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

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

Survival Outcomes and Effect of Early vs. Deferred cART Among HIV-Infected Patients Diagnosed at the Time of an AIDS-Defining Event: A Cohort Analysis

Objectives: We analyzed clinical progression among persons diagnosed with HIV at the time of an AIDS-defining event, and assessed the impact on outcome of timing of combined antiretroviral treatment (cART).Methods: Retrospective, European and Canadian multicohort study.. Patients were diagnosed with HIV from 1997-2004 and had clinical AIDS from 30 days before to 14 days after diagnosis. Clinical progression (new AIDS event, death) was described using Kaplan-Meier analysis stratifying by type of AIDS event. Factors associated with progression were identified with multivariable Cox regression. Progression rates were compared between those starting early (<30 days after AIDS event) or deferred (30-270 days after AIDS event) cART.Results: The median (interquartile range) CD4 count and viral load (VL) at diagnosis of the 584 patients were 42 (16, 119) cells/mu L and 5.2 (4.5, 5.7) log(10) copies/mL. Clinical progression was observed in 165 (28.3%) patients. Older age, a higher VL at diagnosis, and a diagnosis of non-Hodgkin lymphoma (NHL) (vs. other AIDS events) were independently associated with disease progression. Of 366 patients with an opportunistic infection, 178 (48.6%) received early cART. There was no significant difference in clinical progression between those initiating cART early and those deferring treatment (adjusted hazard ratio 1.32 [95% confidence interval 0.87, 2.00], p = 0.20).Conclusions: Older patients and patients with high VL or NHL at diagnosis had a worse outcome. Our data suggest that earlier initiation of cART may be beneficial among HIV-infected patients diagnosed with clinical AIDS in our setting

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

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

Sensitivities of a Standard Test Method for the Determination of the pHe of Bioethanol and Suggestions for Improvement

An assessment of the sensitivities of the critical parameters in the ASTM D6423 documentary standard method for the measurement of pHe in (bio)ethanol has been undertaken. Repeatability of measurements made using the same glass electrode and reproducibility between different glass electrodes have been identified as the main contributors to the uncertainty of the values produced. Strategies to reduce the uncertainty of the measurement have been identified and tested. Both increasing the time after which the pHe measurement is made following immersion in the sample, and rinsing the glass electrode with ethanol prior to immersion in the sample, have been shown to be effective in reducing the uncertainty of the numerical value produced. However, it is acknowledged that the values produced using these modified approaches may not be directly compared with those obtained using the documentary ASTM method since pHe is defined operationally by the process used to measure it