Search

Background: As transgender people initiate gender-affirming hormone therapy (GAHT), they are exposed to exogenous sex hormones that have effects that have not yet been fully studied. While exogenous estrogen is associated with a risk of venous thrombosis, the full impact of estrogen on the liver is unknown. Conversely, the erroneous attribution of risks from GAHT presents a barrier to treatment for some patients. We present a case of obliterative portal venopathy (OPV) and possible DILI occurring after the initiation of estrogen in a transgender woman. Case presentation: A 28-year-old transgender woman on GAHT was referred to hepatology for liver enzyme elevations. She did not have any notable comorbid conditions, family history, or psychosocial history. Lab and imaging workup were unremarkable, and the patient underwent liver biopsy. The patient's biopsy results showed OPV. The patient continued GAHT at a lower dose and liver enzyme elevations resolved. Conclusions: OPV is a vascular disease that falls under the category of porto-sinusoidal vascular disorder. Patients with this condition can present with or without overt clinical signs of portal hypertension. Porto-sinusoidal vascular disorder is rare and given the timing and possible dose dependence, it might be reasonable to consider that the observed OPV was influenced by the exogenous estrogen administered in an association not previously reported. Alternatively, the patient's continued estrogen treatment without ill effect could suggest that the events were not connected and that the fear of harm could have served as a barrier to the patient receiving indicated care. [ABSTRACT FROM AUTHOR]

Background: Cleft lip and palate are often accompanied by maxillary asymmetry and midface hypoplasia. However, there has been limited examination of the symmetry of the zygoma in these patients. In this study, computed tomography scans prior to alveolar bone grafting are utilized to examine zygomatic symmetry through width, projection, and volume. Methods: Retrospective review was conducted of patients with nonsyndromic unilateral cleft lip and palate with eligible scans prior to alveolar bone grafting at our institution. Anterior zygomatic width, posterior zygomatic width, and zygomatic projection were measured on axial images oriented to the Frankfort horizontal, and three-dimensional digital models of each zygoma were created from the computed tomography data to estimate zygoma volume. These measurements were then compared on cleft and noncleft sides. Results: Twenty-two patients were included in this study. The mean (95% CI) zygoma volume of the cleft side and non-cleft side was 4219 mm3 (3858-4574 mm3) and 4286 mm3 (3932-4660 mm3), respectively, with a mean difference of −67 mm3 ([−402-266 mm3]; P =.704). The zygomatic projection of the cleft side was 43 mm (41-45 mm) in comparison to 47 cm (45-49 mm) for the non-cleft side. Mean difference in zygomatic projection was −4 mm (−5 to −2 mm, P <.001). Mean anterior zygomatic width was greater on the cleft side (42 mm [41-44 mm]) than the non-cleft side (41 mm [40-42 mm]; P =.037). No significant difference was found between posterior zygomatic width of the cleft side (59 mm [58-60 mm]) and non-cleft side (58 mm [57-59 mm]; P =.118). Conclusions: Upon preoperative image analysis in patients with non-syndromic, unilateral lip and palate clefts, zygomatic projection was significantly different between cleft and non-cleft sides. Evaluation of zygoma asymmetry should be included as a component of the physical exam when assessing a patient with unilateral cleft lip and palate, as improved awareness of existing zygomatic asymmetry could aid in setting patient expectations, improving satisfaction/outcomes, and in planning for potential surgical correction. [ABSTRACT FROM AUTHOR]

An open‐label, randomized, crossover study in healthy volunteers compared the reversal of remifentanil‐induced respiratory depression by intranasal (IN) naloxone hydrochloride (4 mg) to IN nalmefene (2.7 mg) (NCT 04828005). Subjects were administered a hypercapnic gas mixture which produces an elevation in minute ventilation (MV), a result of the ventilatory response to hypercapnia. Subjects breathed a hypercapnic gas mixture through a tight‐fitting mask for an initial period of 46 min prior to a series of mask "holidays" introduced to reduce subject discomfort and encourage study completion. Ten minutes after initiating the hypercapnic gas mixture, a remifentanil bolus was administered, and an infusion continued for the study duration. Subjects were administered either naloxone or nalmefene 15 min after initiating the remifentanil infusion and MV monitored for 21 min followed by a mask holiday. Both nalmefene and naloxone produced a time‐dependent reversal of remifentanil‐induced reductions in MV measured 2.5–20 min post administration. At the primary endpoint (5 min post administration), nalmefene increases in MV (5.75 L/min) were nearly twice that produced by naloxone (3.01 L/min) (P <.0009); the point estimate favors nalmefene, demonstrating non‐inferiority and superiority. In this model of opioid‐induced respiratory depression, nalmefene has a more rapid onset of action than naloxone, which required 20 min to achieve a comparable reversal of respiratory depression. Both nalmefene and naloxone were well tolerated by healthy volunteers. This rapid onset of action may prove particularly valuable in an era when over 90% of fatalities are linked to synthetic opioid overdose. [ABSTRACT FROM AUTHOR]

Introduction: Using a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the m-opioid receptor antagonists naloxone and nalmefene. Methods: This translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µopioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment. Results: Following simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene. Conclusion: Simulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl. [ABSTRACT FROM AUTHOR]

Previous work has found that people feel significantly moresatisfied with explanations of psychological phenomena whenthose explanations contain neuroscience information — evenwhen this information is entirely irrelevant to the logic of theexplanations. This seductive allure effect was firstdemonstrated by Weisberg, Keil, Goodstein, Rawson, & Gray(2008), and has since been replicated several times inindependent labs (e.g., Fernandez-Duque, Evans, Christian, &Hodges, 2014; Rhodes, Rodriguez, & Shah, 2014; Weisberg,Taylor, & Hopkins, 2015). However, these studies onlyexamined psychological explanations with addedneuroscience information. The current study thus investigatedthe generality of this effect and found that the seductive allureeffect occurs across several scientific disciplines wheneverthe explanations include reference to smaller components ormore fundamental processes. These data suggest that peoplehave a general preference for reductive explanations.

BackgroundThe development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence.MethodsIn March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders.Results and conclusionsBased on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success.

Play helps children learn language, the authors claim, and they review the evidence for it. They suggest that play benefits children's language development because it incorporates many of the socially interactive and cognitive elements known to enhance language skills. Although much of this evidence proves correlational, they point to a series of recent intervention studies that offer evidence of a key variable linking play and language: adult support. In particular, guided play during which adults scaffold child-initiated learning seems ideal for developing language skills. Based on this evidence, they argue that understanding the efficacy of play for learning requires paying careful attention to the type of play involved and to its results.

Here, the authors report the creation of trion-polaritons in monolayer MoSe2 in an open microcavity exhibiting strong nonlinear interactions, one order of magnitude bigger than those observed for exciton polaritons in GaAs.

Jordan Skolnick,1 Claire Chou,1 John Miklavcic1,2 1Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA; 2School of Pharmacy, Chapman University, Irvine, CA 92618, USACorrespondence: John MiklavcicSchmid College of Science and Technology, Chapman University Tel +1 714-516-5520Fax +1 714-532-6048Email miklavcic@chapman.eduAbstract: Human milk provides optimal infant nutrition for early life development. However, there are situations in which human milk feeding is not the most viable option for infant nutrition. Some factors include maternal illness, lactation insufficiency, storage complications, and time constraints. As a result, modern infant formula has become a substitute or alternative when breastfeeding is not possible or is inadequate for infants. In the optimal design of formula, many factors are considered in creating a product that is safe and provides a nutritional profile either equivalent to human milk or in optimal alignment with infant needs. Human milk composition serves as a reference for infant formula formulation. The purpose of this literature review is to provide a synopsis of recent advances in infant formula research in the past 5 years (2014– 2018). Specifically, the breadth of bioactive components of human milk that are not yet available in infant formulas and dose optimization requirements in full-term infants are reviewed. The nutritional value of infant formulas has been improved by adding functional bioactive ingredients such as choline, strains of probiotics, and prebiotic oligosaccharides. There are considerable variations in the composition of available infant formulas between manufacturers and across different countries. Formulas still generally lack important contents such as antibodies and exosomes that are present in human milk. Some of the adverse health outcomes associated with formula feeding as compared with human milk feeding are attributed to the different composition of the foods. This literature review summarizes the most recent research aimed at advancing infant formula composition to narrow the difference in health outcomes between human milk and formula-fed infants.Keywords: nutrition, neonate, pediatrics, infant formula, ganglioside, miRNA

Background:. Patients with unilateral cleft lip often require secondary procedures due to asymmetric fullness or deficiencies along the mucosal free margin of the upper lip. Here, we describe our technique for mucosal advancement and repair to attain symmetry. Methods:. Maneuvers to obtain vermilion and mucosal height include (1) use of a tailored vermilion flap; (2) supraperiosteal release of the lesser segment; (3) backcut “poker incision” to mobilize the mucosal flap on the lesser segment; (4) transverse release of mucosa across the greater segment; (5) accurate reduction along vermilion-mucosal junction; and (6) bilateral medial mucosal advancement. To examine postoperative outcomes, photographic data were available for 14 patients with unilateral complete cleft lip. The Cleft Lip Component Symmetry Index was then calculated as a ratio of upper lip height on cleft to noncleft sides, where an index of 1 indicates symmetry. Results:. Sixteen consecutive patients underwent unilateral cleft lip repair with this technique over a 3-year period, none of whom have required secondary operations. The symmetry index for 14 of 16 patients was 1.02 ± 0.11 (95% confidence interval [0.96, 1.08], P = 0.56), demonstrating satisfactory upper lip symmetry. Conclusions:. Postoperative asymmetry after unilateral cleft lip repair, particularly along the free margin, continues to be a common problem, necessitating secondary procedures. The technique of mucosal repair merits more careful attention than it has previously received, and here we describe in detail a method that has allowed for improved symmetry.

Background: Colorectal cancer is the third largest cause of cancer-related mortality worldwide. Although current treatments with chemotherapeutics have allowed for management of colorectal cancer, additional novel treatments are essential. Intervening with the metabolic reprogramming observed in cancers called “Warburg Effect,” is one of the novel strategies considered to combat cancers. In the metabolic reprogramming pathway, pyruvate dehydrogenase kinase (PDK1) plays a pivotal role. Identification and characterization of a PDK1 inhibitor is of paramount importance. Further, for efficacious treatment of colorectal cancers, combinatorial regimens are essential. To this end, we opted to identify a PDK1 inhibitor using computational structure-based drug design FINDSITE comb and perform combinatorial studies with 5-FU for efficacious treatment of colorectal cancers. Methods: Using computational structure-based drug design FINDSITE comb , stearic acid (SA) was identified as a possible PDK1 inhibitor. Elucidation of the mechanism of action of SA was performed using flow cytometry, clonogenic assays. Results: When the growth inhibitory potential of SA was tested on colorectal adenocarcinoma (DLD-1) cells, a 50% inhibitory concentration (IC 50 ) of 60 µM was recorded. Moreover, SA inhibited the proliferation potential of DLD-1 cells as shown by the clonogenic assay and there was a sustained response even after withdrawal of the compound. Elucidation of the mechanism of action revealed, that the inhibitory effect of SA was through the programmed cell death pathway. There was increase in the number of apoptotic and multicaspase positive cells. SA also impacted the levels of the cell survival protein Bcl-2. With the aim of achieving improved treatment for colorectal cancer, we opted to combine 5-fluorouracil (5-FU), the currently used drug in the clinic, with SA. Combining SA with 5-FU, revealed a synergistic effect in which the IC 50 of 5-FU decreased from 25 to 6 µM upon combination with 60 µM SA. Further, SA did not inhibit non-tumorigenic NIH-3T3 proliferation. Conclusions: We envision that this significant decrease in the IC 50 of 5-FU could translate into less side effects of 5-FU and increase the efficacy of the treatment due to the multifaceted action of SA. The data generated from the current studies on the inhibition of colorectal adenocarcinoma by SA discovered by the use of the computational program as well as synergistic action with 5-FU should open up novel therapeutic options for the management of colorectal adenocarcinomas.