A Case of Iatrogenic Cushing's Syndrome following Use of an Over-the-Counter Arthritis Supplement.

Background: Iatrogenic Cushing's syndrome is commonly seen as a complication of chronic steroid use. While most often associated with the use of prescription oral steroids, rare cases result from unintentional steroid exposure. In particular, numerous complementary and alternative medicines have been found to contain steroids not previously known to users. Case Presentation. Here, we present a case of iatrogenic Cushing's syndrome caused by prolonged ingestion of dexamethasone found within an over-the-counter arthritis supplement called Artri King. Conclusion: A thorough history of medication use to include over-the-counter medications and supplements may be required to identify the source of exogenous glucocorticoids in iatrogenic Cushing's syndrome.

Impact of Prepectoral versus Subpectoral Tissue Expander Placement on Outcomes in Delayed-Immediate Autologous Patients Who Undergo Postmastectomy Radiation Therapy.

BACKGROUND: Delayed-immediate autologous (DIA) breast reconstruction is a safe and flexible operative strategy for patients undergoing postmastectomy radiation therapy (PMRT). Traditionally, tissue expanders (TE) are placed in the subpectoral position, but the development of acellular dermal matrix material has led to increased use of prepectoral placement strategies. Our aim was to compare the outcomes of both TE placement strategies in DIA patients who underwent PMRT and determine whether they experienced outcomes similar to those in non-PMRT patients. METHODS: A retrospective analysis of four patient groups (314 total patients) who underwent DIA reconstruction from 2012 to 2019 was performed. Ninety-eight non-PMRT prepectoral (PP), 106 non-PMRT subpectoral (SP), 39 PMRT PP, and 71 PMRT SP patients were compared. Demographics, TE complications, flap complications, and the use of large inferior skin patches were analyzed. RESULTS: A significantly lower percentage of the PMRT PP cohort required large inferior skin patches (30.6% versus 55.7%; P < 0.05) and multiflap procedures (15.4% versus 47.9%; P < 0.001) than the PMRT SP cohort. PMRT ( P < 0.0001), SP placement ( P < 0.05), body mass index ( P < 0.05), autoimmune diseases ( P < 0.05), and bilateral mastectomy ( P < 0.001) were identified as factors predictive of patients requiring a large inferior patch by means of multivariable analysis. More SP patients experienced flap postoperative breast complications compared with PP patients (35.8% versus 12.2%; P < 0.0001). CONCLUSION: DIA patients who undergo PMRT will require more skin and flaps if SP TE placement is chosen over PP TE placement. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Diffusion-weighted MR imaging and utility of ADC measurements in characterizing nerve and muscle changes in diabetic patients on ankle DWI studies: a cross-sectional study.

OBJECTIVE: To evaluate the utility of apparent diffusion coefficient (ADC) measurements from ankle MRI diffusion-weighted imaging (DWI) studies in identifying neuropathic changes in diabetic patients. METHODS: In total, 109 consecutive ankle MRI scans (n = 101 patients) at a single tertiary care county hospital from November 1, 2019, to July 11, 2021, who met the inclusion criteria were identified. Patients were divided into 2 cohorts: diabetic (n = 62) and non-diabetic (n = 39). Demographics, HgbA1c, neuropathy diagnosis, and image quality data were collected. Abductor hallucis (AH) ADC mean and minimum (min) values and posterior tibial nerve (PTN) ADC mean and minimum values were measured. Student t-test and Pearson's correlation coefficient analysis were performed using R. RESULTS: Diabetic patients had significantly higher mean and min ADC values (× 10-3 mm2/s) of the AH muscle (mean: 1.77 vs 1.39, p < 0.001; min: 1.51 vs 1.06, p < 0.001) and PTN (mean: 1.65 vs 1.18, p < 0.001; min: 1.33 vs 0.95, p < 0.001) compared to non-diabetic patients. HgbA1c positively correlated with AH and PTN ADC mean values (AH: p = 0.036; PTN: p = 0.004). CONCLUSION: Our data suggests that an increasing diffusivity of water as quantified by ADC across neuronal and muscular membranes is a consequence of the pathophysiology of the disease. Thus, ankle MRI-DWI studies are useful in identifying neuropathic changes in diabetic patients and quantifying the severity noninvasively. KEY POINTS: • Diabetic patients had significantly higher mean and minimum ADC values of the abductor hallucis muscle and posterior tibial nerve compared to non-diabetic patients. • HgbA1c positively correlated with ADC mean values (AH: p = 0.036; PTN: p = 0.004) suggesting that an increasing diffusivity of water across neuronal and muscular membranes is a consequence of the pathophysiology of diabetic neuropathy. • Ankle MRI DWI can be used clinically to non-invasively identify neuropathic changes due to diabetes mellitus.

Evaluating the Efficacy of Povidone-Iodine Solution Infection Prophylaxis in Immediate Tissue Expander-Based Breast Reconstruction: A Controlled Retrospective Analysis.

Background: There is currently no consensus among plastic surgeons regarding the optimal infection prophylaxis for immediate tissue expander placement following mastectomy. The goal of this study was to determine whether irrigation with 1 L of standard triple antibiotic solution (TAS) can achieve similar infection rates compared to a regimen of 180 mL of TAS with povidone-iodine solution (Betadine) painted on the field immediately prior to the placement of the expander. Methods: The 2 regimens were compared via retrospective propensity matching of all patients of the 2 senior authors who underwent bilateral tissue expander placement immediately following mastectomy with one of 3 mastectomy surgeons from January 2013 to December 2019 (n = 281). Groups were controlled for mastectomy surgeon, mastectomy type, mastectomy weight, age, race, body mass index, diabetes, hypertension, smoking, smoking status, prepectoral/subpectoral placement, use of acellular dermal matrix, operating room time, and duration of postoperative antibiotics. Results: Compared to the Betadine cohort (n = 65), the non-Betadine cohort (n = 65) experienced a similar rate of infections (13.8% vs 12.3%, P = 1.00), including major injections requiring intravenous antibiotic treatment (10.8% vs 9.2%, P = 1.00), after propensity matching. Infections in the non-Betadine cohort did not grow different bacteria on culture, require different antibiotic coverage, or result in prolonged duration of average antibiotic therapy (12.0 days vs 19.3 days, P = .19). Rates of subsequent expander washout and exchange (P = 1.00) and overall complications that required return to the operating room (P = .826) were similar between groups. Conclusion: The addition of Betadine solution to TAS added no benefit to infection prophylaxis or reduction of surgical complications in immediate tissue expander placement procedures.

Historique: Il n'y a pas de consensus entre les plasticiens au sujet de la prophylaxie optimale de l'infection lors de l'installation immédiate d'expanseurs tissulaires après une mastectomie. La présente étude visait à déterminer si l'irrigation à l'aide d'un litre de solution antibiotique triple (SAT) standard peut susciter un taux d'infection semblable à une posologie de 180 mL de SAT au moyen d'une solution de povidone-iode (BetadineMD) appliquée sur le champ opératoire immédiatement avant l'installation de l'expanseur. Méthodologie: Les chercheurs ont comparé les deux posologies par appariement rétrospectif des coefficients de propension de tous les patients des deux auteurs principaux, qui se sont fait installer des expanseurs tissulaires bilatéraux par l'un des trois chirurgiens ayant réalisé les mastectomies entre janvier 2013 et décembre 2019 (n=281). Les groupes ont été contrôlés en fonction du chirurgien ayant réalisé la mastectomie, du type et du poids de la mastectomie, de l'âge, de la race de l'indice de masse corporelle, du diabète, de l'hypertension, du tabagisme, du statut tabagique, de l'installation prépectorale ou subpectorale, du recours à une matrice dermique acellulaire, du temps passé en salle d'opération et de la durée de l'antibiothérapie postopératoire. Résultats: La cohorte qui n'avait pas pris de BetadineMD (n=65) a présenté un taux d'infection semblable à celle qui en avait pris (n=65; 12,3% par rapport à 13,8% p=1,00), y compris des injections majeures nécessitant une antibiothérapie par voie intraveineuse (9,2% par rapport à 10,8%, p=1,00) après l'appariement des coefficients de propension. Les infections dans la cohorte qui n'avait pas pris de BetadineMD n'ont pas révélé de bactéries différentes après la mise en culture, exigé une couverture antibiotique différente, ni entraîné une prolongation de la durée moyenne de l'antibiothérapie (12,0 jours par rapport à 19,3 jours, p=0,19). Le taux d'affaissement et d'échange subséquent des expanseurs (p =1,00) ainsi que le taux de complications globales qui ont entraîné un retour en salle d'opération (p = 0,826) étaient semblables entre les groupes. Conclusion: L'ajout d'une solution de BetadineMD à la SAT n'ajoutait rien à la prophylaxie de l'infection ni à la réduction des complications chirurgicales lors de l'installation immédiate d'expanseurs tissulaires.

Influence of Triple-Negative versus Luminal A Breast Cancer Subtype on Choice of Autologous versus Implant-Based Delayed-Immediate Breast Reconstruction.

BACKGROUND: Triple-negative (TN) and luminal A breast cancer molecular subtypes have divergent clinical and prognostic characteristics for breast cancer patients. Our study aims to compare the reconstructive choice of these two groups from the time they receive a tissue expander (TE) to the time they complete autologous or implant-based breast reconstruction. METHODS: A total of 255 patients who underwent delayed-immediate breast reconstruction with TE placement from 2013 to 2017 diagnosed with either TN (n = 73) or luminal A (n = 182) invasive breast cancer subtype seen by two surgeons at a single institution were identified. Preference of autologous and implant-based reconstruction was analyzed, along with TE complications, race, age, body mass index (BMI), smoking, adjuvant therapy, and comorbidities. RESULTS: There was a significant difference in the choice of implant- or autologous-based reconstruction among these two groups (p < 0.05). A greater proportion of luminal A patients underwent implant-based reconstruction (63.47%) and a greater proportion of TN patients underwent autologous-based reconstruction (53.13%). With regard to TE outcomes, there was no significant difference between the two groups with regard to duration of TE placement by reconstructive type or TE surgical complications. Significantly, more TN patients underwent radiation therapy (p < 0.01) and neoadjuvant chemotherapy (p < 0.0001) than luminal A patients. BMI, comorbidities, radiation therapy, and overall TE complications were identified as predictive factors of patients electing for autologous reconstruction over implants. CONCLUSION: TN breast cancer patients mostly chose autologous-based reconstruction, while luminal A patients chose implant-based reconstruction. Both patient groups carried their TEs for similar duration with similar complication profile. Radiation therapy is likely a major factor in the decision for the type of delayed-immediate reconstruction among this population.

A Crowdsourced Evaluation of Facial Averageness and Attractiveness.

BACKGROUND: Evolutionary psychologists have demonstrated that humans are attracted to individuals who possess average anatomy for the population. OBJECTIVES: The aim of this study was to prove that a composite of average facial features would be more attractive to raters than the cohort utilized to create the composite. METHODS: The male and female cohorts each consisted of 41 standardized frontal-view monochrome photographs, with 1 composite image derived from the other 40 real images. Amazon Mechanical Turk, a widely used crowdsourcing platform, was utilized to obtain ratings of images ranging from 1 to 7, with 1 and 7 being least and most attractive, respectively. The strength of the preference for the composite over the real images was assessed by the difference between the mean rating of the composite and real images. RESULTS: In total, 870 and 876 respondents were recruited to rate the male and female cohorts, respectively. For the male and female cohorts, the composite image was rated significantly higher than the rest of the cohort overall and across all ages, genders, and countries of residence (all P < 0.0001). For both cohorts, the strength of the preference was significantly higher for European respondents and lower for South American and nonbinary respondents (all P < 0.05). CONCLUSIONS: This study reveals that average facial anatomy is perceived as most attractive across all demographics, a finding that is hoped to serve as a stepping stone for further studies leading to objective cosmetic quantifications and integrating evidence-based medicine into aesthetic surgery.

Characterizing conventional ankle MRI findings of nerve and muscle changes in diabetic patients: a case-control study.

BACKGROUND: Foot and ankle amputation is a feared complication of diabetic neuropathy and diabetes mellitus (DM) accounts for 80% of all in-hospital amputations. Magnetic resonance neurography is an effective tool in characterizing neuromuscular sequelae of the disease. However, conventional ankle MRI is more commonly performed and has not been studied to assess neuromuscular changes of DM. OBJECTIVE: The objective is to characterize neuromuscular changes of diabetic patients in a case-control study using conventional ankle MRI. METHODS: Between November 2019 and July 2021, 110 consecutive ankle MRI scans (n = 102 patients) at our county hospital were reviewed and met the inclusion criteria. Patients were divided into two cohorts, diabetic (N = 63) and non-diabetic (N = 39). Demographics, HgbA1c, and reason for MRI study were collected via retrospective chart review. The presence of intramuscular edema-like signal, pattern of the edema, muscle fatty infiltration, and measurements of the cross-sectional area of the posterior, medial, and lateral tibial nerves (PTN, MPN, and LPN) was recorded blinded to the clinical findings by two readers. RESULTS: Muscle edema-like signal was much more likely to be found in DM (odds ratio 19.5, 95% CI 7.0-54.6, p < 0.001). DM also showed increase of 0.87 in the mean grade of muscle fatty infiltration (p < 0.001). There were higher rates of nerve T2 hyperintensity (odds ratio 14.0, 95% CI 3.1-62.7, p < 0.001) and the measured areas of the PTN, MPN, and LPN were also larger in DM compared to their non-diabetic counterparts (PTN: 0.16 cm2 vs. 0.10 cm2, p < 0.01; MPN: 0.09 cm2 vs. 0.05 cm2, p < 0.01; LPN: 0.07 cm2 vs. 0.04 cm2, p < 0.05). CONCLUSION: Conventional ankle MRIs can be used to detect DM-related neuromuscular changes.

Cerebral Salt Wasting Syndrome in the Setting of Hypovolemic Isotonic Hyponatremia: A Case Report.

Cerebral salt wasting syndrome (CSWS) is a condition characterized as the loss of sodium secondarily due to an intracranial process, commonly following the neurosurgical resection of mass lesions. This condition leads to a hypovolemic hypotonic hyponatremia. The identification of this syndrome is often mistaken for syndrome of inappropriate anti-diuretic hormone (SIADH). The treatment for both conditions is vastly different. Given the risk of mortality when balancing sensitivities in hyponatremia and its commonality in clinical scenarios, a distinction is crucial. In this case report, we discuss a patient who presented with CSWS following the surgical resection of a pituitary adenoma. She subsequently developed hypernatremia, treated with DDAVP for the suspicion of diabetes insipidus. Once this was discontinued, she further presented with worsening hyponatremia. This hyponatremia persisted even after the discontinuation of DDAVP, with no significant intervention leading to hypovolemic isotonic hyponatremia, supporting a diagnosis of CSWS. Our findings stress the importance of the proper identification of hyponatremia with guided treatment following neurosurgical intervention and give physicians an insight into the anomalies of hyponatremia that should be further discussed.

Weak binding to the A2RE RNA rigidifies hnRNPA2 RRMs and reduces liquid-liquid phase separation and aggregation.

hnRNPA2 is a major component of mRNA transport granules in oligodendrocytes and neurons. However, the structural details of how hnRNPA2 binds the A2 recognition element (A2RE) and if this sequence stimulates granule formation by enhancing phase separation of hnRNPA2 has not yet been studied. Using solution NMR and biophysical studies, we find that each of the two individual RRMs retain the domain structure observed in complex with RNA but are not rigidly confined (i.e. they move independently) in solution in the absence of RNA. hnRNPA2 RRMs bind the minimal rA2RE11 weakly but at least, and most likely, two hnRNPA2 molecules are able to simultaneously bind the longer 21mer myelin basic protein A2RE. Upon binding of the RNA, NMR chemical shift deviations are observed in both RRMs, suggesting both play a role in binding the A2RE11. Interestingly, addition of short A2RE RNAs or longer RNAs containing this sequence completely prevents in vitro phase separation of full-length hnRNPA2 and aggregation of the disease-associated mutants. These findings suggest that RRM interactions with specific recognition sequences alone do not account for nucleating granule formation, consistent with models where multivalent protein:RNA and protein:protein contacts form across many sites in granule proteins and long RNA transcripts.

Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4.

OBJECTIVE: To determine the clinical and molecular features in patients with amyotrophic lateral sclerosis 4 (ALS4) due to mutations in the senataxin (SETX) gene and to develop tools for evaluating SETX variants. METHODS: Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual-energy x-ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function. RESULTS: We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlates with disease duration (thigh fat fraction R2 = 0.35, p = 0.01; lower leg fat fraction R2 = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than upper extremities (average fat z scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function. INTERPRETATION: We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R-loop levels in patient-derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. ANN NEUROL 2020;87:547-555.

Meta-analysis of Genetic Modifiers Reveals Candidate Dysregulated Pathways in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that has significant overlap with frontotemporal dementia (FTD). Mutations in specific genes have been identified that can cause and/or predispose patients to ALS. However, the clinical variability seen in ALS patients suggests that additional genes impact pathology, susceptibility, severity, and/or progression of the disease. To identify molecular pathways involved in ALS, we undertook a meta-analysis of published genetic modifiers both in patients and in model organisms, and undertook bioinformatic pathway analysis. From 72 published studies, we generated a list of 946 genes whose perturbation (1) impacted ALS in patient populations, (2) altered defects in laboratory models, or (3) modified defects caused by ALS gene ortholog loss of function. Herein, these are all called modifier genes. We found 727 modifier genes that encode proteins with human orthologs. Of these, 43 modifier genes were identified as modifiers of more than one ALS gene/model, consistent with the hypothesis that shared genes and pathways may underlie ALS. Further, we used a gene ontology-based bioinformatic analysis to identify pathways and associated genes that may be important in ALS. To our knowledge this is the first comprehensive survey of ALS modifier genes. This work suggests that shared molecular mechanisms may underlie pathology caused by different ALS disease genes. Surprisingly, few ALS modifier genes have been tested in more than one disease model. Understanding genes that modify ALS-associated defects will help to elucidate the molecular pathways that underlie ALS and provide additional targets for therapeutic intervention.

The SH3 domain of Fyn kinase interacts with and induces liquid-liquid phase separation of the low-complexity domain of hnRNPA2.

Liquid-liquid phase separation of proteins and nucleic acids into membraneless organelles (MLOs) spatially organizes cellular components and reactions. The RNA-binding protein heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) carries mRNA targets in MLOs called transport granules in neurons and oligodendrocytes. At sites of local translation, hnRNPA2 is phosphorylated by the tyrosine protein kinase Fyn, releasing the mRNA for translation. Fyn recognizes targets through its SH3 domain (Fyn-SH3). However, hnRNPA2 lacks canonical SH3-binding sequences, raising the question of how Fyn-SH3 binds hnRNPA2 in phase-separated transport granules. Here, we characterize the structural details of the interaction of the hnRNPA2 low-complexity domain (LC) with Fyn-SH3 and the effect of Fyn-SH3 on hnRNPA2 phase separation. We combined in vitro microscopy and solution NMR spectroscopy to evaluate assembly of hnRNPA2 and Fyn-SH3 into in vitro phase-separated granules and probe the structural details of their interaction. We observed that Fyn-SH3 induces hnRNPA2 LC phase separation and that Fyn-SH3 is incorporated into in vitro hnRNPA2 LC granules. Moreover, we identified hnRNPA2 LC interaction sites on the surface of Fyn-SH3. Our data offer a structural view of how hnRNPA2 LC may interact with Fyn. To our knowledge, our study provides the first example of a single globular domain inducing phase separation of a disordered MLO scaffold protein.

Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation.

hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutated in a syndrome characterized by the degeneration of neurons (bearing features of amyotrophic lateral sclerosis [ALS] and frontotemporal dementia), muscle, and bone. Here we provide a unified structural view of hnRNPA2 self-assembly, aggregation, and interaction and the distinct effects of small chemical changes-disease mutations and arginine methylation-on these assemblies. The hnRNPA2 low-complexity (LC) domain is compact and intrinsically disordered as a monomer, retaining predominant disorder in a liquid-liquid phase-separated form. Disease mutations D290V and P298L induce aggregation by enhancing and extending, respectively, the aggregation-prone region. Co-aggregating in disease inclusions, hnRNPA2 LC directly interacts with and induces phase separation of TDP-43. Conversely, arginine methylation reduces hnRNPA2 phase separation, disrupting arginine-mediated contacts. These results highlight the mechanistic role of specific LC domain interactions and modifications conserved across many hnRNP family members but altered by aggregation-causing pathological mutations.