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Pigmented villonodular synovitis (PVNS) is a rare neoplastic proliferation of large joints, including the knee, with both localized PVNS (LPVNS) and diffuse PVNS (DPVNS) types. DPVNS is known to recur at a higher rate following resection; however, there is little evidence comparing patient-reported outcomes (PROs) between the two types. The purpose of this study was to compare PROs between patients with LPVNS and DPVNS involving the knee 2 years after surgical resection. We hypothesized that DPVNS would have worse 2-year PROs than LPVNS.Sixteen patients who underwent arthroscopic resection of pathology-confirmed PVNS involving the knee were enrolled in a prospective registry. Several PROs, including six Patient-Reported Outcomes Measurement Information System (PROMIS) domains and the International Knee Documentation Committee (IKDC) Subjective Knee Form, were assessed at baseline and at 2 years postoperatively. Mean scores between LPVNS and DPVNS groups were compared using a Wilcoxon exact test, while categorical variables were compared using a Fisher's exact test.Eleven patients (seven LPVNS and four DPVNS) completed both the baseline and 2-year PRO surveys. There were no significant differences in the demographic variables between groups, including age, body mass index, or prior surgical history ( p  < 0.05). There was a trend toward higher mean PRO scores in the DPVNS group at 2 years postoperatively in all measures, despite lower reported baseline levels of activity as measured by Marx Activity Rating Scale (26.3 vs. 76.7, p  = 0.02). The DPVNS group also trended toward more improvement in PROMIS Physical Function (9.7 vs. -2.7), PROMIS Pain Interference (-9.0 vs. -2.5), PROMIS Anxiety (-5.4 vs. -4.4), and IKDC (26.7 vs. 18.9). However, these differences did not reach statistical significance ( p  < 0.05). There were two recurrences in the DPVNS group and none in the LPVNS group.Patients with knee DPVNS do not report worse outcomes 2 years after arthroscopic resection compared with LPVNS patients., Competing Interests: R.J.L.: none declared.B.W.C.: none declared.D.J.V.: general support (the James Lawrence Kernan Hospital Endowment Fund Inc.).L.E.H.: none declared.M.P.K.: none declared.N.L.L.: grants/contracts (VA, OREF, and MSCRF); leadership/faculty roles (AANA Research Committee and JCJP Editorial Board).S.J.M.: support for meetings and/or travel (Arthrex Inc. and Supreme Orthopedic Systems LLC).J.D.P.: none declared.R.F.H.III: general support (the James Lawrence Kernan Hospital Endowment Fund Inc.)., (Thieme. All rights reserved.)

Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = -0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The mechanistic target of rapamycin (mTOR), a serine-threonine-specific kinase, is a cellular energy sensor, integrating growth factor and nutrient signaling. In the collecting duct (CD) of the kidney, the epithelial sodium channel (ENaC) essential in the determination of final urine Na+ losses, has been demonstrated to be upregulated by mTOR, using cell culture and mTOR inhibition in ex vivo preparations. We tested whether CD-principal cell (PC) targeted deletion of mTOR using Cre-lox recombination would affect whole-body sodium homeostasis, blood pressure, and ENaC regulation in mice. Male and female CD-PC mTOR knockout (KO) mice and wild-type (WT) littermates (Cre-negative) were generated using aquaporin-2 (AQP2) promoter to drive Cre-recombinase. Under basal conditions, KO mice showed a reduced (∼30%) natriuretic response to benzamil (ENaC) antagonist, suggesting reduced in vivo ENaC activity. WT and KO mice were fed normal sodium (NS, 0.45% Na+) or a very low Na+ (LS, <0.02%) diet for 7-days. Switching from NS to LS resulted in significantly higher urine sodium losses (relative to WT) in the KO with adaptation occurring by day 2. Blood pressures were modestly (∼5-10 mm Hg) but significantly lower in KO mice under both diets. Western blotting showed KO mice had 20-40% reduced protein levels of all three subunits of ENaC under LS or NS diet. Immunohistochemistry (IHC) of kidney showed enhanced apical-vs.-cellular localization of all three subunits with LS, but a reduction in this ratio for γ-ENaC in the KO. Furthermore, the KO kidneys showed increased ubiquitination of α-ENaC and reduced phosphorylation of the serum and glucocorticoid regulated kinase, type 1 [serum glucocorticoid regulated kinase (SGK1)] on serine 422 (mTOR phosphorylation site). Taken together this suggests enhanced degradation as a consequence of reduced mTOR kinase activity and downstream upregulation of ubiquitination may have accounted for the reduction at least in α-ENaC. Overall, our data support a role for mTOR in ENaC activity likely via regulation of SGK1, ubiquitination, ENaC channel turnover and apical membrane residency. These data support a role for mTOR in the collecting duct in the maintenance of body sodium homeostasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Fluitt, Brown, Scott, Gadicherla and Ecelbarger.)

Di-(2-ethylhexyl) phthalate (DEHP) is a well-known endocrine disruptor and it is ubiquitously distributed in the environment. However, very few studies have investigated the effects of short-term exposure to environmentally realistic concentrations of DEHP during early developmental stages and its chronic effects. This study monitored the long-term effects of transient exposure to DEHP in early life stages (F 0 generation) and its subsequent fertilization success in F 1 generation using Japanese medaka, Oryzias latipes , as model organism. Embryos (4 h post-fertilization, 4 hpf) of Japanese medaka were exposed to 0.001 ppb, 0.1 ppb, or 10 ppb DEHP for 21 days and returned to control water (without DEHP) for maturation (4 months old). At day 9 of the exposure study, mortality was significantly increased in medaka embryos (before hatching) treated with 0.001 ppb and 10 ppb DEHP. Continual exposure of young hatchlings for an additional 12 days (a total of 21 days of exposure) resulted in a significant increase in mortality in fish exposed to 0.001 ppb, 0.1 and 10 ppb DEHP. Significant reduction in egg production was observed in adult female medaka (4 months old) with prior exposure to 0.1 ppb and 10 ppb DEHP for 21 days during early development. Fertilization and hatching success were also significantly reduced in breeding pairs with prior exposure to 0.001 ppb, 0.1 ppb and 10 ppb DEHP during early life stage. Histological analysis of adult male gonads revealed a significant decline in mature sperm count accompanied by an increase in interstitial space in fish exposed to 0.1 ppb and 10 ppb DEHP during early development. Likewise, the amount of vitellogenic (mature) oocytes observed in the ovaries of adult female with transient exposure to 0.1 ppb and 10 ppb DEHP was significantly reduced when compared with the solvent control group. Our data suggest that transient exposure to ultra low concentrations of DEHP during sensitive time windows of development results in irreversible reproductive impairment which may impact fish populations negatively., (© 2020 The Authors.)

Aim: To evaluate personnel involved in scarce drug prioritization and distribution and the criteria used to inform drug distribution during times of shortage among pediatric hematologists/oncologists., Methods: Using the American Society of Pediatric Hematology/Oncology (ASPHO) membership list, a 20 question survey of pediatric hematologists/oncologists was conducted via email to evaluate personnel involved in scarce drug prioritization and distribution and criteria used to inform scarce drug distribution., Results: Nearly 65% of the 191 study respondents had patients directly affected by drug shortages. Most physicians find out about shortages from the pharmacist ( n = 179, 98%) or other doctors ( n = 75, 41%). One third of respondents do not know if there is a program or policy for handling drug shortages at their institution. The pharmacist was the most commonly cited decision maker for shortage drug distribution ( n = 128, 70%), followed by physicians ( n = 109, 60%). One fourth of respondents did not know who makes decisions about shortage drug distribution at their institution. The highest priority criterion among respondents was use of the shortage drug for curative, rather than palliative intent and lowest priority criterion was order of arrival or first-come first-served., Conclusion: Despite pediatric hematology/oncology physicians and patients being heavily impacted by drug shortages, institutional processes for handling shortages are lacking. There is significant disparity between how decisions for distribution of shortage drugs are currently made and how study respondents felt those decisions should be made. An institution-based, and more importantly, a societal approach to drug shortages is necessary to reconcile these disparities., Competing Interests: Conflict-of-interest statement: None.

We report the case of a 45-year-old postpartum female at low risk for coronary artery disease (CAD) who presented with chest pain, a normal electrocardiogram (ECG) and elevation of serial troponin-T levels. Coronary angiography revealed dissection of the first obtuse marginal branch of the left circumflex coronary artery. The patient was treated medically and discharged home safely. Spontaneous coronary artery dissection (SCAD) is a rare condition. In the absence of CAD, it is seen most frequently in young females during the peripartum period. Insult from the hemodynamic stresses during pregnancy and labor combined with the underlying pregnancy related arterial wall changes is the proposed mechanism of dissection in this setting. The normal ECG in the presence of an acute myocardial infarction (AMI) in this case also demonstrates the occasional electrically silent ECG that can occur during acute compromise of the left circumflex coronary artery.

Objective: To estimate if membrane sweeping increases the rate of prelabor rupture of membranes., Methods: This randomized trial of term, uncomplicated pregnancies included 300 patients. Patients were randomly assigned into sweep or no-sweep groups, with patients and delivering providers blinded to group allocation. Only the examining provider in the clinic was unblinded to group allocation. Membranes were then swept or not swept at each weekly visit from 38 weeks of gestation onward, depending on the randomization. Data collected included parity, cervix examination at each visit, estimated gestational age at delivery, rupture of membranes, and maternal or fetal complications., Results: A total of 162 patients were randomly assigned to the membrane sweep group and 138 to the no-sweep group. There was no difference in baseline characteristics or obstetric and neonatal outcomes between the groups. The average gestational age at delivery and induction rate were not different. The overall prelabor rupture of membranes rate was not significantly higher in the membrane sweep group (12% compared with 7%) (P=.19); however, patients with a cervix more than 1 cm dilated at time of membrane sweeping were more likely to have prelabor rupture of membranes if they were in the membrane sweep group (9.1% compared with 0%; relative risk 1.10, 95% confidence interval 1.03-1.18)., Conclusion: No benefit in gestational age at delivery or reduction of postmaturity occurred from membrane sweeping. Although the overall prelabor rupture of membranes rates were similar, patients with membrane sweeping occurring at more than 1 cm cervical dilation may be at increased risk of prelabor rupture of membranes., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00294242., Level of Evidence: I.

Phenolic antioxidants inhibit the induction of inflammatory cytokines by inflammatory stimuli. Here, we analyzed the mechanism by which the antioxidants inhibit LPS-induced expression of tumor necrosis factor alpha (TNFalpha) in macrophages. Hydroquinone and tert-butyl hydroquinone, prototypes of phenolic antioxidants, block lipopolysaccharide (LPS)-induced transcription of TNFalpha and a nuclear factor (NF)-kappaB-mediated reporter gene expression, suggesting NF-kappaB as a target in the inhibition. Analyses of the NF-kappaB activation pathway revealed that the antioxidants do not inhibit LPS-induced activation of the IkappaB kinase activity, degradation of IkappaBalpha, or translocation of activated NF-kappaB into the nucleus, but they do block the formation of NF-kappaB/DNA binding complexes. In vitro experiments showed that the antioxidants do not directly interfere with DNA binding of NF-kappaB. Structure-activity analyses suggest that inhibition of NF-kappaB function involves the redox cycling property of the antioxidants. These findings implicate a redox-sensitive factor important for the binding of NF-kappaB to its DNA recognition sequence as a target molecule in the inhibition of NF-kappaB function and inflammatory cytokine expression by phenolic antioxidants.