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Disruptions to the maternally inherited allele UBE3A, encoding for an E3 ubiquitin ligase, leads to the manifestation of Angelman Syndrome (AS). While this disorder is rare, the symptoms are severe and lifelong including but not limited to: intractable seizures, abnormal EEG's, ataxic gait, lack of speech, and most notably an abnormally happy demeanor with easily provoked laughter. Currently, little is known about the neurophysiological underpinnings of UBE3A leading to such globally severe phenotypes. Utilizing the newest AS rat model, comprised of a full UBE3A deletion, we aimed to elucidate novel mechanistic actions and potential therapeutic targets. This report demonstrates for the first time that catalytically active UBE3A protein is detectable within cerebrospinal fluid (CSF) of wild type rats but distinctly absent in AS rat CSF. Microdialysis within the rat hippocampus also showed that UBE3A protein is located in the interstitial fluid of wild type rat brains but absent in AS animals. This protein maintains catalytic activity and appears to be regulated in a dynamic activity-dependent manner. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder caused by the loss of the UBE3A gene within the central nervous system. Although we have identified the gene responsible for AS, we still have a long way to go to fully understand its function in vivo. Here we report that UBE3A is present within normal cerebrospinal fluid (CSF) but distinctly absent in AS CSF. Furthermore, we demonstrate that UBE3A is secreted and that this may occur in a dynamic activity-dependent fashion. Extracellular UBE3A maintained its ubiquitinating activity, thus suggesting that UBE3A may have a novel role outside of neurons. Autism Res 2021, 14: 645-655. © 2021 International Society for Autism Research and Wiley Periodicals LLC.

Isolation of Shigella in the bloodstream is a rare sequela of Shigella infections. Shigellemia typically occurs in patients with immature immune responses or in immunocompromised adults. Herein, we present a case of shigellemia in a 40-year-old male who presented with diabetic ketoacidosis (DKA), severe diarrhea, hypovolemic hyponatremia, and altered mental status. Stool cultures were found to be positive for Shigella, and broad-spectrum antibiotic therapy was initiated. Because of the patient’s reported sexual exposures, a rapid HIV point of care test was done and returned negative. In spite of intervention, the patient’s vitals, labs, and symptoms failed to improve, and he developed septic shock requiring pressor support in the intensive care unit. Further workup for the etiology of the patient’s sepsis included a CT abdomen and pelvis which showed findings concerning infectious colitis. Blood cultures later returned positive for Shigella, which was found to be resistant to multiple antibiotics. The patient was started on IV ceftriaxone with an improvement of and eventual resolution of symptoms. Shigellemia is a rare complication of infection with Shigella and necessitates further workup to avoid overlooking potential predisposing factors such as HIV or other immunocompromising conditions. Its susceptibilities should also be evaluated, as Shigella strains are more frequently becoming resistant to antibiotics that had previously been the therapies of choice.

Objective: To assess the acceptability, safety and efficacy of the PPH Butterfly, a new uterine compression device, in women with postpartum haemorrhage (PPH). Design: A phase two clinical device trial using matched historical controls, with accompanying grounded theory study. Setting: UK university consultant obstetric unit. Population: women with PPH after vaginal birth unresponsive to initial oxytocin therapy. Outcomes were compared to historical controls matched on blood loss, parity and type of birth. Methods: after oral consent, trained staff used the device in additional to normal care. Main Outcome Measures: The primary outcome was additional blood loss >1000mls. Qualitative interviews assessed device feasibility and acceptability. Results: Of the 57 recruits, two-thirds were primiparous and almost half had undergone operative birth. Two percent of recruited women had additional blood loss of over 1000mls compared to 8% of 113 controls (adjusted odds ratio 0.13, 95% CI (0.02 to 1.09)). Women treated with the device received significantly more additional treatments and had higher rates of exclusive breast-feeding at discharge. There were no serious adverse events related to the device. In 47 interviews, participants, birth partners, clinicians and attending midwives viewed the device positively. Clinicians found it useful to stop blood loss and diagnose the source of bleeding. Conclusions: the PPH Butterfly is acceptable and may have clinical benefits: it is a promising device for PPH management. Funding: National Institute for Health Research invention for innovation (i4i) program (II-LA-0715-200008) Keywords: postpartum haemorrhage, childbirth, oxytocin, third stage of labour, uterine compression. Registration: prospective ISRCTN (15452399); www.isrctn.com/ISRCTN15452399

Introduction. The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions. Materials and Methods. In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( F 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded. Results. At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( χ 2 10.4; p < 0.001 ), neutrophil-to-lymphocyte (NL) ratio ( χ 2 7.6; p = 0.006 ), and platelet count ( χ 2 5.39; p = 0.02 ), along with age ( χ 2 87.6; p < 0.001 ) and gender ( χ 2 17.3; p < 0.001 ), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality OR = 3.40 (2.40-4.82), while the OR for a RDW > 13.7 % was 4.09 (2.87-5.83); a platelet count > 166,000 /μL was, conversely, protective (OR: 0.45 (0.32-0.63)). Conclusion. Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.

Two experiments were conducted to evaluate the effects of Fe injection timing after birth on suckling and subsequent nursery and growing-finishing pig performance. The injectable Fe source used in both experiments was GleptoForte (Ceva Animal Health, LLC., Lenexa, KS). GleptoForte contains gleptoferron which is a Fe macromolecule complex. In Exp. 1, a total of 324 newborn pigs (DNA 241 × 600, initially 1.6 ± 0.04 kg body weight [BW]) within 27 litters were used. Two days after birth, all piglets were weighed, and six barrows and six gilts per litter were allotted to 1 of 6 treatments consisting of no Fe injection or 200 mg of injectable Fe provided in a single injection on d 2, 4, 6, 8, or 10 of age. Pigs were weaned (~21 d of age) and allotted to nursery pens with all pigs in each pen having received the same Fe treatment. In Exp. 2, a total of 1,892 newborn pigs (PIC 359 × C40; initially 1.5 ± 0.02 kg BW) within 172 litters were used. One day after birth, piglets were weighed, and 11 pigs within each litter were allotted to 1 of 6 treatments consisting of no Fe injection or 200 mg of injectable Fe provided on d 1, 3, 5, or 7 of age, or 200 mg on d 1 plus 200 mg on d 12 of age. Pigs were weaned (19 d of age) and placed in a commercial wean-to-finish facility in a total of 15 pens with equal representation of treatments in each pen. In both experiments, not providing an Fe injection after birth decreased (P < 0.05) preweaning average daily gain (ADG), weaning weight, and hemoglobin and hematocrit values compared with all other treatments. In Exp. 1, increasing the age that piglets received an Fe injection until 4 or 6 d after birth provided marginal evidence for an improvement (quadratic; P = 0.070) in preweaning ADG. For the nursery period, increasing the age that piglets received an Fe injection improved (quadratic; P = 0.013) d 80 BW, but there was no evidence of a difference (P > 0.10) in d 173 BW at the end of the grow-finish period. In Exp. 2, increasing the age that piglets received a 200 mg Fe injection showed no evidence of difference (P > 0.10) for subsequent nursery and growing-finishing ADG. In both experiments, hemoglobin and hematocrit values were decreased (linear; P < 0.05) at weaning with increasing age when pigs received an Fe injection. These experiments suggest that providing a 200 mg Fe injection within 7 d after farrowing is sufficient for optimizing preweaning and subsequent growth performance.

Weaned pigs (n=1,722; 5.9 kg BW) were used in a 53-d study evaluating the effects of Fe injection timing on subsequent nursery pig performance. Treatments consisted of a negative control for piglets receiving no Fe injection or 200-mg of injectable Fe (GleptoForte, Ceva Animal Health, Lenexa, KS) provided on d 1, 3, 5, or 7 of age, or 200-mg on d 1 plus an additional 200-mg injection on d 12. At weaning, pigs were placed in a commercial wean-to-finish facility in a total of 15 pens with equal representation of treatments in each pen. Pigs were weighed on d 73 after birth to determine subsequent nursery growth performance. Growth data were analyzed (GLIMMIX procedure of SAS) as a completely randomized design with individual pig as the experimental unit and pen as a random effect. Increasing the age that piglets received a 200-mg Fe injection showed no evidence of difference (P >0.10) for subsequent nursery ADG (Table 1). Not providing an Fe injection after birth decreased (P=0.0001) subsequent nursery ADG and decreased (P=0.0001) d 73 BW compared to all other treatments. Providing a 200-mg injection of Fe on d 1 plus a 200-mg injection on d 12 decreased (P=0.010) subsequent nursery ADG and decreased (P=0.024) d 73 BW compared to pigs receiving a 200-mg injection on d 1 only. There was no evidence of difference (P >0.10) for nursery mortality amongst the treatments. These results suggest that providing a 200-mg Fe injection within 7 d after farrowing is sufficient for optimizing subsequent nursery growth performance. The additional 200-mg Fe injection at d 12 decreased subsequent nursery growth performance and ending BW.

A total of 140 weanling pigs (241 × 600, DNA, Columbus, NE; initially 5.5 ± 0.79 kg body weight) were used in a 32-d study evaluating the effects of increasing dietary Fe from either iron sulfate (FeSO4) or iron carbonate (FeCO3) on nursery pig growth performance and blood Fe status. The pigs used for this trial did not receive an Fe injection after birth in order to increase the sensitivity to added dietary Fe after weaning. Pigs were weaned at approximately 21 d and allotted to pens based on the initial weight in a completely randomized block design with five pigs in each pen and four pens per treatment. Experimental treatments were arranged as a 2 × 3 + 1 factorial with main effects of dietary Fe source (FeSO4 vs. FeCO3) and level (10, 30, or 50 mg/kg of added Fe) plus a negative control with no additional dietary Fe. The basal diet contained 40 mg/kg total dietary Fe based on ingredient contributions and was formulated with an Fe-free trace mineral premix. Experimental diets were formulated below the pigs recommended Fe requirement based on NRC (2012) estimates. Experimental diets were fed in pellet form in a single phase for the duration of the trial. From day 0 to 32, there was no evidence for source × level interactions for growth performance, hemoglobin (Hb), or hematocrit (Hct) values. There was no evidence for a difference (P > 0.10) in dietary Fe source. Providing increasing Fe levels in the diet from either FeSO4 or FeCO3 improved (P < 0.05) average daily gain, average daily feed intake, gain-to-feed ratio, and increased (P < 0.05) Hb and Hct values. A day effect (P = 0.001) was observed for both Hb and Hct with values increasing throughout the study. Increasing dietary Fe levels in the diet from either FeSO4 or FeCO3 increased (linear; P < 0.05) Hb and Hct values on days 14, 21, and 32. In summary, these data suggest that the micronized form of FeCO3 is a source of Fe that can be added to nursery diets to yield similar responses to those observed from FeSO4 supplementation. Similar to previous research, increasing dietary Fe improved the growth performance and increased Hb and Hct values when pigs have low Fe status at weaning.

A total of 336 newborn pigs (DNA 241 × 600, initially 1.75 ± 0.05 kg bodyweight [BW]) from 28 litters were used in a 63-d study evaluating the effects of increasing injectable Fe dose on suckling and subsequent nursery pig performance and blood Fe status. GleptoForte (Ceva Animal Health, LLC, Lenexa, KS) contains gleptoferron which is an Fe macromolecule complex that is commercially used as an injectable Fe source for suckling piglets. On the day of processing (day 3 after birth), all piglets were weighed and 6 barrows and 6 gilts per litter were allotted within sex to 1 of 6 treatments in a completely randomized design. Treatments consisted of a negative control receiving no Fe injection and increasing injectable Fe to achieve either 50, 100, 150, 200 mg, or 200 mg plus a 100 mg injection on day 11 after birth. Pigs were weaned (~21 d of age) and allotted to nursery pens based on BW and corresponding treatment in a completely randomized design. During lactation, increasing injectable Fe up to 100 mg improved (quadratic; P < 0.05) average daily gain (ADG) and day 21 BW with no further improvement thereafter. There was no evidence of differences (P > 0.10) observed between the 200 mg and 200 mg + 100 mg treatments for growth. For the nursery period, increasing Fe dosage increased (linear; P < 0.05) ADG, average daily feed intake, and day 42 BW. There was no evidence of differences (P > 0.10) between the 200 mg and 200 mg + 100 mg treatments for nursery growth. For blood criteria, significant treatment × day interactions (P = 0.001) were observed for hemoglobin (Hb) and hematocrit (Hct). The interactions occurred because pigs that had

Newborn pigs (n=1,892; 1.5 kg BW) were used in a 20-d study evaluating the effects of Fe injection timing after birth on preweaned pig performance and blood criteria. A total of 172 litters were used. One d after farrowing, piglets were weighed, and 11 pigs within each litter were allotted to 1 of 6 treatments in a CRD. Treatments consisted of pigs receiving no Fe injection or 200-mg of injectable Fe (GleptoForte, Ceva Animal Health, Lenexa, KS) provided on d 1, 3, 5, or 7 of age, or 200-mg on d 1 plus 200-mg on d 12. 1 pig/litter received no Fe injection and 2 pigs/litter were placed on all other treatments. Piglets were weighed on d 1 and 20 after birth to determine growth performance and bled on d 20 to determine Fe status. Increasing the age that piglets received the Fe injection tended to decrease (linear; P=0.080) ADG. Not providing an Fe injection decreased (P=0.0001) overall ADG and d 20 BW compared to all other treatments. Hemoglobin and Hct decreased (linear; P< 0.05) with increasing age when pigs received an Fe injection. There was no evidence of differences (P >0.10) between the pigs receiving a 200-mg injection on d 1 and d 12 compared to those receiving the Fe on d 1 only. Pigs not provided an Fe injection had decreased (P=0.0001) Hb and Hct values compared to pigs receiving an Fe injection. Pigs receiving the 200-mg injection on d 1 and 12 had increased (P=0.0001) Hb and Hct values compared to pigs receiving 200-mg on d 1 only. Results suggest that providing a 200-mg Fe injection within 7 d after farrowing is sufficient for optimizing preweaning growth performance. The additional 200-mg Fe injection at d 12 did not influence growth performance but does increase Hb and Hct at weaning.

Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. © 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS.

Weaned pigs (n = 311; 5.9 kg BW) were used in a 59-d study evaluating the effects of Fe injection timing after birth on nursery pig performance and hematological criteria. Pigs were weaned at 21 d and allotted to pens based on preweaning Fe treatment with BW balanced across pens within a treatment with 5 or 6 pigs/pen and 10 pens/treatment. The preweaning treatments were a negative control receiving no Fe injection or 200-mg of injectable Fe (Gleptoforte, Ceva Animal Health, Lenexa, KS) provided in a single injection on d 2, 4, 6, 8, or 10 after birth. All pigs were fed common diets after weaning that contained 110 mg/kg of added Fe as FeSO4 provided from the trace mineral premix. Growth data were analyzed as a completely randomized design with pen as the experimental unit. Hematological criteria were measured as a repeated measure with pig as the experimental unit. Overall, increasing the age of pigs receiving a 200-mg Fe injection from 2 to 4 or 6 d after birth increased (quadratic; P = 0.013) d 80 ending BW with a decrease in BW when Fe was provided on d 8 or 10 (Table 1). Not providing an Fe injection after birth worsened (P < 0.05) ADG, ADFI, and d 80 ending BW. Significant treatment×day interactions (P < 0.001) were observed for Hgb and Hct values. These interactions occurred because pigs not receiving an Fe injection after birth had values that increased from d 21 to 35 while pigs receiving an Fe injection had values that decreased from d 21 to 35. While it is common practice to provide an Fe injection within the first 48 hours of birth, these results suggest delaying injection until d 4 or 6 may increase nursery final weight.

Hayden E Hundley,1 Mark E Hudson,2,3 Ajay D Wasan,3,4 Trent D Emerick3,4 1Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 2Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 3University of Pittsburgh Physicians, Pittsburgh, PA, USA; 4Division of Chronic Pain, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Objective: The aim of this study is to identify scheduling inefficiencies and to develop a personalized schedule based on diagnosis, service time (face-to-face time between the patient and the provider), and patient wait time using a Gantt diagram in a chronic pain clinic.Design: This is an observational prospective cohort quality improvement (QI) study.Setting: This study was carried out at a single outpatient multidisciplinary pain management clinic in a university teaching hospital.Subjects: New and established chronic pain patients at the University of Pittsburgh Medical Center (UPMC) Montefiore Chronic Pain Clinic were recruited for this study.Methods: Time tracking data for each phase of clinic visit and pain-related diagnoses were collected from 81 patients on 5 clinic days in March 2016 for patient flow analysis.Results: A Gantt diagram was created using Microsoft Excel® software. Areas of overbooking and underbooking were identified. Median service times (minutes) differed dramatically based on the diagnosis and were highest for facial pain (23 [IQR, 15–31]) and chronic abdominal and/or pelvic pain (21.5 [IQR, 16–27]) and lowest for myalgia. Abdominal and/or pelvic pain and facial pain median service times consistently exceeded the 15-minute allocation for return visits.Conclusion: Schedule efficiency analysis using the Gantt diagram identified trends of overbooking and underbooking and inefficiencies in examination room utilization. A 15-minute appointment for all return patients is unrealistic due to variation of service times for some diagnoses. Scheduling appointments based on the diagnosis is an innovative approach that may reduce scheduling inefficiencies and improve patient satisfaction and the overall quality of care. To the best of our knowledge, this type of scheduling diagram has not been used in a chronic pain clinic. Keywords: quality of health care, chronic pain, outcome assessment, pain management, physician performance, referral and consultation, satisfaction, strategic planning&nbsp

Hypothalamic orexin neurons project to numerous brain areas, including the ventral tegmental area (VTA), which is involved in motivation and food-seeking behavior. Here we address how exogenously administered orexin-A and endogenous orexin 1 receptor (OX1R) activation in the VTA affects feeding behavior. We hypothesized that orexin-A and OX1R antagonist SB334867 delivered to the VTA, at doses that were subthreshold for effect when injected into the ventricle, would affect intake of palatable foods in multiple test situations. We first used a hedonic feeding model in which satiated rats selectively consume a high-fat diet (HFD). Intra-VTA orexin-A stimulated additional consumption of chow and increased HFD intake in this model. In ad libitum-fed rats given daily 30-min test sessions, intra-VTA orexin-A also increased intake of HFD and 0.1 M sucrose. Further analysis of licking patterns revealed that that VTA orexin-A increased meal size and licking burst size only toward the end of the meal. Consistent with this finding, a subthreshold dose of VTA orexin-A prevented intake suppression induced by gastrointestinal nutrient infusion. Surprisingly, intra-VTA orexin-A had no effect on operant responding for sucrose pellets on a progressive ratio schedule of reinforcement. A role for endogenous VTA OX1R stimulation is supported by our finding that bilateral VTA injection of the selective OX1R antagonist SB334867 suppressed 0.1 M sucrose intake. Together, our data suggest that OX1R activity in the VTA facilitates food intake, potentially by counteracting postingestive negative feedback that would normally suppress feeding later in a meal.

A total of 300 nursery pigs (initially 5.9 ± 0.05 kg BW) were used in a 42-d growth trial to evaluate the effects of feeding a therapeutic level of chlortetracycline (CTC) with or without direct fed microbials (DFM) on growth performance and antimicrobial resistance (AMR) of fecal Escherichia coli. CTC is a broad-spectrum in-feed antibiotic commonly used in the swine industry. Weaned pigs (~21 d of age) were allotted to pens based on initial BW and fed a common starter diet for 4 d. Pens were then blocked by BW and allotted to dietary treatments in a completely randomized block design. Dietary treatments were arranged in a 2 × 3 factorial consisting of combinations of CTC (none vs. 400 mg/kg from days 0 to 42) and DFM (0 vs. 0.05% DFM 1 vs. 0.05% DFM 2). Fecal samples were collected from three randomly selected pigs from each pen on days 0, 21, and 42 for E. coli isolation and AMR determination. Overall, pigs fed diets containing CTC had improved (P < 0.001) ADG, ADFI, and BW compared to those not fed CTC with no evidence for any effect of either DFM 1 or DFM 2. Regardless of CTC, inclusion of DFM 2 in diets improved (P < 0.05) ADFI from days 0 to 14 and on day 14 BW compared to diets that did not include DFM 2. The addition of CTC with or without DFMs to nursery pig diets increased (P < 0.05) the probability of AMR to tetracycline and ceftiofur of fecal E. coli isolates, but this resistance generally decreased (P < 0.05) over time. A decrease (P < 0.05) in AMR to ampicillin and tetracycline (TET) throughout the trial was observed, while resistance to ceftriaxone decreased (P < 0.020) from days 0 to 21 and increased from days 21 to 42 amongst dietary treatments regardless of CTC or DFM inclusion in the diet. A CTC × DFM × day interaction (P < 0.015) was observed for streptomycin, whereby from days 21 to 42 AMR increased in diets containing either CTC or DFM 1 alone, but the combination decreased resistance. There was no evidence for any effect of DFMs on AMR of fecal E. coli isolates to any other antibiotics evaluated. In conclusion, therapeutic levels of added CTC with or without DFM inclusion improved nursery pig performance, but increased AMR of fecal E. coli isolates to TET and ceftiofur. A moderate improvement in intake and day 14 BW was observed when DFM 2 was included in the diet with or without CTC, but, except for streptomycin, there was no evidence that added dietary DFMs affected resistance of fecal E. coli to antibiotics.

Formaldehyde-based feed additives are approved in the US for Salmonella control and reducing bacterial contamination in animal feed. However, we hypothesize formaldehyde inclusion in swine diets may influence gut microbial composition due to its antimicrobial properties which might negatively influence microbial populations and pig growth performance. Also, formaldehyde inclusion in diets is known to reduce the dietary availability of amino acids. Therefore, our study was conducted to characterize if the effects of feed formaldehyde-treatment are due to influences on microbial population or diet amino acid (AA) sources. Dietary treatments were arranged in a (2 × 2) + 1 factorial with formaldehyde treatment (none vs. 1000 ppm formaldehyde) and crystalline AA inclusion (low vs. high) with deficient AA content plus a positive control diet to contain adequate AA content without dietary formaldehyde. Treating diets with formaldehyde reduced growth rate (P = 0.001) while the AA inclusion had no evidence of impact. Formaldehyde reduced feed bacterial content and altered fecal microbial communities (P

Newborn pigs (n = 324; 1.6 kg BW) were used in an 19-d study evaluating the effects of Fe injection timing after birth on preweaned pig performance and blood criteria. A total of 27 litters were used, with the number of pigs per sow equalized on each day of farrowing. Two d after farrowing, all piglets were weighed, and six barrows and six gilts within each litter were allotted to 1 of 6 treatments in a CRD. Treatments consisted of a negative control receiving no Fe injection or 200 mg of injectable Fe (Gleptoforte, Ceva Animal Health, Lenexa, KS) provided on d 2, 4, 6, 8, or 10 after farrowing. Piglets were weighed and bled on d 2, 12, and 21 after birth to determine growth performance and blood Fe status. Overall, increasing the age that piglets received a 200 mg Fe injection until 4 or 6 d after birth tended to increase (quadratic; P = 0.065) ADG (Table 1). Not providing an Fe injection tended to decrease (P = 0.070) overall ADG and decreased (P = 0.0003) d 21 BW compared to all other treatments. Significant treatment×day interactions (P < 0.001) were observed for hemoglobin (Hgb) and hematocrit (Hct). The interactions occurred because pigs injected with 200 mg of Fe on d 2, 4, 6, or 8 after birth had increasing values until d 21 after birth, while pigs receiving a 200 mg Fe injection on d 10 after birth had decreasing values to d 12 then increasing values to d 21. Pigs not provided an Fe injection after birth had decreasing values to d 21. These results suggest that providing a 200 mg Fe injection on d 4 or 6 after farrowing provided the greatest preweaning growth performance and blood Fe status until weaning.

Hindbrain glucagon-like peptide 1 (GLP-1) neurons project to numerous forebrain areas, including the lateral septum (LS). Using a fluorescently labeled GLP-1 receptor (GLP-1R) agonist, Exendin 4 (Ex4), we demonstrated GLP-1 receptor binding throughout the rat LS. We examined the feeding effects of Ex4 and the GLP-1R antagonist Exendin (9–39) (Ex9) at doses subthreshold for effect when delivered to the lateral ventricle. Intra-LS Ex4 suppressed overnight chow and high-fat diet (HFD) intake, and Ex9 increased chow and HFD intake relative to vehicle. During 2-h tests, intra-LS Ex9 significantly increased 0.25 M sucrose and 4% corn oil. Ex4 can cause nausea, but intra-LS administration of Ex4 did not induce pica. Furthermore, intra-LS Ex4 had no effect on anxiety-like behavior in the elevated plus maze. We investigated the role of LS GLP-1R in motivation for food by examining operant responding for sucrose on a progressive ratio (PR) schedule, with and without a nutrient preload to maximize GLP-1 neuron activation. The preload strongly suppressed PR responding, but blockade of GLP-1R in the intermediate subdivision of the LS did not affect motivation for sucrose under either load condition. The ability of the nutrient load to suppress subsequent chow intake was significantly attenuated by intermediate LS Ex9 treatment. By contrast, blockade of GLP-1R in the dorsal subdivision of the LS increased both PR responding and overnight chow intake. Together, these studies suggest that endogenous activity of GLP-1R in the LS influence feeding, and dLS GLP-1Rs, in particular, play a role in motivation.

Acute kidney injury (AKI) is common and portends mortality in several neonatal cohorts. Fluid overload is independently associated with poor outcomes in children and adults but has not been extensively studied in neonates. Between February 2010 and May 2011, we followed 58 neonates who met the following criteria: birth weight >2,000 g, gestational age ≥34 weeks, 5-min Apgar ≤7, and parental consent. Serum creatinine (SCr) was measured daily for first 4 days of life. AKI was defined as a rise in SCr of > 0.3 mg/dl or persistent SCr above 1.5 mg/dl. AKI was present in 9/58 (15.6 %) neonates and was associated with higher birth weight, being male, lower 5-min Apgar scores, lower cord pH, delivery room intubation, and absence of maternal pre-eclampsia. Percent weight accumulation at day 3 of life was higher in those with AKI [median = 8.2, interquartile range (IQR) = 4.4–21.6)] than without AKI (median = −4 (IQR = −6.5 to 0.0) (p

To identify urine biomarkers predictive of acute kidney injury (AKI) in infants admitted to level 2 and 3 neonatal intensive care units with birth weight2000 g and 5-minute Apgar score ≤ 7.A nested case-control study was performed comparing 8 candidate urine AKI biomarkers in infants with AKI (defined as a rise in serum creatinine of at least 0.3 mg/dL or a serum creatinine elevation ≥ 1.7 mg/dL persisting for 3 days) and 24 infants from the described cohort without AKI. Urine was analyzed for neutrophil gelatinase-associated lipocalin, osteopontin, cystatin C, albumin, β(2) microglobulin, epithelial growth factor, uromodulin (UMOD), and kidney injury molecule 1.Compared with the infants without AKI, those with AKI had higher levels of urine cystatin C (1123 pg/mL [95% CI, 272-4635 pg/mL] vs 90 pg/mL [95% CI, 39-205 pg/mL]; P.004; area under the receiver operating characteristic curve [AUC] = 0.82), lower levels of UMOD (11.0 pg/mL [95% CI, 5.7-21.4 pg/mL] vs 26.2 pg/mL [95% CI, 17.4-39.4 pg/mL]; P.03; AUC = 0.77), and lower levels of epithelial growth factor (6.7 pg/mL [95% CI, 4.0-11.3 pg/mL] vs 17.4 pg/mL [95% CI, 12.7-23.8 pg/mL; P = .003; AUC = 0.82). Although the differences were not statistically significant, levels of urine neutrophil-associated gelatinase lipocalin, kidney injury molecule 1, and osteopontin trended higher in infants with AKI.Urinary biomarkers can predict AKI in neonates admitted to level 2 and 3 neonatal intensive care units.

Summary: Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.