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Background: Autologous fat grafting (AFG) has shown promise in the treatment of complex wounds, with trials reporting good healing rates and safety profile. We aim to investigate the role of AFG in managing complex anorectal fistulas. Methods: This was a retrospective review of a prospectively maintained IRB-approved database. We examined the rates of symptom improvement, clinical closure of fistula tracts, recurrence, complications, and worsening fecal incontinence. Perianal disease activity index (PDAI) was obtained for patients undergoing combination of AFG and fistula plug treatment. Results: In total, 52 unique patients underwent 81 procedures, of which Crohn's was present in 34 (65.4%) patients. The majority of patients previously underwent more common treatments such as endorectal advancement flap or ligation of intersphincteric fistula tract. Fat-harvesting sites and processing technique were selected by the plastic surgeons based on availability of trunk fat deposits. When analyzing patients by their last procedure, 41 (80.4%) experienced symptom improvement, and 29 (64.4%) experienced clinical closure of all fistula tracts. Recurrence rate was 40.4%, and complication rate was 15.4% (7 postoperative abscesses requiring I&D and 1 bleeding episode ligated at bedside). The abdomen was the most common site of lipoaspirate harvest at 63%, but extremities were occasionally used. There were no statistically significant differences in outcomes when comparing single graft treatment to multiple treatments, Crohn's and non-Crohn's, different methods of fat preparation, and diversion. Conclusion: AFG is a versatile procedure that can be done in conjunction with other therapies and does not interfere with future treatments if recurrence occurs. It is a promising and affordable method to safely address complex fistulas. [ABSTRACT FROM AUTHOR]

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p < 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203–24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients. [ABSTRACT FROM AUTHOR]

The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing–remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpBOCR 0.485, CI 95% 0.264–0.893, p = 0.020). This result was confirmed also for 12-month MRI activity (ExpBOCR 0.248 CI 95% 0.065–0.948, p = 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile. [ABSTRACT FROM AUTHOR]

Background: Rectal neuroendocrine tumors comprise 20% of neuroendocrine tumors in the alimentary tract, but there is controversy surrounding the optimal management of this disease. The purpose of this study is to better define treatment for patients with rectal neuroendocrine tumors. Methods: Using the National Cancer Database, we analyzed patients with rectal neuroendocrine tumors between 2004 and 2015. Patients with metastatic disease and missing treatment data were excluded. We examined overall survival stratified by tumor size, treatment type, and presence of positive lymph nodes using Kaplan-Meier analysis with log-rank test. Cox proportional hazard regression model was performed to identify factors associated with overall survival. Results: In total, 17,448 patients with rectal neuroendocrine tumors were identified; 16,531 of these patients met inclusion criteria. The majority of patients had tumors ≤ 10 mm (9216 patients, 79.8%), and approximately 90% underwent local excision. The probability of 5-year overall survival was significantly higher for patients with smaller tumors (≤ 10 mm: 94.1% 11–20 mm: 85.7%, > 20 mm: 71.8%; p < 0.001) and those with no positive lymph nodes (91.4% versus 53.3%, p < 0.001). The probability of 5-year overall survival differed based on treatment modality (local excision: 93.6%, radical resection: 79.1%, observation alone: 77.1%; p < 0.001). On multivariable Cox regression, when compared to local excision, radical resection was not associated with a difference in overall survival but observation alone was associated with significantly worse OS (HR = 2.750, p < 0.001). Conclusions: There is a significant difference in overall survival between patients who underwent local excision versus observation alone. Excision of the tumor should be offered to all patients with rectal neuroendocrine tumors who are appropriate surgical candidates, regardless of the tumor size. [ABSTRACT FROM AUTHOR]

Pediatric emergency nurses who are directly involved in clinical care are in key positions to identify the needs and concerns of patients and their families. The 2010 Institute of Medicine report on the future of nursing supports the active participation of nurses in the design and implementation of solutions to improve health outcomes. Although prior efforts have assessed the need for research education within the Pediatric Emergency Care Applied Research Network (PECARN), no systematic efforts have assessed nursing priorities for research in the pediatric ED setting. The Delphi technique was used to reach consensus among emergency nurses in the PECARN network regarding research priorities for pediatric emergency care. The Delphi technique uses an iterative process by offering multiple rounds of data collection. Participants had the opportunity to provide feedback during each round of data collection with the goal of reaching consensus about clinical and workforce priorities. A total of 131 nurses participated in all 3 rounds of the survey. The participants represented the majority of the PECARN sites and all 4 regions of the United States. Through consensus 10 clinical and 8 workforce priorities were identified. The PECARN network provided an infrastructure to gain expert consensus from nurses on the most current priories that researchers should focus their efforts and resources. The results of the study will help inform further nursing research studies (for PECARN and otherwise) that address patient care and nursing practice issues for pediatric ED patients. [ABSTRACT FROM AUTHOR]

Abstract Calcium phosphate cements (CPCs) are frequently used as synthetic bone substitute, but their intrinsic low fracture toughness impedes their application in highly loaded skeletal sites. However, fibers can be used to reduce the brittleness of these CPCs provided that the affinity between the fibers and cement matrix facilitates the transfer of loads from the matrix to the fibers. The aim of the present work was to improve the interface between hydrophobic polylactic acid (PLA) microfibers and hydrophilic CPC. To this end, calcium-binding alendronate groups were conjugated onto the surface of PLA microfibers via different strategies to immobilize a tunable amount of alendronate onto the fiber surface. CPCs reinforced with PLA fibers revealed toughness values which were up to 50-fold higher than unreinforced CPCs. Nevertheless, surface functionalization of PLA microfibers with alendronate groups did not improve the mechanical properties of fiber-reinforced CPCs. [ABSTRACT FROM AUTHOR]

Extracellular matrices are mainly composed of a mixture of different biopolymers and therefore the use of two or more building blocks for the development of tissue-mimicking hydrogels is nowadays an attractive strategy in tissue-engineering. Multi-component hydrogel systems may undergo phase separation, which in turn can lead to new, unexpected material properties. The aim of this study was to understand the role of phase separation on the mechanical properties and 3D printability of hydrogels composed of triblock copolymers of polyethylene glycol (PEG) and methacrylated poly( N -(2-hydroxypropyl) methacrylamide-mono/dilactate) (pHPMAlac) blended with methacrylated hyaluronic acid (HAMA). To this end, hydrogels composed of different concentrations of PEG/pHPMAlac and HAMA, were analyzed for phase behavior and rheological properties. Subsequently, phase separation and rheological behavior as function of the two polymer concentrations were mathematically processed to generate a predictive model. Results showed that PEG/pHPMAlac/HAMA hydrogels were characterized by hydrophilic, HAMA-richer internal domains dispersed in a more hydrophobic continuous phase, composed of PEG/pHPMAlac, and that the volume fraction of the dispersed phase increased by increasing HAMA concentration. Storage modulus, yield stress and viscosity increased with increasing HAMA concentration for low/medium HAMA contents (≤0.75% w/w), while a further increase of HAMA resulted in a decrease of the mentioned properties. On the other hand, by increasing the concentration of PEG/pHPMAlac these rheological properties were enhanced. The generated models showed a good fitting with experimental data, and were used to identify an exemplary 3D printability window for PEG/pHPMAlac/HAMA hydrogels, which was verified by rheological characterization and preparation of 3D printed scaffolds. In conclusion, a clear relationship between phase separation and rheological behavior in these two-component hydrogels can be described by complex functions of the two polymer concentrations. The predictive model generated in this study can be used as a valid tool for the identification of hydrogel compositions with desired, selected characteristics. [ABSTRACT FROM AUTHOR]

Porphyrin functionalized Au nanoparticles show many interesting applications and many efforts have been devoted to the assembly of charged porphyrin structures in order to improve their water solubility. In this work, we report on the functionalization of gold nanoparticles with porphyrin modified in meso-positions with uncharged polyethylene glycol chains in order to obtain nanosystems soluble both in water, and in some non-aqueous media. The functionalization steps were monitored by some spectroscopic techniques such as UV–Vis, steady-state and time resolved fluorescence and dynamic light scattering. The final functionalized Au nanoparticles were characterized by scanning transmission electron microscopy and X-ray photoelectron spectroscopy. These modified gold nanoparticles showed the porphyrin characteristic emission properties and were effective for 1 O 2 generation. Finally, the laser scanning confocal microscopy results demonstrated a sub-cellular localization of the porphyrin-functionalized gold nanoparticles, with the maintenance of the porphyrin-characteristic emission properties. [ABSTRACT FROM AUTHOR]

The aim of this study was to design a hydrogel system based on methacrylated chondroitin sulfate (CSMA) and a thermo-sensitive poly( N -(2-hydroxypropyl) methacrylamide-mono/dilactate)-polyethylene glycol triblock copolymer (M 15 P 10 ) as a suitable material for additive manufacturing of scaffolds. CSMA was synthesized by reaction of chondroitin sulfate with glycidyl methacrylate (GMA) in dimethylsulfoxide at 50 °C and its degree of methacrylation was tunable up to 48.5%, by changing reaction time and GMA feed. Unlike polymer solutions composed of CSMA alone (20% w/w), mixtures based on 2% w/w of CSMA and 18% of M 15 P 10 showed strain-softening, thermo-sensitive and shear-thinning properties more pronounced than those found for polymer solutions based on M 15 P 10 alone. Additionally, they displayed a yield stress of 19.2 ± 7.0 Pa. The 3D printing of this hydrogel resulted in the generation of constructs with tailorable porosity and good handling properties. Finally, embedded chondrogenic cells remained viable and proliferating over a culture period of 6 days. The hydrogel described herein represents a promising biomaterial for cartilage 3D printing applications. [ABSTRACT FROM AUTHOR]

• Chronic immunosuppression is crucial in preventing NMSOD relapses. • CD27+ B cells might be a useful biomarker to guide RTX retreatment in AQP4-IgG positive patients. • Relapses in anti-MOG NMSOD occurred regardless of B cell depletion. Several studies have shown the efficacy of rituximab (RTX) in preventing relapses in patients suffering from Neuromyelitis Optica spectrum disorder (NMSOD) and have explored different therapeutic schemes. Given the extreme inter-individual variability of the disease course, there is the need to identify biomarkers to tailor the retreatment schedule and dosage. This review aimed to identify the most useful biomarker to guide reinfusion and, in turn, the optimal retreatment schedule of RTX for NMSOD. The literature search was conducted in the Web of Science, Scopus and Pubmed electronic databases. We limited document type to articles written in English and published up to 28 February 2022. Inclusion criteria were: (i) Patients affected by NMSOD and treated with RTX, (ii) followed up for at least one year and for whom Annualized Relapse rate (ARR) was collected over a period of at least 12 months before and after therapy initiation and (iii) induction protocols consisting of 375 mg / m2 / week for four weeks or 1000 mg infused once or twice two weeks apart. Collected information was: first authors' name, publication year, study design, sample size, sex, age, percentage of patients positive for antibodies to aquaporin 4 (AQP4-IgG), maintenance regimen, primary outcome, mean ARR pre-therapy and mean ARR post-therapy initiation, percentage of relapse-free patients. The primary outcome that we considered was the ARR reduction. Further, we considered the number of relapses that occurred when B cells and memory B cells were under the chosen threshold and the percentage of relapse-free patients when available. Among 31 potentially eligible studies, 9 fulfilled the inclusion criteria. ARR reduction was not comparable between studies. The studies that monitored CD19+ and CD27+ cell kinetics showed a higher number of relapses when CD19+ lymphocyte count was below the threshold compared to the number of relapses that occurred when CD27+ cell count was below the threshold. Further, a higher percentage of patients achieved the relapse-free condition with a reinfusion schedule when CD27+ reached 0, 05% of peripheral blood mononuclear cells (PBMCs) compared to the reinfusion when CD19+ reached 0, 1% of PBMCs. To date, the optimal retreatment schedule for RTX in NMOSD has not yet been determined. However, the presented findings suggest that CD27+ B cells might be a reliable biomarker to guide retreatment in AQP4-IgG positive patients, at least in the first six months from the infusion. Further effort is needed to identify those factors influencing anti-CD20 therapy effectiveness to tailor dosage and treatment schedule to achieve the most favourable risk/benefit ratio. [ABSTRACT FROM AUTHOR]

• Lymphopenia is reported in 20.7% of RRMS patients taking Ocrelizumab. • Among T cells, the treatment predominantly impacts CD8 cells. • CD8 T cell decrease is more pronounced in patients with lymphopenia. In the phase III, OPERA I and OPERA II, clinical trial lymphopenia was reported in 20.7% of relapsing–remitting multiple sclerosis (RRMS) patients taking Ocrelizumab (OCR). The objective of this study was to investigate the effect of OCR on lymphocyte subtypes in MS patients with and without lymphopenia. Retrospective study comparing lymphocyte subtypes in OCR-treated MS patients with low (G1) and normal (G2) absolute lymphocyte count (ALC) at the six-month follow-up (cut-off: 1000 × 106/L). Mann Whitney U test was used to compare ALC, CD19, CD4 T, CD8 T and NK cell counts at baseline and at the six-month follow up between the two groups. A linear mixed model was applied to compare changes in ALC, and subset counts and proportions between patients with and without lymphopenia. We performed the same analyses in a subpopulation of naïve to treatment patients to exclude the possible influence of the previous disease modifying therapy (DMT) in the different kinetics observed between the two groups. : One hundred sixty-seven patients were included (G1, n = 34; G2, n = 133). At the six-month follow-up, compared with baseline, in the whole population we observed a significant reduction in ALC (p <0.0001), CD19 (p <0.0001) and CD8 T (p <0.0288) lymphocytes. We also found and increase in CD4/CD8 ratio after six months of treatment (p = 0.0098). G1 showed a lower ALC than G2 at baseline. At six months, mean ALC was 896.41 ± 156.25 × 106/L in G1 and 1909.9 ± 629.07 × 106/L in G2. CD4 and CD8 T cell mean counts were lower (p < 0.0001) in G1 than G2. At the linear mixed model analysis, we found a more pronounced increase in CD8 T percentage in G2 than G1 (p = 0.008). In the naïve to treatment group fifty patients were included. CD4 and CD8 T cell mean counts at six months were lower (p = 0.0074 and p = 0.0032, respectively) in G1 than G2. At the linear mixed model analysis, we found a more pronounced decrease of CD8 T cell count in G1 than G2 (p = 0.0103). Furthermore, we found an increase in CD8 T percentage in G2 whereas a profound decrease of CD8 T percentage was observed in G1 (p = 0.0052). After adjusting for confounders, significantly positive correlations were noted between ALC and both CD4 and CD8 T cell counts. Negative correlation was observed between ALC and CD4/CD8 ratio driven by low CD8 T cell counts. OCR decreases ALC. Among T cells, the treatment predominantly impacts CD8 cells. However, CD8 T cell decrease was more pronounced in patients with lymphopenia. Further studies are needed to establish the relationship between the effect of OCR on ALC and CD8 T cells and its potential implication in the early clinical response and risk for viral infections. [ABSTRACT FROM AUTHOR]

Abstract: A fast screening protocol was developed for the simultaneous determination of nine anti-estrogenic agents (aminoglutethimide, anastrozole, clomiphene, drostanolone, formestane, letrozole, mesterolone, tamoxifen, testolactone) plus five of their metabolites in human urine. After an enzymatic hydrolysis, these compounds can be extracted simultaneously from urine with a simple liquid–liquid extraction at alkaline conditions. The analytes were subsequently analyzed by fast-gas chromatography/mass spectrometry (fast-GC/MS) after derivatization. The use of a short column, high-flow carrier gas velocity and fast temperature ramping produced an efficient separation of all analytes in about 4min, allowing a processing rate of 10samples/h. The present analytical method was validated according to UNI EN ISO/IEC 17025 guidelines for qualitative methods. The range of investigated parameters included the limit of detection, selectivity, linearity, repeatability, robustness and extraction efficiency. High MS-sampling rate, using a benchtop quadrupole mass analyzer, resulted in accurate peak shape definition under both scan and selected ion monitoring modes, and high sensitivity in the latter mode. Therefore, the performances of the method are comparable to the ones obtainable from traditional GC/MS analysis. The method was successfully tested on real samples arising from clinical treatments of hospitalized patients and could profitably be used for clinical studies on anti-estrogenic drug administration. [Copyright &y& Elsevier]

Abstract: 7,12-Dimethylbenzanthracene (DMBA) is an abundant environmental contaminant, which undergoes bioactivation, primarily by the CYP1 family, both in liver and extra-hepatic tissues. Dietary acetylsalicylic acid (ASA) has been recently reported to inhibit DMBA-mediated mammary tumour formation in rats. Chemopreventive substances may reduce the risk of developing cancer by decreasing metabolic enzymes responsible for generating reactive species (phase I enzymes) and/or increasing phase II enzymes that can deactivate radicals and electrophiles. To test these hypotheses, Sprague-Dawley female rats were orally administered ASA as lysine acetylsalicylate (50mg per capita/day for 21 days in water), DMBA (10mg per capita in olive oil on day 7, 14, and 21), ASA and DMBA in combination, and vehicles only, respectively. Six rats for each group were sacrificed on day 8, 15, and 22. The DMBA-mediated increase in hepatic CYP1A expression and related activities was not significantly affected by ASA, which, conversely, enhanced in a time-dependent manner the liver reduced glutathione content (up to 52%) and the activity of NAD(P)H-quinone oxidoreductase (up to 34%) in DMBA-treated rats. It is proposed that the positive modulation of the hepatic antioxidant systems by ASA may play a role in the chemoprevention of mammary tumourigenesis induced by DMBA in the female rat. [Copyright &y& Elsevier]

Abstract: To investigate whether nandrolone decanoate (ND)-pretreatment can modulate (1) β-adrenoceptor expression and (2) myocardial contractility in response to β-adrenoceptors stimulation with isoproterenol (ISO), in hearts of both normal and stressed rats. Rats were treated with 15mg/(kgday) of Deca-Durabolin (ND, 1ml i.m.) or with vehicle (oil) for 14 days. The day after the last injection, the dose–response to ISO (1×10−8, 5×10−8 and 10−7 M), was studied in isolated rat hearts harvested from unstressed animals (unstressed + vehicle (control) or unstressed + ND) or from stressed animals (stressed + vehicle or stressed + ND): acute stress protocol consisted in restrain for 1h immediately before sacrifice. ND-pretreatment increased β2-adrenoceptor expression. In baseline conditions all hearts had a similar left ventricular developed pressure (LVDP) and maximum rate of increase of LVDP (dP/dtmax). In hearts of unstressed+vehicle or unstressed+ND, ISO caused a similar increase in LVDP (+90–100%) and dP/dt max (+120–150%). However, hearts of stressed+vehicle animals showed a marked depression of inotropic response to ISO (i.e. for ISO 1×10−8,−55% in LVDP response versus unstressed). Yet, in hearts of stressed+ND-animals the effect of stress was reversed, showing the highest response to ISO (i.e. for ISO 1×10−7, +30% LVDP response versus unstressed). The ND-induced β2-adrenoceptor overexpression does not affect ISO-response in unstressed animals. However, acute stress induces a down-regulation of ISO-response, which is reversed by ND-pretreatment. Since the physiological post-stress down-regulation of adrenergic-response is absent after nandrolone treatment, the heart may be exposed to a sympathetic over-stimulation. This might represent a risk for cardiovascular incidents in anabolic steroid addicts under stressing conditions. [Copyright &y& Elsevier]

Abstract: Objective:: This analysis was conducted to evaluate the impact of pioglitazone (PIO), both as monotherapy and as part of combination therapy, on glycemic and lipid parameters and adverse events in elderly patients with type 2 diabetes. Methods:: This was a post hoc analysis of pooled data, truncated at 1 year, from patients aged ≥65 years with type 2 diabetes in 4 multicenter, randomized, double-blind, parallel-group trials. For inclusion in these trials, patients were required to be between the ages of 35 and 75 years and to have had poorly controlled type 2 diabetes, a glycosylated hemoglobin (HbA1c) value between 7.5% and 11.0%, and stable or worsening glycemic control for at least 3 months. Blood samples were obtained at baseline and every 4 to 10 weeks thereafter for determination of HbA1c, fasting plasma glucose (FPG), and lipid parameters (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], total cholesterol [TC], TC:HDL-C ratio, and free fatty acids). Results:: Data from 891 elderly patients (age range, 69.1–69.8 years) were included: 282 who received PIO, 123 metformin (MET), 142 sulfonylurea (SU), 105 SU + PIO, 107 SU + MET, 63 MET + PIO, and 69 MET + SU. With a few exceptions, all treatment groups were similar at baseline. From baseline to week 52, none of the changes in HbA1c and FPG between each treatment group and its comparator were significant. The adjusted mean (SE) percent changes in HDL-C for the monotherapies were 17.95% (1.11) for PIO, 10.71% (1.70) for MET, and 5.17% (1.51) for SU (both comparisons, P < 0.05). For the combination therapies, the adjusted mean percent changes in HDL-C were 16.77% (1.84) for SUPIO versus 7.87% (1.75) for SUMET (P < 0.05), and 16.34% (2.34) for MET + PIO versus 0.11% (2.19) for METSU (P < 0.05). The adjusted mean percent changes in LDL-C for the monotherapies were 7.00% (1.28) for PIO, −0.68% (1.91) for MET, and −6.77% (1.73) for SU (both comparisons, P < 0.05). For the combination therapies, the adjusted mean percent change in LDL-C was significant for METPIO compared with METSU (13.62% [2.69] vs −4.32% [2.58], respectively; P < 0.05). The adjusted mean percent change in TG was significant for MET + PIO compared with MET + SU (−10.93% [4.44] vs 8.37% [4.15], respectively; P < 0.05). The adjusted mean percent changes in TC for the monotherapies were 6.16% (0.88) for PIO, −1.77% (1.35) for MET, and −6.90% (1.19) for SU (both comparisons, P < 0.05). For the combination therapies, the adjusted mean percent changes in TC were 2.67% (1.45) for SUPIO versus −1.40% (1.39) for SUMET (P < 0.05) and 7.89% (1.85) for METPIO compared with −1.19% (1.73) for METSU (P < 0.05). The differences in change in the TC:HDL-C ratio were not significant between groups. The adjusted mean changes in free fatty acids for the monotherapies were −0.14 (0.02) mmol/L for PIO, −0.001 (0.03) mmol/L for MET, and −0.07 (0.02) mmol/L for SU (both comparisons, P < 0.05). For the combination therapies, the adjusted mean change in free fatty acids was significant for SU + PIO compared with SUMET (−0.12 [0.03] vs 0.06 [0.03] mmol/L, respectively; P < 0.05). PIO monotherapy was associated with the lowest incidence of hypoglycemia (1.4%) among the 7 treatment groups. The SUPIO group had the highest incidence of weight gain (4.8%). The rate of deaths was <2% in all the treatment groups; no adverse event associated with death was considered related to study medication. Conclusions:: In this post hoc analysis of data from elderly patients participating in 4 randomized clinical trials, PIO effectively controlled glycemic and lipid parameters over 52 weeks and was well tolerated. The effects seen in this analysis were comparable to those in the overall study populations. [Copyright &y& Elsevier]

• Effectiveness of ocrelizumab is confirmed in clinical practice. • Higher BMI could influence CD20 repopulation after the treatment with Ocrelizumab. • Lymphocytes and immunoglobulins m reduce during anti-CD20 therapy with no effect on safety on the short follow up. Ocrelizumab (OCR) is a humanized monoclonal antibody targeting CD20 antigen exposed on B cells surface. Kinetic of B-cells repopulation after depletion therapy shows high intra and inter-individual variability. The aim of this study was to explore the influence of Body Mass Index (BMI) on kinetic of B-cell repopulation after treatment with OCR and on treatment response. 108 Multiple Sclerosis (MS) patients were enrolled at the time of the first dose of OCR administration and prospectively evaluated. Clinical, instrumental activity and disability progression were analyzed. According to B cells count, patients were divided into two groups: with fast (FR) and with slow (SR) repopulation rate, respectively. Significant reduction of disease activity was observed in all patients and a stabilization of disease was obtained in progressive patients. Patients with FR had higher BMI compared to patients with a SR (p <0.001). Contrariwise no correlation between repopulation rate and treatment effectiveness was disclosed. In a real world setting we confirmed the effectiveness of OCR in relapsing remitting and progressive patients; patients with higher BMI had a FR. This suggests considering BMI for administration schedule although further investigations with longer follow up could improve treatment protocol and patient selection. [ABSTRACT FROM AUTHOR]

Study Objective: Recognition of pediatric sepsis is a key clinical challenge. We evaluate the performance of a sepsis recognition process including an electronic sepsis alert and bedside assessment in a pediatric emergency department (ED).Methods: This was a cohort study with quality improvement intervention in a pediatric ED. Exposure was a positive electronic sepsis alert, defined as elevated pulse rate or hypotension, concern for infection, and at least one of the following: abnormal capillary refill, abnormal mental status, or high-risk condition. A positive electronic sepsis alert prompted team assessment or huddle to determine need for sepsis protocol. Clinicians could initiate team assessment or huddle according to clinical concern without positive electronic sepsis alert. Severe sepsis outcome defined as activation of the sepsis protocol in the ED or development of severe sepsis requiring ICU admission within 24 hours.Results: There were 182,509 ED visits during the study period, with 86,037 before electronic sepsis alert implementation and 96,472 afterward, and 1,112 (1.2%) positive electronic sepsis alerts. Overall, 326 patients (0.3%) were treated for severe sepsis within 24 hours. Test characteristics of the electronic sepsis alert alone to detect severe sepsis were sensitivity 86.2% (95% confidence interval [CI] 82.0% to 89.5%), specificity 99.1% (95% CI 99.0% to 99.2%), positive predictive value 25.4% (95% CI 22.8% to 28.0%), and negative predictive value 100% (95% CI 99.9% to 100%). Inclusion of the clinician screen identified 43 additional electronic sepsis alert-negative children, with severe sepsis sensitivity 99.4% (95% CI 97.8% to 99.8%) and specificity 99.1% (95% CI 99.1% to 99.2%). Electronic sepsis alert implementation increased ED sepsis detection from 83% to 96%.Conclusion: Electronic sepsis alert for severe sepsis demonstrated good sensitivity and high specificity. Addition of clinician identification of electronic sepsis alert-negative patients further improved sensitivity. Implementation of the electronic sepsis alert was associated with improved recognition of severe sepsis. [ABSTRACT FROM AUTHOR]

Abstract The measure of the acid concentration in an organic media is a common issue in chemistry. With the aim to overcome this problem in a facile and inexpensive way, the spectroscopic properties of a PEGylate porphyrin derivative, the 5,10,15,20-p-(ω-methoxypolyethyleneoxyphenyl) porphyrin (P), as an acidity sensor were tested. Its behaviour was analysed in toluene and several fuels through acid titration experiments. In each case, examining UV–vis and fluorescence spectroscopic data, the disappearance of the free-base porphyrin derivative Uv–vis signals (B- and Q-bands) and the increasing of new bands, as a consequence of the added acid, was monitored. On the basis of these data it was possible to evaluate the presence of acid in several organic media as toluene, gasoline, diesel, and jet fuel, using our porphyrin derivative in very low amount (about 3 ppm). Finally, in order to exclude the risk of a negative contribution of P in ash formation, the complete oxidation of the porphyrin compound under common engine's combustion conditions was also ascertained. Graphical abstract Image 1 Highlights • This PEGylate porphyrin derivative is soluble in most classes of solvents. • Its acid sensing capability was tested in toluene, gasoline, diesel and jet fuel. • The acidity of the fuels was monitored through the spectroscopic variations of the porphyrin derivative. • The molecules of the sensor system, burned together with the fuel, does not leave any carbonaceous trace. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2)-low is a newly defined category with HER2 1+ or 2+ expression by immunohistochemistry (IHC) and lack of HER2 gene amplification measured by in situ hybridization (ISH). Much remains unknown about the HER2-low status across tumor types and changes in HER2 status between primary and metastatic samples. HER2 expression by IHC was evaluated in 4701 patients with solid tumors. We have evaluated the HER2 expression by IHC and amplification by ISH in paired breast and gastric/gastroesophageal (GEJ) primary and metastatic samples. HER2 expression was correlated with ERBB2 genomic alterations evaluated by next-generation sequencing (NGS) in non-breast, non-gastric/GEJ samples. HER2 expression (HER2 IHC 1-3+) was found in half (49.8%) of the cancers, with HER2-low (1 or 2+) found in many tumor types: 47.1% in breast, 34.6% in gastric/GEJ, 50.0% in salivary gland, 46.9% in lung, 46.5% in endometrial, 46% in urothelial, and 45.5% of gallbladder cancers. The concordance evaluation of HER2 expression between primary and metastatic breast cancer samples showed that HER2 3+ remained unchanged in 87.1% with a strong agreement between primary and metastatic samples, with a weighted kappa (Κ) of 0.85 (95% confidence interval 0.79-0.91). ERBB2 alterations were identified in 117 (7.5%) patients with non-breast, non-gastric/GEJ solid tumors who had NGS testing. Of 1436 patients without ERBB2 alterations, 512 (35.7%) showed any level HER2 expression by IHC. Our results show that HER2-low expression is frequently found across tumor types. These findings suggest that many patients with HER2-low solid tumors might benefit from HER2-targeted therapies. • HER2-low expression (1-2+ by IHC) was common across many solid tumors (41.1%). • A significant number of patients without ERBB2 alterations (35.7%) had HER2 expression (≥1+). • Changes between the primary and metastatic breast and gastric samples highlight the importance of HER2 re-testing. • HER2 protein expression by IHC complements genomics to identify actionable therapeutic targets. [ABSTRACT FROM AUTHOR]