Using deep learning for pruning region detection and plant organ segmentation in dormant spur-pruned grapevines.

Even though mechanization has dramatically decreased labor requirements, vineyard management costs are still affected by selective operations such as winter pruning. Robotic solutions are becoming more common in agriculture, however, few studies have focused on grapevines. This work aims at fine-tuning and testing two different deep neural networks for: (i) detecting pruning regions (PRs), and (ii) performing organ segmentation of spur-pruned dormant grapevines. The Faster R-CNN network was fine-tuned using 1215 RGB images collected in different vineyards and annotated through bounding boxes. The network was tested on 232 RGB images, PRs were categorized by wood type (W), orientation (Or) and visibility (V), and performance metrics were calculated. PR detection was dramatically affected by visibility. Highest detection was associated with visible intermediate complex spurs in Merlot (0.97), while most represented coplanar simple spurs allowed a 74% detection rate. The Mask R-CNN network was trained for grapevine organs (GOs) segmentation by using 119 RGB images annotated by distinguishing 5 classes (cordon, arm, spur, cane and node). The network was tested on 60 RGB images of light pruned (LP), shoot-thinned (ST) and unthinned control (C) grapevines. Nodes were the best segmented GOs (0.88) and general recall was higher for ST (0.85) compared to C (0.80) confirming the role of canopy management in improving performances of hi-tech solutions based on artificial intelligence. The two fine-tuned and tested networks are part of a larger control framework that is under development for autonomous winter pruning of grapevines. Supplementary Information: The online version contains supplementary material available at 10.1007/s11119-023-10006-y.

Dark Energy Survey Year 1 Results: Cosmological Constraints from Cluster Abundances, Weak Lensing, and Galaxy Correlations.

We present the first joint analysis of cluster abundances and auto or cross-correlations of three cosmic tracer fields: galaxy density, weak gravitational lensing shear, and cluster density split by optical richness. From a joint analysis (4×2pt+N) of cluster abundances, three cluster cross-correlations, and the auto correlations of the galaxy density measured from the first year data of the Dark Energy Survey, we obtain Ω_{m}=0.305_{-0.038}^{+0.055} and σ_{8}=0.783_{-0.054}^{+0.064}. This result is consistent with constraints from the DES-Y1 galaxy clustering and weak lensing two-point correlation functions for the flat νΛCDM model. Consequently, we combine cluster abundances and all two-point correlations from across all three cosmic tracer fields (6×2pt+N) and find improved constraints on cosmological parameters as well as on the cluster observable-mass scaling relation. This analysis is an important advance in both optical cluster cosmology and multiprobe analyses of upcoming wide imaging surveys.

Bone metastases from differentiated thyroid carcinoma: current knowledge and open issues.

Bone represents the second most common site of distant metastases in differentiated thyroid cancer (DTC). The clinical course of DTC patients with bone metastases (BM) is quite heterogeneous, but generally associated with low survival rates. Skeletal-related events might be a serious complication of BM, resulting in high morbidity and impaired quality of life. To achieve disease control and symptoms relief, multimodal treatment is generally required: radioiodine therapy, local procedures-including surgery, radiotherapy and percutaneous techniques-and systemic therapies, such as kinase inhibitors and antiresorptive drugs. The management of DTC with BM is challenging: a careful evaluation and a personalized approach are essential to improve patients' outcomes. To date, prospective studies focusing on the main clinical aspects of DTC with BM are scarce; available analyses mainly include cohorts assembled over multiple decades, small samples sizes and data about BM not always separated from those regarding other distant metastases. The aim of this review is to summarize the most recent evidences and the unsolved questions regarding BM in DTC, analyzing several key issues: pathophysiology, prognostic factors, role of anatomic and functional imaging, and clinical management.

Detection of Cross-Correlation between Gravitational Lensing and γ Rays.

In recent years, many γ-ray sources have been identified, yet the unresolved component hosts valuable information on the faintest emission. In order to extract it, a cross-correlation with gravitational tracers of matter in the Universe has been shown to be a promising tool. We report here the first identification of a cross-correlation signal between γ rays and the distribution of mass in the Universe probed by weak gravitational lensing. We use data from the Dark Energy Survey Y1 weak lensing data and the Fermi Large Area Telescope 9-yr γ-ray data, obtaining a signal-to-noise ratio of 5.3. The signal is mostly localized at small angular scales and high γ-ray energies, with a hint of correlation at extended separation. Blazar emission is likely the origin of the small-scale effect. We investigate implications of the large-scale component in terms of astrophysical sources and particle dark matter emission.

Sourdough bacterial dynamics revealed by metagenomic analysis in Brazil.

This study dealt with the influence of the temperature on the bacterial dynamics of two spontaneously fermented wheat sourdoughs, propagated at 21 ±â€¯1 °C (SD1) and 30 ±â€¯1 °C (SD2), during nine backslopping steps (BS1 to BS9). Proteobacteria was the only phylum found in flour. Escherichia hermannii was predominant, followed by Kosakonia cowanii, besides species belonging to the genera Pantoea and Pseudomonas. After one step of propagation, Clostridium and Bacillus cereus group became predominant. Lactobacillus curvatus was found at low relative abundance. For the second backslopping step, Clostridium was flanked by L. curvatus and Lactobacillus farciminis. From BS4 (6th day) onward, lactic acid bacteria (LAB) became predominant. L. farciminis overcame L. curvatus and remained dominant until the end of propagations for both sourdoughs. At 21 °C, Bacillus, Clostridium, Pseudomonas, and Enterobacteriaceae were gradually inhibited. At the end of propagation, SD1 harbored only LAB. Otherwise, the temperature of 30 °C favored the persistence of atypical bacteria in SD2, as Pseudomonas and Enterobacteriaceae. Therefore, the temperature of 21 °C was more suitable for sourdough propagation in Brazil. This study enhanced the knowledge of temperature's influence on microbial assembly and contributed to the elucidation of sourdough microbial communities in Brazil.

Lysozyme affects the microbial catabolism of free arginine in raw-milk hard cheeses.

Lysozyme (LZ) is used in several cheese varieties to prevent late blowing which results from fermentation of lactate by Clostridium tyrobutyricum. Side effects of LZ on lactic acid bacteria population and free amino acid pattern were studied in 16 raw-milk hard cheeses produced in eight parallel cheese makings conducted at four different dairies using the same milk with (LZ+) or without (LZ-) addition of LZ. The LZ-cheeses were characterized by higher numbers of cultivable microbial population and lower amount of DNA arising from lysed bacterial cells with respect to LZ + cheeses. At both 9 and 16 months of ripening, Lactobacillus delbrueckii and Lactobacillus fermentum proved to be the species mostly affected by LZ. The total content of free amino acids indicated the proteolysis extent to be characteristic of the dairy, regardless to the presence of LZ. In contrast, the relative patterns showed the microbial degradation of arginine to be promoted in LZ + cheeses. The data demonstrated that the arginine-deiminase pathway was only partially adopted since citrulline represented the main product and only trace levels of ornithine were found. Differences in arginine degradation were considered for starter and non-starter lactic acid bacteria, at different cheese ripening stages.

PATHWAYS OF SPINDLE FORMATION IN DROSOPHILA MITOTIC AND MEIOTIC CELLS.

Spindle assembly relies on three main classes of microtubules (MTs): MTs nucleated by the centrosomes, MTs nucleated near the chromosomes/kinetochores and MTs nucleated from preexisting MTs through the augmin-based pathway. Here, we review the roles of these microtubule generation pathways in Drosophila spindle assembly. The extant results indicate that female meiotic cells, male meiotic cells, larval brain cells and S2 tissue culture cells exploit specific pathway combinations for generating the MTs necessary for spindle formation. Thus, different Drosophila cell types have specific modes of spindle assembly, which might be related to specific functional and developmental requirements.

FACTORS GOVERNING THE PATTERN OF SPINDLE MICROTUBULE REGROWTH AFTER TUBULIN DEPOLYMERIZATION.

We analyzed the pattern of spindle microtubule (MT) regrowth after cold- or colcemid-induced MT depolymerization in Drosophila S2 cells. Cold-induced MT disassembly at low temperature (­2 °C) destroyed kinetochore-driven MT regrowth without affecting astral MT formation. Conversely, colcemid-induced MT depolymerization strongly impaired centrosome-dependent MT nucleation, allowing kinetochore-driven MT regrowth. Collectively, these results indicate that the kinetochore- and the centrosome-mediated MT assembly pathways exploit molecular mechanisms that are at least in part different.

Peptides derived from phage display libraries as potential neutralizers of Shiga toxin-induced cytotoxicity in vitro and in vivo.

AIMS: To use the phage display technique to develop peptides with the capability to neutralize the cytotoxicity induced by Stx1 and Stx2 toxins produced by Shiga toxin-producing Escherichia coli (STEC). METHODS AND RESULTS: The phage display technique permitted the development of three peptides, named PC7-12, P12-26 and PC7-30, which bind to the globotriaosylceramide (Gb3) receptor for Shiga toxins produced by STEC. Moreover, these peptides were capable of competing efficiently with the Shiga toxins for binding to Gb3. The peptides described herein partially inhibited the Stx-induced cytotoxicity of cell-free filtrates of STEC O157 : H7 and purified Stx toxins in Vero cells. The inhibition of lethality induced by Stx toxins in mice indicated that peptide PC7-30 inhibited the lethality caused by Stx1 (2LD50) in mice. CONCLUSIONS: The phage display technique permitted the development of peptides that inhibited the cytotoxicity induced by Stx toxins in vitro. Peptide PC7-30 inhibited the lethality of Stx1 in vivo; this molecule would be a promising candidate for the development of therapeutic agents for STEC-related diseases in humans. SIGNIFICANCE AND IMPACT OF THE STUDY: The selection of Gb3, the common receptor for Stx1 and Stx2, may contribute to the development of efficient neutralizers for both toxins, and our approach would be an interesting alternative for the development of therapeutic molecules for the treatment of diseases caused by STEC strains.

Two-year follow-up after microsurgical discectomy and dynamic percutaneous stabilization in degenerate and herniated lumbar disc: clinical and neuroradiological outcome.

AIM: Lumbar disc herniation associated with back pain is often related to disc degeneration. Back pain after microdiscectomy often persists, prejudicing clinical outcome and quality of life. To this day, the evolution of disc degeneration after classical microdiscectomy has never been proven. Percutaneous dynamic stabilization after microdiscectomy has been proposed as a novel surgical strategy for treatment of back pain with herniated disc. However, clinical results are still debated and no evidences about the long-term evolution of back pain and relationships between neuroradiological imaging and clinical outcome have been provided. We report our preliminary observations concerning the clinical and neuroradiological outcome of 11 patients treated with microdiscectomy and dynamic percutaneous lumbo-sacral stabilization, after a long-term follow-up (2-years). METHODS: This was an uncontrolled case series. The study included 11 patients (3 F, 8 M) with L5-S1 discal herniation and degeneration underwent microdiscectomy and percutaneous dynamic stabilization, from December 2008 to November 2009. All the patients were symptomatic with back and leg pain non-responsive to long-term (8-12 months) medical and physical treatments. VAS and Satisfaction Index were used, respectively, for evaluation of clinical outcome and general postoperative patients' satisfaction. Modic and Pfirrmann scores were used for evaluation of neuroradiological outcome. All the patients underwent to microdiscectomy and implantation of the same percutaneous device for dynamic stabilization of the middle vertebral column during the same surgery. Modic, Pfirrmann, VAS and Satisfaction Index scores were collected before surgery and over the follow-up (45 days, 1 and 2 years). MRI and dynamic X-Ray 2 years after surgery were compared to the preoperative imaging. RESULTS: Motion preservation at the functional spinal unit after surgery was demonstrated in all the cases. All patients reported a reduction or complete resolution of back and leg pain, they were satisfied and came back to normal socio-professional life. No modification of the preoperative Pfirrmann was observed, even in those patients who experienced restoration of back pain. No surgical complications nor device failures were reported. CONCLUSION: Percutaneous minimally invasive lumbo-sacral dynamic stabilization after microdiscectomy seems a reliable and effective technique in order to obtain a resolution of back pain and seems to prevent the Pfirrmann worsening, over a long-term follow-up.

Segmentation of Parmigiano Reggiano dairies according to cheese-making technology and relationships with the aspect of the cheese curd surface at the moment of its extraction from the cheese vat.

Parmigiano Reggiano cheese dairies develop specific cheese-making strategies to adapt the variable characteristics of raw, not standardized milk to the final goal of obtaining cheese consistent with the standard. Analyzing 1,175 cheese-making reports from 30 out of 383 dairies associated with the Parmigiano Reggiano Consortium in 2010 and 2011, 4 groups of Parmigiano Reggiano dairies using specific cheese-making technologies were discriminated by means of multiple linear discriminant analysis. Cheese makers manage cheese-making practices to obtain curd with different roughness properties, classified according to jargon words such as "rigata" and "giusta" or synonyms, because they believe that the roughness of the cheese curd surface immediately after the extraction from the vat is associated with different whey-draining properties and to the final outcome of the cheese. The aspect of the surfaces of the curds produced by the 4 groups of dairies was different according to the technology applied by each group. Cutting of the coagulum when it is still soft for a longer time and faster cooking of the cheese curd grains were associated with a less rough appearance of the surface of the curd, whereas under the opposite conditions, cutting the coagulum when it is firm for a shorter time, led to a curd with a rougher surface. These findings partially support the traditional feeling of Parmigiano Reggiano cheese makers, who consider the curd surface aspect one of the main drivers for their technological choices; to date, however, no data are provided about correlation between the aspect of the curd and the quality of the ripened cheese. If a sufficiently strong correlation could be demonstrated by the future development of the research, the operational effectiveness of Parmigiano Reggiano dairies will be able to largely benefit from the availability of sound and early process markers.

Nonstarter lactic acid bacteria volatilomes produced using cheese components.

In long-ripened cheese, flavor formation occurs during ripening. The metabolism of lactic acid bacteria (LAB) leads to the production of different compounds that contribute to the flavor of cheese. The contribution of LAB to the formation of cheese flavor has previously been studied. However, the specific nonstarter LAB (NSLAB) metabolic reactions in ripened cheese that lead to the formation of flavor compounds remain unclear. In ripened cheese, the nutrient sources available include small peptides or amino acids, citrate, lactate, free fatty acids, and starter LAB cell lysis products. Thus, the aim of this study was to evaluate the ability of NSLAB to produce volatile flavor compounds by using an in vitro system that used only the nutrients available in ripened cheese as the energy source. Moreover, the potential contribution of the NSLAB volatilome on total cheese flavor is discussed. For this purpose, the production of volatile compounds on cheese-based medium (CBM) and on starter LAB lysed cell medium (LCM) by 2 Lactobacillus casei and 2 Lactobacillus rhamnosus strains, previously isolated from ripened Parmigiano Reggiano cheese, was investigated. The generated volatile compounds were analyzed with head-space gas chromatography mass spectrometry. Overall, ketones, aldehydes, alcohols, and acids were the most abundant compounds produced. Differences in volatilome production were found between NSLAB grown in LCM and CBM. The catabolic metabolism of amino acids and fatty acids were required for NSLAB growth on LCM. Conversely, pyruvate metabolism was the main catabolic pathway that supported growth of NSLAB in CBM. This study can be considered a first step toward a better understanding of how microbiota involved in the long ripening of cheese may contribute to the development of cheese flavor.

Organization and maintenance of Drosophila telomeres: the roles of terminin and non-terminin proteins.

Drosophila telomeres are elongated by occasional transposition of specialized retroelements rather than telomerase activity, and are assembled independently of the sequence of the DNA termini. Drosophila telomeres are capped by terminin, a complex formed by the HOAP, Moi, Ver and HipHop proteins that localize exclusively at telomeres and protect them from fusion events. Other proteins required to prevent end-to-end fusion include HP 1 Eff/UbcD 1, ATM, the components of the Mrel 1-Rad50-Nbs (MRN) complex, and the Woc transcription factor. The terminin proteins are encoded by fast-evolving genes and are not evolutionarily conserved outside the Drosophila species. In contrast, the non-terminin telomere capping proteins are not fast-evolving, do not localize only at telomeres and are conserved from yeasts to mammals. We propose that following telomerase loss, Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent manner, and that non-terminin proteins did not evolve as rapidly as terminin because of the functional constraints imposed by their involvement in diverse cellular processes. This hypothesis suggests that the Drosophila non-terminin proteins might correspond to ancestral telomere-associated proteins with homologues in other organisms including humans.

Reliable method for assessing the COD mass balance of a submerged anaerobic membrane bioreactor (SAMBR) treating sulphate-rich municipal wastewater.

The anaerobic treatment of sulphate-rich wastewater causes sulphate reducing bacteria (SRB) and methanogenic archaea (MA) to compete for the available substrate. The outcome is lower methane yield coefficient and, therefore, a reduction in the energy recovery potential of the anaerobic treatment. Moreover, in order to assess the overall chemical oxygen demand (COD) balance, it is necessary to determine how much dissolved CH(4) is lost in the effluent. The aim of this study is to develop a detailed and reliable method for assessing the COD mass balance and, thereby, to establish a more precise methane yield coefficient for anaerobic systems treating sulphate-rich wastewaters. A submerged anaerobic membrane bioreactor (SAMBR) treating sulphate-rich municipal wastewater was operated at 33 °C for an experimental period of 90 d, resulting in a high COD removal (approximately 84%) with a methane-enriched biogas of 54 ± 15% v/v. The novelty of the proposed methodology is to take into account the sulphide oxidation during COD determination, the COD removed only by MA and the dissolved CH(4) lost with the effluent. The obtained biomethanation yield (333 L CH(4) kg(-1) COD(REM MA)) is close to the theoretical value, which confirms the reliability of the proposed method.

[Physical performance in patients with amyotrophic lateral sclerosis and its relationship with wheelchairs and walking aids use]. / Desempeño físico en pacientes con esclerosis lateral amiotrófica y su relación con el uso de silla de ruedas y ayuda para la marcha.

INTRODUCTION AND OBJECTIVES: Gait deficits and falls in patients with amyotrophic lateral sclerosis (ALS) restrict mobility. The aim of this study is to examine the appropriate use of walking aids and wheelchairs, based on the risk of falling and walking speed of patients with ALS. METHODS: Retrospective data from patients from the ALS clinic were included. Age, gender, evolution time, wheelchair use, walking aids, gait speed and the Berg Balance Scale were registered. Categorical variables were related to the Chi Square test and Fisher's exact test. RESULTS: Fifty eight patients met the inclusion criteria. Twenty-seven (46.55%) had adequate use of a wheelchair based on walking speed (p=.50). This association decreases to 6% in patients who walked at a speed lower than 0.88m/s. Forty-two (70.69%) had adequate use of an assistive device based on the risk of falls (p=.001). Of the subgroup with Berg Balance score ≤ 45, 38% did not use the appropriate device (p=.06). CONCLUSION: Patients with severe gait and balance deficits had inappropriate use of walking aids and/or wheelchairs. The findings of this study may mean a contribution that could be considered in the clinical evaluations of patients with ALS to minimize risks and improve the participation of this group of people.

cDNA-amplified fragment length polymorphism to study the transcriptional responses of Lactobacillus rhamnosus growing in cheese-like medium.

AIMS: Lactobacillus rhamnosus is a dominant species during Parmigiano Reggiano cheese ripening and exhibits a great adaptability to unfavourable growth conditions. Gene expression of a Lact. rhamnosus, isolated from Parmigiano Reggiano cheese, grown in a rich medium (MRS) and in a cheese-like medium (CB) has been compared by a novel cDNA-amplified fragment length polymorphism (cDNA-AFLP) protocol. METHODS AND RESULTS: Two techniques, capillary and gel electrophoresis cDNA-AFLP, were applied to generate unique transcript tags from reverse-transcribed messenger RNA using the immobilization of biotinylated 3'-terminal cDNA fragments on streptavidin-coated Dynabeads. The use of three pairs of primers allowed detecting 64 genes expressed in MRS and 96 in CB. Different transcripts were observed when Lact. rhamnosus was cultured on CB and MRS. CONCLUSIONS: The cDNA-AFLP approach proved to be able to show that Lact. rhamnosus modifies the expression of a large part of genes when cultivated in CB compared with growth under optimal conditions (MRS). In particular, the profiles of the strain grown in CB were more complex probably because the cells activate different metabolic pathways to generate energy and to respond to the environmental changes. SIGNIFICANCE AND IMPACT OF STUDY: This is the first research on Lact. rhamnosus isolated from cheese and represents one of the few concerning bacterial transcriptomic analysis towards cDNA-AFLP approaches.

Genetic diversity in proteolytic enzymes and amino acid metabolism among Lactobacillus helveticus strains.

Lactobacillus helveticus CNRZ 32 is recognized for its ability to decrease bitterness and accelerate flavor development in cheese, and has also been shown to release bioactive peptides in milk. Similar capabilities have been documented in other strains of Lb. helveticus, but the ability of different strains to affect these characteristics can vary widely. Because these attributes are associated with enzymes involved in proteolysis or AA catabolism, we performed comparative genome hybridizations to a CNRZ 32 microarray to explore the distribution of genes encoding such enzymes across a bank of 38 Lb. helveticus strains, including 2 archival samples of CNRZ 32. Genes for peptidases and AA metabolism were highly conserved across the species, whereas those for cell envelope-associated proteinases varied widely. Some of the genetic differences that were detected may help explain the variability that has been noted among Lb. helveticus strains in regard to their functionality in cheese and fermented milk.

Changes in the aerobic vaginal bacterial mucous load after treatment with intravaginal sponges in anoestrous ewes: effect of medroxiprogesterone acetate and antibiotic treatment use.

Intravaginal sponges (IS) impregnated with progestagens are widely used for oestrous synchronization in ewes. As progestogens depress the immuno response, the first aim was to determine whether medroxiprogesterone acetate (MAP) content affects the vaginal bacteria number (VBN) in IS-treated anoestrous ewes. The second aim was to compare the effectiveness of different antibiotic treatments to control the VBN increase caused by IS. In both experiments, IS were inserted during 14 days in anoestrous ewes. In the first, 11 ewes received commercial sponges (50 mg MAP), and 10 ewes received placebo sponges. For the second experiment, IS were inserted in three groups (n = 12/group), containing oxytetracycline im (20 mg/kg); injected into the sponge (0.02 mg), or control (no antibiotic). At sponge withdrawal, all ewes received 300 UI eCG. Mucous samples were collected from the vagina before sponge insertion, at sponge withdrawal, 24, 48 and 72 h later, and the VBN (colony-forming units per ml; CFU/ml) was counted after 48-h incubation. Medroxiprogesterone content did not affect VBN (log CFU/ml: 4.3 ± 0.2 vs 4.4 ± 0.2 with and without MAP, respectively). Bacterial number increased from 3.5 ± 0.2 at sponge insertion to 6.9 ± 0.1 at sponge withdrawal (p < 0.0001) and decreased the following day to 4.3 ± 0.2 (p < 0.0001). In the second experiment, VBN increased at sponge withdrawal (p < 0.0001) in all groups and decreased the following day (p < 0.0001). The CFU/ml at sponge withdrawal was lower in ewes treated with antibiotics (p < 0.0001), being even lower when local rather than systemic antibiotic was administered (log CFU/ml: 3.3 ± 1.8 vs 7.2 ± 1.8). The day of oestrous VBN was similar for all treatments and similar to that observed before sponge insertion. We concluded that MAP does not influence the increase in VBN, as the main effect is provoked by the sponge device itself, and local antibiotic treatment resulted in a lower bacterial growth than systemic treatments.

Natural whey starter for Parmigiano Reggiano: culture-independent approach.

AIMS: The aim of this work was to obtain a deeper insight into the knowledge of microbial composition of Parmigiano Reggiano natural whey starters through different culture-independent methods. METHODS AND RESULTS: Eighteen different Parmigiano Reggiano natural whey starters sampled from three different provinces of this cheese production area and the nonacidified wheys from which they arose have been studied by length heterogeneity polymerase chain reaction (LH-PCR) and fluorescent in situ hybridization (FISH). A high microbial composition variability between different samples has been observed. CONCLUSIONS: Revealing different images of the same community, LH-PCR and FISH have given a more accurate view of the not well-known Parmigiano Reggiano whey starter ecosystem. SIGNIFICANCE AND IMPACT OF THE STUDY: New lights have been shed on Parmigiano Reggiano natural whey starters microbial composition, highlighting how culture-independent approach could be used and improved to study this and other food ecosystems.

Advances in the therapy of bacterial bloodstream infections.

BACKGROUND: Advances in the diagnostic and therapeutic management of patients with bloodstream infections (BSIs) have been achieved in the last years, improving clinical outcome. However, mortality associated with some pathogens, such as Staphylococcus aureus and Enterococcus spp., is still high. In addition, the spread of antibiotic resistance, mainly among Gram-negative bacteria, reduces treatment options in some circumstances. Therefore, interest in new drugs, combination regimens and optimal dosing schedules is rising. OBJECTIVES: Our aim is to summarize the current evidence on available antibiotic regimens for patients with bacterial BSI, focusing on drug choice, combination regimens and optimal dosing schedules. We selected bacteria that are difficult to manage because of virulence factors (i.e. methicillin-susceptible S. aureus), tolerance to antibiotic activity (i.e. Enterococcus faecalis), and/or susceptibility patterns (i.e. methicillin-resistant S. aureus, vancomycin-resistant enterococci, carbapenem-resistant Enterobacteriaceae, multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii). SOURCES: MEDLINE search with English language and publication in the last 5 years as limits. CONTENT AND IMPLICATIONS: The literature gaps on the use of new drugs, the uncertainties regarding the use of combination regimens, and the need to optimize dosing schedules in some circumstances (e.g. augmented renal clearance, renal replacement therapy, high inoculum BSI sources, and isolation of bacteria showing high MICs) have been revised.