Single-cell transcriptional analysis of human endothelial colony-forming cells from patients with low VWF levels.

von Willebrand factor (VWF) plays a key role in normal hemostasis, and deficiencies of VWF lead to clinically significant bleeding. We sought to identify novel modifiers of VWF levels in endothelial colony-forming cells (ECFCs) using single-cell RNA sequencing (scRNA-seq). ECFCs were isolated from patients with low VWF levels (plasma VWF antigen levels between 30 and 50 IU/dL) and from healthy controls. Human umbilical vein endothelial cells were used as an additional control cell line. Cells were characterized for their Weibel Palade body (WPB) content and VWF release. scRNA-seq of all cell lines was performed to evaluate for gene expression heterogeneity and for candidate modifiers of VWF regulation. Candidate modifiers identified by scRNA-seq were further characterized with small-interfering RNA (siRNA) experiments to evaluate for effects on VWF. We observed that ECFCs derived from patients with low VWF demonstrated alterations in baseline WPB metrics and exhibit impaired VWF release. scRNA-seq analyses of these endothelial cells revealed overall decreased VWF transcription, mosaicism of VWF expression, and genes that are differentially expressed in low VWF ECFCs and control endothelial cells (control ECs). An siRNA screen of potential VWF modifiers provided further evidence of regulatory candidates, and 1 such candidate, FLI1, alters the transcriptional activity of VWF. In conclusion, ECFCs from individuals with low VWF demonstrate alterations in their baseline VWF packaging and release compared with control ECs. scRNA-seq revealed alterations in VWF transcription, and siRNA screening identified multiple candidate regulators of VWF.

Analysis of Sexual Dimorphic Features of the Jawline and Chin in White Celebrity Faces.

BACKGROUND: The jawline greatly influences facial shape and contributes to facial dimorphism. Analysis of lower facial shape and sexual dimorphic differences in contemporary attractive white faces can advance the goals of lower facial aesthetics and facial gender-affirming surgery (FGAS). METHODS: Full-face, front-view photos of 47 white female and 21 white male celebrities were included from a list generated using GQ magazine's Highest Paid Models issue, People Magazine's Beautiful issue (1991-2022), and celebrities featured on lifestyle websites. Facial landmarks were detected through a facial analysis program using Vision framework and MATLAB. After converting pixel distances to absolute distances, lower face measurements were compared between males and females. RESULTS: The mean lower facial height was 6.08 cm in females and 7.00 cm in males (P value<0.001). The mean bigonial width was 11.21 cm in females and 12.30 cm in males (P value<0.001). The ratio of facial height to lower facial height was 2.98 in females and 2.76 in males (P value<0.001), signifying that symmetry in facial thirds is more prevalent in attractive female faces, while a longer lower face is more common in attractive male faces. The greatest differences in female and male facial contours were at gonial angles and chin. CONCLUSIONS: Analysis of contemporary white celebrity faces demonstrated significantly wider and longer lower facial measurements in males. The overall contour of the female lower face was more tapered at the gonial angles and chin compared to males. These results are important when planning lower facial rejuvenation or FGAS, as lower face size and proportions influence perceived gender and attractiveness.

Effect of Facial Feminization Surgery (FFS) on Eyelid Anatomic Features.

Facial feminization surgery (FFS) improves gender dysphoria. The brows and eyes are crucial in perceived gender, yet brow and eyelid surgeries are relatively underutilized. This study aimed to determine rates of brow and eyelid surgeries as part of FFS and characterize pre- and postoperative periocular features. We conducted a retrospective review to identify all patients with the diagnosis of gender dysphoria who underwent FFS at a single academic institution from 2019 to 2022. Thirty-four patients comprising 38 surgical cases were included. Twelve (35%) eyelid surgeries and 27 (79%) brow lifts were performed. Baseline eyelid measurements did not differ between brow lift and nonbrow lift cases. Those undergoing brow lift and eyelid surgery were older in age (p = 0.022), had a higher rate of negative canthal tilt (p = 0.050), and smaller baseline margin-reflex distance 1 (p = 0.014) than patients who had brow lift alone. Brow lift increased tarsal platform show (p ≤ 0.001) and lash-to-brow distance (p ≤ 0.001), and upper blepharoplasty increased tarsal platform show (p = 0.01). Rates of brow lift are high at our institution, and patients are appropriately selected for eyelid surgery in FFS. Brow lift and upper blepharoplasty can feminize anatomical features when using standards described for cisgender cohorts. The impact of periocular features on gender perception in transgender patients warrants further study.

HSF1, Aging, and Neurodegeneration.

Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome and maintenance of proteostasis as a protective mechanism in response to stress. Research in this particular area has accelerated dramatically over the past three decades following successful isolation, cloning, and characterization of HSF1. The intricate multi-protein complexes and transcriptional activation orchestrated by HSF1 are fundamental processes within the cellular QC machinery. Our primary focus is on the regulation and function of HSF1 in aging and neurodegenerative diseases (ND) which represent physiological and pathological states of dysfunction in protein QC. This chapter presents an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function viz-à-viz age-dependent and neuron-specific vulnerability to ND. We discuss the structural domains of HSF1 with emphasis on the intrinsically disordered regions and note that disease proteins associated with ND are often structurally disordered and exquisitely sensitive to changes in cellular environment as may occur during aging. We propose a hypothesis that age-dependent changes of the intrinsically disordered proteome likely hold answers to understand many of the functional, structural, and organizational changes of proteins and signaling pathways in aging - dysfunction of HSF1 and accumulation of disease protein aggregates in ND included.Structured AbstractsIntroduction: Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome as a cyto-protective mechanism in response to stress. There is cumulative evidence of age-related deterioration of this QC mechanism that contributes to disease vulnerability. OBJECTIVES: Herein we discuss the regulation and function of HSF1 as they relate to the pathophysiological changes of protein quality control in aging and neurodegenerative diseases (ND). METHODS: We present an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function vis-à-vis age-dependent and neuron-specific vulnerability to neurodegenerative diseases. RESULTS: We examine the impact of intrinsically disordered regions on the function of HSF1 and note that proteins associated with neurodegeneration are natively unstructured and exquisitely sensitive to changes in cellular environment as may occur during aging. CONCLUSIONS: We put forth a hypothesis that age-dependent changes of the intrinsically disordered proteome hold answers to understanding many of the functional, structural, and organizational changes of proteins - dysfunction of HSF1 in aging and appearance of disease protein aggregates in neurodegenerative diseases included.

Specific targeting of ovarian tumor-associated macrophages by large, anionic nanoparticles.

Immunotherapy is emerging as one of the most effective methods for treating many cancers. However, immunotherapy can still introduce significant off-target toxicity, and methods are sought to enable targeted immunotherapy at tumor sites. Here, we show that relatively large (>100-nm) anionic nanoparticles administered intraperitoneally (i.p.) selectively accumulate in tumor-associated macrophages (TAMs). In a mouse model of metastatic ovarian cancer, fluorescently labeled silica, poly(lactic-co-glycolic acid), and polystyrene nanoparticles administered i.p. were all found to selectively accumulate in TAMs. Quantifying silica particle uptake indicated that >80% of the injected dose was in TAMs. Particles that were smaller than 100 nm or cationic or administered intravenously (i.v.) showed no TAM targeting. Moreover, this phenomenon is likely to occur in humans because when freshly excised human surgical samples were treated with the fluorescent silica nanoparticles no interaction with healthy tissue was seen but selective uptake by TAMs was seen in 13 different patient samples. Ovarian cancer is a deadly disease that afflicts ∼22,000 women per year in the United States, and the presence of immunosuppressive TAMs at tumors is correlated with decreased survival. The ability to selectively target TAMs opens the door to targeted immunotherapy for ovarian cancer.

Short Stay Management of Locally Advanced Breast Cancer Using Immediate Local Thoracoabdominal Advancement Flap and Enhanced Recovery After Surgery Protocol.

BACKGROUND: Patients with locally advanced invasive breast cancer (LABC) are often considered inoperable, because of the anticipated chest wall defect and need for complex reconstruction. We present a series of patients who underwent mastectomy with extensive skin resection and immediate chest wall reconstruction using a local thoracoabdominal advancement flap (TAAF). All patients were managed after surgery with an ERAS (Enhanced Recovery After Surgery) protocol, to decrease length of stay in hospital. We also present 1 patient who subsequently had satisfactory bilateral delayed breast reconstruction with pedicled latissimus dorsi myocutaneous flaps with prepectoral silicone implants. METHODS: This is a single-surgeon, single-institution retrospective chart review of patients with LABC who underwent mastectomy with skin resection and local TAAF from May 2017 to October 2019, with minimum 3-month follow-up. RESULTS: Thirteen patients met inclusion criteria. Twelve of 13 patients presented with stage III or IV invasive breast cancer, with skin involvement. The mean chest wall defect measured 248.7 cm2 (140-336 cm2; SD, 63.2 cm2), and all were successfully reconstructed with immediate local TAAF. There were no intraoperative complications, but 1 patient developed a postop hematoma. The mean hospital stay was 1.3 nights, with 9 patients (69.2%) staying less than 23 hours and 4 patients (30.8%) staying 2 nights. Nine patients (69.2%) underwent adjuvant therapy, beginning on average 32 days (13-55 days; SD, 13.1 days) after surgery. The mean follow-up time was 13.8 months (4.5-31.6 months; SD, 9.2 months). One patient underwent successful delayed bilateral breast reconstruction with pedicled latissimus dorsi myocutaneous flaps and silicone implant placement. CONCLUSIONS: Our study demonstrates that reconstruction with local TAAF is an outpatient procedure that reliably provides durable, immediate chest wall coverage, after mastectomy in patients with LABC. This technique has a short operative time, low blood loss, and low complication rate, allowing timely adjuvant therapy. Using an ERAS postop protocol we were able to reduce mean hospital stay to 1.3 days. Compared with other described techniques of reconstruction, the additional scars and donor site morbidity are minimal, allowing for delayed breast reconstruction. We also present survival outcomes data on these surgically managed patients.

QUANTITATIVE TOPOGRAPHIC CURVATURE MAPS OF THE POSTERIOR EYE UTILIZING OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: Deformations of the retina such as staphylomas in myopia or scleral flattening in high intracranial pressure can be challenging to quantify with en face imaging. We describe an optical coherence tomography-based method for the generation of quantitative posterior eye topography maps in normal and pathologic eyes. METHODS: Using "whole eye" optical coherence tomography, we corrected for subjects' optical distortions to generate spatially accurate posterior eye optical coherence tomography volumes and created local curvature (KM, mm-1) topography maps for each consented subject. We imaged nine subjects, three normal, two with myopic degeneration, and four with papilledema including one that was imaged longitudinally. RESULTS: Normal subjects mean temporal KM was 0.0923 mm-1, nasal KM was 0.0927 mm-1, and KM local variability was 0.0162 mm-1. In myopic degeneration, subjects KM local variability was higher at 0.0836 mm-1. In papilledema subjects nasal KM was flatter compared with temporal KM (0.0709 vs. 0.0885 mm-1). Mean intrasession KM repeatability for all subjects was 0.0036 mm-1. CONCLUSION: We have developed an optical coherence tomography based method for quantitative posterior eye topography that offers the ability to analyze local curvature with micron scale resolution and offers the potential to help clinicians and researchers characterize subtle, local retinal deformations earlier in patients and follow their development over time.

Unique Techniques Utilizing Rib Grafts for Mandibular Reconstruction in the Pediatric Population.

INTRODUCTION: Pediatric mandibular reconstruction requires a grafted segment of sufficient height and stability to support dental implant placement. Double barreling and mandibular distraction osteogenesis (MDO) after reconstruction are two techniques to achieve this, but they have only been reported with fibular grafts. Rib grafts not only have a lower donor site morbidity than fibular grafts, but they also provide adequate defect coverage in children. As such, we propose their use with either a double barrel technique or with MDO. METHODS: Three pediatric patients underwent mandibular resection and reconstruction using rib grafting. One patient underwent single rib graft placement with subsequent vertical rib distraction. In the remaining two patients, a double-barreled rib technique was used, stacked horizontally in one patient and vertically in the other. RESULTS: From March 2018 to May 2019, three patients with an average age of 11 underwent resection of mandibular tumors or tumor-like lesions followed by immediate reconstruction with rib graft. Due to postoperative wound complications, the graft was completely removed in one patient. The remaining two patients had an uneventful recovery with dental implants planned for one and fully osseointegrated in the other. None of the patients experienced donor-site complications. CONCLUSION: This case series supports the utility and versatility of autogenous rib grafts as a reconstructive option in children. Not only is rib an excellent bone source with low donor site morbidity, but its height can be augmented through MDO or double barreling, facilitating the successful placement of implants and oral rehabilitation in pediatric patients.

Nasoalveolar Molding: Assessing the Burden of Care.

ABSTRACT: Over the last 3 years a shift at our institution has taken place in which patients who would have been offered nasoalveolar molding (NAM) as an adjunct to cleft lip repair (repair after 3 months) have instead undergone early cleft lip repair (ECLR) (2-5 weeks of life) without NAM. This study sought to examine the financial and social impact of the transition away from NAM to ECLR. The efficacy of NAM is limited by patient compliance to a rigorous treatment schedule requiring weekly visits for appliance adjustments. Nasoalveolar molding patients required an average of 11 dental visits, accounting for $2132 in indirect lost income per family. Average direct charges for NAM totaled $12,290 for the hospital, physician, and appliance costs. Over the entire study period, the cumulative direct cost of NAM separate from the surgical repair of the lip was $970,910. Following the introduction of ECLR as an alternative to NAM with standard lip repair, NAM usage decreased by 48% and unilateral cleft lip patients undergoing NAM decreased by 86%. Those diverted from NAM to ECLR resulted in a decreased healthcare cost burden of $368,700 ($111,727 per year). In addition to the time burden, the financial burden of NAM is significant. Early cleft lip repair without NAM is more cost effective. Nasoalveolar molding has significantly decreased utilization since the implementation of ECLR. We believe that ECLR, with increased experience, long-term data, and increased awareness, has the potential to decrease the burden of health care costs in the United States.

Assessing the Safety of a Novel Neonatal Anesthesia Protocol: A Review of 101 Patients With Early Cleft Lip Repair.

PURPOSE: Our study introduces a novel anesthetic protocol for neonates without using volatile agents with the goal to minimize potentially neurotoxic and pro-apoptotic agents. The authors evaluated the short-term safety and efficacy of our anesthetic protocol in patients undergoing early cleft lip repair (ECLR). METHODS: A retrospective review of ECLR patients who underwent repair before 2.5 months of age within the last 4.3 years was performed. This sample was comprised of 2 groups, those who received either a standard volatile gas-based regimen or a dexmedetomidine-based neonatal anesthetic protocol (DBNAP). Patient demographics, medication dosing, anesthetic time (induction to extubation), major and minor complications, and medication side effects were compared between the 2 cohorts. RESULTS: A total of 101 patients underwent ECLR. All patients were American Society of Anesthesiologists class 1 or 2. Mean age at surgery was 31 ±â€Š13 days and mean anesthetic time was 179 ±â€Š36 minutes. DBNAP was used in 65 patients while the standard anesthetic protocol was used in 36 patients. Patient weight was significantly lower in the DBNAP group (4.01 ±â€Š0.61 versus 4.38 ±â€Š0.72 kg, P  = 0.007). There were no significant differences between the 2 cohorts when comparing anesthetic time, emergence time, complication rate, or medication side effects. CONCLUSION: For patients undergoing ECLR, DBNAP is perioperatively equivalent to the anesthetic standard of care, demonstrating no major complications and acceptable rates of minor complications and medication side effects.

Topography and pachymetry maps for mouse corneas using optical coherence tomography.

The majority of the eye's refractive power lies in the cornea, and pathological changes in its shape can affect vision. Small animal models offer an unparalleled degree of control over genetic and environmental factors that can help elucidate mechanisms of diseases affecting corneal shape. However, there is not currently a method to characterize the corneal shape of small animal eyes with topography or pachymetry maps, as is done clinically for humans. We bridge this gap by demonstrating methods using optical coherence tomography (OCT) to generate the first topography and pachymetry (thickness) maps of mouse corneas. Radii of curvature acquired using OCT were validated using calibration spheres as well as in vivo mouse corneas with a mouse keratometer. The resulting topography and pachymetry maps are analogous to those used diagnostically in clinic and potentially allow for characterization of genetically modified mice that replicate key features of human corneal disease.

Longitudinal changes in symptom-based female and male LUTS clusters.

AIMS: Lower urinary tract symptoms (LUTS) are diverse in type and variable in severity. We examined symptom change within the Symptoms of the Lower Urinary Tract Dysfunction Research Network (LURN) Observational Cohort study identified clusters over time and tested associations with treatments received. METHODS: Patient-reported LUTS and treatment data were collected at multiple time points between baseline and 12 months from the LURN Observational Cohort study. LUTS severity scores were calculated to summarize changes in symptom reporting over time in previously identified LURN clusters. Repeated measures linear regression models tested adjusted associations between cluster membership and severity scores. RESULTS: Four-hundred seventeen men and 396 women were classified into improved, unchanged, and worsened symptoms between baseline and 12 months (men: 44.1%, 40.5%, and 15.3%; women: 55.8%, 33.1%, 11.1%, respectively). Improvement in LUTS severity scores varied by cluster (estimated adjusted mean change from baseline range: -.04 change in standard deviations of severity scores (ΔSD) to -.67 ΔSD). Prostate surgery was associated with improved severity scores (-.63 ΔSD) in men, while stress incontinence surgery was associated with improved severity scores (-.88 ΔSD) in women. CONCLUSION: Symptom improvement varied by cluster indicating response to therapy differs amongst subtypes of patients with LUTS. The differential improvement of patients in clusters suggests mechanistic differences between clusters and may aid in selecting more targeted treatments in the future.

Temporal Fat Grafting in Children With Craniofacial Anomalies.

BACKGROUND: Fat grafting is a common adjunct procedure used to treat temporal fat hollowing in children with craniofacial anomalies. The goal of this study was to assess the surgical and aesthetic outcomes of this procedure. METHODS: We retrospectively reviewed patients who underwent temporal fat grafting at a single tertiary pediatric craniofacial center. The surgical outcome was assessed based on intraoperativeand 30-day postoperative complication rates. The aesthetic outcome was assessed by 3 independent investigators using a 3-point grading scale for preoperative temporal hollowing severity (1 = mild, 2 = moderate, 3 = severe) and a 5-point scale for postoperative improvement (0 = no, 1 = mild, 2 = moderate, 3 = significant, and 4 = complete improvement). RESULTS: Forty-three patients met inclusion criteria. Twenty-seven (63%) were male, 39 (91%) had a history of craniosynostosis, and 18 (42%) had associated syndromes. The mean age at fat grafting was 9.9 years (2.7-20.4, SD = 5.5) with an average follow-up time of 1.6 years (0-5.8, SD = 1.8). The average volume of fat grafted was 8.6 mL (0-30, SD = 5.9) to the right temporal region and 8.6 mL (0-30, SD = 5.8) to the left. There were no intraoperative or postoperative complications. The mean improvement score was 2.9 (1-4, SD = 0.7), demonstrating that most patients experienced moderate to significant improvement. Multiple linear regression analysis demonstrated that syndromic status had a negative impact on the aesthetic outcome (P < 0.001). CONCLUSIONS: These findings demonstrate that fat grafting is an effective method to treat temporal hollowing in children with craniofacial anomalies with no perioperative complications.

Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction.

PolyQ-expanded huntingtin (mHtt) variants form aggregates, termed inclusion bodies (IBs), in individuals with and models of Huntington's disease (HD). The role of IB versus diffusible mHtt in neurotoxicity remains unclear. Using a ponasterone (PA)-inducible cell model of HD, here we evaluated the effects of heat shock on the appearance and functional outcome of Htt103QExon1-EGFP expression. Quantitative image analysis indicated that 80-90% of this mHtt protein initially appears as "diffuse" signals in the cytosol, with IBs forming at high mHtt expression. A 2-h heat shock during the PA induction reduced the diffuse signal, but greatly increased mHtt IB formation in both cytosol and nucleus. Dose- and time-dependent mHtt expression suggested that nucleated polymerization drives IB formation. RNA-mediated knockdown of heat shock protein 70 (HSP70) and heat shock cognate 70 protein (HSC70) provided evidence for their involvement in promoting diffuse mHtt to form IBs. Reporter gene assays assessing the impacts of diffuse versus IB mHtt showed concordance of diffuse mHtt expression with the repression of heat shock factor 1, cAMP-responsive element-binding protein (CREB), and NF-κB activity. CREB repression was reversed by heat shock coinciding with mHtt IB formation. In an embryonic striatal neuron-derived HD model, the chemical chaperone sorbitol similarly promoted the structuring of diffuse mHtt into IBs and supported cell survival under stress. Our results provide evidence that mHtt IB formation is a chaperone-supported cellular coping mechanism that depletes diffusible mHtt conformers, alleviates transcription factor dysfunction, and promotes neuron survival.

The Comprehensive Assessment of Self-Reported Urinary Symptoms: A New Tool for Research on Subtypes of Patients with Lower Urinary Tract Symptoms.

PURPOSE: To improve the potential for finding clinically important subtypes of patients with lower urinary tract symptoms we developed the CASUS (Comprehensive Assessment of Self-reported Urinary Symptoms). We used it to present data on the experiences of lower urinary tract symptoms in treatment seeking women and men from a prospective observational cohort. MATERIALS AND METHODS: We created an initial list of lower urinary tract symptoms that were confirmed in 22 qualitative interviews with providers, and 88 qualitative interviews with care seeking and noncare seeking women and men with lower urinary tract symptoms. Items from extant measures were adopted and revised, and new items were developed. All items were evaluated for understanding in 64 cognitive interviews. Items were administered to a prospective cohort of female and male patients with lower urinary tract symptoms who were seeking care. Analyses were done to describe item response distributions and correlations among item responses separately for women and men. RESULTS: A total of 444 males and 372 females provided responses to the CASUS. Several sets of items showed different relationships for women compared to men. In particular the associations between sensation related items and incontinence related items were generally positive among females but often negative among males. CONCLUSIONS: After using an intensive development process the CASUS addresses a wide range of lower urinary tract symptoms. It should help identify clinically important subtypes of patients. Further, item collection can provide the foundation for shorter measures for use in the clinic and as trial end points.

Patient Characteristics Associated with More Bother from Lower Urinary Tract Symptoms.

PURPOSE: Some patients continue to have bothersome lower urinary tract symptoms despite treatment. We examined characteristics associated with bother from lower urinary tract symptoms in a prospective cohort. MATERIALS AND METHODS: In this 1-year prospective, observational cohort study we obtained data on patients with lower urinary tract symptoms who were seeking care at a total of 6 tertiary care centers in the United States. Participants answered the AUA-SI (American Urological Association Symptom Index) global urinary bother question at study entry and 12 months later. Multilevel logistic and linear regression was used to identify factors associated with worsening bother and bother at 12 months, respectively. RESULTS: Of the 756 participants 121 (16%) had worsened lower urinary tract symptom bother during the study period. When adjusted for other variables, worsened lower urinary tract symptom bother was more likely among men who were nonwhite (OR 1.79, 95% CI 0.94-3.40) or who had diabetes (OR 1.68, 95% CI 0.86-3.27) and among women with diabetes (OR 1.77, 95% CI 0.85-3.67), prior treatment of lower urinary tract symptoms (OR 2.58, 95% CI 1.22-5.46) or a higher depression level (OR 1.29, 95% CI 1.10-1.52). Baseline factors associated with more severe bother at 12 months in men included more severe bother at baseline, nonwhite race, worse urinary frequency and incontinence, and higher levels of stress (p <0.05). Among women more severe bother at baseline, urinary urgency and frequency, and worse physical function were associated with more severe bother at 12 months. CONCLUSIONS: Urinary symptom severity at baseline, race, depression and psychological stress were associated with the bother of lower urinary tract symptoms in a prospective cohort of men and women treated at tertiary care facilities. These findings may inform the clinical care of patients with bothersome lower urinary tract symptoms and direct providers to better prognosticate for patients with challenging lower urinary tract symptoms cases.

Breast implant-associated anaplastic large cell lymphoma, a systematic review and in-depth evaluation of the current understanding.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a T-cell neoplasm that arises in the capsule around breast implants. While an association with implants has been proposed, no causal link has been identified and the pathophysiology and natural history of BIA-ALCL remain unknown. A literature review of 391 articles was performed to assess the current understanding of BIA-ALCL and to provide a balanced and unbiased view of the current controversy surrounding the disease.

Androgen exposure potentiates formation of intratubular communities and renal abscesses by Escherichia coli.

Females across their lifespan and certain male populations are susceptible to urinary tract infections (UTI). The influence of female vs. male sex on UTI is incompletely understood, in part because preclinical modeling has been performed almost exclusively in female mice. Here, we employed established and new mouse models of UTI with uropathogenic Escherichia coli (UPEC) to investigate androgen influence on UTI pathogenesis. Susceptibility to UPEC UTI in both male and female hosts was potentiated with 5α-dihydrotestosterone, while males with androgen receptor deficiency and androgenized females treated with the androgen receptor antagonist enzalutamide were protected from severe pyelonephritis. In androgenized females and in males, UPEC formed dense intratubular, biofilm-like communities, some of which were sheltered from infiltrating leukocytes by the tubular epithelium and by peritubular fibrosis. Abscesses were nucleated by small intratubular collections of UPEC first visualized at five days postinfection and briskly expanded over the subsequent 24 hours. Male mice deficient in Toll-like receptor 4, which fail to contain UPEC within abscesses, were susceptible to lethal dissemination. Thus, androgen receptor activation imparts susceptibility to severe upper-tract UTI in both female and male murine hosts. Visualization of intratubular UPEC communities illuminates early renal abscess pathogenesis and the role of abscess formation in preventing dissemination of infection. Additionally, our study suggests that androgen modulation may represent a novel therapeutic route to combat recalcitrant or recurrent UTI in a range of patient populations.

Bowel function, sexual function, and symptoms of pelvic organ prolapse in women with and without urinary incontinence.

AIMS: Bowel symptoms, pelvic organ prolapse, and sexual dysfunction are common, but their frequency among women with lower urinary tract symptoms (LUTS) has not been well described. Our aims were to describe pelvic floor symptoms among women with and without urinary incontinence (UI) and among subtypes of UI. METHODS: Women with LUTS seeking care at six U.S. tertiary care centers enrolled in prospective cohort study were studied. At baseline, participants completed the Pelvic Floor Distress Inventory (PFDI-20), Pelvic Organ Prolapse/Incontinence Sexual Questionnaire (PISQ-IR), and PROMIS GI Diarrhea, Constipation, and Fecal Incontinence Scales. RESULTS: Mean age among the 510 women was 56.4 ± 14.4 years. Women who reported UI (n = 420) had more diarrhea and constipation symptoms (mean scores 49.5 vs 46.2 [P = 0.01] and 51.9 vs 48.4 [P < 0.01], respectively) at baseline. Among sexually active women, mean PISQ-IR subscale scores were lower among those with UI (condition specific: 89.8 vs 96.7, P < 0.01; condition impact: 79.8 vs 92.5, P < 0.01). Women with mixed urinary incontinence (MUI) (n = 240) reported more prolapse symptoms, fecal incontinence, and worse sexual function compared to those with stress urinary incontinence (SUI) and urgency urinary incontinence (UUI). CONCLUSIONS: Women presenting with LUTS with UI reported significantly worse constipation, diarrhea, fecal incontinence, and sexual function compared to women without UI. In women with UI, sexual function and pelvic organ prolapse (POP) symptoms were worse in those with MUI compared to SUI and UUI.

Repeat Prostate Biopsy Practice Patterns in a Statewide Quality Improvement Collaborative.

PURPOSE: We examined rebiopsies in MUSIC (Michigan Urological Surgery Improvement Collaborative) to understand adherence to guidelines recommending repeat prostate biopsy in patients with multifocal high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation. MATERIALS AND METHODS: We analyzed data on men undergoing repeat biopsy, practice patterns and cancer detection rates. Multivariate regression modeling was used to calculate the proportion of patients undergoing rebiopsy. We used claims data to validate the treatment classification in MUSIC. To understand reasons for not performing rebiopsy we reviewed records of a sample of patients with atypical small acinar proliferation. RESULTS: We identified 5,375 men with a negative biopsy, of whom 411 (7.6%) underwent repeat biopsy. In 718 men with high grade prostatic intraepithelial neoplasia, 350 with atypical small acinar proliferation and 587 with high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation or atypical small acinar proliferation alone at initial biopsy the rebiopsy rate was 20.7%, 42.5% and 55.6%, respectively. The adjusted proportion of patients with rebiopsy in each practice ranged from 0% to 17.2% (p <0.001). The overall cancer detection rate at rebiopsy was 39.3%. It was highest after atypical small acinar proliferation (adjusted probability 0.39, 95% CI 0.30-0.48), and after high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation (adjusted probability 0.50, 95% CI 0.35-0.65). The greatest Gleason 7 or greatest detection rate of 41.1% was found in patients with high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation. Chart review revealed that 45.5% of patients with atypical small acinar proliferation underwent prostate specific antigen testing instead of rebiopsy while 36% failed to undergo rebiopsy despite a recommendation. CONCLUSIONS: Rebiopsy rates vary in Michigan practices with relatively low use in men with high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation or atypical small acinar proliferation alone. Quality improvement strategies should target patients with atypical small acinar proliferation and high grade prostatic intraepithelial neoplasia as they have the highest likelihood of cancer detection.