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Background: Alcohol use disorders (AUD) are common in patients admitted to intensive care units (ICU) and increase the risk for worse outcomes. In this study, we describe factors associated with patient mortality after ICU admission and the effect of chemical dependency (CD) counseling on outcomes in the year following ICU admission. Methods: We retrospectively reviewed patient demographics, hospital data, and documentation of CD counseling by medical providers for all ICU patients with AUD admitted to our institution between January 2017 and March 2019. Primary outcomes were in-hospital and 1-year mortality.Results: Of the 527 patients with AUD requiring ICU care, median age was 56 years (range, 18–86 years). Both in-hospital mortality (12%) and 1-year mortality rates (27%) were high. . Rural patients, comorbidities, older age, need for mechanical ventilation, and complications were associated with increased risk of in-hospital and 1-year mortality. CD counseling was documented for 73% of patients, and 50% of these patients accepted alcohol treatment or resources prior to discharge. CD evaluation and acceptance was associated with a significantly decreased rate of readmission for liver or alcohol-related issues (36% vs. 58%; odds ratio [OR], 0.41; 95% confidence intervals [CI], 0.27–0.61) and 1-year mortality (7% vs. 19.5%; OR, 0.32; 95% CI, 0.16–0.64). CD evaluation alone, regardless of patient acceptance, was associated with a significantly decreased 1-year post-discharge mortality rate (12% vs. 23%; OR, 0.44; 95% CI, 0.25–0.77.) Conclusions: ICU patients with AUD had high in-hospital and 1-year mortality. CD evaluation, regardless of patient acceptance, was associated with a significant decrease in 1-year mortality.

Pre-Intervention Colonoscopy/Endoscopy Results.

Post intervention colonoscopy/endoscopy results.

Cyclic GMP responses in rectal biopsies in subjects receiving linaclotide (Active) or placebo.

Cyclic GMP responses in transverse colon biopsies in subjects receiving linaclotide (Active) or placebo.

Incidence of adverse events by study age.

Cyclic GMP responses in cecal biopsies in subjects receiving linaclotide (Active) or placebo.

Baseline Physical Exam.

Background: The impact of pancreaticoduodenectomy (PD) on absorption of drugs in the duodenum remains largely unknown. We aim to characterize the pharmacokinetics of apixaban in patients who have previously underwent PD. Methods: A single 10 mg dose of apixaban was administered to four volunteers who underwent PD at least 6 months prior. The maximum plasma apixaban concentration (Cmax) and area under the plasma concentration time-curve (AUC0-24, AUC0-inf) were compared against healthy historical control subjects (N=12). Geometric mean ratios (GMR) with 90% confidence interval (CI) were calculated for determination of comparative bioequivalence. Results: In PD patients AUC0-24 and AUC0-inf were 1861 and 2080 ng•hr/mL, respectively. The GMRs of AUC0-24 and AUC0-inf between study subjects and healthy controls were 1.27 (90% CI 0.88-1.83) and 1.18 (90% CI 0.82-1.72). The mean Cmax of apixaban was 201 ng/mL (SD 15.6) occurring at a median Tmax of 3.25 hours (range 2.5-4 hours). The GMR of Cmax between study subjects and healthy controls was 1.12 (90% CI 0.77-1.63). Conclusions: The pharmacokinetic characteristics of apixaban in subjects who have undergone PD are not significantly different from those of healthy controls. No changes in their dosing regimen are recommended. ClinicalTrials.gov Identifier: NCT04191928

It is unclear if the pharmacokinetics of vancomycin are the same during automated peritoneal dialysis (APD), where cycler exchanges may affect the systemic, peritoneal, and urinary disposition of drug. We conducted a prospective pharmacokinetic study evaluating the pharmacokinetics of vancomycin in plasma, dialysis fluid, and urine in peritonitis-negative patients on APD. Patients underwent four drug-free exchanges with 1.5% or 2.5% dextrose following the initial dwell period. Plasma, dialysis fluid, and urine was collected over the course of 7 days for pharmacokinetic analysis. Four patients completed the study with no adverse events. Following a median (range) dwell of 14.6 (14.2-17.6 h), the mean (±SD) observed maximum plasma concentration was 28.7 ± 4.9 mg/L with a mean bioavailability of 98.5 ± 1.4% prior to starting the cycler. The overall mean total plasma clearance estimated from study start to completion was 7.6 ± 1.2 ml/min. Mean total clearance during the dialytic exchange was 13.6 ± 4.9 ml/min. In patients with residual renal function, the mean vancomycin renal clearance was 3.1 ± 1.5 ml/min, representing 21.4%-58.9% of the overall total plasma clearance during the study period. Despite the small sample size, this pilot study suggests that the dwell time has important implications for systemic vancomycin exposure, time to therapeutic plasma concentration, and dosing. Dose is driven by dwell time, whereas the cycler determines the dosing interval. Rapid exchanges from APD will determine the frequency of dosing rather than the adequacy of absorption when vancomycin is given in the peritoneum.

Results from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up‐titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning, and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when up‐titration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 µg/kg/day, 33% titration, and 15% wean rate. Five subjects required adjuvant therapy. Half‐maximal effective concentration (EC50) values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model‐based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.

Neonates born to mothers taking opioids during pregnancy are at risk for neonatal opioid withdrawal syndrome (NOWS), for which there is no recognized standard approach to care. Nonpharmacologic treatment is typically used as a first-line approach for management, and pharmacologic treatment is added when clinical signs are not responding to nonpharmacologic measures alone. Although morphine and methadone are the most commonly used pharmacotherapies for NOWS, buprenorphine has emerged as a treatment option based on its pharmacologic profile and results from initial single site clinical trials. The objective of this report is to provide an overview of NOWS including a summary of ongoing work in the field and to review the state of the science, knowledge gaps, and practical considerations specific to the use of buprenorphine for the treatment of NOWS as discussed by a panel of experts during a virtual workshop hosted by the National Institutes of Health.

OBJECTIVE In the hospital settings, buprenorphine is used for the treatment of patients with neonatal abstinence syndrome. It is extemporaneously compounded and stored in oral plastic syringes. However, limited information exists about the stability of buprenorphine and its compounded formulations when stored under specific conditions. Hence, we developed a stability-indicating high-performance liquid chromatography–mass spectrometry (LC-MS) method to analyze the stability of buprenorphine over time. METHODS A stability-indicating LC-MS method was developed to map the potential degradation peaks of buprenorphine when exposed to acidic, basic, and oxidative conditions. This method was used to study the stability of compounded buprenorphine oral syringes stored under refrigeration (2°C–8°C) and room temperature (25°C ± 2°C with 60% relative humidity). Syringes from each storage condition were assessed for stability using pH meter and stability-indicating LC-MS assay for 30 days. RESULTS Buprenorphine gets completely degraded in the presence of acid at the end of 1 hour of exposure. Various degradation peaks were identified using LC-MS assay for buprenorphine under acidic, basic, and peroxide conditions. Stability study of oral buprenorphine syringes showed no precipitation, cloudiness, or color change during this study at all storage conditions. The LC-MS assay revealed that buprenorphine oral syringes retained greater than 90% of the initial concentrations for 30 days. CONCLUSIONS Highly sensitive stability-indicating LC-MS method was developed for studying the stability of extemporaneously compounded buprenorphine oral syringes. This study demonstrates that buprenorphine extemporaneous formulation prepared according to the manufacturers' recommendations is stable under refrigerated or room temperature conditions for 30 days in oral plastic syringes.

Background Despite the publication of a national patient safety alert in 2016, inadvertent feeding through misplaced nasogastric tubes continues to occur, either through failure to review the radiograph, misinterpretation of it, or failure to communicate the results. Objective The objectives were to determine whether training in a new pathway introduced to avoid these “never events” was followed and whether radiographer comments and prompt communication of results could reduce risk and improve patient safety in relation to nasogastric tube placement in children. Materials and methods Following radiographer training in interpretation of nasogastric tube position and use of a commenting proforma and communication pathway, we reviewed all radiographs obtained to check nasogastric tubes performed over a 13-month period in children 0–16 years of age. Then we assessed accuracy of the radiographer comments, adherence to the pathway, and any practice change in children with misplaced nasogastric tubes. Results We reviewed 282 nasogastric tube check radiographs. For 262 radiographs (92.9%) the pathway was followed correctly. Of the total 282 radiographs, 240 (85%) were immediately reported using the standardised commenting proforma, and 235 radiographer comments were affirmed by the radiologist (97% accuracy, confidence interval 0.95–0.99). Of the immediately reported radiographs, 213 (88.8%) nasogastric tubes were considered to be safe for use. Four (1.7%) of the immediately reported nasogastric tubes were misplaced in a bronchus, and the report communicated to the clinical team resulted in removal or re-siting of the tubes. Conclusion Nasogastric tube check radiographs in children can be reported accurately by radiographers trained in their interpretation and the results promptly communicated to clinical staff, improving safety in relation to nasogastric tube placement in children.

Safeguarding, the action taken to protect children from harm, is an important aspect of paediatric care. Orthopaedic surgeons are often the first healthcare professionals to suspect physical abuse or non-accidental injury (NAI) on the basis of children presenting with unexplained bony injury. Physical harm from inflicted injury, a concept that most orthopaedic surgeons are familiar with, is not the only cause for a safeguarding referral and a comprehensive assessment may reveal concerns regarding: neglect, emotional abuse or sexual abuse. Clinicians caring for children, have to consider all of these factors as a cause for concern and organize onward referral. This article focuses on inflicted skeletal injury, how to recognize and investigate it. Typical fractures of concern are discussed and illustrated along with consideration of differential diagnoses.

Atogepant is a potent, selective, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once‐daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double‐blind, placebo‐controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty‐four participants aged 23–55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well‐tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half‐life of ~ 11 hours, and no evidence of accumulation after once‐daily dosing. Overall, atogepant at a high oral dose is safe and well‐tolerated in healthy participants with no clinically meaningful elevations in ALT.

Lebensbedrohliche Verletzungen wahrend der Schwangerschaft sind ein seltenes Ereignis. Das TraumaRegister DGU® (TR-DGU) erfasst seit 2016, ob bei weiblichen Schwerverletzten eine Schwangerschaft vorlag. Diese Information reicht nicht aus, um eine differenzierte Beurteilung der Versorgungsqualitat zu ermoglichen, weil z. B. Gestationsalter, Zustand der Schwangerschaft bei Entlassung oder Uberleben des Kindes fehlen. Der Arbeitskreis TraumaRegister der Sektion Notfall‑, Intensivmedizin und Schwerverletztenversorgung (Sektion NIS) der Deutschen Gesellschaft fur Unfallchirurgie (DGU) e. V. kam daher zu der Uberzeugung, dass das fetale Outcome bzw. die Intaktheit der Schwangerschaft nach Abschluss der Akutbehandlung ein wichtiges Mas fur die Versorgungsqualitat der schwangeren Frau ist, und beauftragte eine Task Force mit der Ausarbeitung eines geeigneten Datensatzes, um solche Falle besser analysieren zu konnen. Dieser Beitrag stellt das sog. Fetus-Modul im Detail vor. Der Datensatz wurde in einem interdisziplinaren Prozess zusammen mit akkreditierten Fachexperten der Deutschen Gesellschaft fur Gynakologie und Geburtshilfe (DGGG) e. V., der Deutschen Gesellschaft fur Perinatale Medizin (DGPM) e. V. und der Gesellschaft fur Neonatologie und padiatrische Intensivmedizin (GNPI) e. V. erarbeitet. Das Fetus-Modul umfasst 20 Parameter zur Beschreibung der Schwangerschaft, des Zustands von Mutter und Kind bei Aufnahme sowie bei Entlassung. Das Fetus-Modul wird wichtige Daten liefern, um die Prozess- und Ergebnisqualitat der Versorgung von schwer verletzten, schwangeren Frauen messbar zu machen, und um Prognoseinstrumenten entwickeln zu konnen, mit denen Vorhersagen zu Hochrisikokonstellationen fur das Outcome von Mutter und Kind getroffen werden konnen.

Introduction Ultrasound is the modality of choice in the evaluation of neonates and young children with suspected adrenal lesions including adrenal haemorrhage and congenital adrenal hyperplasia. It is also the initial imaging modality in children presenting with an upper abdominal mass, which may be adrenal in origin. Topic discussion: This paper shows adrenal anatomy and demonstrates how the sonographic features change with age. It reviews the imaging features of congenital adrenal lesions, as well as benign and malignant conditions affecting the adrenal gland in childhood. Discussion and Conclusion: Ultrasound is a useful primary imaging modality in the assessment of the adrenal gland in children. Knowledge of the changes of the adrenal gland with age is important when assessing the adrenal gland. Ultrasound is also useful for assessing abdominal masses. However, it cannot differentiate adrenal masses, therefore correlation with biochemical findings, multimodality imaging, and histology is usually required.

Chronic recurrent multifocal osteomyelitis (CRMO) is an auto-inflammatory disorder affecting the skeleton of children and adolescents. Whole-body MRI (WBMRI) is key in the diagnosis and follow-up of CRMO. Imaging protocols should include sagittal short Tau inversion recovery of the spine, imaging of the hands and feet, and T1 images for distinguishing normal bone marrow. CRMO lesions can be metaphyseal, epiphyseal and physeal—potentially causing growth disturbance and deformity. Spinal lesions are common, important and can cause vertebral collapse. Lesion patterns include multifocal tibial and pauci-focal patterns that follow a predictable presentation and course of disease. Common pitfalls of WBMRI include haematopoietic marrow signal, metaphyseal signal early on in bisphosphonate therapy and normal high T2 signal in the hands and feet. Pictorial reporting assists in recording lesions and follow-up over time. The purpose of this paper is to review the different WBMRI protocols, imaging findings, lesion patterns and common pitfalls in children with CRMO

Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1. Its use in combination with rifapentine (RPT), an antituberculosis (TB) antibiotic, may reduce the exposure of DOR compromising viral suppression in those living with HIV-1 co-infected with TB. We conducted a prospective, phase I, open label, two-period, fixed sequence, drug interaction study to evaluate the effect of once-weekly RPT and isoniazid (INH) on the pharmacokinetics (PKs) of DOR in healthy volunteers. DOR 100 mg was administered alone twice-daily for 4 days in period 1. In period 2, once-weekly RPT + INH were co-administered with multiple doses of DOR 100 mg twice-daily for study days 7, 14, and 21. Plasma was obtained for DOR PKs when given alone and co-administered with RPT + INH. Eleven healthy volunteers enrolled and completed the study. The geometric mean ratios and 90% confidence intervals for DOR area under the concentration-time curve from zero to 12 hours (AUC0-12 ) and C12 in the presence of RPT + INH compared with DOR alone were 0.71 (0.60-0.85) and 0.69 (0.54-0.89), respectively. Although exposures were moderately reduced in the presence of RPT + INH, trough DOR values were within the concentration range associated with virological suppression. These results demonstrate that a modest decrease in DOR exposure would unlikely be clinically relevant in a virally suppressed patient co-administered once-weekly RPT + INH.

Aufgrund der lebenslangen Therapie, der hohen Kosten fur das Gesundheitssystem und einer sich andernden Rollenerwartung von Patienten an Arzte ist Multiple Sklerose (MS) ein wichtiges Gebiet der Versorgungsforschung. Erstellung einer Ubersicht uber die Studienlage in Deutschland im Jahr 2020 zur Inanspruchnahme ambulanter medizinischer Leistungen und der Entscheidungsfindung bei Patienten mit MS. Es wurde eine Literaturrecherche in PubMed und weiterfuhrenden Quellen durchgefuhrt, um relevante Veroffentlichungen zu identifizieren und darzustellen. Zur Inanspruchnahme ambulanter medizinischer Leistungen in Deutschland von MS-Patienten gibt es nur wenige Untersuchungen. Bei Allgemein- und Hausarzten sowie Neurologen liegen die hochsten Werte fur die Inanspruchnahme vor, wohingegen Urologen weniger haufig aufgesucht werden. Die Werte fur die Inanspruchnahme von Leistungen von Physiotherapeuten unterscheiden sich stark zwischen den Studien. „Shared decision making“ (SDM) als Modell der Entscheidungsfindung ist in Deutschland unter verschiedenen Gesichtspunkten und Vorgehensweisen untersucht worden. Eine wichtige Voraussetzung fur SDM ist ein ausreichendes Wissen vonseiten der Patienten. Bei den Daten zur Inanspruchnahme ambulanter Leistungen in Deutschland von MS-Patienten sind zum Teil grose Differenzen festzustellen, die durch methodische Unterschiede und Limitationen der Einzelstudien erklart werden konnen. Die Anwendung von SDM bei MS-Patienten wird von verschiedenen Seiten gefordert, jedoch gibt es bisher wenig Evidenz fur einen positiven Effekt auf die Erkrankung.

To determine if treatment with a 5-HT3 antagonist (ondansetron) reduces need for opioid therapy in infants at risk for neonatal opioid withdrawal syndrome (NOWS).A multicenter, randomized, placebo controlled, double blind clinical trial of ninety (90) infants. The intervention arms were intravenous ondansetron or placebo during labor followed by a daily dose of ondansetron or placebo in infants for five days.Twenty-two (49%) ondansetron-treated and 26 (63%) placebo-treated infants required pharmacologic treatment (p 0.05). The Finnegan score was lower in the ondansetron-treated group (4.6 vs. 5.6, p = 0.02). A non-significant trend was noted for the duration of hospitalization. There was no difference in need for phenobarbital or clonidine therapy, or total dose of morphine in the first 15 days of NOWS treatment.Ondansetron treatment reduced the severity of NOWS symptoms; and there was an indication that it could reduce the length of stay.Clinicaltrials.gov NCT01965704.

Platelet protease activated receptor-4 (PAR4) Thr120 is a common genetic variant associated with increased platelet activity. Increased platelet activity is implicated in the pathogenesis of preeclampsia and preterm birth.Compare the rate of preeclampsia and preterm birth in pregnant individuals homozygous for PAR4 Thr120 variant vs not.This is a prospective cohort study of patients who delivered November 2020-July 2021. Maternal blood collected on admission for PAR4 genotyping. The primary outcome was the rate of preeclampsia/gestational hypertension in those with Thr/Thr genotype compared with Ala/Thr or Ala/Ala. Secondary outcomes included rates of preterm birth and placental pathology.Three hundred and twenty singletons were included and 52 (16.3%) were PAR4 Thr/Thr. Those PAR4 Thr/Thr were more likely to be Black (67.3% vs 29.5%, p lt; .001), younger (28 ± 6 vs 31 ± 6, p = .004), and have higher body mass index (35.2 ± 6.8 vs 33.1 ± 7.4, p = .047). There was no difference in preeclampsia/gestational hypertension (19.2% vs 22.8%, p = .705). Those Thr/Thr had a significantly higher rate of preterm birth (15.4% vs 3.7%, adjusted odds ratio [aOR] 4.04 [1.47-11.10], p = .007), indicated preterm birth because of fetal growth restriction or preeclampsia (5.8% vs 0.4%, aOR 10.03 [1.48-67.87], p = .02), spontaneous preterm birth (7.7% vs 2.2%, aOR 4.81 [1.27-18.27], p = .02), and placental intervillous thrombosis (18.5% vs 7.9%, aOR 4.12 [1.14-14.92], p = .03).Platelet receptor PAR4 Thr120 is a common variant associated with an increased risk of placental vascular pathology and preterm birth in homozygous individuals. Although a cohort study cannot establish causation, this strong association warrants further exploration.

Apixaban is frequently used off-label in transplant recipients. However, a potential drug interaction exists with the calcineurin inhibitors. We conducted an open-label drug-drug interaction study to determine the pharmacokinetics of apixaban in lung and kidney transplant recipients who were taking a calcineurin inhibitor. A single dose of apixaban 10 mg was administered orally to kidney and lung transplant recipients maintained on either tacrolimus or cyclosporine, and pharmacokinetic parameters were compared to a reference cohort of 12 healthy subjects who used the same apixaban dose and pharmacokinetic blood sampling. Fourteen participants were enrolled (n = 6 kidney, n = 8 lung), with 10 maintained on tacrolimus and four on cyclosporine. Data from 13 participants was usable. Participants were taking triple therapy immunosuppression and had a mean (SD) of 12 (3) medications. Participants receiving tacrolimus and cyclosporine had area under the plasma concentration-time curve from time zero to infinity (AUC

Background: Apixaban pharmacokinetic properties and some clinical reports suggest cessation 48 hours prior to surgery is safe, but this has not been demonstrated in a naturalistic setting. We sought to measure the residual apixaban exposure in patients who had apixaban held as part of standard of care perioperative management. Methods: This was a prospective, observational study of patients in whom apixaban plasma concentration and anti-Xa activity were measured while at steady state apixaban dosing and again immediately prior to surgery. Clinical management of cessation and resumption of apixaban was at the discretion of the treating physician. Results: Paired blood samples were provided by 111 patients. Ninety-four percent (104/111) of patients had measured apixaban concentrations of ⩽ 30 ng/mL. Only one patient had a value > 50 ng/mL. The median time between the self-reported last dose and presurgery blood sampling was 76 hours (range 32–158) for those who achieved concentrations ⩽ 30 ng/mL and 59 hours (range 49–86) for those > 30 ng/mL. Measured anti-Xa activity correlated well with apixaban exposure. Clinically significant nonmajor bleeding was reported in one patient at 1 week postsurgery. There was one venous thromboembolic event and one stroke in the perioperative period. Conclusion: In a naturalistic setting with a heterogeneous patient population, apixaban discontinuation for at least 48 hours before a procedure resulted in a clinically insignificant degree of anticoagulation prior to a surgical procedure. ClinicalTrials.gov Identifier: NCT02935751

Guanylyl cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of the luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Previous studies revealed that linaclotide, an oral GUCY2C agonist formulated for gastric release, did not persist to activate guanylyl cyclase signaling in the distal rectum. Dolcanatide is an investigational oral uroguanylin analog, substituted with select D amino acids, for enhanced stability and extended persistence to activate GUCY2C in small and large intestine. However, the ability of oral dolcanatide to induce a pharmacodynamic (PD) response by activating GUCY2C in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of oral dolcanatide 27 mg daily for 7 d to healthy volunteers did not activate GUCY2C, quantified as accumulation of its product cyclic GMP, in epithelial cells of the distal rectum. These data reveal that the enhanced stability of dolcanatide, with persistence along the rostral-caudal axis of the small and large intestine, is inadequate to regulate GUCY2C across the colorectum to prevent tumorigenesis. These results highlight the importance of developing a GUCY2C agonist for cancer prevention formulated for release and activity targeted to the colorectum.

The present study investigated the effect of varying trypsin inhibitor activity (TIA) in differently processed soybean expellers on apparent prececal amino acid (AA) digestibility in male broiler chickens. Two different raw soybean batches were treated using varying processing techniques and intensities. In this way, 45 expeller extracted soybean meal (ESBM) variants were created. The processed soybean variants were then merged into a basal diet (160 g/kg crude protein [CP]) at 2 inclusion levels (15%, 30%) resulting in 90 different diets plus one basal diet (0.4 mg/g-8.5 mg/g TIA). All diets contained 0.5% titanium dioxide. A total of 5,460-day-old male broilers (Ross 308) were allocated on d 14 to 546 pens (10 birds/pen) after a starter phase (CP 215 g/kg, 14 g/kg Lysine, 12.5 MJ ME/kg). The 91 experimental diets were fed ad libitum until d 22. Subsequently, birds were euthanized and digesta of the terminal ileum was collected for determination of AA digestibility. TIA depressed the prececal digestibility of every single AA significantly in a straight linear fashion (P0.001). Sulfur-containing AA expressed the strongest suppression by TIA with cystine showing the lowest apparent prececal digestibility measured (10.6% at 23.6 mg/g TIA in raw ESBM). The present data demonstrate that TIA severely depresses digestibility of essential and nonessential AA in a straight linear fashion. On the one hand, this questions the usefulness of defined upper limits of TIA in soy products whereas on the other hand, TIA must be considered when testing raw components for their feed protein value in vivo.

Intraperitoneal vancomycin is the first-line therapy in the management of peritoneal dialysis (PD)-related peritonitis. However, due to the paucity of data, vancomycin dosing for peritonitis in patients on automated peritoneal dialysis (APD) is empiric and based on clinical experience rather than evidence. Studies in continuous ambulatory peritoneal dialysis (CAPD) patients have been used to provide guidelines for dosing and are often extrapolated for APD use, but it is unclear whether this is appropriate. This review summarizes the available pharmacokinetic data used to inform optimal dosing in patients on CAPD or APD. The determinants of vancomycin disposition and pharmacodynamic effects are critically summarized, knowledge gaps explored, and a vancomycin dosing algorithm in PD patients is proposed.

We sought a shortened MOTHER neonatal abstinence syndrome (NAS) and Finnegan score that would retain comparable performance characteristics of the full instrument. Retrospective cohort. In total, 124,170 MOTHER NAS scores between August 2007 and May 2016 from 775 infants (≥36 weeks) were examined. Classification and regression tree model identified the most important subsets of the scored variables. A 9-element shortened scale yielded >90% sensitivity and specificity to predict clinical endpoints based on the full 19-element MOTHER NAS score. Conversion of the data sets to the Finnegan score, and applying the same procedure resulted in a nine-element score with similar performance characteristics. Shortened scoring instruments were identified with the high-predictive power for clinical endpoints based on the 19-element full MOTHER NAS score. There was no substantial variation in performance for age, supporting the current practice of utilizing a single scoring tool regardless of postnatal age.

Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist intended for the acute treatment of migraine attacks. Ubrogepant has a chemical structure distinct from previous small-molecule CGRP receptor antagonists that were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report overall and hepatic safety data from two placebo-controlled phase I trials of ubrogepant, spray-dried oral compressed tablet (SD-OCT) in healthy male volunteers. Trial A was a pharmacokinetic (PK) trial of single (100-400 mg) and multiple (40-400 mg) ascending doses. Trial B was a dedicated hepatic safety trial assessing daily use of ubrogepant 150 mg for 28 days. Serum ALT (as hepatotoxicity biomarker) and PK data are reported. Ubrogepant was well-tolerated in both trials, with a low incidence of adverse events that did not differ greatly from placebo. Changes in mean ALT levels were minimal and similar to placebo. Over 28 days of treatment, the mean percentage change in ALT from baseline was < 5% at all time points. No participant in either trial demonstrated ALT ≥ 3× upper limit of normal at any time. Ubrogepant SD-OCT demonstrated linear PK appropriate for acute treatment of migraine, with rapid uptake (time of maximum plasma concentration (tmax ): 2-3 hours) and no accumulation with daily use. Overall, there was no evidence of ubrogepant-associated hepatotoxicity with daily doses up to 400 mg for 10 days or with daily ubrogepant 150 mg for 28 days. Supratherapeutic dosing is a useful strategy for characterizing hepatic safety in early drug development.

Aim Review of visits to the radiology department related to trampoline injuries in a major trauma centre in the UK over a 6-year period, and analysis of imaging performed, injury type, and seasonal trends in children under 18 years of age. Subject and methods Retrospective review of the Radiology Information System (RIS) for requests and reports between January 2012 and December 2017 containing the search term “tramp*” with an age of Results A total of 1794 children (44% male, mean age 8.15) visited the radiology department 1871 times and received 2343 separate radiographic examinations, ten ultrasound examinations, 20 CT examinations, 19 MR examinations and two nuclear medicine examinations. Seven hundred and eighty-eight children (45.9% male) had injury demonstrated on radiographs (622 fractures and 183 soft-tissue injuries) during 796 visits to radiology. Positive CT, MRI, and US were seen in 55%, 47.3%, and 50% of cases respectively. Children under 7 years of age are more likely to have been injured compared to older children attending for X-rays, with the proportion of injuries seen in 6-year-old children being the highest (63.7%). Trampoline injury-related X-ray requests to radiology rose from 1.7% to 4% per year as a percentage of overall X-ray requests from the emergency department. Conclusion Trampoline injury-related visits to the radiology department and the number of injuries demonstrated on imaging studies have increased over the study period, putting greater pressure on the healthcare system. Younger children are especially prone to injury. Public health campaigns and mandatory national safety standards are needed to increase awareness of potential dangers of recreational trampoline use.

The mesophotic zone off the coast of Bermuda has been explored for macroalgae beginning with the R/V Seahawk cruises of the 1980s and most recently on the Nekton XL Catlin cruise of the R/V Baselin...

Neonates experience dramatic changes in the disposition of drugs after birth as a result of enzyme maturation and environmental adjustment, challenging therapeutic decision making. In this research, we establish postnatal age, postmenstrual age, and body weight as physiologically reasonable predictors of morphine's clearance in neonates. By integrating knowledge of bilirubin, morphine, and other drugs metabolized by glucuronidation pathways from previously published studies, we hypothesize that uridine diphosphate glucuronic acid, a postnatal age-dependent sugar, plays an important role in the metabolism of morphine during the first week of life. This finding can be extended to other drugs metabolized by uridine diphosphate glucuronosyltransferase pathways in neonates and thus has important clinical implications for the use of drugs in this population.

To utilize noninvasive collection of amniotic fluid in the setting of preterm premature rupture of membranes (PPROMs) to report the time concentration profile of azithromycin in amniotic fluid over 7 days from a single dose, and evaluate the correlation between azithromycin concentration and inflammatory markers in amniotic fluid. Prospective cohort study of five pregnant patients admitted with PPROMs and treated with a single 1 g oral azithromycin dose. Amniotic fluid was collected from pads and used to quantify azithromycin concentration as well as TNFa, IL‐1a, IL‐1b, IL‐6, IL‐8, and IL‐10 concentrations. Primary outcome was time/concentration profile of azithromycin in amniotic fluid. Secondary outcome included correlation between azithromycin concentration and cytokine concentrations. Five patients were enrolled. Mean gestational age on admission with PPROM was 27.5 ± 2.3 weeks with a median latency of 7 days (interquartile range [IQR] = 4–13). A median of two samples/day (IQR = 1–3) were collected per participant. Azithromycin was quantified in duplicate; intra‐assay coefficient of variation was 17%. Azithromycin concentration was less than 60 ng/ml after day 3. Azithromycin concentration was positively correlated with IL‐8 (r = 0.38, p = 0.03), IL1a (r = 0.39, p = 0.03), and IL‐1b (r = 0.36, p = 0.04) in amniotic fluid. Azithromycin is detectable in amniotic fluid over 7 days from a single 1 g maternal dose, however, it is not sustained over the range of minimum inhibitory concentration for common genitourinary flora. Based on correlation with specific cytokines, azithromycin penetration in amniotic fluid may relate to maternal monocyte concentration in amniotic fluid in the setting of PPROM.

Aims Osteonecrosis (ON) can cause considerable morbidity in young people who undergo treatment for acute lymphoblastic leukaemia (ALL). The aims of this study were to determine the operations undertaken for ON in this population in the UK, along with the timing of these operations and any sequential procedures that are used in different joints. We also explored the outcomes of those patients treated by core decompression (CD), and compared this with conservative management, in both the pre- or post-collapse stages of ON. Methods UK treatment centres were contacted to obtain details regarding surgical interventions and long-term outcomes for patients who were treated for ALL and who developed ON in UKALL 2003 (the national leukaemia study which recruited patients aged 1 to 24 years at diagnosis of ALL between 2003 and 2011). Imaging of patients with ON affecting the femoral head was requested and was used to score all lesions, with subsequent imaging used to determine the final grade. Kaplan-Meier failure time plots were used to compare the use of CD with non surgical management. Results Detailed information was received for 85 patients who had developed ON during the course of their ALL treatment. A total of 206 joints were affected by ON. Of all joints affected by ON, 21% required arthroplasty, and 43% of all hips affected went on to be replaced. CD was performed in 30% of hips affected by ON. The majority of the hips were grade 4 or 5 at initial diagnosis of ON. There was no significant difference in time to joint collapse between those joints in which CD was performed, compared with no joint-preserving surgical intervention. Conclusion There is a high incidence of surgery in young people who have received treatment for ALL and who have developed ON. Our results suggest that CD of the femoral head in this group of patients does not delay or improve the rates of femoral head survival. Cite this article: Bone Joint J 2021;103-B(3):589–596.

Objective The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. Study Design This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100–199 mg), and low doses ( Results Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14–37] days, intermediate dose 31 [18–45] days, and high dose 35 [20–48] days, p Conclusion Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. Key Points

Life-threatening injuries during pregnancy are a rare occurrence. The TraumaRegister DGUThe data set was developed in an interdisciplinary process together with accredited experts from the German Society for Gynecology and Obstetrics (DGGG), the German Society for Perinatal Medicine (DGPM) and the Society for Neonatology and Pediatric Intensive Care Medicine (GNPI).The fetus module comprises 20 parameters describing the pregnancy, the condition of the mother and child on admission and discharge.The fetus module will provide important data to make the process and outcome quality of care of severely injured pregnant women measurable and to develop prognostic instruments with which predictions about high-risk constellations for the outcome of mother and child can be made.HINTERGRUND: Lebensbedrohliche Verletzungen während der Schwangerschaft sind ein seltenes Ereignis. Das TraumaRegister DGUDer Datensatz wurde in einem interdisziplinären Prozess zusammen mit akkreditierten Fachexperten der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) e. V., der Deutschen Gesellschaft für Perinatale Medizin (DGPM) e. V. und der Gesellschaft für Neonatologie und pädiatrische Intensivmedizin (GNPI) e. V. erarbeitet.Das Fetus-Modul umfasst 20 Parameter zur Beschreibung der Schwangerschaft, des Zustands von Mutter und Kind bei Aufnahme sowie bei Entlassung.Das Fetus-Modul wird wichtige Daten liefern, um die Prozess- und Ergebnisqualität der Versorgung von schwer verletzten, schwangeren Frauen messbar zu machen, und um Prognoseinstrumenten entwickeln zu können, mit denen Vorhersagen zu Hochrisikokonstellationen für das Outcome von Mutter und Kind getroffen werden können.

Background Osteomyelitis is an infection of the bone which can occur in people with diabetic foot ulcers. It can be diagnosed using X-rays, ultrasound, scintigraphy, magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET). Objectives To review the evidence on the diagnostic accuracy of imaging tests to diagnose osteomyelitis in people with diabetic foot ulcers. Methods We conducted a systematic review and meta-analysis. MEDLINE, EMBASE and other databases were searched to July 2018. Risk of bias was evaluated. Diagnostic accuracy was estimated using bivariate meta-analyses. Results Thirty-six studies were included in the meta-analysis. Eight studies were at high risk of bias MRI had high diagnostic accuracy (22 studies: 96.4 % sensitivity (95 % CI 90.7–98.7); 83.8 % specificity (76.0–89.5)). PET scans also had high accuracy (6 studies: 84.3 % sensitivity (52.8–96.3); 92.8 % specificity (75.7–98.2)), and possibly also SPECT, but with few studies (3 studies: 95.6 % sensitivity (76.0–99.3); 55.1 % specificity (19.3–86.3)). Scintigraphy (17 studies: 84.2 % sensitivity (76.8–89.6); 67.7 % specificity (56.2–77.4)), and X-rays (16 studies: 61.9 % sensitivity (50.5–72.1); 78.3 % specificity (62.9–88.5)) had generally inferior diagnostic accuracy. Conclusions MRI and PET both reliably diagnose osteomyelitis in diabetic foot ulcer patients. SPECT may also have good diagnostic accuracy, although evidence is limited. This review confirms most current guidelines, showing that MRI may be the preferable test in most cases, given its wider availability and the lack of potentially harmful ionising radiation.

Due to the necessity for lifelong treatment, high costs for the healthcare system and changes in role expectations of patients towards physicians, multiple sclerosis (MS) is an important topic in healthcare research.The aim of this review is to provide an overview of the current study situation in Germany in 2020 on utilization of outpatient medical resources and shared decision making in patients with MS.For this review a literature search was carried out in PubMed and other extended sources in order to identify and present relevant publications.There are only a few studies on the utilization of outpatient medical resources by patients with MS in Germany. The highest values for utilization were found for general practitioners, family physicians and neurologists whereas urologists were less frequently involved. The values for the utilization of services provided by physiotherapists greatly differed between the studies. Several studies using different approaches to shared decision making in Germany were identified and summarized. An important prerequisite for shared decision making is an adequate knowledge on the side of the patients.Differences in the utilization of outpatient resources by MS patients in Germany can be explained by methodological differences and limitations of the individual studies. The use of shared decision making by MS patients is demanded by various parties but so far there is little evidence for a positive effect on the disease.

To assess the suitability of southern-Australian macroalgae as potential marine resources for fatty acids (FA), and in particular polyunsaturated fatty acids (PUFA), analysis of 61 species, comprising of 11 Chlorophyta, 17 Phaeophyceae (Ochrophyta) and 33 Rhodophyta, was conducted. Total fatty acid (TFA) concentrations varied considerably (between 0.6 and 7.8 in % of dry weight (DW)) between species, with on average the highest concentrations being in the Phaeophyceae, then the Chlorophyta, and with the Rhodophyta recording the lowest average concentrations. Results revealed significant differences in the fatty acid profiles of the three algal groups. Most species exhibit high proportions of PUFA in their fatty acid profile and a low ratio of n-6/n-3 PUFA. These properties highlight the potential for southern-Australian macroalgae to be used for these FA in food, animal feed and nutraceutical applications.

Background Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor available as a single tablet and a three-drug combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) to treat HIV-1 infection. These analyses assessed pharmacokinetic (PK) interactions with coadministration. Methods Two trials were conducted. Study 1: two-period, fixed-sequence; eight healthy participants; Period 1, DOR 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg once daily for 18 days, coadministration of DOR 100 mg on day 14. Study 2: three-period, crossover, 15 healthy participants; Treatment A, DOR 100 mg; Treatment B, 3TC 300 mg + TDF 300 mg; Treatment C, DOR 100 mg + 3TC 300 mg + TDF 300 mg; ≥7-day washout between periods. Results Study 1: geometric mean ratios (GMRs; 90% confidence interval [CI]) of DOR area under the concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and observed plasma concentrations at 24 h post-dose (C24 h; DOR+TDF/DOR) were 0.95 (0.80, 1.12) and 0.94 (0.78, 1.12), respectively. Study 2: GMRs (90% CI) of DOR AUC0–∞ and C24 h (DOR+3TC+TDF/DOR) were 0.96 (0.87, 1.06) and 0.94 (0.83, 1.06), respectively. GMRs (90% CI) of 3TC and tenofovir AUC0–∞ (DOR+3TC+TDF/3TC+TDF) were 0.94 (0.88, 1.00) and 1.11 (0.97, 1.28), respectively. Study drugs were generally well tolerated. Conclusions Multiple doses of TDF did not have a clinically meaningful effect on DOR PK. The PK of DOR were similar when administered alone or in combination with 3TC and TDF. DOR had no meaningful effect on the PK of 3TC and tenofovir.

Apixaban is metabolized by cytochrome P450 (CYP) 3A4 in the liver and intestine, undergoes direct intestinal excretion, and is a substrate to permeability glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) transporters. We examined the drug interactions between cyclosporine and tacrolimus (combined inhibitors of CYP3A4, P‐gp, and BCRP) with apixaban in 12 healthy adult male volunteers. Apixaban 10 mg was administered orally alone, in combination with 100 mg cyclosporine or 5 mg tacrolimus. Co‐administration with cyclosporine resulted in increase in apixaban maximum plasma concentration (C max) and area under the plasma concentration‐time curve from time zero to the last quantifiable concentration (AUC (0‐tlast)) with associated geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of 143% (112, 183) and 120% (97, 148), respectively. Co‐administration with tacrolimus resulted in reduction in apixaban C max and AUC (0‐tlast) with associated GMRs (90% CI) of 87% (69, 112) and 78% (63, 97), respectively. The observed changes in apixaban exposure margins with cyclosporine or tacrolimus are within the range of the historical clinical development program, therefore, apixaban dose adjustments are not warranted.