AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The value of preoperative planning based on navigated transcranical magnetic stimulation for surgical treatment of brain metastases located in the perisylvian area: Functional planning for surgery of perisylvian metastases

Brain metastases are the most common neoplasms in adults. When they are located in eloquent areas, their treatment still appears controversial and not clearly defined. It is therefore essential to provide for a correct preoperative planning to better define extension and characterization of brain metastasis

Vitamin D status and seasonal variation in a pediatric population: Not enough even in summer?

The paper analyzes the results of a study monitoring the Vitamin D status and its seasonal level variation in a pediatric population. In particular, it is discussed whether the levels of Vitamin D could be considered sufficient in the children monitored by the study during the summer season

Build-Up/Wash-Off Monitoring and Assessment for Sustainable Management of First Flush in an Urban Area

The characterization of stormwater runoff on urbanized surfaces by means of comparison between experimental data and simulations is a strict requirement for a sustainable management of urban sewer systems. A monitoring campaign was carried out within a residential area in Puglia (Southern Italy) in order to collect and evaluate quantity and quality data. A strong correlation was observed between COD (Chemical Oxygen Demand) and TSS (Total Suspended Solid) concentrations, whose values exceed water quality standards. TSS was used for calibration of Storm Water Management Model (SWMM) which was then validated with reference to the pollutograph’s shape and the peak-time. The first flush phenomenon occurrence was also investigated by looking at the distribution of pollutant mass vs. volume in stormwater discharges, using the so-called “M(V) curves”. Results show that on average the first 30% of that washed off carries 60% of TSS and provides important information for the design of efficient systems for first flush treatment

Mortality and clinical outcome of Italian patients undergoing orthopaedic surgery: effect of peri-operative blood transfusion

BACKGROUND: Blood transfusion is a relevant issue for elderly and frail patients, as they are often anaemic and have chronic diseases. Transfusion of red blood cells (RBC) can potentially affect morbidity and mortality of elderly patients undergoing major orthopaedic surgery.MATERIALS AND METHODS: We carried out a retrospective analysis of 2,593 patients undergoing major orthopaedic surgery between 2013 and 2017 in a single research institution in the Region of Apulia. The aims of the study were: 1) to describe the characteristics of transfused patients according to a restrictive or liberal strategy of transfusion and haemoglobin (Hb) triggers and targets; 2) to investigate the effect of RBC transfusion on mortality and complications.RESULTS: Older, women and patients with American Society of Anesthesiologists (ASA) score 3-4 were more often transfused. Those with lower admission Hb level had a higher risk of being transfused. Hb triggers were associated with the patients' age. A restrictive transfusion strategy was significantly more frequent in patients undergoing primary knee replacement and in those with higher estimated blood loss. We did not observe any significant difference of complications in patients transfused with a liberal vs restrictive strategy. Logistic regression correcting for potential confounders revealed that sex (males more than females), duration of stay in hospital, hip fracture and Charlson score >4 were good predictors of complications and/ or mortality. Mortality was significantly higher in males and in older patients with ASA score 3-4.DISCUSSION: In this large cohort of Italian patients undergoing major orthopaedic surgery males were significantly more exposed than women to complications and in-hospital mortality. Furthermore, those undergoing urgent surgery because of hip fracture had a 3-fold higher chance of complications. Charlson score >4 and ASA 3-4 are good predictors of complications and mortality, respectively

Mortality and clinical outcome of Italian patients undergoing orthopaedic surgery: effect of peri-operative blood transfusion

BACKGROUND: Blood transfusion is a relevant issue for elderly and frail patients, as they are often anaemic and have chronic diseases. Transfusion of red blood cells (RBC) can potentially affect morbidity and mortality of elderly patients undergoing major orthopaedic surgery.MATERIALS AND METHODS: We carried out a retrospective analysis of 2,593 patients undergoing major orthopaedic surgery between 2013 and 2017 in a single research institution in the Region of Apulia. The aims of the study were: 1) to describe the characteristics of transfused patients according to a restrictive or liberal strategy of transfusion and haemoglobin (Hb) triggers and targets; 2) to investigate the effect of RBC transfusion on mortality and complications.RESULTS: Older, women and patients with American Society of Anesthesiologists (ASA) score 3-4 were more often transfused. Those with lower admission Hb level had a higher risk of being transfused. Hb triggers were associated with the patients' age. A restrictive transfusion strategy was significantly more frequent in patients undergoing primary knee replacement and in those with higher estimated blood loss. We did not observe any significant difference of complications in patients transfused with a liberal vs restrictive strategy. Logistic regression correcting for potential confounders revealed that sex (males more than females), duration of stay in hospital, hip fracture and Charlson score >4 were good predictors of complications and/ or mortality. Mortality was significantly higher in males and in older patients with ASA score 3-4.DISCUSSION: In this large cohort of Italian patients undergoing major orthopaedic surgery males were significantly more exposed than women to complications and in-hospital mortality. Furthermore, those undergoing urgent surgery because of hip fracture had a 3-fold higher chance of complications. Charlson score >4 and ASA 3-4 are good predictors of complications and mortality, respectively

Cisternostomy for malignant middle cerebral artery infarction: proposed pathophysiological mechanisms and preliminary results

Background The ischaemic stroke of the territory of the middle cerebral artery represents an event burdened by high mortality and severe morbidity. The proposed medical treatments do not always prove effective. Decompressive craniectomy allows the ischaemic tissue to shift through the surgical defect rather than to the unaffected regions of the brain, thus avoiding secondary damage due to increased intracranial pressure. In this study, we propose a novel treatment for these patients characterised by surgical fenestration of the cisterns of the skull base. Methods We have treated 16 patients affected by malignant middle cerebral artery ischaemia and treated with cisternostomy between August 2018 and December 2019. The clinical history, neurological examination findings and neuroradiological studies (brain CT, CT angiography, MRI) were performed to diagnose stroke. Clinical examination was recorded on admission and preoperatively using the Glasgow Coma Scale and the National Institutes of Health Stroke Scale. Results The study included 16 patients, 10 males and 6 females. The mean age at surgery was 60.1 years (range 19-73). Surgical procedure was performed in all patients. The patients underwent immediate postoperative CT scan and were in the early hours evaluated in sedation window. In total, we recorded two deaths (12.5%). A functional outcome between mRS 0-3, defined as favourable, was observed in 9 (64.2%) patients 9 months after discharge. A functional outcome between mRS 4-6, defined as poor, was observed in 5 (35.7%) patients 9 months after discharge. Conclusions The obtained clinical results appear, however, substantially overlapping to decompressive craniectomy. Cisternostomy results in a favourable functional outcome after 9 months. This proposed technique permits that the patient no longer should be undergone cranioplasty thus avoiding the possible complications related to this procedure. The results are certainly interesting but higher case numbers are needed to reach definitive conclusions

Personalized Medicine in Mitochondrial Health and Disease: Molecular Basis of Therapeutic Approaches Based on Nutritional Supplements and Their Analogs

Mitochondrial diseases (MDs) may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins, or non-protein-coding mitochondrial RNA. Despite the great variability of affected genes, in the most severe cases, a neuromuscular and neurodegenerative phenotype is observed, and no specific therapy exists for a complete recovery from the disease. The most used treatments are symptomatic and based on the administration of antioxidant cocktails combined with antiepileptic/antipsychotic drugs and supportive therapy for multiorgan involvement. Nevertheless, the real utility of antioxidant cocktail treatments for patients affected by MDs still needs to be scientifically demonstrated. Unfortunately, clinical trials for antioxidant therapies using α-tocopherol, ascorbate, glutathione, riboflavin, niacin, acetyl-carnitine and coenzyme Q have met a limited success. Indeed, it would be expected that the employed antioxidants can only be effective if they are able to target the specific mechanism, i.e., involving the central and peripheral nervous system, responsible for the clinical manifestations of the disease. Noteworthily, very often the phenotypes characterizing MD patients are associated with mutations in proteins whose function does not depend on specific cofactors. Conversely, the administration of the antioxidant cocktails might determine the suppression of endogenous oxidants resulting in deleterious effects on cell viability and/or toxicity for patients. In order to avoid toxicity effects and before administering the antioxidant therapy, it might be useful to ascertain the blood serum levels of antioxidants and cofactors to be administered in MD patients. It would be also worthwhile to check the localization of mutations affecting proteins whose function should depend (less or more directly) on the cofactors to be administered, for estimating the real need and predicting the success of the proposed cofactor/antioxidant-based therapy

Quadro clinico complesso di malattia rara: la sindrome di digeorge tipo 2 associata a sindrome hdr (ipoparatiroidismo, sordita' neurosensoriale, anomalie renali)

M.C. nata alla 36°settimana di gestazione, parto eutocico. Peso 2255 gr, lunghezza 44 cm, c.c. 31.5 cm. Mostra lieve insufficienza respiratoria e ipocalcemia. All’ E.O.: microcefalia, fronte alta, sella nasale ampia, taglio antimongoloide degli occhi, narici anteverse, filtro corto, micrognazia, ipotono assiale, motilità spontanea ridotta,opacità corneale. Esami praticati: Etg cuore: DIA tipo ostium secondum, Etg cerebrale: “due piccole pseudocisti all’incisura caudotalamica e lieve ecogenicità periventricolare in sede frontale”, Etg reni: nella norma, Etg anche: “grave displasia bilaterale". Nel sospetto di malattia genetica si effettuava cariotipo che documentava “cariotipo femminile con delezione parziale del braccio corto del cromosoma 10 (46,XX,del(10)(p14)).La successiva analisi molecolare allargata ai genitori mostrava ”delezione del tratto 10p14-telomerica in eterozigosi e di origine de novo”,mentre risultava assente la delezione nel tratto 22q11-13.Veniva quindi formulata diagnosi di "Sindorme di Di George tipo2 associata a Sindrome HDR1 (ipoparatiroidismo, sordità neurosensoriale e anomalie renali)". Veniva dimessa in terapia con Ca gluconato e Vitamina D. In tempi successivi la piccola veniva sottoposta a manovra riduttiva per la LCA e a intervento per cataratta. La piccola, all’età di 6 mesi veniva condotta a ricovero, presso l'UO di Pediatria dell’ Ospedale “C.S.S.“ di San Giovanni Rotondo, per la comparsa di crisi convulsive subentranti. All'ingresso appariva sofferente, febbrile, gravemente ipotonica e iporeattiva con elevazione degli indici di flogosi, come da sepsi batterica. L' EEG mostrava “onde lente sulle regioni posteriori bilaterali”. Veniva iniziata terapia antibiotica ad ampio spettro e antifungina ev; le crisi recedevano in corso di terapia con Fenobarbitale. Lo studio immunologico documentava deficit dei linfociti T, soprattutto a carico dei CD8 (CD3 26.9%-vn 55-65, CD4 36.2%-vn 29-42, CD8 9.6%vn 19-26) e ipogammaglobulinemia (IgG 188, IgA 11.2, IgM 24 mg/dl). Per la iniziale scarsa risposta alla terapia antibiotica si praticava terapia con Immunoglobuline in vena. I potenziali evocati uditivi evidenziavano “importante innalzamento della soglia uditiva bilaterale”, con indicazione a protesizzazione, e l’Etg reni “modica ectasia delle cavità calico-pieliche e dell’uretere a sinistra”. Nonostante la profilassi antibiotica con Sulfametoxazolo-trimetoprim praticata a domicilio, la piccola ha ripresentato due nuovi episodi settici. La monosomia 10p distale è una malattia cromosomica rara nella quale è deleta l'estremità distale del braccio corto del cromosoma 10. Il fenotipo è variabile ed in rapporto all' estensione del tratto deleto. La nostra paziente presenta una delezione che si estende verso il centromero alla banda 10p14, che spiega Il quadro fenotipico complesso (ipoparatiroidismo, cardiopatia congenita, sordità neurosensoriale, deficit immunitario con infezioni ricorrenti, ritardo psico-motorio, patologie urinarie). La presa in carico è mutidisciplinare. La prognosi è variabile e dipende dai difetti associati