SOX2: Not always eye malformations. Severe genital but no major ocular anomalies in a female patient with the recurrent c.70del20 variant

SOX2 variants have been identified in multiple patients with severe ocular anomalies and pituitary dysfunction, in addition to various systemic features. We investigated a 26-year-old female patient suffering from spastic paraparesis, hypoplasia of corpus callosum, hypogonadotropic hypogonadism (HH) and intellectual disability, who was monitored for over 20 years, allowing a detailed genotype-phenotype correlation along time. Whole exome sequencing on the patient and her relatives identified a de novo SOX2 c.70del20 variant, which has been frequently reported in individuals with SOX2-related anophthalmia. Importantly, our patient lacked major ocular phenotype but showed vaginal agenesis, a feature never reported before. Although the involvement of male urogenital tract (cryptorchidism, hypospadias, small penis), is a well known consequence of SOX2 variants, their effect on the female genitalia has never been properly addressed, even considering the paradoxical female excess of SOX2 cases in the literature. Our findings emphasize the importance of testing for SOX2 variants in individuals with HH and genital anomalies even though anophthalmia or microphthalmia are not observed. Moreover, our case strengthens the role of SOX2 as a master regulator of female gonadal differentiation, as widely demonstrated for other SOX genes related to 46, XX sex reversal, such as SOX3 and SOX9

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Patologia professionale e ambientale da amianto nei primi anni del 2000: una casistica italiana

In considerazione dell’attualità del problema amianto per la medicina ambientale e del lavoro (e in particolare per i cantieri navali), è presentata la casistica della Fondazione maugeri di Pavia, relativa a patologie asbesto-correlate in ex-esposti. I dati confermano che, all’inizio del XXI secolo, le malattie correlate all’asbesto continuano a essere di comune osservazione nella pratica clinica. Dopo oltre 15 anni dall’entrata in vigore della legge 257/1992, gli accertamenti diagnostici eseguiti hanno permesso di diagnosticare -per la prima volta- una patologia causata dall’asbesto in oltre un terzo dei pazienti esaminati (39%). Un’ulteriore dato rilevante è il numero di soggetti risultati affetti da una patologia neoplastica: sono stati diagnosticati 16 casi di mesotelioma maligno, dei quali 14 pleurici, 1 peritoneale e 1 testicolare. È stato inoltre individuato 1 caso di carcinoma polmonare in un soggetto con una pregressa esposizione professionale ad amianto e già affetto da asbestosi. Tali risultati concordano con le proiezioni statistiche che collocano l’Italia tra i paesi con tassi di mortalità più elevati per mesotelioma. La maggior parte dei pazienti affetti da patologie causate da asbesto giunge all’attenzione di medici internisti, pneumologi, oncologi, verso i quali è necessario continuare la sensibilizzazione sulla rilevanza clinica del problema amianto e sull’importanza di un’accurata anamnesi lavorativa e ambientale. Al medico del lavoro che collabora con tali specialisti spetta in particolare il compito di individuare sulla base dei dati clinici, laboratoristici e strumentali, l’esistenza di un eventuale nesso causale tra l’esposizione lavorativa pregressa e tali patologie definendo in tal modo la natura professionale della malattia con le conseguenti ricadute in ambito clinico e medico-legale

Imaging neutron capture cross sections: i-TED proof-of-concept and future prospects based on machine-learning techniques

i-TED is an innovative detection system which exploits Compton imaging techniques to achieve a superior signal-to-background ratio in (n,γ) cross-section measurements using time-of-flight technique. This work presents the first experimental validation of the i-TED apparatus for high-resolution time-of-flight experiments and demonstrates for the first time the concept proposed for background rejection. To this aim both 197Au(n,γ) and 56Fe(n,γ) reactions were measured at CERN n\_TOF using an i-TED demonstrator based on only three position-sensitive detectors. Two \cds detectors were also used to benchmark the performance of i-TED. The i-TED prototype built for this study shows a factor of ∼3 higher detection sensitivity than state-of-the-art \cds detectors in the ∼10~keV neutron energy range of astrophysical interest. This paper explores also the perspectives of further enhancement in performance attainable with the final i-TED array consisting of twenty position-sensitive detectors and new analysis methodologies based on Machine-Learning techniques

Review and new concepts for neutron-capture measurements of astrophysical interest

The idea of slow-neutron capture nucleosynthesis formulated in 1957 triggered a tremendous experimental effort in different laboratories worldwide to measure the relevant nuclear physics input quantities, namely (n,γ) cross sections over the stellar temperature range (from few eV up to several hundred keV) for most of the isotopes involved from Fe up to Bi. A brief historical review focused on total energy detectors will be presented to illustrate how, advances in instrumentation have led, over the years, to the assessment and discovery of many new aspects of s-process nucleosynthesis and to the progressive refinement of theoretical models of stellar evolution. A summary will be presented on current efforts to develop new detection concepts, such as the Total-Energy Detector with γ-ray imaging capability (i-TED). The latter is based on the simultaneous combination of Compton imaging with neutron time-of-flight (TOF) techniques, in order to achieve a superior level of sensitivity and selectivity in the measurement of stellar neutron capture rates

Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial

BackgroundTocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients.MethodsA multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival.ResultsIn the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6-24.0, P=0.52) and 22.4% (97.5% CI: 17.2-28.3, P<0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline.ConclusionsTocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline.Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092)