SARS-CoV-2 infection among hospitalised pregnant women and impact of different viral strains on COVID-19 severity in Italy: a national prospective population-based cohort study.

OBJECTIVE: The primary aim of this article was to describe SARS-CoV-2 infection among pregnant women during the wild-type and Alpha-variant periods in Italy. The secondary aim was to compare the impact of the virus variants on the severity of maternal and perinatal outcomes. DESIGN: National population-based prospective cohort study. SETTING: A total of 315 Italian maternity hospitals. SAMPLE: A cohort of 3306 women with SARS-CoV-2 infection confirmed within 7 days of hospital admission. METHODS: Cases were prospectively reported by trained clinicians for each participating maternity unit. Data were described by univariate and multivariate analyses. MAIN OUTCOME MEASURES: COVID-19 pneumonia, ventilatory support, intensive care unit (ICU) admission, mode of delivery, preterm birth, stillbirth, and maternal and neonatal mortality. RESULTS: We found that 64.3% of the cohort was asymptomatic, 12.8% developed COVID-19 pneumonia and 3.3% required ventilatory support and/or ICU admission. Maternal age of 30-34 years (OR 1.43, 95% CI 1.09-1.87) and ≥35 years (OR 1.62, 95% CI 1.23-2.13), citizenship of countries with high migration pressure (OR 1.75, 95% CI 1.36-2.25), previous comorbidities (OR 1.49, 95% CI 1.13-1.98) and obesity (OR 1.72, 95% CI 1.29-2.27) were all associated with a higher occurrence of pneumonia. The preterm birth rate was 11.1%. In comparison with the pre-pandemic period, stillbirths and maternal and neonatal deaths remained stable. The need for ventilatory support and/or ICU admission among women with pneumonia increased during the Alpha-variant period compared with the wild-type period (OR 3.24, 95% CI 1.99-5.28). CONCLUSIONS: Our results are consistent with a low risk of severe COVID-19 disease among pregnant women and with rare adverse perinatal outcomes. During the Alpha-variant period there was a significant increase of severe COVID-19 illness. Further research is needed to describe the impact of different SARS-CoV-2 viral strains on maternal and perinatal outcomes.

Antithyroid drugs in Graves' hyperthyroidism: differences between "block and replace" and "titration" regimes in frequency of euthyroidism and Graves' orbitopathy during treatment.

PURPOSE: Whereas antithyroid drugs (ATD) are the preferred treatment modality for Graves' hyperthyroidism (GH), there is still controversy about the optimal regimen for delivering ATD. To evaluate whether 'Block and Replace' (B + R) and 'Titration' (T) regimes are equivalent in terms of frequency of euthyroidism and Graves' Orbitopathy (GO) during ATD therapy. METHODS: A prospective multicentre observational cohort study of 344 patients with GH but no GO at baseline. Patients were treated with ATD for 18 months according to B + R or T regimen in line with their institution's policy. RESULTS: Baseline characteristics were similar in both groups. In the treatment period between 6 and 18 months thyrotropin (TSH) slightly increased in both groups, but TSH was on average 0.59 mU/L (95% CI 0.27-0.85) lower in the B + R group at all time points (p = 0.026). Serum free thyroxine (FT4) remained stable during the same interval, with a tendency to higher values in the B + R group. The point-prevalence of euthyroidism (TSH and FT4 within their reference ranges) increased with longer duration of ATD in both groups; it was always higher in the T group than in the B + R group: 48 and 24%, respectively, at 6 months, 81 and 58% at 12 months, and 87 and 63% at 18 months (p < 0.002). There were no significant differences between the B + R and T regimens with respect to the fall in thyrotropin binding inhibiting immunoglobulins (TBII) or thyroid peroxidase antibodies (TPO-Ab). GO developed in 15.9% of all patients: 9.1 and 17.8% in B + R group and T group, respectively, (p = 0.096). GO was mild in 13% and moderate-to-severe in 2%. CONCLUSION: The prevalence of biochemical euthyroidism during treatment with antithyroid drugs is higher during T compared to B + R regimen. De novo development of GO did not differ significantly between the two regimens, although it tended to be higher in the T group. Whether one regimen is clinically more advantageous than the other remains unclear.

Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy.

Although promising, the clinical benefit provided by dendritic cell (DC)-based vaccines is still limited and the choice of the optimal antigen formulation is still an unresolved issue. We have developed a new DC-based vaccination protocol for aggressive and/or refractory lymphomas which combines the unique features of interferon-conditioned DC (IFN-DC) with highly immunogenic tumor cell lysates (TCL) obtained from lymphoma cells undergoing immunogenic cell death. We show that treatment of mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) cell lines with 9-cis-retinoic acid and IFNα (RA/IFNα) induces early membrane exposure of Calreticulin, HSP70 and 90 together with CD47 down-regulation and enhanced HMGB1 secretion. Consistently, RA/IFNα-treated apoptotic cells and -TCLs were more efficiently phagocytosed by DCs compared to controls. Notably, cytotoxic T cells (CTLs) generated with autologous DCs pulsed with RA/IFNα-TCLs more efficiently recognized and specifically lysed MCL or DLBCL cells or targets loaded with several HLA-A*0201 cyclin D1 or HLA-B*0801 survivin epitopes. These cultures also showed an expansion of Th1 and Th17 cells and an increased Th17/Treg ratio. Moreover, DCs loaded with RA/IFNα-TCLs showed enhanced functional maturation and activation. NOD/SCID mice reconstituted with human peripheral blood lymphocytes and vaccinated with autologous RA/IFNα-TCL loaded-IFN-DCs showed lymphoma-specific T-cell responses and a significant decrease in tumor growth with respect to mice treated with IFN-DC unpulsed or loaded with untreated TCLs. This study demonstrates the feasibility and efficacy of the use of RA/IFNα to generate a highly immunogenic TCL as a suitable tumor antigen formulation for the development of effective anticancer DC-based vaccines.

Note: Enhancing the sensitivity of roll-angle measurement with a novel interferometric configuration based on waveplates and folding mirror.

A novel method for very high resolution measurement of roll angle on a transparent plate is developed theoretically and tested experimentally. The new optical configuration is based on the interferometric readout of phase shift accumulated on the double passage through half wave plate, together with a careful control of polarization state by means of quarter wave plate, and optimizing the tilt of the folding mirror. Sensitivity to roll angle is greatly enhanced and a gain coefficient exceeding 700 is found theoretically, based on Jones' matrix analysis, with a 6-fold increase respect to previous results. In the experimental setup, at the optimum 36° incidence to retroreflector, we measured a gain coefficient of 340. Correspondingly, with an interferometer phase meter resolving 0.01°, a roll-angle resolution 0.1-arc sec is attained.

Non-invasive assessment of lung elastance in patients with acute respiratory distress syndrome.

BACKGROUND: Chest wall mechanics can be abnormal in patients with acute respiratory disease syndrome (ARDS). Therefore, partitioning respiratory system between lungs and chest wall at the bedside is useful to optimize ventilator settings. A non-invasive method for assessing lung elastance (EL), called lung barometry, was previously described on an animal model. METHODS: This prospective study was designed to compare EL assessed by lung barometry (ELLB) versus esophageal pressure (ELPeso). In sedated, paralyzed patients, PEEP was progressively increased from 5 to 40cmH2O then decreased from 40 to 5cmH2O by step of 5cmH2O every two minutes. ELLB was assessed for each step as the ratio between the change in PEEP and the induced end-expiratory lung volume change measured by direct spirometry. ELPeso was calculated from esophageal pressure measurement at each PEEP. EL and the ratio between EL and respiratory system elastance (ERS) calculated with the two methods were compared. RESULTS: Twenty six adult patients with early onset moderate or severe ARDS were included. There was a linear correlation between ELLB and ELPeso during the increase and decrease of PEEP (R²=0.26 and 0.42, respectively). Concordance using Bland and Altman method demonstrated bias and large limits of agreement during the increase (-0.5 cmH2O/L; -25 to 24 cmH2O/L) and during the decrease in PEEP (-0.3 cmH2O/L; -21 to 20 cmH2O/L). There were no linear correlation between ELLB/ERS and ELPeso/ERS during the increase and the decrease of PEEP (R²=0.00; R²=0.00, respectively). CONCLUSION: In ARDS patients, lung barometry method cannot be used instead of the esophageal pressure measurement to assess EL.

Ultrafast Control and Rabi Oscillations of Polaritons.

We report the experimental observation and control of space and time-resolved light-matter Rabi oscillations in a microcavity. Our setup precision and the system coherence are so high that coherent control can be implemented with amplification or switching off of the oscillations and even erasing of the polariton density by optical pulses. The data are reproduced by a quantum optical model with excellent accuracy, providing new insights on the key components that rule the polariton dynamics.

Strong CD8+ T cell antigenicity and immunogenicity of large foreign proteins incorporated in HIV-1 VLPs able to induce a Nef-dependent activation/maturation of dendritic cells.

Virus-like particles (VLPs) are excellent tools for vaccines against pathogens and tumors. They can accommodate foreign polypeptides whose incorporation efficiency and immunogenicity however decrease strongly with the increase of their size. We recently described the CD8(+) T cell immune response against a small foreign antigen (i.e., the 98 amino acid long human papilloma virus E7 protein) incorporated in human immunodeficiency virus (HIV)-1 based VLPs as product of fusion with an HIV-1 Nef mutant (Nef(mut)). Here, we extended our previous investigations by testing the antigenic/immunogenic properties of Nef(mut)-based VLPs incorporating much larger heterologous products, i.e., human hepatitis C virus (HCV) NS3 and influenza virus NP proteins, which are composed of 630 and 498 amino acids, respectively. We observed a remarkable cross-presentation of HCV NS3 in dendritic cells challenged with Nef(mut)-NS3 VLPs, as detected using a NS3 specific CD8(+) T cell clone as well as PBMCs from HCV infected patients. On the other hand, when injected in mice, Nef(mut)-NP VLPs elicited strong anti-NP CD8(+) T cell and CTL immune responses. In addition, we revealed the ability of Nef(mut) incorporated in VLPs to activate and mature primary human immature dendritic cells (iDCs). This phenomenon correlated with the activation of Src tyrosine kinase-related intracellular signaling, and can be transmitted from VLP-challenged to bystander iDCs. Overall, these results prove that Nef(mut)-based VLPs represent a rather flexible platform for the design of innovative CD8(+) T cell vaccines.

Maternal mortality in Italy: a record-linkage study.

OBJECTIVE: To detect maternal deaths, analyse associated causes and compute absolute and specific maternal mortality ratio among five Italian regions in response to a recent ranking of Italy by the Lancet as having the lowest maternal mortality ratio among 181 countries. DESIGN: Record-linkage study. SETTING: Five Italian regions. POPULATION: All women aged 15-49 years resident in the participating regions, with one or more hospitalisations for pregnancy or any pregnancy outcome between 2000 and 2007. METHODS: Maternal deaths have been identified by record linkage between the Death Registry and the Hospital Discharge Database. Different time periods were analysed according to local data availability. Cases have been selected and causes of death have been classified according to the 10th International Classification of Diseases. MAIN OUTCOME MEASURE: Maternal mortality ratio. RESULTS: Underreporting of official figures based on death certification in the participating regions is 63%. A total of 118 maternal deaths have been identified resulting in a maternal mortality ratio of 11.8, compared with the official figure of 4.4, per 100,000 live births. Haemorrhage, thromboembolism, and hypertensive disorders of pregnancy are the leading causes of direct deaths. CONCLUSIONS: This study implies that only 37% of all maternal deaths are included in the official data. Our analysis shows a predominance of direct obstetric deaths, which implies that emphasis is needed on improvements of obstetric care.

[Efficacy, safety and cost of sedation with sevoflurane in intensive care unit]. / Efficacité, tolérance et coût d'une sédation par sévoflurane en réanimation.

OBJECTIVES: To study efficacy, systemic and cerebral haemodynamic, and cost of sedation with sevoflurane after midazolam failure. STUDY DESIGN: Prospective observational study in a mixed intensive care unit. PATIENTS AND METHODS: Mechanically ventiled patients in whom deep sedation failed (Ramsay score<5 despite midazolam 10mg/h and fentanyl 400µg/h) were enrolled. Sedation with sevoflurane and fentanyl (200µg/h) was performed during 48 hours. Sevoflurane was administered with a dedicated filter (AnaConDa™) and sevoflurane infusion rate was adjusted in order to achieve a Ramsay score ≥5. Ramsay score, mean arterial blood pressure, norepinephrine dose/24h, intracranial pressure and cerebral perfusion pressure in patients with brain injury were measured. Directs costs for sedation were calculated. An analysis of variance for repeated measures compared values between D0 (intravenous sedation), D1 and D2 (inhaled sedation). RESULTS: Twenty-five patients (age=51 [38-63], SAPS II=43 [33-49]) were enrolled. Ramsay score was 4 [4,5] at D0 and 6 [6] at D1 and D2 (P<0.05 vs D0). Mean arterial pressure was significantly lower at D1 (80 [73-86] mmHg) as compared to D0 (84 [77-92] mmHg) and D2 (84 [78-91] mmHg) (P<0,05). Norepinephrine consumption was lower at D2 as compared to D1 (P<0,05). Intracranial pressure was lower at D1 (9 [5-13] mmHg) and D2 (11 [7-15] mmHg) as compared to D0 (12 [7-17] mmHg) (P<0.05). PPC was stable at D1 and increased at D2. Directs costs were significantly increased with sevoflurane. CONCLUSION: Sevoflurane is an effective and safe alternative to midazolam in ICU patients associated with a moderate increase in costs.

Phase II trial of single-agent oral vinorelbine in elderly (> or =70 years) patients with advanced non-small-cell lung cancer and poor performance status.

BACKGROUND: Elderly patients with advanced non-small-cell lung cancer (NSCLC) with poor performance status (PS) are a special population requiring particular attention. Single-agent oral vinorelbine could be an attractive option. PATIENTS AND METHODS: A total of 43 patients with stage IIIB-IV NSCLC and Eastern Cooperative Oncology Group (ECOG) PS of two or more with good functional status were prospectively recruited. Oral vinorelbine was administered at the dose of 60 mg/m(2) on days 1-8 every 3 weeks. Primary end points were response rate and safety. RESULTS: Overall response rate was 18.6% with 8 partial responses; 18 of 43 (41.8%) experienced stable disease lasting >12 weeks and 17 of 43 (39.6%) disease progression for an overall clinical benefit of 60.4%. Median time to progression was 4.0 (range 2-22) months and median overall survival 8.0 (range 3-35) months. Treatment was well tolerated. Of 187 cycles, we did not observe any grade 3/4 toxicity with the exception of a single not-febrile G3 neutropenia. Regardless of severity, main toxic effects observed were nausea in 48.1% and vomiting in 22.9% of patients, anemia in 43.2%, fatigue in 32.6% and leukopenia in 23.2%. CONCLUSION: Single-agent oral vinorelbine is extremely safe in elderly patients with advanced NSCLC and ECOG PS of two or more and may represent a valid option in this very special population.

Inhibition of human immunodeficiency virus (HIV-1) infection in human peripheral blood leucocytes-SCID reconstituted mice by rapamycin.

The capacity of the immunomodulatory drug rapamycin (RAPA) to inhibit replication of the CCR5 strain of human immunodeficiency virus (HIV) in vitro prompted us to test its effects in a murine preclinical model of HIV infection. RAPA (0.6 or 6 mg/kg body weight) or its vehicle were administered daily, per os, to SCID mice reconstituted with human peripheral blood leucocytes (hu-PBL) starting 2 days before the intraperitoneal challenge with the R5 tropic SF162 strain of HIV-1 (1000 50% tissue culture infective dose/ml). Relative to hu-PBL-SCID mice that received no treatment, HIV-infected hu-PBL-SCID mice treated with the vehicle control for 3 weeks exhibited a severe depletion of CD4(+) cells (90%), an increase in CD8(+) cells and an inversion of the CD4(+)/CD8(+) cell ratio. In contrast, treatment of HIV-infected mice with RAPA prevented a decrease in CD4(+) cells and the increase of CD8(+) cells, thereby preserving the original CD4(+):CD8(+) cell ratio. Viral infection also resulted in the detection of HIV-DNA within peritoneal cells and spleen, and lymph node tissues of the vehicle-treated mice within 3 weeks of the viral challenge. In contrast, treatment with RAPA decreased cellular provirus integration and reduced HIV-RNA levels in the blood. Furthermore, in co-cultivation assays, spleens from RAPA-treated mice exhibited a reduced capacity for infecting allogeneic T cells which was dose-dependent. These data show that RAPA possesses powerful anti-viral activity against R5 strains of HIV in vivo and support the use of additional studies to evaluate the potential application of this drug in the management of HIV patients.

The CAP-CR study: direct medical costs in Italian metastatic colorectal cancer patients on first-line infusional 5-fluorouracil or oral capecitabine.

AIM: To describe the healthcare resource consumption of metastatic colorectal cancer (MCRC) patients in the Italian healthcare setting. METHODS: A retrospective chart analysis estimating direct medical costs of first-line infusional 5-Fluorouracil (5-FU) or oral Capecitabine (CAP), associated or not with other chemotherapies, from the Italian Healthcare Service (IHCS) and Hospital (H) perspectives. RESULTS: 202 subjects were analysed. CAP patients (N=66) were older, with a more compromised clinical status and received less chemotherapy agents in association than 5-FU patients (N=136). From the IHCS perspective, mean total costs per patient were 12,029 euro and 5,781 euro in the 5-FU and CAP arms respectively; 7,338 euro and 4,688 euro from the H perspective. The infusional administration route of 5-FU was a cost driver from both perspectives. Sensitivity analyses found the results to be robust to variations in base case parameters. CONCLUSIONS: Management of MCRC by oral chemotherapies may be an economically advantageous option to both IHCS and hospitals.

[Trichomonas tenax in pulmonary and pleural diseases]. / Pleuro-pneumopathie à Trichomonas tenax.

INTRODUCTION: Trichomonas is a protozoan rarely incriminated in pulmonary or pleural disorders. CASE: An 84-year-old man, under treatment for chronic lymphoid leukemia with hypogammaglobulinemia, was hospitalized for respiratory distress and fever due to bilateral pulmonary and pleural disorders. Direct examination of the bronchoalveolar lavage fluid revealed a flagella protozoan identified as Trichomonas tenax. DISCUSSION: Although Trichomonas is rare in pulmonary disorders, when it occurs, T. tenax appears to be the most common species. Treatment with metronidazole was effective.

Primary chemotherapy with gemcitabine, epirubicin and taxol (GET) in operable breast cancer: a phase II study.

This trial was conducted to assess the activity and tolerability of the gemcitabine, epirubicin, taxol triplet combination in patients with operable breast cancer. After core biopsy, 43 women with stage II-IIIA breast cancer were treated with gemcitabine 1000 mg m(-2) over 30 min on days 1 and 4, epirubicin 90 mg m(-2) as an intravenous bolus on day 1, and taxol 175 mg m(-2) as a 3-h infusion on day 1, every 21 days for four cycles. The primary end point was the percentage of pathological complete responses (pCR) in the breast; secondary end points were tolerability, clinical response rates, overall and progression-free survival, tumour biomarkers before and after primary chemotherapy (PCT). All patients were included in safety and survival analyses; 41 eligible patients were evaluated for response. The overall clinical response rate was 87.8% (95% CI 77.8-97.8), with 26.8% complete responses (95% CI 13.3-40.3). A pCR in the breast was observed in six patients (14.6%; 95% CI 3.8-25.4); 15 patients (36.6%; 95% CI 21.9-51.3) had negative axillary lymph nodes. Grade 4 neutropenia was observed in 67.4% of the patients; febrile neutropenia occurred in 1.9% of cycles (granulocyte colony-stimulating factor was used in 3.2% of the cycles to shorten the duration of neutropenia). A statistically significant difference between Mib-1 at baseline (> or =20% in 71.4% of the patients) and at definitive surgery (28.6%, P < 0.05) was observed. The gemcitabine, epirubicin, taxol regimen is active and well tolerated as PCT for operable breast cancer. This combination allows the administration of full doses of active agents with a low incidence of febrile neutropenia.

[Refractory oedema: think about systemic capillary leak syndrome]. / Syndrome oedémateux réfractaire: penser au syndrome d'hyperperméabilité capillaire idiopathique.

Systemic Capillary Leak Syndrome (SCLS) is a rare and recently discovered disease. The diagnosis must be evoked in front of an hypovolaemic shock associated with a refractory anasarca. We report an observation of SCLS and then discuss the diagnostic and therapeutic difficulties. SCLS is diagnosed when a patient meet a compatible clinical situation with an hypoalbuminemia in spite of relative hemoconcentration. Evidence of a monoclonal gammapathy constitute an additional clue.

Quantitative spatial analysis of the distribution of NADPH-diaphorase-positive neurons in the developing and mature rat retina.

NADPH-diaphorase (NADPH-d) histochemistry labels a subpopulation of nitric oxide-synthesizing amacrine cells in the inner nuclear layer of the rat retina. We have studied their morphology and distribution in postnatal and adult rats in whole-mounted retinae. NAPDH-d-positive neurons are detected as early as postnatal day (P)5, especially in the peripheral retina; intense labeling of somata and long lengths of dendrites is obtained between P10 and P18, after which only the somata exhibit NADPH-d activity. The density and number of these cells increase progressively from P7 to P14, with a significantly higher density in the central retina as compared to the periphery. The sociology of these cells was analyzed quantitatively studying the Voronoi domains: a polygon area can be drawn that delineates the territory of the map that is closer to the cell than to any other cell of the map. In addition, we calculated the conformity ratio of Cook, i.e., the mean nearest neighbor distance/standard deviation of all the nearest neighbor distances, in order to reveal whether or not these cells are regularly distributed through the retina. We find that the distribution of the NADPH-d-positive cells tends to be regular throughout the retina: the local coefficient of variation (obtained by comparing the size of each Voronoi polygon area to those of its neighbors) tends to regularity at P14 and remains unaltered through maturity. Therefore, as other cell types, NADPH-d-positive amacrine cells are almost regularly distributed from the time of eye opening and nitric oxide may play a role in the development of retinal circuitry and in the regulation of retinal blood flow.

Identification, localization and functional in vitro and in vivo activity of oxytocin receptor in the rat penis.

We recently found that the oxytocin receptor (OTR) is expressed in the human and rabbit corpus cavernosum and mediates contractility in vitro. The present study extended our investigations to the rat, and explored whether OTR regulates penile detumescence in vivo. Real-time RT-PCR quantitatively characterized the distribution of OTR mRNA in the male genital tract. Specific transcripts for OTR were expressed in all the tissues investigated. Penile expression of OTR was comparable to that observed in testis and prostate. Western blot analysis detected a single band of the expected molecular mass for OTR in all tissues examined, including rat penis. Expression of OTR protein in rat penile extracts was further confirmed by binding studies, using the OTR selective radiolabeled ligand 125I-OTA (K(d) = 17 +/- 6.5 pM, B(max)=15.7 +/- 5 fmoles/mg protein). OTR was immunolocalized to the endothelial and smooth muscle compartments of cavernous spaces and blood vessels. In rat corpus cavernosum strips, oxytocin (OT) and an OTR selective agonist ([Thr4,Gly7]OT) induced identical increases in tension, while different vasopressin agonists were less active. In vivo, OT intra-cavernous injection (ICI) dose-dependently inhibited intracavernous pressure (ICP) increase elicited by either electrical stimulation of the cavernous nerve or ICI of papaverine with similar IC(50)s (117.7 +/- 37 mU). The OTR antagonist, atosiban, counteracted the contractile effect of OT both in vitro and in vivo. Atosiban alone significantly increased ICP at lower stimulation frequencies (2 Hz = P<0.001 and 4 Hz = P<0.05 vs control), but not at the maximal frequency (16 Hz). Our data showed that OTR is present in the rat penis and mediates contractility both in vitro and in vivo, therefore suggesting a role for OT in maintaining penile detumescence.