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Abstract Background Foreign body (FB) ingestions cause lead toxicity in pediatric patients. These ingestions result in continued lead absorption until passage or removal from the gastrointestinal (GI) tract. Whole-bowel irrigation (WBI) is frequently recommended to aid in the removal of FBs, however effectiveness of this practice is not clear. Methods We performed a retrospective chart review of pediatric patients (<18 years old) admitted for treatment of lead toxicity at an academic pediatric medical center from 1 January 2017 through 31 October 2023. We abstracted patient age, identity of ingested FB, lead concentrations, duration of WBI, maximum flow rate of WBI, success or failure of FB passage, performance and results of endoscopy, and duration of hospital stay. Results Nine cases with radiopaque FB suspected to be lead were treated with WBI. Three cases resulted in the complete expulsion of the ingested FB. Four patients underwent endoscopic removal after WBI median duration of 47.5 h (range 27–80.5 h). One patient failed to clear despite 168.5 h of WBI. Conclusion WBI did not lead to the clearance of all FBs in this series. Practitioners should consider early endoscopic removal if WBI does not result in passage of the FB within the first 48 h.

Tramadol is an adulterant of illicit opioids. As it is a serotonin-norepinephrine reuptake inhibitor as well as a μ-opioid agonist, tramadol adulteration may worsen overdose signs and symptoms or affect the amount of naloxone patients receive. This is a multicenter, prospective cohort of adult patients with suspected opioid overdoses who presented to one of eight United States emergency departments and were included in the Toxicology Investigators Consortium's Fentalog Study. Patient serum was analyzed via liquid chromatography quadrupole time-of-flight mass spectroscopy to detect opioids, novel psychoactive substances, and adulterants. Patients were separated into groups of those with tramadol detected versus no tramadol detected. Differences in naloxone administration, intubation, performance of cardiopulmonary resuscitation (CPR), or death between those exposed or not exposed to tramadol were evaluated. From September 21, 2020 – October 31, 2021; 2298 patients were screened and 537 met inclusion criteria. Eighty-one patients (15 %) tested positive for tramadol. There was no significant difference found between those who reported chronic prescription opioid use (p = 0.81) or reported chronic pain (p = 0.27). Additionally, no difference was found between groups in the number of patients receiving a single, second, or third dose of naloxone (p = 0.25; 0.92; 0.59) or the proportion initiated on a naloxone infusion (p = 0.84). Similarly, there was no difference in outcomes of intubation, CPR, or death (p = 0.26; 0.75; 0.29). Tramadol was identified in a subset of patients presenting to the Emergency Department with opioid overdoses suggesting adulteration of illicitly manufactured fentanyl with tramadol. Its presence was not associated with a lack of treatment response, difference in severity of overdose, or increased risk of complications.

In parallel to the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO 2022), an alternative International Consensus Classification (ICC) has been proposed. To evaluate the impact of the new classifications on AML diagnoses and ELN-based risk classification, we analyzed 717 MDS and 734 AML non-therapy-related patients diagnosed according to the revised 4th WHO edition (WHO 2017) by whole genome and transcriptome sequencing. In both new classifications, the purely morphologically defined AML entities decreased from 13% to 5%. Myelodysplasia-related (MR) AML increased from 22% to 28% (WHO 2022) and 26% (ICC). Other genetically-defined AML remained the largest group, and the abandoned AML-RUNX1 was mainly reclassified as AML-MR (WHO 2022: 77%; ICC: 96%). Different inclusion criteria of AML-CEBPA and AML-MR (i.a. exclusion of TP53 mutated cases according to ICC) were associated with differences in overall survival. In conclusion, both classifications focus on more genetics-based definitions with similar basic concepts and a large degree of agreement. The remaining non-comparability (e.g., TP53 mutated AML) needs additional studies to definitely answer open questions on disease categorization in an unbiased way.

Homologous desensitization of G protein-coupled receptors is thought to occur in several steps: binding of G protein-coupled receptor kinases (GRKs) to receptors, receptor phosphorylation, kinase dissociation, and finally binding of β -arrestins to phosphorylated receptors. It generally is assumed that only the last step inhibits receptor signaling. Investigating the parathyroid hormone (PTH) receptor → inositol phosphate pathway, we report here that GRKs can inhibit receptor signaling already under nonphosphorylating conditions. GRKs phosphorylated the PTH receptor in membranes and in intact cells; the order of efficacy was GRK2>GRK3>GRK5. Transient transfection of GRKs with the PTH receptor into COS-1 cells inhibited PTH-stimulated inositol phosphate generation. Such an inhibition also was seen with the kinase-negative mutant GRK2-K220R and also for a C-terminal truncation mutant of the PTH receptor that could not be phosphorylated. Several lines of evidence indicated that this phosphorylation-independent inhibition was exerted by an interaction between GRKs and receptors: (a) this inhibition was not mimicked by proteins binding to G proteins, phosducin, and GRK2 C terminus, (b) GRKs caused an agonist-dependent inhibition (= desensitization) of receptor-stimulated G protein GTPase-activity (this effect also was seen with the kinase-inactive GRK2-mutant and the phosphorylation-deficient receptor mutant), and (c) GRKs bound directly to the PTH receptor. These data suggest that signaling by the PTH receptor already is inhibited by the first step of homologous desensitization, the binding of GRKs to the receptors.

In AML patients, recurrent mutations were shown to persist in remission, however, only some have a prognostic value and persistent mutations might therefore reflect a re-established premalignant state or truly active disease causing relapse. We aimed to dissect the nature of co-mutations in NPM1 mutated AML where the detection of NPM1 transcripts allows highly specific and sensitive detection of complete molecular remission (CMR). We analysed 150 consecutive patients who achieved CMR following intensive treatment by next generation sequencing on paired samples at diagnosis, CMR and relapse (38/150 patients). Patients with persistence or the acquisition of non-DTA (DNMT3A, TET2, ASXL1) mutations at CMR (23/150 patients, 15%) have a significantly worse prognosis (EFS HR = 2.7, p = 0.003; OS HR = 3.6, p = 0.012). Based on clonal evolution analysis of diagnostic, CMR and relapse samples, we redefine pre-malignant mutations and include IDH1, IDH2 and SRSF2 with the DTA genes in this newly defined group. Only the persistence or acquisition of CHOP-like (clonal hematopoiesis of oncogenic potential) mutations was significantly associated with an inferior outcome (EFS HR = 4.5, p = 0.0002; OS HR = 5.5, p = 0.002). Moreover, the detection of CHOP-like mutations at relapse was detrimental (HR = 4.5, p = 0.01). We confirmed these findings in a second independent whole genome sequencing cohort.