The impact of face-mask mandates on all-cause mortality in Switzerland: a quasi-experimental study.

BACKGROUND: Whereas there is strong evidence that wearing a face mask is effective in reducing the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), evidence on the impact of mandating the wearing of face masks on deaths from coronavirus disease 2019 (COVID-19) and all-cause mortality is more sparse and likely to vary by context. Focusing on a quasi-experimental setting in Switzerland, we aimed to determine (i) the effect of face-mask mandates for indoor public spaces on all-cause mortality; and (ii) how the effect has varied over time, and by age and sex. METHODS: Our analysis exploited the fact that between July and October 2020, nine cantons in Switzerland extended a face-mask mandate at different time points from being restricted to public transportation only to applying to all public indoor places. We used both a Difference-in-Differences approach with fixed-effects for canton and week and an event-study approach. RESULTS: In our main Difference-in-Differences model, the face-mask mandate was associated with a 0.3% reduction in all-cause mortality [95% confidence interval (CI): -3.4% to 2.7%; P = 0.818]. This null effect was confirmed in the event-study approach and a variety of robustness checks. Combining the face-mask mandate with social distancing rules led to an estimated 5.1% (95% CI: -7.9% to -2.4%; P = 0.001) reduction in all-cause mortality. CONCLUSIONS: Mandating face-mask use in public indoor spaces in Switzerland in mid-to-late 2020 does not appear to have resulted in large reductions in all-cause mortality in the short term. There is some suggestion that combining face-mask mandates with social distancing rules reduced all-cause mortality.

Tofacitinib Decreases Autophagy of Fibroblast-Like Synoviocytes From Rheumatoid Arthritis Patients.

The pathway of Janus tyrosine kinases (JAKs) has a central role in the pathogenesis of Rheumatoid Arthritis (RA) by regulating multiple immune functions and cytokine production. The JAK inhibitor tofacitinib is effective in RA patients not responding to methotrexate or TNF-inhibitors. Since hyperactive autophagy has been associated with impaired apoptosis of RA fibroblast-like synoviocytes (FLS), we aimed to investigate the role of tofacitinib in modulating autophagy and apoptosis in these cells. FLS isolated from RA biopsies were cultured with tofacitinib in presence of autophagy inducer rapamycin and in serum deprivation condition. Levels of autophagy, apoptosis, and citrullinated proteins were analyzed by western blot, flow cytometry, immunocytofluorescence, and Real-Time PCR. Rapamycin induced an increase in RA-FLS autophagy while the levels of autophagy marker LC3-II were reduced after in vitro treatment with tofacitinib. The analysis of autophagic flux by specific fluorescence dye confirmed the reduction of autophagy in RA FLS. The treatment with tofacitinib did not influence apoptosis of RA FLS. Modulation of the autophagic process by tofacitinib did not significantly change citrullination. The results of this study demonstrate that tofacitinib is able to modulate autophagy of FLS contributing to its effectiveness in RA patients.

Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome.

BACKGROUND: Thrombocytopenia is a manifestation associated with primary antiphospholipid syndrome (PAPS), and many studies have stressed the leading role played by platelets in the pathogenesis of antiphospholipid syndrome (APS). Platelets are highly specialized cells, and their activation involves a series of rapid rearrangements of the actin cytoskeleton. Recently, we described the presence of autoantibodies against D4GDI (Rho GDP dissociation inhibitor beta, ARHGDIB) in the serum of a large subset of SLE patients, and we observed that anti-D4GDI antibodies activated the cytoskeleton remodeling of lymphocytes by inhibiting D4GDI and allowing the upregulation of Rho GTPases, such as Rac1. Proteomic and transcriptomic studies indicate that D4GDI is very abundant in platelets, and small GTPases of the RHO family are critical regulators of actin dynamics in platelets. METHODS: We enrolled 38 PAPS patients, 15 patients carrying only antiphospholipid antibodies without clinical criteria of APS (aPL carriers) and 20 normal healthy subjects. Sera were stored at - 20 °C to perform an ELISA test to evaluate the presence of anti-D4GDI antibodies. Then, we purified autoantibodies anti-D4GDI from patient sera. These antibodies were used to conduct in vitro studies on platelet activation. RESULTS: We identified anti-D4GDI antibodies in sera from 18/38 (47%) patients with PAPS, in sera from 2/15(13%) aPL carriers, but in no sera from normal healthy subjects. Our in vitro results showed a significant 30% increase in the activation of integrin αIIbß3 upon stimulation of platelets from healthy donors preincubated with the antibody anti-D4GDI purified from the serum of APS patients. CONCLUSIONS: In conclusion, we show here that antibodies anti-D4GDI are present in the sera of PAPS patients and can prime platelet activation, explaining, at least in part, the pro-thrombotic state and the thrombocytopenia of PAPS patients. These findings may lead to improved diagnosis and treatment of APS.

Glycogen changes in the liver cells of young rats following isoprenaline treatment. (Histochemical and ultrastructural investigations).

Glycogen changes were investigated by light and electron microscopy in the liver cells of newborn rats following isoprenaline (IPR) treatment either for 1 day (2 intraperitoneal injections at 12 h interval), or for 8 days (2 intraperitoneal injections daily). On the day following the interruption of both treatments glycogen depletion was observed as compared to control rats, as evaluated by PAS reaction and confirmed by higher total phosphorylase activity. During this stage electron microscopy revealed mainly alpha-particles of glycogen associated to highly dilated smooth endoplasmic reticulum (SER) after 1-day-treatment, and to mostly increased SER after prolonged treatment. In the animals submitted to prolonged IPR administration and sacrificed at later times, glycogen masses intensely PAS-positive were strongly increased, while the activity of total phosphorylase proved accordingly lower than in the rats sacrificed at earlier times. Electron microscopy examination confirmed an increased amount of glycogen (alpha- and beta-particles) differently distributed: beta-particles were more numerous in the liver of the rats sacrificed on the last day of the experiment. At this time SER didn't appear modified as compared to control rats.

Salts as a source of metals in dialysis fluids: an assessment study by means of neutron activation analysis.

Thirty-nine trace metals were determined by neutron activation analysis (NAA) in nine salts (glucose, NaCl, KCl, CaCl2, MgCl2, Na-lactate, Na-acetate, NaHCO3 and NaOH), from different European producers, used in the preparation of dialysis fluids. Metal concentrations vary widely from less than 1 ng g-1 to several micrograms per gram. The data are used to assess the potential metal contribution of the salts to a hypothetical dialysis fluid. A comparison of these calculations with NAA of commercial haemodialysis solutions, and water used for their preparation, suggests that salts are the main source of metal contamination of the dialysate. Despite this, the chemical purity of the salts analyzed is considered to be good and it would be unrealistic to expect a clearly better chemical quality on a commercial scale. In order to protect the health of dialysis patients against abnormal metal exposure, toxicological research directed towards the estimation of the effective daily metal exposure and the determination of possible metal overloads in dialysis patients is necessary. A standardization of the dialysis systems actually used is also an important aspect if uncontrolled metal contamination of the dialysis fluid is to be avoided.

Determination of aluminum by neutron activation analysis in human lung tissue and in chemicals for dialysis of uremic patients.

Aluminum (Al) determination in human lung tissue, in chemicals for dialysis fluids, and in commercially available dialysis solutions is carried out using both Instrumental and Radiochemical Neutron Activation Analysis (INAA and RNAA). For some matrices, pre-and post-irradiation Al separations are tested. Chelex 100 resin and HDEHP, this latter adsorbed both on teflon and polyurethane foam, are employed for the pre-irradiation Al separations. The postirradiation procedures are performed using roughly the same schemes; the conventional Al precipitation as hydroxide is also carried out. Al values found in lungs of workers exposed to Al containing dust appear to be much higher than those found for unexposed people. Chemicals analyzed seem pure enough to give suitable dialysis solutions; for commercially available dialysis fluids, a 10-fold reduction of Al content should be convenient.

Gallium distribution in several human brain areas.

Gallium is an element of increasing biological interest: It is involved in problems related to environmental pollution (Ga compounds are used in electronics industry) and to clinical treatments (Ga radionuclides are employed to detect neoplastic lesions). Moreover, since its chemical behavior is similar to that of aluminum, gallium could play a role in the health effects attributed to this element. Data on naturally occurring Ga levels in human samples from healthy subjects are scanty; regarding the brain, the only reliable values available in the literature were published by Hamilton in 1972/73. In this work, the gallium distribution in several human brain areas, evaluated by radiochemical neutron activation analysis (RNAA), was found to be dishomogeneous. The element concentration determined in dry samples was, in any case, lower than the ppb level.

Effects of isoprenaline treatment on the rat liver parenchyma. Ultrastructural investigations.

Ultrastructural modifications of liver cells were studied in adult rats treated with high doses of isoprenaline for 8 days and subsequently sacrificed at various times up to 25 days from the beginning of treatment. The most evident changes were observed at the earliest times after the end of treatment. They involved both the nucleus (changes in shape and chromatin organization) and cytoplasmic organelles such as the rough endoplasmic reticulum and the smooth endoplasmic reticulum, the latter exhibiting marked dilation and increase, while glycogen generally appeared to be decreased. At later times after the end of treatment, these changes tended to disappear, while there was an increase of peroxisomes and particularly of lysosomes, which exhibited a clearly polymorphic pattern.