Techniques in Management of Cholesteatoma: Subtotal Petrosectomy; Blind Sac Closure.

Subtotal petrosectomy plays a critical role in the management of late-stage cholesteatoma. This procedure is indicated either for recurrent cholesteatoma that has failed prior surgical therapies or when life-threatening infectious complications are present. By exenterating all diseased areas of the temporal bone and closing off the ear canal, subtotal petrosectomy has a much greater chance of removing cholesteatoma and preventing recidivism.

Emulating the Delivery of Sawtooth Proton Arc Therapy Plans on a Cyclotron-Based Proton Beam Therapy System.

Purpose: To evaluate and compare the deliverability of 'sawtooth' proton arc therapy (PAT) plans relative to static intensity modulated proton therapy (IMPT) at a cyclotron-based clinical facility. Methods: The delivery of single and dual arc Sawtooth PAT plans for an abdominal CT phantom and multiple clinical cases of brain, head and neck (H&N) and base of skull (BoS) targets was emulated under the step-and-shoot and continuous PAT delivery regimes and compared to that of a corresponding static IMPT plan. Results: Continuous PAT delivery increased the time associated with beam delivery and gantry movement in single/dual PAT plans by 4.86/7.34 min (brain), 7.51/12.40 min (BoS) and 6.59/10.57 min (H&N) on average relative to static IMPT. Step-and-shoot PAT increased this delivery time further by 4.79 min on average as the delivery was limited by gantry motion. Conclusions: The emulator can approximately model clinical sawtooth PAT delivery but requires experimental validation. No clear benefit was observed regarding beam-on time for sawtooth PAT relative to static IMPT.

Evaluation of a Novel Emergency General Surgery Handover: A Prospective Feasibility Study.

INTRODUCTION: High-quality health information handovers are critical to optimal patient care and trainee education. The purposes of this study were to assess the feasibility of implementing an emergency general surgery (EGS) morning handover and to explore its impact upon markers of clinical care. METHODS: This prospective feasibility study was conducted at a single academic tertiary-care medical center following implementation of a novel EGS morning handover process. We assessed organizational perspective through a two-part anonymous survey delivered to the EGS service staff (n = 29) and collected feasibility metrics daily at the morning handover meetings. Exploratory clinical metrics of quality improvement were compared between parallel 5-month periods preimplementation and postimplementation of the handover. Data were compared by descriptive statistics. RESULTS: One hundred and seventeen patients from March 1, 2022, to July 31, 2022, and 185 patients from March 1, 2023, to July 31, 2023, were identified prehandover and posthandover implementation, respectively, with an increase in time to operating room posting by 49% (95% confidence interval [CI]: 1.03-2.14) and no statistically significant change in length of stay. The average duration of the formalized EGS morning handover was 14 min (95% CI: 12:18-15:42) having an average of 12 questions asked (95% CI: 9.98-14.02) and an average attendance of 70% from essential personnel. Eighty-four percent of postimplementation survey responses indicated positive regard toward the new EGS handover. CONCLUSIONS: The implementation of an EGS morning handover is feasible, necessitating further studies to define the impact of the EGS morning handover upon clinical outcomes.

Clinical and Biological Perspectives on Noncanonical Esophageal Squamous Cell Carcinoma in Rare Subtypes.

Esophageal squamous cell carcinoma (ESCC) remains the most common malignancy of the esophagus worldwide. Environmental and lifestyle exposures such as alcohol and tobacco have been well defined in the pathogenesis of ESCC, acting in concert with cell intrinsic epigenomic, genomic and transcriptomic changes. However, a variety of nonenvironmental etiologies including Fanconi anemia, lichen planus, chronic mucocutaneous candidiasis, esophageal epidermoid metaplasia, epidermolysis bullosa, tylosis, esophageal atresia, and achalasia receive minimal attention despite a high risk of ESCC in these diseases. The goal of this review was to promote clinical recognition and suggest a diagnostic framework for earlier detection of ESCC in patients with these rare diseases. In all the discussed conditions, a change in symptoms should trigger a prompt endoscopic evaluation, and endoscopic surveillance programs with advanced imaging techniques and chromoendoscopy should be considered. Moreover, we leverage the convergence of these diseases on ESCC to identify common mechanisms underlying malignant transformation including aberrant proliferation, mucosal barrier dysfunction, increased inflammation, and genome instability. In this study, we summarize the clinical presentation, pathologic findings, potential screening strategies, and common mechanisms of malignant transformation associated with these rare diseases that drive ESCC.

What Do People Want to Know About Cochlear Implants: A Google Analytic Study.

OBJECTIVE: Identify the questions most frequently asked online about cochlear implants (CI) and assess the readability and quality of the content. METHODS: A Google search engine observational study was conducted via a search response optimization (SEO) tool. The SEO tool listed the questions generated by Google's "People Also Ask" (PAA) feature for the search queries "cochlear implant" and "cochlear implant surgery." The top 50 PAA questions for each query were conceptually classified. Sourced websites were evaluated for readability, transparency and information quality, and ability to answer the question. Readability and accuracy in answering questions were also compared to the responses from ChatGPT 3.5. RESULTS: The PAA questions were commonly related to technical details (21%), surgical factors (18%), and postoperative experiences (12%). Sourced websites mainly were from academic institutions, followed by commercial companies. Among all types of websites, readability, on average, did not meet the recommended standard for health-related patient education materials. Only two websites were at or below the 8th-grade level. Responses by ChatGPT had significantly poorer readability compared to the websites (p < 0.001). These online resources were not significantly different in the percentage of accurately answering the questions (websites: 78%, ChatGPT: 85%, p = 0.136). CONCLUSIONS: The most searched topics were technical details about devices, surgical factors, and the postoperative experience. Unfortunately, most websites did not meet the ideal criteria of readability, quality, and credibility for patient education. These results highlight potential knowledge gaps for patients, deficits in current online education materials, and possible tools to better support CI candidate decision-making. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Investigating quantitative histological characteristics in renal pathology using HistoLens.

HistoLens is an open-source graphical user interface developed using MATLAB AppDesigner for visual and quantitative analysis of histological datasets. HistoLens enables users to interrogate sets of digitally annotated whole slide images to efficiently characterize histological differences between disease and experimental groups. Users can dynamically visualize the distribution of 448 hand-engineered features quantifying color, texture, morphology, and distribution across microanatomic sub-compartments. Additionally, users can map differentially detected image features within the images by highlighting affected regions. We demonstrate the utility of HistoLens to identify hand-engineered features that correlate with pathognomonic renal glomerular characteristics distinguishing diabetic nephropathy and amyloid nephropathy from the histologically unremarkable glomeruli in minimal change disease. Additionally, we examine the use of HistoLens for glomerular feature discovery in the Tg26 mouse model of HIV-associated nephropathy. We identify numerous quantitative glomerular features distinguishing Tg26 transgenic mice from wild-type mice, corresponding to a progressive renal disease phenotype. Thus, we demonstrate an off-the-shelf and ready-to-use toolkit for quantitative renal pathology applications.

Effect of drug therapies on self-reported chemosensory outcomes after COVID-19.

Objective: The aim of this study was to assess the relative efficacy of medications used following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on self-reported alterations in taste and/or smell function. Methods: Seven hundred and fourteen persons with self-reported postcoronavirus disease 2019 (post-COVID-19) chemosensory disorders were personally interviewed regarding specific medications they were administered following the acute phase of the disease. The dependent measure-self-reported total recovery of chemosensory symptoms-was subjected to stepwise logistic regression. Independent predictors included demographic and clinical variables, in addition to specific medications used to mitigate disease symptoms (i.e., systemic corticosteroids, oseltamivir, vitamin C, ibuprofen, hydroxychloroquine, azithromycin, ivermectin, nitazoxanide, anticoagulants, and zinc). Results: The median time between COVID-19 symptom onset and the interviews was 81 days (interquartile range: 60-104). Of the 714 subjects, 249 (34.9%) reported total recovery of their chemosensory function; 437 (61.2%) had at least one treatment since the beginning of the disease. Women and those with more comorbidities had undergone more treatments. The recovery rates of the treated and nontreated groups did not differ significantly. Nonetheless, respondents who had used nitazoxanide tended to have a higher rate of self-reported taste or smell recovery. Those who took oral zinc were less likely to improve. Conclusions: No medication employed during the first months after SARS-CoV-2 infection had a clear positive effect on returning self-reported smell or taste function to normal, although nitrazoxide trended in a positive direction. Oral zinc had a negative effect on the reported recovery of these senses.

Achieving an Optimal Outcome After Stage 1 Palliation for Hypoplastic Left Heart Syndrome and Variants: Frequency, Associated Factors, and Subsequent Outcomes.

BACKGROUND: We sought to measure frequency of achieving an optimal outcome after stage 1 palliation (S1P) for hypoplastic left heart syndrome and variants, determine factors associated with optimal outcomes, and compare outcomes after stage 2 palliation (S2P) using the National Pediatric Cardiology Quality Improvement Collaborative database (2008-2016). METHODS AND RESULTS: This is a retrospective cohort study with optimal outcome defined a priori as meeting all of the following: (1) discharge after S1P in <19 days (top quartile), (2) no red flag or major event readmissions before S2P, and (3) performing S2P between 90 and 240 days of age. Optimal outcome was achieved in 256 of 2182 patients (11.7%). Frequency varied among centers from 0% to 25%. Factors independently associated with an optimal outcome after S1P were higher gestational age (odds ratio [OR], 1.1 per week [95% CI, 1.0-1.2]; P=0.02); absence of a genetic syndrome (OR, 2.5 [95% CI, 1.2-5]; P=0.02); not requiring a post-S1P catheterization (OR, 2.7 [95% CI, 1.5-4.8]; P=0.01), intervention (OR, 1.5 [95% CI, 1.1-2]; P=0.006), or a procedure (OR, 4.5 [95% CI, 2.8-7.1]; P<0.001) before discharge; and not having a post-S1P complication (OR, 2.7 [95% CI, 1.9-3.7]; P<0.001). Those with an optimal outcome after S1P had improved S2P outcomes including shorter length of stay, less ventilator days, shorter bypass time, and fewer postoperative complications. CONCLUSIONS: Identifying patients at lowest risk for poor outcomes during the home interstage period could shift necessary resources to those at higher risk, alter S2P postoperative expectations, and improve quality of life for families at lower risk.

Bichectomy Surgery and EMG Masticatory Muscles Function in Adult Women: A Longitudinal Study.

AIM: This longitudinal study aimed to evaluate the electromyographic activity of the masseter and temporal muscles in adult women who underwent buccal fat removal. MATERIALS AND METHODS: The sample consisted of 20 healthy adult women with no temporomandibular dysfunction and normal occlusion, who were assessed before, 30, and 60 days after the surgery. The electromyographic signal of the masseter and temporal muscles was captured through mandibular tasks including rest, protrusion, right and left laterality, and maximum voluntary contraction with and without parafilm. The results obtained were tabulated and the Shapiro-Wilk normality test was performed, which indicated a normal distribution. Statistical analysis was performed using the repeated measures test (p < 0.05). RESULTS: Significant differences were observed between time periods in maximum voluntary contraction for the left masseter muscle (p = 0.006) and in maximum voluntary contraction with parafilm for the right temporal (p = 0.03) and left temporal (p = 0.03) muscles. CONCLUSION: Bichectomy surgery did not modify the electromyographic activity of the masseter and temporal muscles during the rest task but may have influenced variations in the electromyographic signal during different mandibular tasks after 60 days of surgery, suggesting compensatory adaptations and functional recovery. CLINICAL SIGNIFICANCE: Understanding the impact of buccal fat removal surgery on the stomatognathic system function provides insights into postoperative functional recovery and potential compensatory adaptations, guiding clinical management and rehabilitation strategies for patients undergoing such procedures. How to cite this article: Cardoso AHDLS, Palinkas M, Bettiol NB, et al. Bichectomy Surgery and EMG Masticatory Muscles Function in Adult Women: A Longitudinal Study. J Contemp Dent Pract 2024;25(3):207-212.

Impact of Combinatorial Histone Modifications on Acetyllysine Recognition by the ATAD2 and ATAD2B Bromodomains.

The ATPase family AAA+ domain containing 2 (ATAD2) protein and its paralog ATAD2B have a C-terminal bromodomain (BRD) that functions as a reader of acetylated lysine residues on histone proteins. Using a structure-function approach, we investigated the ability of the ATAD2/B BRDs to select acetylated lysine among multiple histone post-translational modifications. The ATAD2B BRD can bind acetylated histone ligands that also contain adjacent methylation or phosphorylation marks, while the presence of these modifications significantly weakened the acetyllysine binding activity of the ATAD2 BRD. Our structural studies provide mechanistic insights into how ATAD2/B BRD-binding pocket residues coordinate the acetyllysine group in the context of adjacent post-translational modifications. Furthermore, we investigated how sequence changes in amino acids of the histone ligands impact the recognition of an adjacent acetyllysine residue. Our study highlights how the interplay between multiple combinations of histone modifications influences the reader activity of the ATAD2/B BRDs, resulting in distinct binding modes.

Prevention of post-operative adhesions: Model development and pilot outcomes of human placental stem cell-based interventions.

BACKGROUND: Abdominal adhesions are the most common surgical complication and without reliable prophylactics. This study presents a novel rat model for abdominal adhesions and reports pilot results of human placental stem cell (hPSC)-based therapies. METHODS: Forty-four (n = 44) male Sprague-Dawley rats (250-350 g) were used in the experiment. Of these, thirty-eight (n = 38) were included in a preliminary data set to determine a minimum treatment effect. Adhesions were created in a reproducible model to the abdominal wall and between organs. Experimental groups included the control group (Model No Treatment, MNT), Plasmalyte A (Media Alone, MA, 10 mL), hPSC (5 × 106 cells/10 mL Plasmalyte A), hPSC-CM (hPSC secretome, conditioned media) in 10 mL Plasmalyte A, Seprafilm™ (Baxter, Deerfield, IL), and sham animals (laparotomy only). Treatments were inserted intraperitoneally (IP) and the study period was 14 days post-operation. Results are reported as the difference between means of an index statistic (AIS, Animal Index Score) and compared by ANOVA with pairwise comparison. RESULTS: The overall mean AIS was 23 (SD 6.16) for the MNT group with an average of 75% of ischemic buttons involved in abdominal adhesions. Treatment groups MA (mean overall AIS 17.33 SD 6.4), hPSC (mean overall AIS 13.86 SD 5.01), hPSC-CM (mean overall AIS 13.13 SD 6.15), and Seprafilm (mean overall AIS 13.43 SD 9.11) generated effect sizes of 5.67, 9.14, 9.87, and 9.57 decrease in mean overall AIS, respectively, versus the MNT. DISCUSSION: The presented rat model and scoring system represent the clinical adhesion disease process. hPSC-based interventions significantly reduce abdominal adhesions in this pilot dataset.

Changes in Perceived Emotions in Facial Paralysis Patients After Depressor Anguli Oris Excision.

OBJECTIVES: Depressor anguli oris (DAO) excision can improve clinician-graded, objective, and patient-reported smile outcomes in patients with nonflaccid facial paralysis (NFFP). However, no prior research has studied changes in perceived emotions after surgery. This study quantifies changes in perceived emotions with smiling after DAO excision in the largest case series presented to date. METHODS: Prospectively collected data from patients with NFFP who underwent DAO excision at a tertiary care facial nerve center were reviewed. Patient-reported, clinician-graded, and objective smile metrics were compared before and after surgery. Videos of faces at rest and while smiling were analyzed by artificial intelligence-derived facial expression analysis software to quantify perceived emotions. RESULTS: Sixty-eight patients underwent isolated DAO excision between August 2021 and August 2023. Patients conveyed significantly more perceived happiness with smile and at rest after surgery (p < 0.001 and p = 0.012, respectively). DAO excision improved oral commissure excursion (p < 0.001), dental show (p < 0.001), and smile angle (p < 0.001) symmetry. Patients reported significant improvements in smiling and social function after surgery. CONCLUSIONS: This study demonstrates DAO excision increases perceived happiness conveyed by patients with NFFP while smiling and at rest. It confirms improved objective, clinician-graded, and patient-reported smile outcomes after surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:4028-4035, 2024.

Targeted sequencing for hereditary breast and ovarian cancer in BRCA1/2-negative families reveals complex genetic architecture and phenocopies.

Approximately 20% of breast cancer cases are attributed to increased family risk, yet variation in BRCA1/2 can only explain 20%-25% of cases. Historically, only single gene or single variant testing were common in at-risk family members, and further sequencing studies were rarely offered after negative results. In this study, we applied an efficient and inexpensive targeted sequencing approach to provide molecular diagnoses in 245 human samples representing 134 BRCA mutation-negative (BRCAX) hereditary breast and ovarian cancer (HBOC) families recruited from 1973 to 2019 by Dr. Henry Lynch. Sequencing identified 391 variants, which were functionally annotated and ranked based on their predicted clinical impact. Known pathogenic CHEK2 breast cancer variants were identified in five BRCAX families in this study. While BRCAX was an inclusion criterion for this study, we still identified a pathogenic BRCA2 variant (p.Met192ValfsTer13) in one family. A portion of BRCAX families could be explained by other hereditary cancer syndromes that increase HBOC risk: Li-Fraumeni syndrome (gene: TP53) and Lynch syndrome (gene: MSH6). Interestingly, many families carried additional variants of undetermined significance (VOUSs) that may further modify phenotypes of syndromic family members. Ten families carried more than one potential VOUS, suggesting the presence of complex multi-variant families. Overall, nine BRCAX HBOC families in our study may be explained by known likely pathogenic/pathogenic variants, and six families carried potential VOUSs, which require further functional testing. To address this, we developed a functional assay where we successfully re-classified one family's PMS2 VOUS as benign.

Nascent shifts in renal cellular metabolism, structure, and function due to chronic empagliflozin in prediabetic mice.

Sodium-glucose cotransporter, type 2 inhibitors (SGLT2i) are emerging as the gold standard for treatment of type 2 diabetes (T2D) with renal protective benefits independent of glucose lowering. We took a high-level approach to evaluate the effects of the SGLT2i, empagliflozin (EMPA) on renal metabolism and function in a prediabetic model of metabolic syndrome. Male and female 12-wk-old TallyHo (TH) mice, and their closest genetic lean strain (Swiss-Webster, SW) were treated with a high-milk-fat diet (HMFD) plus/minus EMPA (@0.01%) for 12-wk. Kidney weights and glomerular filtration rate were slightly increased by EMPA in the TH mice. Glomerular feature analysis by unsupervised clustering revealed sexually dimorphic clustering, and one unique cluster relating to EMPA. Periodic acid Schiff (PAS) positive areas, reflecting basement membranes and mesangium were slightly reduced by EMPA. Phasor-fluorescent life-time imaging (FLIM) of free-to-protein bound NADH in cortex showed a marginally greater reliance on oxidative phosphorylation with EMPA. Overall, net urine sodium, glucose, and albumin were slightly increased by EMPA. In TH, EMPA reduced the sodium phosphate cotransporter, type 2 (NaPi-2), but increased sodium hydrogen exchanger, type 3 (NHE3). These changes were absent or blunted in SW. EMPA led to changes in urine exosomal microRNA profile including, in females, enhanced levels of miRs 27a-3p, 190a-5p, and 196b-5p. Network analysis revealed "cancer pathways" and "FOXO signaling" as the major regulated pathways. Overall, EMPA treatment to prediabetic mice with limited renal disease resulted in modifications in renal metabolism, structure, and transport, which may preclude and underlie protection against kidney disease with developing T2D.NEW & NOTEWORTHY Renal protection afforded by sodium glucose transporter, type 2 inhibitors (SGLT2i), e.g., empagliflozin (EMPA) involves complex intertwined mechanisms. Using a novel mouse model of obesity with insulin resistance, the TallyHo/Jng (TH) mouse on a high-milk-fat diet (HMFD), we found subtle changes in metabolism including altered regulation of sodium transporters that line the renal tubule. New potential epigenetic determinants of metabolic changes relating to FOXO and cancer signaling pathways were elucidated from an altered urine exosomal microRNA signature.

Using Concurrent Complication Reporting to Evaluate Resident Critical Thinking and Enhance Adult Learning.

OBJECTIVE: Critical thinking and accurate case analysis is difficult to quantify even within the context of routine morbidity and mortality reporting. We designed and implemented a HIPAA-compliant adverse outcome reporting system that collects weekly resident assessments of clinical care across multiple domains (case summary, complications, error analysis, Clavien-Dindo Harm, cognitive bias, standard of care, and ACGME core competencies). We hypothesized that incorporation of this system into the residency program's core curriculum would allow for identification of areas of cognitive weakness or strength and provide a longitudinal evaluation of critical thinking development. DESIGN: A validated, password-protected electronic platform linked to our electronic medical record was used to collect cases weekly in which surgical adverse events occurred. General surgery residents critiqued 1932 cases over a 4-year period from 3 major medical centers within our system. These data were reviewed by teaching faculty, corrected for accuracy and graded utilizing the software's critique algorithm. Grades were emailed to the residents at the time of the review, collected prospectively, stratified, and analyzed by post-graduate year (PGY). Evaluation of the resident scores for each domain and the resultant composite scores allowed for comparison of critical thinking skills across post-graduate year (PGY) over time. SETTING: Data was collected from 3 independently ACGME-accredited surgery residency programs over 3 tertiary hospitals within our health system. PARTICIPANTS: General surgery residents in clinical PGY 1-5. RESULTS: Residents scored highest in properly identifying ACGME core competencies and determining Clavien-Dindo scores (p < 0.006) with no improvement in providing accurate and concise clinical summaries. However, residents improved in recording data sufficient to identify error (p < 0.00001). A positive linear trend in median scores for all remaining domains except for cognitive bias was demonstrated (p < 0.001). Senior residents scored significantly higher than junior residents in all domains. Scores > 90% were never achieved. CONCLUSIONS: The use of an electronic standardized critique algorithm in the evaluation and assessment of adverse surgical case outcomes enabled the measure of residents' critical thinking skills. Feedback in the form of teaching faculty-facilitated discussion and emailed grades enhanced adult learning with a steady improvement in performance over PGY. Although residents improved with PGY, the data suggest that further improvement in all categories is possible. Implementing this standardized critique algorithm across PGY allows for evaluation of areas of individual resident weakness vs. strength, progression over time, and comparisons to peers. These data suggest that routine complication reporting may be enhanced as a critical thinking assessment tool and that improvement in critical thinking can be quantified. Incorporation of this platform into M&M conference has the potential to augment executive function and professional identity development.

Odours of caterpillar-infested trees increase testosterone concentrations in male great tits.

Trees release Herbivore-Induced Plant Volatiles (HIPVs) into the air in response to damage inflicted by insects. It is known that songbirds use those compounds to locate their prey, but more recently the idea emerged that songbirds could also use those odours as cues in their reproductive decisions, as early spring HIPVs may contain information about the seasonal timing and abundance of insects. We exposed pre-breeding great tits (Parus major) to the odours of caterpillar-infested trees under controlled conditions, and monitored reproduction (timing of egg laying, number of eggs, egg size) and two of its main hormonal drivers (testosterone and 17ß-estradiol in males and females, respectively). We found that females exposed to HIPVs did not advance their laying dates, nor laid larger clutches, or larger eggs compared to control females. 17ß-estradiol concentrations in females were also similar between experimental and control birds. However, males exposed to HIPVs had higher testosterone concentrations during the egg-laying period. Our study supports the hypothesis that insectivorous songbirds are able to detect minute amounts of plant odours. The sole manipulation of plant scents was not sufficient to lure females into a higher reproductive investment, but males increased their reproductive effort in response to a novel source of information for seasonal breeding birds.

Stat5 induces androgen receptor (AR) gene transcription in prostate cancer and offers a druggable pathway to target AR signaling.

Androgen receptor (AR) drives prostate cancer (PC) growth and progression, and targeting AR signaling is the mainstay of pharmacological therapies for PC. Resistance develops relatively fast as a result of refueled AR activity. A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR expression in castrate-resistant PC (CRPC). This study uncovers an unexpected function of active Stat5 signaling, a known promoter of PC growth and clinical progression, as a potent inducer of AR gene transcription. Stat5 suppression inhibited AR gene transcription in preclinical PC models and reduced the levels of wild-type, mutated, and truncated AR proteins. Pharmacological Stat5 inhibition by a specific small-molecule Stat5 inhibitor down-regulated Stat5-inducible genes as well as AR and AR-regulated genes and suppressed PC growth. This work introduces the concept of Stat5 as an inducer of AR gene transcription in PC. Pharmacological Stat5 inhibitors may represent a new strategy for suppressing AR and CRPC growth.

CSF1R inhibition promotes neuroinflammation and behavioral deficits during graft-versus-host disease in mice.

ABSTRACT: Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognized, in which brain-infiltrating donor major histocompatibility complex (MHC) class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early after transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients, in which CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signaling after transplant failed to reverse GVHD-induced behavioral changes. Moreover, we observed aberrant behavior in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.

Barriers to Accessing Congenital Heart Surgery in Low- and Middle-Income Countries: A Systematic Review.

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly. Ninety percent of children with CHD are born in low- and middle-income countries (LMICs), where over 90% of patients lack access to necessary treatments. Reports on barriers to accessing CHD care are limited. Accordingly, it is difficult to design evidence-based interventions to increase access to congenital cardiac surgical care in LMICs. OBJECTIVE: We performed a qualitative systematic review to understand barriers to accessing congenital cardiac surgical care in LMICs. METHODS: We conducted a search of Ovid MEDLINE and CINAHL databases to identify relevant articles from January 2000 to May 2021. We then used a thematic analysis to summarize qualitative data into a framework of preoperative, perioperative, and postoperative barriers. RESULTS: Our search yielded 1,585 articles, of which 67 satisfied the inclusion criteria. Notable preoperative barriers included delayed diagnosis, insufficient caregiver education, financial constraints, difficulty reaching treatment centers, sociocultural stigma of CHD, sex-based discrimination of patients with CHD, and Indigeneity. Perioperative barriers included lack of hospital resources and workforce, need for prolonged hospitalization, and strained physician-patient relationships. Many patients faced barriers postoperatively and into adulthood due to a shortage of critical care resources, inadequate caregiver counseling and patient education, lack of follow-up, and debt from hospital bills and missed work. CONCLUSION: Reducing neonatal and childhood mortality begins with recognizing barriers to accessing health care. Our systematic review identifies and classifies challenges in accessing CHD in LMICs and suggests solutions to major barriers.