patients treated with tocilizumab as compared to standard of care in 2020. Concomitantly and up to February 2021 a number of small sample size randomized trials (RCTs) were showing discrepant results. These RCTs had a number of issues: small sample size, various designs and inclusion criteria and different dosages of tocilizumab used. The confidence interval of the meta-analytic estimate for the RCT results was consistent with the hypothesis of no efficacy of tocilizumab. In our opinion, this was mainly because the meta-analysis included small and heterogeneous studies. These results led to a delay in the inclusion of tocilizumab in guidelines which occurred only in the summer of 2021. IMPLICATIONS: Although observational studies are unable to control for unmeasured confounding, they can be put together quickly during a pandemic and promptly provide important information. The large sample size allows us to investigate effect measure modifiers and better target interventions. It is key that the effect size is somewhat large (RR>2), all sources of bias are properly accounted for and the direct evidence is weighted against these factors. It appears to us that for tocilizumab, not having dismissed the results of carefully designed and analysed observational studies in 2020 could have prevented many deaths over those months

Breast tuberculosis: A case report of primary type mammary tuberculosis

Mammary tuberculosis is exceptional in developed countries. It can mimic an abscess or a granulomatous mastitis. In subjects coming from endemic areas, it is necessary to suspect a tuberculosis infection in case of recurrent mastitis refractory to antibiotics. Positivity of Quantiferon-TB Gold assay can help to confirm the clinical suspicion

Targeted photoimmunotherapy for cancer

Photodynamic therapy (PDT) is a clinically approved procedure that can exert a curative action against malignant cells. The treatment implies the administration of a photoactive molecular species that, upon absorption of visible or near infrared light, sensitizes the formation of reactive oxygen species. These species are cytotoxic and lead to tumor cell death, damage vasculature, and induce inflammation. Clinical investigations demonstrated that PDT is curative and does not compromise other treatment options. One of the major limitations of the original method was the low selectivity of the photoactive compounds for malignant over healthy tissues. The development of conjugates with antibodies has endowed photosensitizing molecules with targeting capability, so that the compounds are delivered with unprecedented precision to the site of action. Given their fluorescence emission capability, these supramolecular species are intrinsically theranostic agents

A comparative study of electrochemical, spectroscopic and structural properties of phenyl, thienyl and furyl substituted ethylenes

a detailed electrochemical and photophysical comparative study of three parallel series of phenyl, thienyl and furyl substituted ethylenes has been carried out, implemented by the computational calculation of selected terms. Relationships have been highlighted between molecular structure (number and type of aromatic rings) and important functional properties (in particular, electronic features and oligomerization ability). Interestingly, some of the studied heteroaryl-ethylenes show emission in the solid state displaying an aggregation-induced emission behavior

Rituximab in people living with HIV affected by immune-mediated renal diseases: a case-series

Over the last two decades, rituximab (RTX) has played an important role in the treatment of some lymphoproliferative malignancies and immune-mediated diseases. RTX administration is generally safe and well-tolerated, but side effects including late-onset neutropenia, hypogammaglobulinemia, hepatitis B reactivation and rare cases of progressive multifocal leukoencephalopathy have been observed after its administration. Although there are no absolute contraindications regarding its use in people living with HIV (PLWH), the prescription of this drug has been principally limited in patients with oncohematological diseases. In this report, we described the outcome of four PLWH who underwent RTX therapy after the diagnosis of immune-mediated renal disease. The main RTX-associated adverse effects were leukopenia, late-onset neutropenia and decline of CD4+ and CD8+ T-cell counts. In addition, two of the four patients experienced pneumonia requiring hospitalization within six months from the last RTX infusion. We suggest that RTX should be used with caution in PLWH until further evidence emerges on its safety profile in this vulnerable population

Benefits and medium-term outcome of the Sorin Pericarbon Freedom stentless aortic prosthesis in cases of acute bacterial endocarditis

OBJECTIVES The aim of this study is to evaluate the ease of use and the advantages of Sorin Pericarbon Freedom (SPF) stentless valve in cases of acute bacterial endocarditis and to check the intermediate-term results after the implant of SPF with respect to resistance to infection, valve deterioration and durability. METHODS Between June 2003 and February 2015, 26 patients with active aortic valve bacterial endocarditis underwent aortic valve replacement with SPF pericardial stentless aortic prosthesis. The mean age was 57 \ub1 18 years; 73% of the patients were in preoperative NYHA class III and VI. Mean Logistic EuroSCORE was 14.2 \ub1 12.7. Endocarditis occurred in 18 patients with native valves, and in 9 patients with prosthetic valves (4 mechanical aortic valve prostheses; 5 aortic bioprostheses). Aortic root abscesses were observed in 16 cases (61.5%). Surgery was emergent in 3 cases (11.5%). Redo surgery was performed in 9 cases (35%). Cumulative follow-up was 126.8 patient-years (mean 4.9 \ub1 3.3 years). RESULTS Operative hospital mortality was 0% for all patients. Residual mean prosthetic gradient at discharge was 9.4 \ub1 3.6 mmHg. Neither residual aortic incompetence nor residual abscess cavity was observed at discharge. Mean ejection fraction at discharge was 54 \ub1 8% (Min; Max: 35%; 65%). A total of 4 patients died at follow-up, all for non-cardiac causes. One patient was lost to follow-up. Two patients (8%) underwent non-valve-related reoperation with 0% mortality. Residual mean gradient at follow-up was 7.2 \ub1 2.1 mmHg. Three patients (17%) presented with mild/moderate aortic incompetence and 89% of patients were in NYHA Class I-II at follow-up. At 9 years, actuarial freedom from valve-related reoperation and from structural valve deterioration was 100%. CONCLUSIONS The SPF aortic prosthesis is a true pericardial stentless prosthesis suitable for the treatment of acute bacterial endocarditis. Intermediate-time results in terms of freedom from reoperation, structural valve deterioration and resistance to infections are satisfactory. Haemodynamic performances are excellent since a complete exclusion of aortic root abscesses is achieved without any reduction of the aortic annular diameter, usually due to marsupialization or patch closure of the infected cavities

Chiral biobased ionic liquids with cations or anions including bile acid building blocks as chiral selectors in voltammetry

Chiral ionic liquids (CILs), or ionic liquids (ILs) with chiral additives, are very attractive chiral media for enantioselective electroanalysis, on account of their high chiral structural order at the electrochemical interphase. A family of molecular salts with CIL properties is now introduced, based on the chiral steroid building block of deoxycholic acid implemented either in the anion or cation. Testing them as chiral additives in a commercial achiral IL, they enable voltammetric discrimination of the enantiomers of a model chiral probe on disposable screen-printed electrodes in terms of peak potential differences, which is the most desirable transduction mode of the enantiorecognition event. The probe enantiomer sequence is the same for all selectors, consistent with their sharing the same chiral building block configuration. This proof-of-concept widens the application fields of bile acid derivatives as chiral selectors, while also enriching the still very few CIL families so far explored for applications in chiral electroanalysis