A folding inhibitor of the HIV-1 Protease

Being the HIV-1 Protease (HIV-1-PR) an essential enzyme in the viral life cycle, its inhibition can control AIDS. The folding of single domain proteins, like each of the monomers forming the HIV-1-PR homodimer, is controlled by local elementary structures (LES, folding units stabilized by strongly interacting, highly conserved, as a rule hydrophobic, amino acids). These LES have evolved over myriad of generations to recognize and strongly attract each other, so as to make the protein fold fast and be stable in its native conformation. Consequently, peptides displaying a sequence identical to those segments of the monomers associated with LES are expected to act as competitive inhibitors and thus destabilize the native structure of the enzyme. These inhibitors are unlikely to lead to escape mutants as they bind to the protease monomers through highly conserved amino acids which play an essential role in the folding process. The properties of one of the most promising inhibitors of the folding of the HIV-1-PR monomers found among these peptides is demonstrated with the help of spectrophotometric assays and CD spectroscopy

Systemic capillary leak syndrome : is methylene blue the silver bullet?

Background. Systemic capillary leak syndrome (SCLS) is a rare disorder characterized by unexplained, recurrent episodes of transient, abrupt increase in endothelial permeability, leading to severe hypotension, generalized edema, and hemoconcentration. Case Report. We report the case of a patient suffering from systemic capillary leak syndrome and present a possible interpretation of the pathophysiology of this condition. Besides the classical triad of hypotension, edema, and hemoconcentration, we recorded increased levels of methemoglobin, an index of NO overproduction. We present a possible interpretation of the pathophysiology of this condition based on the fast and complete reversal of symptoms after methylene blue administration (which opposes NO-induced effects) and speculate that increased NO levels could be implicated in the pathophysiology of the capillary leak phase. Why should an emergency physician be aware of this? The safety of this treatment and its fluid- and cathecolamine-sparing effect deserve consideration and further research

Risk factors associated with bacteremia in COVID-19 patients admitted to intensive care unit: a retrospective multicenter cohort study

Purpose: This multicenter observational study was done to evaluate risk factors related to the development of BSI in patients admitted to ICU for COVID-19. Methods: All patients with COVID-19 admitted in two COVID-19 dedicated ICUs in two different hospital between 02–2020 and 02–2021 were recruited. Result: 537 patients were included of whom 265 (49.3%) experienced at least one BSI. Patients who developed bacteremia had a higher SOFA score [10 (8–12) vs 9 (7–10), p < 0.001], had been intubated more frequently [95.8% vs 75%, p < 0.001] and for a median longer time [16 days (9–25) vs 8 days (5–14), p < 0.001]. Patients with BSI had a median longer ICU stay [18 days (12–31.5) vs 9 days (5–15), p < 0.001] and higher mortality [54% vs 42.3%, p < 0.001] than those who did not develop it. Development of BSI resulted in a higher SOFA score [aHR 1.08 (95% CI 1.03–1.12)] and a higher Charlson score [csAHR 1.15 (95% CI 1.05–1.25)]. Conclusion: A high SOFA score and a high Charlson score resulted associated with BSI’s development. Conversely, immunosuppressive therapy like steroids and tocilizumab, has no role in increasing the risk of bacteremia

Impact of endometriosis on obstetric outcome after natural conception: a multicenter Italian study

Purpose To evaluate obstetric outcome in women with endometriosis who conceive naturally and receive standard obstetric care in Italy. Methods Cases were consecutive women with endometriosis managed in eleven Italian referral centers. Controls were women in whom endometriosis was excluded. All women filled in a questionnaire addressing previous natural pregnancies. Marginal logistic regression models were fitted to evaluate the impact of endometriosis on obstetric outcome. A post hoc analysis was performed within the endometriosis group comparing women with severe adenomyosis versus women with absent or mild adenomyosis. Results Three hundred and fifty-five pregnancies in endometriosis group and 741 pregnancies in control group were included. Women with endometriosis had a higher risk of preterm delivery < 34 weeks (6.4% vs 2.8%, OR 2.42, 95% CI 1.22–4.82), preterm delivery < 37 weeks (17.8% vs 9.7%, OR 1.98, 95% CI 1.23–3.19), and neonatal admission to Intensive Care Unit (14.1% vs 7.0%, OR 2.04, 95% CI 1.23–3.36). At post hoc analysis, women with endometriosis and severe adenomyosis had an increased risk of placenta previa (23.1% vs 1.8%, OR 16.68, 95% CI 3.49–79.71), cesarean delivery (84.6% vs 38.9%, OR 8.03, 95% CI 1.69–38.25) and preterm delivery < 34 weeks (23.1% vs 5.7%, OR 5.52, 95% CI 1.38–22.09). Conclusion Women with endometriosis who conceive naturally have increased risk of preterm delivery and neonatal admission to intensive care unit. When severe adenomyosis is coexistent with endometriosis, women may be at increased risk of placenta previa and cesarean delivery. Trial registration Clinical trial registration number: NCT03354793

GrailQuest & HERMES: Hunting for Gravitational Wave Electromagnetic Counterparts and Probing Space-Time Quantum Foam

Within Quantum Gravity theories, different models for space-time quantisation predict an energy dependent speed for photons. Although the predicted discrepancies are minuscule, GRB, occurring at cosmological distances, could be used to detect this signature of space-time granularity with a new concept of modular observatory of huge overall collecting area consisting in a fleet of small satellites in low orbits, with sub-microsecond time resolution and wide energy band (keV-MeV). The enormous number of collected photons will allow to effectively search these energy dependent delays. Moreover, GrailQuest will allow to perform temporal triangulation of high signal-to-noise impulsive events with arc-second positional accuracies: an extraordinary sensitive X-ray/Gamma all-sky monitor crucial for hunting the elusive electromagnetic counterparts of GW. A pathfinder of GrailQuest is already under development through the HERMES project: a fleet of six 3U cube-sats to be launched by 2021/22

The PROVENT-C19 registry: A study protocol for international multicenter SIAARTI registry on the use of prone positioning in mechanically ventilated patients with COVID-19 ARDS

Background The worldwide use of prone position (PP) for invasively ventilated patients with COVID-19 is progressively increasing from the first pandemic wave in everyday clinical practice. Among the suggested treatments for the management of ARDS patients, PP was recommended in the Surviving Sepsis Campaign COVID-19 guidelines as an adjuvant therapy for improving ventilation. In patients with severe classical ARDS, some authors reported that early application of prolonged PP sessions significantly decreases 28-day and 90-day mortality. Methods and analysis Since January 2021, the COVID19 Veneto ICU Network research group has developed and implemented nationally and internationally the "PROVENT-C19 Registry", endorsed by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care. . .'(SIAARTI). The PROVENT-C19 Registry wishes to describe 1. The real clinical practice on the use of PP in COVID-19 patients during the pandemic at a National and International level; and 2. Potential baseline and clinical characteristics that identify subpopulations of invasively ventilated patients with COVID-19 that may improve daily from PP therapy. This web-based registry will provide relevant information on how the database research tools may improve our daily clinical practice. Conclusions This multicenter, prospective registry is the first to identify and characterize the role of PP on clinical outcome in COVID-19 patients. In recent years, data emerging from large registries have been increasingly used to provide real-world evidence on the effectiveness, quality, and safety of a clinical intervention. Indeed observation-based registries could be effective tools aimed at identifying specific clusters of patients within a large study population with widely heterogeneous clinical characteristics. Copyright

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 (740%) had emergency surgery and 280 (248%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (261%) patients. 30-day mortality was 238% (268 of 1128). Pulmonary complications occurred in 577 (512%) of 1128 patients; 30-day mortality in these patients was 380% (219 of 577), accounting for 817% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 175 [95% CI 128-240], p<00001), age 70 years or older versus younger than 70 years (230 [165-322], p<00001), American Society of Anesthesiologists grades 3-5 versus grades 1-2 (235 [157-353], p<00001), malignant versus benign or obstetric diagnosis (155 [101-239], p=0046), emergency versus elective surgery (167 [106-263], p=0026), and major versus minor surgery (152 [101-231], p=0047). 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

When more is not better: 10 'don'ts' in endometriosis management. An ETIC* position statement

41noETIC Endometriosis Treatment Italian ClubopenA network of endometriosis experts from 16 Italian academic departments and teaching hospitals distributed all over the country made a critical appraisal of the available evidence and definition of 10 suggestions regarding measures to be de-implemented. Strong suggestions were made only when high-quality evidence was available. The aim was to select 10 low-value medical interventions, characterized by an unfavorable balance between potential benefits, potential harms, and costs, which should be discouraged in women with endometriosis. The following suggestions were agreed by all experts: do not suggest laparoscopy to detect and treat superficial peritoneal endometriosis in infertile women without pelvic pain symptoms; do not recommend controlled ovarian stimulation and IUI in infertile women with endometriosis at any stage; do not remove small ovarian endometriomas (diameter <4 cm) with the sole objective of improving the likelihood of conception in infertile patients scheduled for IVF; do not remove uncomplicated deep endometriotic lesions in asymptomatic women, and also in symptomatic women not seeking conception when medical treatment is effective and well tolerated; do not systematically request second-level diagnostic investigations in women with known or suspected non-subocclusive colorectal endometriosis or with symptoms responding to medical treatment; do not recommend repeated follow-up serum CA-125 (or other currently available biomarkers) measurements in women successfully using medical treatments for uncomplicated endometriosis in the absence of suspicious ovarian cysts; do not leave women undergoing surgery for ovarian endometriomas and not seeking immediate conception without post-operative long-term treatment with estrogen-progestins or progestins; do not perform laparoscopy in adolescent women (<20 years) with moderate-severe dysmenorrhea and clinically suspected early endometriosis without prior attempting to relieve symptoms with estrogen-progestins or progestins; do not prescribe drugs that cannot be used for prolonged periods of time because of safety or cost issues as first-line medical treatment, unless estrogen-progestins or progestins have been proven ineffective, not tolerated, or contraindicated; do not use robotic-assisted laparoscopic surgery for endometriosis outside research settings. Our proposal is to better address medical and surgical approaches to endometriosis de-implementing low-value interventions, with the aim to prevent unnecessary morbidity, limit psychological distress, and reduce the burden of treatment avoiding medical overuse and allowing a more equitable distribution of healthcare resources.openAlio, L; Angioni, S; Arena, S; Bartiromo, L; Bergamini, V; Berlanda, N; Bonin, C; Busacca, M; Candiani, M; Centini, G; D’Alterio, M N; Di Cello, A; Exacoustos, C; Fedele, L; Frattaruolo, M P; Incandela, D; Lazzeri, L; Luisi, S; Maiorana, A; Maneschi, F; Martire, F; Massarotti, C; Mattei, A; Muzii, L; Ottolina, J; Perandini, A; Perelli, F; Pino, I; Porpora, M G; Raimondo, D; Remorgida, V; Seracchioli, R; Solima, E; Somigliana, E; Sorrenti, G; Venturella, R; Vercellini, P; Viganó, P; Vignali, M; Zullo, F; Zupi, EAlio, L; Angioni, S; Arena, S; Bartiromo, L; Bergamini, V; Berlanda, N; Bonin, C; Busacca, M; Candiani, M; Centini, G; D’Alterio, M N; Di Cello, A; Exacoustos, C; Fedele, L; Frattaruolo, M P; Incandela, D; Lazzeri, L; Luisi, S; Maiorana, Anna; Maneschi, F; Martire, F; Massarotti, C; Mattei, A; Muzii, L; Ottolina, J; Perandini, A; Perelli, F; Pino, Ida; Porpora, M G; Raimondo, D; Remorgida, V; Seracchioli, R; Solima, E; Somigliana, E; Sorrenti, G; Venturella, R; Vercellini, P; Vigano', Paola; Vignali, M; Zullo, F; Zupi,

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