Acute intoxication caused by three common synthetic cannabinoids: The experience of a large, urban, tertiary care hospital.

BACKGROUND: Synthetic cannabinoids (SC) are chemical substances, which activate cannabinoid receptors in a similar fashion to tetrahydrocannabinol, but with increased efficacy, and are used as illicit recreational drugs. OBJECTIVE: Our objective was to characterize the clinical manifestations and management of three specific, common SC exposures in a cohort of patients presenting to the emergency department of our institution. METHODS: Retrospective case series of patients admitted to an urban tertiary care center between August 1, 2018 and December 31, 2021, with confirmed SC use and positive urinary immunoassay testing for AB-FUBINACA, 4F-MDMB-BUTINACA and ACHMINACA. RESULTS: 58 patients met inclusion criteria during the 3-year study period; median age was 35 years, 60% were male, 31% patients were exposed to >1 substance, and 31% needed hospital addition. The most common physical signs were cardiovascular (54%) and neuropsychiatric (45%). Severe outcomes included coma and seizures, necessitating intubation in 4 patients, and acute renal injury in 7 patients. CONCLUSION: SC are potentially harmful drugs of abuse which can lead to life-threatening complications. Acute care personnel should be aware of the broad range of signs and symptoms of SC use. Testing with short turn around times is available to assess SC use.

Aldolase positively regulates of the canonical Wnt signaling pathway.

The Wnt signaling pathway is an evolutionary conserved system, having pivotal roles during animal development. When over-activated, this signaling pathway is involved in cancer initiation and progression. The canonical Wnt pathway regulates the stability of ß-catenin primarily by a destruction complex containing a number of different proteins, including Glycogen synthase kinase 3ß (GSK-3ß) and Axin, that promote proteasomal degradation of ß-catenin. As this signaling cascade is modified by various proteins, novel screens aimed at identifying new Wnt signaling regulators were conducted in our laboratory. One of the different genes that were identified as Wnt signaling activators was Aldolase C (ALDOC). Here we report that ALDOC, Aldolase A (ALDOA) and Aldolase B (ALDOB) activate Wnt signaling in a GSK-3ß-dependent mechanism, by disrupting the GSK-3ß-Axin interaction and targeting Axin to the dishevelled (Dvl)-induced signalosomes that positively regulate the Wnt pathway thus placing the Aldolase proteins as novel Wnt signaling regulators.

Novel At-Home Mother's Milk Conductivity Sensing Technology as an Identification System of Delay in Milk Secretory Activation Progress and Early Breastfeeding Problems: Feasibility Assessment.

BACKGROUND: Prolonged exclusive breastfeeding is a public health priority and a personal desire by mothers; however, rates are low with milk supply challenges as a predominant cause. Early breastfeeding management at home is key. Milk electrolytes, mainly sodium ions, are accepted as biomarkers of secretory activation processes throughout the first weeks after birth and predictors for prolonged breastfeeding success, although they are not incorporated into routine care practice. OBJECTIVE: The aim of this study was to test the feasibility of a novel handheld smartphone-operated milk conductivity sensing system that was designed to compute a novel parameter, milk maturation percent (MM%), calculated from milk sample conductivity for tracking individual secretory activation progress in a real-world home setting. METHODS: System performance was initially evaluated in data collected from laboratory-based milk analysis, followed by a retrospective analysis of observational real-world data gathered with the system, on the spot in an at-home setting, implemented by lactation support providers or directly by mothers (N=592). Data collected included milk sample sensing data, baby age, and self-reported breastfeeding status and breastfeeding-related conditions. The data were retroactively classified in a day after birth-dependent manner. Results were compared between groups classified according to breastfeeding exclusivity and breastfeeding problems associated with ineffective breastfeeding and low milk supply. RESULTS: Laboratory analysis in a set of breast milk samples demonstrated a strong correlation between the system's results and sodium ion levels. In the real-world data set, a total of 1511 milk sensing records were obtained on the spot with over 592 real-world mothers. Data gathered with the system revealed a typical time-dependent increase in the milk maturation parameter (MM%), characterized by an initial steep increase, followed by a moderate increase, and reaching a plateau during the first weeks postpartum. Additionally, MM% levels captured by the system were found to be sensitive to breastfeeding status classifications of exclusive breastfeeding and breastfeeding problems, manifested by differences in group means in the several-day range after birth, predominantly during the first weeks postpartum. Differences could also be demonstrated for the per-case time after birth-dependent progress in individual mothers. CONCLUSIONS: This feasibility study demonstrates that the use of smart milk conductivity sensing technology can provide a robust, objective measure of individual breastfeeding efficiency, facilitating remote data collection within a home setting. This system holds considerable potential to augment both self-monitoring and remote breastfeeding management capabilities, as well as to refine clinical classifications. To further validate the clinical relevance and potential of this home milk monitoring tool, future controlled clinical studies are necessary, which will provide insights into its impact on user and care provider satisfaction and its potential to meet breastfeeding success goals.

Calculating the appropriate prophylactic dose of cefazolin in women undergoing cesarean delivery.

BACKGROUND AND OBJECTIVES: Surgical site infection and other postoperative complications are relatively common in obstetrical procedures, and they are associated with morbidity, prolonged hospital stay, and readmissions. Appropriate levels of antimicrobial agents given directly before skin incision can prevent the establishment of surgical-related infection caused by endogenous microorganisms present on the woman's skin. We aimed to determine serum concentrations of cefazolin given to pregnant women prior to scheduled cesarean delivery and to compare their drug concentrations and pharmacokinetics in 2 weight groups. STUDY DESIGN: We conducted a prospective cohort analysis of the pharmacokinetics of cefazolin in women undergoing cesarean delivery (August 2017 to September 2018). One or two grams of intravenous cefazolin was administered within 30 min prior to skin incision to women weighing <80 kg and ≥80 kg, respectively. Maternal serum samples were obtained at skin incision and 30 min later. The serum concentration of cefazolin was measured by high-pressure liquid chromatography. Antimicrobial coverage was defined as being appropriate when the cefazolin levels were above the minimal inhibitory concentration. Pharmacokinetic parameters were estimated using a one-compartment model. RESULTS: A total of 61 women were enrolled, of whom 47 underwent cesarean delivery (study group). The mean time that had elapsed between drug administration to incision was 13 ± 6.9 min (95% confidence interval 10.6-16.2 min). The drug levels after 30 min in women who weighed >80 kg and in women who received 2 g cefazolin, after 30 min from incision differed significantly (87.0 ± 26.0 vs 55.4 ± 16.6 µg/ml, p = .0001). CONCLUSION: A single 1- or 2-g dose of cefazolin provides serum concentrations above minimal inhibitory concentrations for susceptible pathogens in most women undergoing scheduled cesarean delivery.

A flow cytometry-based reporter assay identifies macrolide antibiotics as nonsense mutation read-through agents.

UNLABELLED: A large number of human diseases are caused by nonsense mutations. These mutations result in premature protein termination and the expression of truncated, usually nonfunctional products. A promising therapeutic strategy for patients suffering from premature termination codon (PTC)-mediated disorders is to suppress the nonsense mutation and restore the expression of the affected protein. Such a suppression approach using specific antibiotics and other read-through promoting agents has been shown to suppress PTCs and restore the production of several important proteins. Here, we report the establishment of a novel, rapid, and very efficient method for screening stop-codon read-through agents. We also show that, in both mammalian cells and in a transgenic mouse model, distinct members of the macrolide antibiotic family can induce read-through of disease-causing stop codons leading to re-expression of several key proteins and to reduced disease phenotypes. Taken together, our results may help in the identification and characterization of well-needed customized pharmaceutical PTC suppression agents. KEY MESSAGES: Establishment of a flow cytometry-based reporter assay to identify nonsense mutation read-through agents. Macrolide antibiotics can induce read-through of disease-causing stop codons. Macrolide-induced protein restoration can alleviate disease-like phenotypes.

14-3-3 and ß-catenin are secreted on extracellular vesicles to activate the oncogenic Wnt pathway.

Aberrant activation of the canonical Wnt signal transduction pathway is involved in a large number of human diseases. ß-catenin, the key effector protein of the canonical Wnt pathway, functions in the nucleus with T-cell factor/lymphoid enhancer factor (TCF/LEF) to activate expression of Wnt target genes. Here we show that members of the 14-3-3 protein family bind disheveled-2 (Dvl-2) and glycogen synthase-3ß (GSK-3ß) to attenuate the interaction between GSK-3ß and ß-catenin. Importantly, 14-3-3 and ß-catenin form "bleb-like" structures and are secreted via extracellular vesicles to induce Wnt signaling activity in target cells. Our data suggest a novel way of transducing the oncogenic Wnt signal in which ß-catenin is regulated by 14-3-3ζ through the formation of "oncosomes" that contain both the 14-3-3 and ß-catenin proteins.