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Objective: To assess the variations of Interleukin-6 (IL-6) in patients with SARS-CoV-2 infection treated with Tocilizumab (TCZ) alone or in association with hemoadsorption (HA). Design: Retrospective. Setting: An Intensive Care Unit (ICU) admitting mechanically ventilated patients with SARS-CoV-2 pneumonia. Patients: Four adult patients. Interventions: We compared the blood values of IL-6, C-reactive protein (CRP) and of other biochemical variables including the PaO2/FiO2 in two patients who received TCZ alone and in other 2 in whom it was associated with the HA (TCZ-HA) due to the presence of impending or established organ failures other than the lung. All variables were measured before, during and after the treatment. Main results: In all patients, the IL-6 increased during the treatment; after its termination, its values sharply decreased only in those treated also with HA; conversely, the CRP decreased in all patients; the PaO2/FiO2 increased in three patients and remained stable in the remaining one. Both the TCZ and the HA were well tolerated; all patients were weaned from the mechanical ventilation and discharged from the hospital. Limitations: Although the limited number of patients does not allow to draw firm conclusions, the increase of the IL-6 of can be ascribed to its displacement from cellular and soluble receptors, whereas its decrease is likely due to the scavenging effect exerted by the HA. Although the association TCZ-HA could be valuable in the treatment of the Cytokine Release Storm (CRS) associated with the SARS-CoV-2, the HA could be more effective as it neutralizes a wider panel of inflammatory mediators.

Germline-activating mutations in HRAS cause Costello syndrome (CS), a cancer prone multisystem disorder characterized by reduced postnatal growth. In CS, poor weight gain and growth are not caused by low caloric intake. Here, we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via reactive oxygen species-dependent AMP-activated protein kinase α and p38 hyperactivation, occurs in primary fibroblasts of CS patients, resulting in accelerated glycolysis and increased fatty acid synthesis and storage as lipid droplets. An accelerated autophagic flux was also identified as contributing to the increased energetic expenditure in CS. Concomitant inhibition of p38 and PI3K signaling by wortmannin was able to rescue both the dysregulated glucose intake and accelerated autophagic flux. Our findings provide a mechanistic link between upregulated HRAS function, defective growth and increased resting energetic expenditure in CS, and document that targeting p38 and PI3K signaling is able to revert this metabolic dysfunction.

Biallelic mutations in B3GALT6, coding for a galactosyltransferase involved in the synthesis of glycosaminoglycans (GAGs), have been associated with various clinical conditions, causing spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1 or SEMDJL Beighton type), Al-Gazali syndrome (ALGAZ), and a severe progeroid form of Ehlers-Danlos syndrome (EDSSPD2). In the 2017 Ehlers-Danlos syndrome (EDS) classification, Beta3GalT6-related disorders were grouped in the spondylodysplastic EDSs together with spondylodysplastic EDSs due to B4GALT7 and SLC39A13 mutations. Herein, we describe a patient with a previously unreported homozygous pathogenic B3GALT6 variant resulting in a complex phenotype more severe than spondyloepimetaphyseal dysplasia with joint laxity type 1, and having dural ectasia and aortic dilation as additionally associated features, further broadening the phenotypic spectrum of the Beta3GalT6-related syndromes. We also document the utility of repeating sequencing in patients with uninformative exomes, particularly when performed by using "first generations" enrichment capture methods.

The aim of the study was to evaluate the results of an all arthroscopic technique for the treatment of massive rotator cuff tears using the long head of biceps as a graft to reconstruct the superior capsule and to reinforce the cuff. A retrospective review of a consecutive series of arthroscopic repair of massive rotator cuff tears using the long head of biceps tendon was conducted. Twenty-five patients underwent surgery, and none were lost at follow-up. Minimum follow-up period was more than 12 months. Constant, UCLA and VAS scores as clinical outcome were analyzed. Time for surgical procedures was also registered. Two alternative procedures (transosseous or anchors) were employed to fix laterally the long head of biceps to the greater tuberosity and to reinforce the cuff. This choice was essentially determined by the bone quality of the greater tuberosity. All patients of both groups (Transosseous: 15 and Anchors: 10) showed a significant improvement of clinical and functional scores. Difference of the operative times between two procedures was statistically significant in favor of the anchor approach. No intraoperative complications were recorded. Postoperative shoulder stiffness was found in two male patients. In no case biceps tenodesis was performed: Popeye sign was easily detected in 16 patients but they did not complain any superior arm pain and weakness. This technique represents a valid solution for treatment of massive rotator cuff tears resulting safe, easier and cost saving in comparison with other published techniques.

Objective To develop a longitudinal algorithm combining two biomarkers, CA125 and HE4, for early detection of ovarian cancer in women with BRCA mutations. Methods Women with BRCA mutations and intact ovaries were invited to participate in a novel ovarian cancer early detection prospective study. The Risk of Ovarian Cancer Algorithm (ROCA) identifying significant increases above each woman's baseline in serum CA125 and HE4 was performed every four months; abnormal risks triggered a subsequent ultrasound. The study first used a risk algorithm for only CA125, a second algorithm was developed for HE4 and finally a risk algorithm combining the two biomarkers was implemented. The ROCA strategy was compared to Standard of Care (SOC) surveillance strategy. Results A total of 149 women enrolled in the ROCA arm while 43 women enrolled in the SOC arm. Abnormal scores were found in 24% of ROCA CA125 tests, 16% if ROCA CA125 or the novel ROCA HE4 were used independently and reduced to 8% using the new two-marker ROCA, significantly lower than the 15% of abnormal tests seen in the SOC arm (p = 0.042). The average false positive rate among women without ovarian cancer for two-marker ROCA for referral to ultrasound was 6.6% (specificity 93.4%), and for the two-marker ROCA plus ultrasound for referral to surgical consultation was 1.7% (specificity 98.3%). Conclusion A newly developed two-marker ROCA administered every 4 months had lower call-back rates than SOC surveillance. Having established high specificity, the two-marker ROCA score deserves further evaluation for sensitivity in a larger trial.

Rotavirus group A remains a major cause of diarrhea in infants and young children worldwide. The permanent emergence of new genotypes puts the potential effectiveness of vaccines under serious questions. Thirteen VP1 structures with mutations mapping to the RNA entry site were analyzed using molecular dynamics simulations, and the results were combined with the experimental findings reported previously. The results revealed structural fluctuations in the protein-protein recognition sites and in the bottleneck of the RNA entry site that may affect the interaction of different proteins and delay the initiation of the viral replication, respectively. Altogether, the structural analysis of VP1 in the region crucial for the initiation of the viral replication, mainly the bottleneck site, may boost efforts to develop antivirals, as they might complement the available vaccines.

Background: Humeral shaft fractures account for 1% to 3% of all fractures and approximately 20% of all fracture involving the humerus. The prevalence of non-union for diaphyseal humeral fractures has been reported as 1% to 10% after non-surgical and 10% to 15% after surgical management. Various devices used in treatment of humeral diaphyseal non-union are limited contact dynamic compression plates, locking compression plate (LCP), wave plates, humerus interlocking nail (IMN), Ilizarov external fixators and bone graft struts. Case Description: A 68-year-old man reported a humeral shaft fracture on the left side, due to a simple fall. It was reduced and fixed by IMN. He underwent clinical and radiological follow up. Three months after the intervention, due to persistent pain and impaired function of the left shoulder, the nail was removed and a cemented endoprosthesis was implanted. 3 years later, unsatisfied with the results, he came to our attention and was diagnosed an atrophic non-union in the site of the previous humeral shaft fracture. Moreover, the exams showed a rotator cuff insufficiency. It was decided to perform a single-stage intervention to achieve two goals: cure the humeral shaft non-union and restore the function of the left shoulder. The cemented endoprosthesis was removed, followed by an extensive curettage of the non-union site. A reverse prosthesis was implanted, with an extra-long stem used to stabilize the non-union site, as it was an IMN. An allograft was harvested from a cadaver femur and fixed with two metal cerclages. The patient underwent clinical and radiological follow-up. Complete healing was achieved 8 months later. Conclusion: Humeral shaft nonunion still represent a pathology that pose a serious problem to the surgeon. A correct management should include an accurate pre-operative planning, to achieve the best result possible for the patient.

Different surgical techniques (open and arthroscopic) have been described for the treatment of post-traumatic recurrent anterior instability. The aim of the surgery is to restore when possible, normal shoulder anatomy by repairing the underlying pathology responsible for the instability. Sometimes other surgical techniques are indicated. The purpose of this retrospective study was to investigate the long-term clinical and radiographic results and complications of the open Latarjet procedure after a minimum follow-up of 24 years.A retrospective study was performed for 67 patients treated with an open Latarjet procedure in a single center. Forty of these 67 patients returned for follow-up evaluation and clinical/radiological examination during the year 2018, having had a minimum of 24-year follow-up. Clinical outcomes were analyzed using two functional scores, in addition to the ROM and strength assessment. Radiographic evaluation included several views (AP views in neutral, internal and external rotation and a comparative Bernageau view) RESULTS: A total of 40 patients underwent an open Latarjet procedure. All the patients were avaible for follow-up at an average of 25.6 years. Clinically, no patient reported any episode of dislocation at the time of follow-up. The mean Rowe score and the Walch-Duplay score were 84.5 (range 45-100) and 83.5 (range 55-100), respectively. Non-union/fibrous union was reported in 12.5% of cases, partial resorption of the graft was found in 7.5% of cases, while total resorption was found in 5% of cases. Osteoarthritis was identified in 52.5% (21) of the patients.This long-term follow-up study demonstrated that the open Latarjet procedure is a safe and reliable technique for recurrent anterior shoulder instability. The Latarjet procedure provides good long-term stability although associated with a slight limitation in external rotation.Level III; retrospective cohort comparison; treatment study.

Objective: To assess the variations of the blood levels of immunoglobulins (Ig) in septic shock patients treated with an Ig preparation enriched in IgM and IgA (eIg).Design: The blood levels of Ig in survivors (S) and non-survivors (NS) of a group of septic shock patients were measured before the initial administration (D0) and 1 (D1), 4 (D4), and 7 (D7) days thereafter. The SAPS II score, the capillary permeability, the primary site of infection, the antibiotic appropriateness, and the outcome at 28 days were also assessed.Results: In the interval D0–D7, the IgM increased significantly only in the S while remained stable in NS; the IgA significantly increased in both groups; the IgG did not vary significantly in both groups. At D4, the capillary permeability significantly decreased in S but not in NS.Conclusions: The kinetics of the different classes of Ig after eIg were different between S and NS. This could be related either to (a) different capillary permeability in the two groups or to (b) higher Ig consumption in NS. Further studies to confirm the benefits of eIg in the treatment of sepsis syndrome and to define the specific target population and the correct eIg dose are warranted.

Vesicle biogenesis, trafficking and signaling via the ER-Golgi network support essential processes during development and their disruption can lead to neurodevelopmental disorders and neurodegeneration. We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi structure and function, cause a neurodevelopmental disease showing microcephaly and progressive cortical atrophy, with microsomia and rib anomalies in severely affected subjects, suggesting a pleiotropic effect. All microcephaly-associated variants clustered in the guanine nucleotide binding pocket and perturbed the biochemical behavior of the protein by stabilizing it in a GTP-bound state. Functional analysis proved the disruptive consequences of the variants on Golgi integrity, and brain and body plan formation. In-depth analysis in zebrafish embryos expressing ARF3 mutants traced back the developmental alterations to defective gastrulation cell movements as the earliest detectable effect. Our findings document a role of ARF3 in Golgi homeostasis and demonstrate an obligate dependence for early development.

Objective: Cardiofaciocutaneous syndrome (CFCS) is a rare developmental disorder caused by upregulated signaling through the RAS-mitogen-activated protein kinase (MAPK) pathway, mostly resulting from de novo activating BRAF mutations. Children with CFCS are prone to epilepsy, which is a major life-threatening complication. The aim of our study was to define the natural history of epilepsy in this syndrome and exploring genotype–phenotype correlations. Methods: We performed an observational study, including 34 patients with molecularly confirmed diagnosis (11 males, mean age: 15.8 years). The mean follow-up period was 9.2 years. For all patients, we performed neurological examination, cognitive assessment when possible, neuroimaging, electrophysiological assessment and systematic assessment of epilepsy features. Correlation analyses were performed, taking into account gender, age of seizure onset, EEG features, degree of cognitive deficits, type of mutation, presence of non-epileptic paroxysmal events and neuroimaging features. Results: Epilepsy was documented in 64% of cases, a higher prevalence compared to previous reports. Patients were classified into three groups based on their electroclinical features, long-term outcome and response to therapy. A genotype–phenotype correlation linking the presence/severity of epilepsy to the nature of the structural/functional consequences of mutations was observed, providing a stratification based on genotype to improve the clinical management of these patients.

Mary S Anthony,1 Mary Anne Armstrong,2 Darios Getahun,3 Delia Scholes,4 Jennifer Gatz,5 Renate Schulze-Rath,6 Debbie Postlethwaite,2 Maqdooda Merchant,2 Amy L Alabaster,2 Giulia Chillemi,2 Tina Raine-Bennett,2 Fagen Xie,3 Vicki Y Chiu,3 Theresa M Im,3 Harpreet S Takhar,3 Michael Fassett,3 Jane Grafton,4 David Cronkite,4 Laura Ichikawa,4 Susan D Reed,4,7 Siu Lui Hui,5 Mary E Ritchey,1 Catherine W Saltus,8 Elizabeth B Andrews,1 Kenneth J Rothman,8 Alex Asiimwe,6 Richard Lynen,9 Juliane Schoendorf101RTI Health Solutions, Research Triangle Park, NC, USA; 2Kaiser Permanente Northern California, Oakland, CA, USA; 3Kaiser Permanente Southern California, Pasadena, CA, USA; 4Kaiser Permanente Washington, Seattle, WA, USA; 5Regenstrief Institute, Indianapolis, IN, USA; 6Bayer AG, Berlin, Germany; 7University of Washington, Seattle, WA, USA; 8RTI Health Solutions, Waltham, MA, USA; 9Bayer HealthCare, Whippany, NJ, USA; 10Bayer OY, Espoo, FinlandObjective: To validate algorithms identifying uterine perforations and intrauterine device (IUD) expulsions and to ascertain availability of breastfeeding status at the time of IUD insertion.Study design and setting: Four health care systems with electronic health records (EHRs) participated: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Southern California (KPSC), Kaiser Permanente Washington (KPWA), and Regenstrief Institute (RI). The study included women ≤50 years of age with an IUD insertion. Site-specific algorithms using structured and unstructured data were developed and a sample validated by EHR review. Positive predictive values (PPVs) of the algorithms were calculated. Breastfeeding status was assessed in a random sample of 125 women at each research site with IUD placement within 52 weeks postpartum.Results: The study population included 282,028 women with 325,582 IUD insertions. The PPVs for uterine perforation were KPNC 77%, KPSC 81%, KPWA 82%, and RI 47%; PPVs for IUD expulsion were KPNC 77%, KPSC 87%, KPWA 68%, and RI 37%. Across all research sites, breastfeeding status at the time of IUD insertion was determined for 94% of those sampled.Conclusions: Algorithms with a high PPV for uterine perforation and IUD expulsion were developed at 3 of the 4 research sites. Breastfeeding status at the time of IUD insertion could be determined at all research sites. Our findings suggest that a study to evaluate the associations of breastfeeding and postpartum IUD insertions with risk of uterine perforation and IUD expulsion can be successfully conducted retrospectively; however, automated application of algorithms must be supplemented with chart review for some outcomes at one research site due to low PPV.Keywords: electronic health records, intrauterine device, breastfeeding, validation study, algorithm, postpartum

The periaqueductal gray is a mesencephalic structure involved in modulation of responses to stressful stimuli. Structural connections between the periaqueductal gray and the cerebellum have been described in animals and in a few diffusion tensor imaging studies. Nevertheless, these periaqueductal gray–cerebellum connectivity patterns have yet to be fully investigated in humans. The objective of this study was to qualitatively and quantitatively characterize such pathways using high-resolution, multi-shell data of 100 healthy subjects from the open-access Human Connectome Project repository combined with constrained spherical deconvolution probabilistic tractography. Our analysis revealed robust connectivity density profiles between the periaqueductal gray and cerebellar nuclei, especially with the fastigial nucleus, followed by the interposed and dentate nuclei. High-connectivity densities have been observed between vermal (Vermis IX, Vermis VIIIa, Vermis VIIIb, Vermis VI, Vermis X) and hemispheric cerebellar regions (Lobule IX). Our in vivo study provides for the first time insights on the organization of periaqueductal gray–cerebellar pathways thus opening new perspectives on cognitive, visceral and motor responses to threatening stimuli in humans.

The fracture avulsion of the greater tuberosity (GT) represents 2% of all humerus fractures, but the true incidence is likely to be higher, being challenging the initial diagnosis on radiograph. The fracture avulsion of the GT could have different treatments: nondisplaced or minimally displaced fractures are treated conservatively, whereas for displaced or comminuted fractures surgical treatment is preferred. The most important finding of this study is the employment of an all-arthroscopic transosseous augmented technique for the treatment of a displaced humeral GT fracture avulsion. This technique shows all the advantages of the transosseous fixation and arthroscopic approach., Technique Video Video 1 The video shows a novel transosseous arthroscopic technique for the treatment of fracture avulsion of the greater tuberosity.

Intramuscular fat content (IMF) is a complex trait influencing the technological and sensorial features of meat products and determining pork quality. Thus, we aimed at analyzing through RNA-sequencing the Semimembranosus muscle transcriptome of Italian Large White pigs to study the gene networks associated with IMF deposition. Two groups of samples were used; each one was composed of six unrelated pigs with extreme and divergent IMF content (0.67 ± 0.09% in low IMF vs. 6.81 ± 1.17% in high IMF groups) that were chosen from 950 purebred individuals. Paired-end RNA sequences were aligned to Sus scrofa genome assembly 11.1 and gene counts were analyzed using WGCNA and DeSeq2 packages in R environment. Interestingly, among the 58 differentially expressed genes (DEGs), several were related to primary cilia organelles (such as Lebercilin 5 gene), in addition to the genes involved in the regulation of cell differentiation, in the control of RNA-processing, and G-protein and ERK signaling pathways. Together with cilia-related genes, we also found in high IMF pigs an over-expression of the Fibroblast Growth Factor 2 (FGF2) gene, which in other animal species was found to be a regulator of ciliogenesis. Four WGCNA gene modules resulted significantly associated with IMF deposition: grey60 (P = 0.003), darkturquoise (P = 0.022), skyblue1 (P = 0.022), and lavenderblush3 (P = 0.030). The genes in the significant modules confirmed the results obtained for the DEGs, and the analysis with "cyto- Hubba" indicated genes controlling RNA splicing and cell differentiation as hub genes. Among the complex molecular processes affecting muscle fat depots, genes involved in primary cilia may have an important role, and the transcriptional reprogramming observed in high IMF pigs may be related to an FGF-related molecular cascade and to ciliogenesis, which in the literature have been associated with fibro-adipogenic precursor differentiation.

BACKGROUND Glenohumeral osteoarthritis (OA) is a common cause of pain and disability affecting nearly a third of the world's population over 60 years of age. As in other joints, shoulder arthroplasty appears to be the most effective treatment. The implant design has evolved during time transitioning to shorter humeral stem lengths or even stemless components. AIM To evaluate the medium-term outcome and survival of a cementless humeral head resurfacing (HHR) in a group of patients affected with OA or avascular necrosis. METHODS This is a retrospective study of prospectively collected data using HHR in 23 patients (15 female and 8 male) after a 7.4 year follow-up. The collected data included clinical and radiographical evaluation. The Constant score, the visual analogue scale, and a clinical evaluation of range of motion were registered pre- and postoperatively. Fifteen patients affected with OA (2 cases of mild, 6 moderate, and 7 severe) and 10 with avascular necrosis (stage III according to Cruess classification) were enrolled. X-rays were evaluated to detect loosening signs, degenerative changes, and superior humeral head migration. Magnetic resonance preoperatively was also performed to assess the rotator cuff status. Tendon integrity was mandatory to implant the HHR. RESULTS In total, 19 patients (21 shoulders) completed the follow-up. Data on 4 shoulders, in 4 patients, were lost because of prosthesis failure. The global revision rate was 16%. A statistically significant improvement in the mean Constant score, visual analogue scale, and range of motion have been reported. No signs of loosening were registered, while in 12 cases a glenoid erosion was found. The osteophytes appeared 7 times on the humeral side and 12 on the glenoid. Superior humeral migration was recorded in only 1 case. CONCLUSION HHR remains a reasonable option in patients with an intact rotator cuff for the treatment of OA and avascular necrosis.

Our evolutionary and structural analyses revealed that the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) spike gene is a complex mosaic resulting from several recombination events. Additionally, the fixation of variants has mainly been driven by purifying selection, suggesting the presence of conserved structural features. Our dynamic simulations identified two main long-range covariant dynamic movements of the novel glycoprotein, and showed that, as a result of the evolutionary duality, they are preserved. The first movement involves the receptor binding domain with the N-terminal domain and the C-terminal domain 2 and is maintained across human, bat and pangolin coronaviruses. The second is a complex network of long-range dynamics specific to SARS-CoV-2 involving the novel PRRA and the conserved KR*SF cleavage sites, as well as conserved segments in C-terminal domain 3. These movements, essential for host cell binding, are maintained by hinges conserved across human, bat, and pangolin coronaviruses glycoproteins. The hinges, located around Threonine 333 and Proline 527 within the N-terminal domain and C-terminal domain 2, represent candidate targets for the future development of novel pan-coronavirus inhibitors. In summary, we show that while recombination created a new configuration that increased the covariant dynamic movements of the SARS-CoV-2 glycoprotein, negative selection preserved its inter-domain structure throughout evolution in different hosts and inter-species transmissions.

The fracture-avulsion of the greater tuberosity represents the 2% of all humerus fracture, but the true incidence is likely to be higher, being challenging the initial diagnosis on X-ray. The fracture-avulsion of the greater tuberosity could have different treatment: Non-displaced or minimal displaced fractures are treated conservatively, while for the displaced or comminuted ones the surgical treatment is preferred.

Objectiveto assess the variations of the blood levels of immunoglobulins (Ig) in septic shock patients treated with an Ig preparation enriched in IgM and IgA (eIg).DesignThe blood levels of Ig in survivors (S) and non-survivors (NS) of a group of septic shock patients were measured before the initial administration (D0) and one (D1), four (D4) and seven (D7) days thereafter. The SAPS II score, the capillary permeability, the primary site of infection, the antibiotic appropriateness, the microorganisms isolated and the outcome at 28 days were also assessed.ResultsIn the interval D0-D7 the IgM increased significantly only in the S while remained stable in NS; the IgA significantly increased in both groups; the IgG did not vary significantly in both groups. At D7 the capillary permeability significantly decreased in S but not in NS.ConclusionsThe kinetics of the different classes of Ig after eIg were different between S and NS. This could be related either to (a) different capillary permeability in the two groups and/or (b) higher Ig consumption in NS. Further studies to confirm the benefits of eIg in the treatment of sepsis syndrome, to define the specific target population and the correct eIg dose are warranted.

Purpose: To evaluate the short-term outcomes of rotator cuff repair in the presence of a greater tuberosity cyst (GTC) using a transosseous repair technique. Methods: This study included patients who underwent arthroscopic rotator cuff tear repair with a transosseous technique and were evaluated clinically and by postoperative magnetic resonance imaging (MRI) after 1 year. The inclusion criteria were based on the results of preoperative MRI and were as follows: patients identified as having a repairable full-thickness rotator cuff tear associated with the presence of cystic changes at the tendon insertion site of the greater tuberosity, defined as a GTC involving the footprint area of the torn tendon (supraspinatus and/or infraspinatus tendons). Results: We evaluated 25 patients. The mean preoperative and postoperative American Shoulder and Elbow Surgeons scores were 39.48 (P = .530) and 84.64 (P = .035), respectively; Constant shoulder scores, 38.96 (P < .005) and 80.28 (P = .425), respectively; and University of California–Los Angeles shoulder rating scale scores, 10.6 (P = .045) and 29.04 (P = .315), respectively. The GTC mapping system was easily adopted in all the MRI examinations independently from the quality of the images. The GTCs were mostly located in the superficial anterolateral section of the humeral head and in both the posterolateral sections (superficial and deep). Conclusions: Arthroscopic transosseous rotator cuff repair led to significant mid-term improvement and satisfactory subjective outcomes with low complication and failure rates in this study. The GTC mapping system could be useful to evaluate GTCs and to aid surgeons in the choice of the best surgical technique. Level of Evidence: Level IV, therapeutic case series.

Graphical abstract Using an visuo-audio spatial task, a novel version of the Posner task, we support the idea that auditory and visual attentional systems are governed by modality-specific processes and provide novel evidence for audiovisual links in endogenous covert spatial attention., Highlights • Facilitation was observed for right-sided auditory stimuli in a new visuo-audio task. • Auditory space has dynamic nature, which adapts to changes in visual space. • Sound localization was enhanced by visual cues. • Crossmodal links in spatial attention were found between audition and vision. • These findings have theoretical and translational implications for future studies., Visuospatial attention is asymmetrically distributed with a leftward bias (i.e. pseudoneglect), while evidence for asymmetries in auditory spatial attention is still controversial. In the present study, we investigated putative asymmetries in the distribution of auditory spatial attention and the influence that visual information might have on its deployment. A modified version of the Posner task (i.e. the visuo-audio spatial task [VAST]) was used to investigate spatial processing of auditory targets when endogenous orientation of spatial attention was mediated by visual cues in healthy adults. A line bisection task (LBT) was also administered to assess the presence of a leftward bias in deployment of visuospatial attention. Overall, participants showed rightward and leftward biases in the VAST and the LBT, respectively. In the VAST, sound localization was enhanced by visual cues. Altogether, these findings support the existence of a facilitation effect for auditory targets originating from the right side of space and provide new evidence for crossmodal links in endogenous spatial attention between vision and audition.

Rotavirus group A remains a major cause of diarrhea in infants and young children worldwide. The permanently emergence of new genotypes puts the potential effectiveness of vaccines under serious question. Thirteen VP1 mutants were analyzed using molecular dynamic simulations and the results were combined with the experimental findings, reported previously. The results revealed structural fluctuations and secondary structure change of VP1 protein that may alter its function during viral replication/transcription. Altogether, the structural analysis of VP1 may boost efforts to develop antivirals, as they might complement the available vaccines.

This pilot study obtained preliminary data on the effectiveness of an online, self-guided cognitive behavioral therapy-based psychoeducational program for coping with a potential experience of cyberbullying. The aim of the increasing resilience to cyberbullying (IRCB) program was to increase adolescents' likelihood of employing coping skills that may be helpful for a victim of cyberbullying, and to increase confidence in their ability to cope and/or help a friend cope with an experience of cyberbullying. Online questionnaires were administered to participants at baseline (preprogram

Type II diabetes mellitus (T2DM) is characterized by the presence of amyloid deposits of the human islet amyloid polypeptide (hIAPP) in pancreatic beta-cells. A wealth of data supports the hypothesis that hIAPP's toxicity is related to an abnormal interaction of amyloids with islet cell membranes. Thus, many studies aimed at finding effective therapies for T2DM focus on the design of molecules that are able to inhibit hIAPP's amyloid growth and the related membrane damage as well. Based on this view and inspired by its known anti-amyloid properties, we have functionalized resveratrol with a phosphoryl moiety (4'-O-PR) that improves its solubility and pharmacological properties. A second resveratrol derivative has also been obtained by conjugating resveratrol with a dimyristoylphosphatidyl moiety (4'-DMPR). The use of both compounds resulted in abolishing both amyloid growth and amyloid mediated POPC/POPS membrane damage in tube tests. We propose that a mixture of a water-soluble anti-aggregating compound and its lipid-anchored derivative may be employed as a general strategy to prevent and/or to halt amyloid related membrane damage.

Introduction Gambling disorder (GD) is a major public health concern with currently no validated and efficacious treatments approved. In this single case study, we report the short- and long-term effect of bilateral transcranial direct current stimulation (tDCS) of dorsolateral prefrontal cortex (DLPFC) on craving and impulse control in a subject with GD. Methods The patient is a 26-year-old Caucasian male with an 8-year history of GD as well as alcohol and cocaine misuse. Treatment consisted of twice-a-day stimulation for 10 days. According to the literature, both the left (to control craving) and the right (to control emotional impulses) DLPFC were stimulated. Patients subsequently received tDCS once a week for 3 months and then once every 2 weeks for another 3 months. Results After 10 days of treatment, the subject reported improved psychiatric symptoms (depression, anxiety, and impulsivity), as well as reduced gambling craving symptom severity. After 3 and 6 months of treatment, the clinical picture further improved. Discussion This is the first report of tDCS effectiveness in a single case study of GD. Therapeutic effects, both on the addictive behavior and on psychiatric comorbid symptomatology, were lasting and continued over 6 months of tDCS maintenance treatment. Future case–control studies are required to test the efficacy of this tool in patients with GD.

Superior capsular reconstruction (SCR) demonstrated its efficacy as a treatment option available in patients affected with irreparable posterosuperior rotator cuff tears without any signs of arthritis. Originally, the fascia lata autograft was fixed medially to the glenoid (with two or more anchors) and laterally to the greater tuberosity (with a compression double-row technique using four anchors or three transosseous tunnels). Additionally, side-to-side sutures were used to anteriorly and posteriorly connect the graft to the native residual rotator cuff tissue. However, the fascia lata as an autograft has a disadvantage related to the donor-site morbidity. To solve this aspect, allografts were employed with initial promising results. Nowadays, SCR is to be considered a technically demanding and expensive procedure, because of the cost of the allograft plus that of all the anchors employed to fix it. The Arthroscopic Biceps Chillemi's technique addresses these concerns in performing SCR and presents numerous advantages being a safe, easier, time and cost-saving way compared to the other published techniques. This technique has only one conditio sine qua non: the presence of the long head of the biceps tendon (LHB), used as an autograft. This condition may be interpreted as a disadvantage of this procedure in the presence of some anatomic variations of the intra-articular portion of the LHB and the very rare absence of the tendon or in case of partial or complete rupture of the LHB tendon associated with a rotator cuff tear.

Ferric citrate is an approved phosphate binder for use in patients with chronic kidney disease on dialysis. Clinical trials demonstrated that ferric citrate controlled serum phosphorus levels and increased iron stores. The aim of this retrospective chart review was to evaluate real-world bone mineral and anemia parameter data from patients treated with ferric citrate. 92 adult dialysis patients taking ferric citrate (average starting dose of 6 tablets/day) for at least 6 months were included. Bone mineral, anemia, and iron biomarker levels were extracted from patient medical records before and during the first 6 months of ferric citrate treatment; 21 (23%) patients were phosphate binder naive, and 71 (77%) patients had been on other phosphate binders. Before starting ferric citrate, 22% of patients had serum phosphorus ≤ 5.5 mg/dL, increasing to 65% of patients at 6 months of treatment (month 6). Mean (standard error of the mean (SEM)) baseline serum phosphorus was 6.55 ± 0.17 mg/dL decreasing to 5.40 ± 0.17 mg/dL at month 6. Mean (SEM) baseline hemoglobin, ferritin, and transferrin saturation were 10.6 ± 0.2 g/dL, 734 ± 65 ng/mL, and 27.1 ± 1.6%, respectively, and 11.1 ± 0.2 g/dL, 947 ± 66 ng/mL, and 37 ± 1.9%, respectively, at month 6. The serum phosphorus and anemia biomarker levels observed in this retrospective chart review were similar to those seen in clinical trials. .

// Federica Costa 1, * , Denise Toscani 1, * , Antonella Chillemi 2 , Valeria Quarona 2 , Marina Bolzoni 1 , Valentina Marchica 1, 6 , Rosanna Vescovini 3 , Cristina Mancini 4 , Eugenia Martella 4 , Nicoletta Campanini 4 , Chiara Schifano 5 , Sabrina Bonomini 5 , Fabrizio Accardi 1, 5 , Alberto L. Horenstein 2 , Franco Aversa 1, 5 , Fabio Malavasi 2 and Nicola Giuliani 1, 5, 6 1 Department of Medicine and Surgery, University of Parma, Parma, Italy 2 Laboratory of Immunogenetics, Department of Medical Sciences and CeRMS, University of Torino, Torino, Italy 3 Clinical Medicine Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy 4 Pathology, “Azienda Ospedaliero-Universitaria di Parma”, Parma, Italy 5 Hematology and BMT Center, “Azienda Ospedaliero-Universitaria di Parma”, Parma, Italy 6 CoreLab, “Azienda Ospedaliero-Universitaria di Parma”, Parma, Italy * These authors contributed equally to this work Correspondence to: Nicola Giuliani, email: nicola.giuliani@unipr.it Keywords: multiple myeloma, CD38, osteoclast, bone disease, immunotherapy Received: October 27, 2016 Accepted: April 29, 2017 Published: May 16, 2017 ABSTRACT It is known that multiple myeloma (MM) cells express CD38 and that a recently developed human anti-CD38 monoclonal antibody Daratumumab mediates myeloma killing. However, the expression of CD38 and other functionally related ectoenzymes within the MM bone niche and the potential effects of Daratumumab on bone cells are still unknown. This study firstly defines by flow cytometry and immunohistochemistry the expression of CD38 by bone marrow cells in a cohort of patients with MM and indolent monoclonal gammopathies. Results indicate that only plasma cells expressed CD38 at high level within the bone niche. In addition, the flow cytometry analysis shows that CD38 was also expressed by monocytes and early osteoclast progenitors but not by osteoblasts and mature osteoclasts. Indeed, CD38 was lost during in vitro osteoclastogenesis. Consistently, we found that Daratumumab reacted with CD38 expressed on monocytes and its binding inhibited in vitro osteoclastogenesis and bone resorption activity from bone marrow total mononuclear cells of MM patients, targeting early osteoclast progenitors. The inhibitory effect was not observed from purified CD14 + cells, suggesting an indirect inhibitory effect of Daratumumab. Interestingly, all-trans retinoic acid treatment increased the inhibitory effect of Daratumumab on osteoclast formation. These observations provide a rationale for the use of an anti-CD38 antibody-based approach as treatment for multiple myeloma-induced osteoclastogenesis.

The current model of the basal ganglia system based on the ‘direct’, ‘indirect’ and ‘hyperdirect’ pathways provides striking predictions about basal ganglia function that have been used to develop deep brain stimulation approaches for Parkinson’s disease and dystonia. The aim of this review is to challenge this scheme in light of new tract tracing information that has recently become available from the human brain using MRI-based tractography, thus providing a novel perspective on the basal ganglia system. We also explore the implications of additional direct pathways running from cortex to basal ganglia and between basal ganglia and cerebellum in the pathophysiology of movement disorders.

In recent years, extracellular vesicles (EVs), cell-derived micro and nano-sized structures enclosed in a double-layer membrane, have been in the spotlight for their high potential in diagnostic and therapeutic applications. Indeed, they act as signal mediators between cells and/or tissues through different mechanisms involving their complex cargo and exert a number of biological effects depending upon EVs subtype and cell source. Being produced by almost all cell types, they are found in every biological fluid including milk. Milk EVs (MEVs) can enter the intestinal cells by endocytosis and protect their labile cargos against harsh conditions in the intestinal tract. In this study, we performed a metabolomic analysis of MEVs, from three different species (i.e., bovine, goat and donkey) by mass spectroscopy (MS) coupled with Ultrahigh-performance liquid chromatography (UHPLC). Metabolites, both common or specific of a species, were identified and enriched metabolic pathways were investigated, with the final aim to evaluate their anti-inflammatory and immunomodulatory properties in view of prospective applications as a nutraceutical in inflammatory conditions. In particular, metabolites transported by MEVs are involved in common pathways among the three species. These metabolites, such as arginine, asparagine, glutathione and lysine, show immunomodulating effects. Moreover, MEVs in goat milk showed a greater number of enriched metabolic pathways as compared to the other kinds of milk.

Ubiquitination, a post-translational modification that involves a covalent attachment of ubiquitin to a protein substrate, is essential for cellular homeostatic maintenance. At the end of a three-enzyme cascade, E3 ubiquitin ligases (E3s) recruit substrates and promote or directly catalyze ubiquitin transfer to targets. These enzymes largely determine the specificity of the ubiquitination reaction. Genetic alteration, abnormal expression, or dysfunction of E3s account for the occurrence and progression of human cancers. Indeed, excessive degradation of relevant tumor-suppressor molecules and impaired disposal of oncogenic proteins have been linked to tumorigenesis. This review focuses on the emerging roles of HECT-type E3s in tumorigenesis, and emphasizes how perturbations of these enzymes contribute to cancer pathogenesis.

We assessed the feasibility, patient acceptability of and compliance of a new surveillance strategy for ovarian cancer surveillance in women with BRCA mutations, based on assessments of serum CA125 and HE4 every 4 months (Risk of Ovarian Cancer Algorithm (ROCA) arm), compared to Standard of Care (SOC) surveillance with CA125 blood tests and pelvic ultrasounds every 6 months.Women were recruited 6/13/16-9/11/17 from an integrated health care system in California for this non-randomized prospective cohort study. Women were invited to participate in a novel serum biomarker surveillance strategy using ROCA or they could opt to be in the standard of care control arm with ultrasound and CA 125 every 6 months. Outcomes assessed included compliance, self-reported distress using the Impact of Event Scale (IES) and cancer anxiety using the Cancer Worry Scale.There were 159 women in the ROCA arm and 43 in the SOC arm. Overall, compliance was higher in the ROCA arm (83.2%) than in SOC (51.9%), p 0.0001. Based on the IES, ROCA arm women reported less feelings about intrusion and avoidance at 12 months compared to baseline; the difference approached significance for intrusion (7.6% vs 4.1% severe, p = 0.057) and was statistically significant for avoidance (20.8% vs 9.9% severe, p = 0.034).This pilot demonstrated that compliance was high with blood tests performed every four months for ovarian cancer surveillance. Moreover, ROCA women had lower stress scores over time than SOC women. Given the lack of clinical utility and poor compliance shown with traditional ultrasound and CA125 tests, further investigation is warranted of longitudinal biomarker surveillance for early detection of ovarian cancer.