Treating Thalassemia Patients with Luspatercept: An Expert Opinion Based on Current Evidence

Luspatercept has recently been approved for the treatment of beta-thalassemia and its use in clinical practice has been increasing. As it is the first erythroid maturation drug available for this diagnosis, the expertise about its use is still limited. To address this point, and to promote awareness and guide the clinical use of luspatercept in beta-thalassemia, this paper was developed as a consensus by experts from the Italian Society of Thalassemia and Hemoglobinopathies (SITE). After a brief presentation of the core features of luspatercept, a comprehensive set of questions is addressed, covering relevant aspects for the practical management of this new therapeutic option

DELWAVE 1.0: deep learning surrogate model of surface wave climate in the Adriatic Basin

We propose a new point-prediction model, the DEep Learning WAVe Emulating model (DELWAVE), which successfully emulates the behaviour of a numerical surface ocean wave model (Simulating WAves Nearshore, SWAN) at a sparse set of locations, thus enabling numerically cheap large-ensemble prediction over synoptic to climate timescales. DELWAVE was trained on COSMO-CLM (Climate Limited-area Model) and SWAN input data during the period of 1971–1998, tested during 1998–2000, and cross-evaluated over the far-future climate time window of 2071–2100. It is constructed from a convolutional atmospheric encoder block, followed by a temporal collapse block and, finally, a regression block. DELWAVE reproduces SWAN model significant wave heights with a mean absolute error (MAE) of between 5 and 10 cm, mean wave directions with a MAE of 10–25°, and a mean wave period with a MAE of 0.2 s. DELWAVE is able to accurately emulate multi-modal mean wave direction distributions related to dominant wind regimes in the basin. We use wave power analysis from linearised wave theory to explain prediction errors in the long-period limit during southeasterly conditions. We present a storm analysis of DELWAVE, employing threshold-based metrics of precision and recall to show that DELWAVE reaches a very high score (both metrics over 95 %) of storm detection. SWAN and DELWAVE time series are compared to each other in the end-of-century scenario (2071–2100) and compared to the control conditions in the 1971–2000 period. Good agreement between DELWAVE and SWAN is found when considering climatological statistics, with a small (≤ 5 %), though systematic, underestimate of 99th-percentile values. Compared to control climatology over all wind directions, the mismatch between DELWAVE and SWAN is generally small compared to the difference between scenario and control conditions, suggesting that the noise introduced by surrogate modelling is substantially weaker than the climate change signal.</p

Genome sequencing of Prototheca zopfii genotypes 1 and 2 provides evidence of a severe reduction in organellar genomes

Abstract Prototheca zopfii (P. zopfii, class Trebouxiophyceae, order Chlorellales, family Chlorellaceae), a non-photosynthetic predominantly free-living unicellular alga, is one of the few pathogens belonging to the plant kingdom. This alga can affect many vertebrate hosts, sustaining systemic infections and diseases such as mastitis in cows. The aim of our work was to sequence and assemble the P. zopfii genotype 1 and genotype 2 mitochondrial and plastid genomes. Remarkably, the P. zopfii mitochondrial (38 Kb) and plastid (28 Kb) genomes are models of compaction and the smallest known in the Trebouxiophyceae. As expected, the P. zopfii genotype 1 and 2 plastid genomes lack all the genes involved in photosynthesis, but, surprisingly, they also lack those coding for RNA polymerases. Our results showed that plastid genes are actively transcribed in P. zopfii, which suggests that the missing RNA polymerases are substituted by nuclear-encoded paralogs. The simplified architecture and highly-reduced gene complement of the P. zopfii mitochondrial and plastid genomes are closer to those of P. stagnora and the achlorophyllous obligate parasite Helicosporidium than to those of P. wickerhamii or P. cutis. This similarity is also supported by maximum likelihood phylogenetic analyses inferences. Overall, the P. zopfii sequences reported here, which include nuclear genome drafts for both genotypes, will help provide both a deeper understanding of the evolution of Prototheca spp. and insights into the corresponding host/pathogen interactions

Midwives autonomy in discharge women after physiological childbirth

BACKGROUND: International literature identifies the midwife as the professional figure deals with women and newborns in the context of childbirth; it is however found to be still difficult to ensure this continuity of care. In Italy both the national laws and the indications of Emilia Romagna region promote this practice, ensuring the midwives management of the low risk women immediately after childbirth. The aim of the study is to investigate and describe the midwives autonomy as regards the post-partum discharge. METHODS: The computerised medical records were consulted to identify the mothers after childbirth who can be discharged independently by the obstetrician following the guidelines of the Emilia-Romagna region. RESULT S: A retrospective analysis of 1371 medical records related to the period January-June 2017 showed that 41% of discharges were managed handled by the midwives, while the remaining 59% by obstetricians. Fifty-seven percent of the women followed by the family counselling service were discharged by the obstetricians and 43% independently by the midwives. Considering the women followed by a private physician 62% were discharged by the obstetricians and 38% by the midwives. CONCLUSIONS: The study shows that, in a short time from the beginning of the project, the results as regards midwives autonomy were excellent. Indeed the midwives discharges does not differed significantly from the medical ones, and care continuity between the hospital and territory is strengthened. Further studies must include questionnaires concerning satisfaction of the mother not administered in this sample of women

Evidence of Common Isolates of Streptococcus agalactiae in Bovines and Humans in Emilia Romagna Region (Northern Italy)

Streptococcus agalactiae (group B Streptococcus, GBS) is one of the most important agents of bovine mastitis and causes remarkable direct and indirect economic losses to the livestock sector. Moreover, this species can cause severe human diseases in susceptible individuals. To investigate the zoonotic potential of S. agalactiae, 203 sympatric isolates from both humans and cattle, isolated in the same time frame (2018) and in the same geographic area (Emilia Romagna region, Northern Italy), were characterized by molecular capsular typing (MCT), pilus island typing (PI), and multi-locus sequence typing (MLST). In addition, antibiotic-resistant phenotypes were investigated. The distribution of the allelic profiles obtained by combining the three genotyping methods (MCT-PI-MLST) resulted in 64 possible genotypes, with greater genetic variability among the human compared to the bovine isolates. Although the combined methods had a high discriminatory power (&gt;96,2%), five genotypes were observed in both species (20,9% of the total isolates). Furthermore, some of these strains shared the same antibiotic resistance profiles. The finding of human and bovine isolates with common genotypes and antibiotic resistance profiles supports the hypothesis of interspecies transmission of S. agalactiae between bovines and humans

Minireview: Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy

In this review, we discuss the available experimental evidences supporting the chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer and the biological basis for their possible role as anticancer agents. Although the comprehension of the mechanisms underlying the effects of these drugs on colon cancer cells is incomplete, research efforts in identifying the biochemical pathway by which NSAIDs exert their chemopreventive effect have provided a rationale for the potential use of NSAIDs alone or in combination with conventional and experimental anticancer agents in the treatment of colorectal cancer. In this paper, we review three main issues: (i) the role of COX-2 in colon cancer, (ii) the common death pathways between NSAIDs and anticancer drugs; and (iii) the biological basis for the combination therapy with COX-2 selective inhibitors and new selective inhibitors of growth factor signal transduction pathways. (C) 2003 Cancer Research UK

Age-related changes in bile acid synthesis and hepatic nuclear receptor expression

BACKGROUND:Recent data highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme of bile acid synthesis, cholesterol 7alpha-hydroxylase, in cellular and animal models. This study was designed to analyze the effects of age on cholesterol 7alpha-hydroxylase and related nuclear receptor expression in human livers.DESIGN:Surgical liver biopsies were obtained in 23 patients requiring operation on the gastrointestinal tract. mRNA levels of cholesterol 7alpha-hydroxylase and related nuclear receptors and co-activators were assayed by quantitative real-time RT-PCR. Serum levels of 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, were assayed by gas-liquid chromatography:mass spectrometry.RESULTS:Ageing was inversely correlated with serum 7alpha-hydroxy-4-cholesten-3-one and with cholesterol 7alpha-hydroxylase mRNA levels (r = -0.44 and r = -0.45 on a semi-log scale, respectively, P < 0.05). Among different nuclear factors, cholesterol 7alpha-hydroxylase mRNA best correlated with hepatocyte nuclear factor-4 (r = 0.55 on a log scale, P < 0.05); hepatocyte nuclear factor-4 levels were also inversely correlated with age (r = -0.64 on a semi-log scale, P < 0.05). Age was inversely correlated with serum insulin-like growth factor-I levels, which were directly correlated with hepatocyte nuclear factor-4 and cholesterol 7alpha-hydroxylase expression. No suppressive effect of short heterodimer partner expression on cholesterol 7alpha-hydroxylase was observed.CONCLUSIONS:Ageing associates with reduced bile acid synthesis, possibly related to decreased hepatic expression of hepatocyte nuclear factor-4 and consequently of cholesterol 7alpha-hydroxylase. Age-related modifications of the growth hormone/insulin-like growth factor axis might play a role. These findings may help to elucidate the pathophysiology of age-related modifications of cholesterol metabolism

Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes

In vitro models that better reflect in vivo epithelial barrier (patho-)physiology are urgently required to predict adverse drug effects. Here we introduce extracellular matrix-supported intestinal tubules in perfused microfluidic devices, exhibiting tissue polarization and transporter expression. Forty leak-tight tubules are cultured in parallel on a single plate and their response to pharmacological stimuli is recorded over 125 h using automated imaging techniques. A study comprising 357 gut tubes is performed, of which 93% are leak tight before exposure. EC50-time curves could be extracted that provide insight into both concentration and exposure time response. Full compatibility with standard equipment and user-friendly operation make this Organ-on-a-Chip platform readily applicable in routine laboratories