TLR2 Supports γδ T cell IL-17A Response to ocular surface commensals by Metabolic Reprogramming.

The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival γδ T cells to prevent pathogenic infection. The commensal Corynebacterium mastitidis (C. mast) elicits protective IL-17 responses from conjunctival Vγ4 T cells through a combination of γδ TCR ligation and IL-1 signaling. Here, we identify Vγ6 T cells as a major C. mast-responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that Vγ6 cells require not only extrinsic (via dendritic cells) but also intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes responsible for metabolic shift to fatty acid oxidation to support Il17a transcription. We identify one key transcription factor, IκBζ, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal γδ T cells.

Sympathetic arousal among depressed college students: Examining the interplay between psychopathology and social activity.

Depressed individuals exhibit altered sensitivity to both positive and negative social contact, and may not reap the same psychological and emotional benefits to socializing as non-depressed individuals. Although depressive symptoms and loneliness predict social withdrawal and decreased pleasure, little is currently understood about immediate affective arousal dynamics during real-time socializing. Using a novel ambulatory protocol that tracked both objective features of affective arousal (electrodermal activity) and subjective valence (self-reported) during college students' social interactions, we evaluated the moderating role of depression and loneliness symptoms on the associations between socializing with others (specifically, with a romantic partner, a close friend, or a group of friends) and the arousal and valence dimensions of affect. Among a racially and ethnically diverse sample of 118 college students (64% African American/Black/Continental African, 20% Latinx, 8% Asian, and 8% White) recruited from a large, predominantly White Midwestern university, those lower in depression and loneliness symptomatology evinced decreased average arousal (Β = -0.10, SE = 0.04, p < .01) when in relaxed and intimate socializing contexts (e.g., with a romantic partner and a close friend), consistent with the idea that these contexts facilitate important opportunities for psychological rest and recovery. Those lower in depression and loneliness symptoms also showed higher average arousal when socializing in the energizing context of being with a group of friends. Overall, the results suggest psychopathology is reflected in patterns of sympathetic arousal when socializing, with more depressed and lonely individuals generally feeling worse while receiving fewer psychophysiological rewards in multiple socializing contexts.

Plasma microbial cell-free DNA following chimeric antigen receptor T cell therapy in pediatric patients with relapsed/refractory leukemia.

Chimeric antigen receptor (CAR) T cell therapy is a promising treatment for pediatric patients with relapsed or refractory B cell acute lymphoblastic leukemia (R/R B ALL). Cytokine release syndrome (CRS) is a common toxicity after CAR T cell therapy and fever is often the first symptom. Differentiating CRS from infection after CAR T cell therapy can be challenging. Plasma microbial cell free DNA (mcfDNA) is a novel diagnostic tool which allows for qualitative and quantitative assessment of over 1000 organisms. This pilot study sought to characterize mcfDNA results in pediatric patients with R/R B ALL in the first 2 months after CAR T cell therapy.

The impact of estradiol supplementation on endometrial thickness and intrauterine insemination outcomes.

The impact of estrogen supplementation during the follicular/proliferative phase on the endometrial lining thickness (EMT) prior to intrauterine insemination (IUI) remains largely unstudied. Our study examined changes in EMT and rates of clinical pregnancy, miscarriage, and live birth for all patients who completed an IUI cycle at Stanford Fertility Center from 2017-2023 (n = 2281 cycles). Cycles with estradiol supplementation (n = 309) were compared to reference cycles without supplementation (n = 1972), with the reference cohort further categorized into cycles with a pre-ovulatory EMT of < 7 mm ("thin-lining", n = 536) and ≥ 7 mm ("normal-lining", n = 1436). The estradiol group had a statistically significant greater change in EMT from baseline to ovulation compared to the thin-lining reference groups (2.4 mm vs 1.9 mm, p < =0.0001). Similar rates of clinical pregnancy and live birth were observed. After adjusting for age, BMI, race/ethnicity, infertility diagnosis, and EMT at trigger, the estradiol cohort had a significantly increased odds of miscarriage versus the entire reference cohort (2.46, 95 % confidence interval [1.18, 5.14], p = 0.02). Thus, although estradiol supplementation had a statistically significant increase in EMT compared to IUI cycles with thin pre-ovulatory EMT (<7 mm), this change did not translate into improved IUI outcomes such as increased rates of clinical pregnancy and live birth or decreased rate of miscarriage. Our study suggests that supplemental estradiol does not appear to improve IUI outcomes.

Real-world effectiveness of ustekinumab and vedolizumab in TNF-exposed pediatric patients with ulcerative colitis.

OBJECTIVES: Vedolizumab (VDZ) and ustekinumab (UST) are second-line treatments in pediatric patients with ulcerative colitis (UC) refractory to antitumor necrosis factor (anti-TNF) therapy. Pediatric studies comparing the effectiveness of these medications are lacking. Using a registry from ImproveCareNow (ICN), a global research network in pediatric inflammatory bowel disease, we compared the effectiveness of UST and VDZ in anti-TNF refractory UC. METHODS: We performed a propensity-score weighted regression analysis to compare corticosteroid-free clinical remission (CFCR) at 6 months from starting second-line therapy. Sensitivity analyses tested the robustness of our findings to different ways of handling missing outcome data. Secondary analyses evaluated alternative proxies of response and infection risk. RESULTS: Our cohort included 262 patients on VDZ and 74 patients on UST. At baseline, the two groups differed on their mean pediatric UC activity index (PUCAI) (p = 0.03) but were otherwise similar. At Month 6, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p = 0.76). Our primary model showed no difference in CFCR (odds ratio: 0.81; 95% confidence interval [CI]: 0.41-1.59) (p = 0.54). The time to biologic discontinuation was similar in both groups (hazard ratio: 1.26; 95% CI: 0.76-2.08) (p = 0.36), with the reference group being VDZ, and we found no differences in clinical response, growth parameters, hospitalizations, surgeries, infections, or malignancy risk. Sensitivity analyses supported these findings of similar effectiveness. CONCLUSIONS: UST and VDZ are similarly effective for inducing clinical remission in anti-TNF refractory UC in pediatric patients. Providers should consider safety, tolerability, cost, and comorbidities when deciding between these therapies.

Comparing binary & ordinal definitions of urinary & stool continence outcomes: Data from the National Spina Bifida Patient Registry.

INTRODUCTION: The National Spina Bifida Patient Registry (NSBPR) assesses bladder and bowel incontinence using ordinal categories, but prior NSBPR analyses employed binary classification. Our aims were to 1) perform the first NSBPR analysis of bladder and bowel incontinence as ordinal outcomes to compare to the binary definition and subject variables; 2) explore the correlation of incontinence with undergarment usage, and 3) assess incontinence status following continence surgeries. METHODS: Data from NSBPR participants' most recent clinic visit from 2013 to 2020 were analyzed. Ordinal categories of incontinence were compared to previously used binary definitions. Incontinence surgical outcomes were analyzed for those with data at least three months post-operatively. Chi-square tests evaluated associations among categorical variables. Univariate and ordinal logistic regression models were used to test associations of ordinal incontinence status with patient and condition factors. Statistical tests were 2-sided; p values < 0.05 were considered significant. RESULTS: Analysis of 7217 individuals using ordinal incontinence outcomes showed little difference from previously used binary outcomes. The final multivariable logistic regression models with ordinal multinomial outcomes showed that associations of incontinence with age, sex, race/ethnicity, health insurance, level of lesion, and continence management technique were similar to prior studies. Among those reporting never being incontinent of both bladder and bowel, 14% reported using protective undergarments. Of the 500 individuals who had bladder outlet surgery, 38% reported never being incontinent of urine. Of 1416 individuals who had appendicostomy (ACE) bowel surgery, 48% reported never being incontinent of stool. DISCUSSION: Our current analysis showed that ordinal continence outcome classification had similar continence findings as previous studies using the binary definition of continence. Expanding the binary definition of continence to include monthly episodes of incontinence did not greatly increase the proportion of continent individuals and, therefore, would have not likely made meaningful differences in continence outcomes in prior NSBPR analyses. However, it is known that even mild incontinence can affect quality of life, therefore, capturing any level of incontiennce is of clinical importance. Confirmation of the association of continence outcomes with sociodemographic, condition-related, and interventional factors with both approaches further validates previous analyses using the binary definition of continence. CONCLUSION: The previously used binary definition of bladder and bowel continence appears robust. Undergarment choice was a poor surrogate for reported incontinence. After bladder and bowel continence surgeries, 38% and 48%, respectively, reported never being incontinent.

Fatigue and Quality of Life in Children with Hearing Loss or Obstructive Sleep Apnea.

OBJECTIVE: To investigate the fatigue levels of children with hearing loss (HL) and obstructive sleep apnea (OSA), hypothesizing that the fatigue experienced by children with HL is under-recognized. STUDY DESIGN: Cross-sectional survey. METHODS: We identified children aged 2-18 with HL, OSA, sleep-disordered breathing (SDB), and controls from a pediatric otolaryngology clinic and sleep center. Children and/or parents completed the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL MFS), Hearing Environments And Reflection on Quality of Life (HEAR-QL), and OSA-18. RESULTS: Responses of 50 children with HL, 79 with OSA, and 18 with SDB were compared with those of 49 recruited controls (RC) and literature controls (LC). Children with HL or OSA had higher fatigue than controls in the PedsQL MFS self-reported (HL 65.4, OSA 54.7, RC 71.8, LC 80.5, p < 0.001) and parent-reported (HL 64.6, OSA 59.3, RC 75.2, LC 89.6, p < 0.001). Children with HL had Cognitive Fatigue similar to that of children with OSA (self 60.4 vs. 49.5, p = 0.170; parent 56.0 vs. 56.7, p = 0.998), though with decreased Sleep/Rest Fatigue (self 67.8 vs. 56.3, p = 0.033; parent 69.8 vs. 57.5, p = 0.001). Children with HL or OSA had lower disease-related quality of life (QOL) than controls in the HEAR-QL and OSA-18, respectively. Stratification with disease severity revealed no differences in fatigue. CONCLUSION: Children with HL or OSA experience higher fatigue and lower QOL than controls. Similar Cognitive Fatigue in both groups suggests under-recognized fatigue in children with HL. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:443-451, 2024.

Use of Socioeconomic Demographic Data in Studies on Pediatric Unilateral Hearing Loss: A Scoping Review.

OBJECTIVES: Social determinants of health (SDOH) (healthcare access and quality, education access and quality, socioeconomic status, social and cultural context, neighborhood and built environment) ( Healthy People 2030 ) have been shown to impact a wide range of health-related outcomes and access to care. Given the medical and nonmedical costs associated with children with unilateral hearing loss (UHL), the varied insurance coverage for hearing healthcare services, and the differences in hearing aid utilization rates between children of different sociodemographic classes, the sociodemographic information of children with UHL enrolled in research studies should be collected to ensure the generalizability of hearing healthcare interventions. Therefore, the objective of this scoping review is to assess the reporting of SDOH data for participants in studies of pediatric UHL and its comparison to population trends. DESIGN: Two searches of published literature were conducted by a qualified medical librarian. Two reviewers then evaluated all candidate articles. Study inclusion parameters were from 2010 to present, peer-reviewed studies with prospective study design, and participant population including children (age 0 to 18 years old) with UHL. RESULTS: Two literature searches using PubMed Medline and Embase found 442 and 3058 studies each for review. After abstract and paper review, 87 studies were included in final qualitative review, with 22 of these studies reporting race distribution of participants, 15 reporting insurance status or family income, and 12 reporting the maternal education level. CONCLUSIONS: Sociodemographic data are not commonly reported in research studies of children with UHL. In reported samples, research participants are more likely to have private insurance and higher family income compared with overall population distribution. These demographic biases may affect the generalizability of study results to all children with UHL. Further evaluation is warranted to evaluate whether participant recruitment affects outcomes that reflect the overall population.

Platelet-rich plasma infusion as an adjunct treatment for persistent thin lining in frozen embryo transfer cycles: first US experience report.

PURPOSE: To study effect of intrauterine infusion of platelet-rich plasma (PRP) on endometrial growth in the setting of thin endometrial lining in patients with prior cancelled or failed frozen embryo transfer (FET) cycles. MATERIALS AND METHODS: Single-arm cohort study of forty-six patients (51 cycles) with endometrial lining thickness (EMT) < 6 mm in prior cancelled or failed FET cycles requesting intrauterine PRP treatment in upcoming FET cycle. The primary outcomes were final EMT in FET cycle and change in EMT after PRP. The secondary outcomes were overall pregnancy rate, clinical pregnancy rate, miscarriage rate, ongoing pregnancy, and live birth rates. RESULTS: The mean pre-PRP EMT in all FET cycles was 4.0 ± 1.1 mm, and mean post-PRP EMT (final) was 7.1 ± 1.0 mm. Of 51 cycles, 33 (64.7%) reached ≥ 7 mm after PRP administration. There was a significant difference between pre-PRP EMT and post-PRP EMT in all FET cycles, with mean difference of 3.0 ± 1.5 mm. Three cycles were cancelled for failure to reach adequate lining. Total pregnancy rate was 72.9% in our cohort of 48 cycles that proceeded to transfer. Clinical pregnancy rate was 54.2% (26/48 FET cycles); clinical miscarriage rate was 14.3% (5/35 pregnancies). Twenty six women had live birth (18 with EMT ≥ 7 mm and 8 with EMT < 7 mm). Response to PRP was not correlated with any pre-cycle characteristics. CONCLUSION: We demonstrate a significant improvement in lining thickness and pregnancy rates in this challenging cohort of women after PRP infusion, with no adverse events. Cost-effectiveness of PRP with benefits and alternatives should be carefully considered.

Difficult decisions, filtration surgery, and the heartbreak of the numerator.

A 70-year-old man had progressive and severe glaucoma in each eye. He was intolerant to dorzolamide, brimonidine, and netarsudil. Each eye had prior selective laser trabeculoplasty (SLT) as well as phacoemulsification plus minimally invasive glaucoma surgery (MIGS) 6 years before current presentation (iStent [Glaukos Corp.] in the right eye and Cypass [Alcon Laboratories, Inc.] in the left eye). Postoperative acuities were 20/20 and 20/25 in the right and left eyes, respectively. When his left eye progressed with loss of central acuity despite peak intraocular pressures (IOPs) in the middle to upper teens, neuro-ophthalmology consultation was obtained (Figure 1JOURNAL/jcrs/04.03/02158034-202401000-00017/figure1/v/2023-12-22T124801Z/r/image-tiff). That workup included magnetic resonance imaging scan and hematologic screening, but all results were negative, and the neuro-ophthalmic consultant concluded that the vision loss was likely on the basis of glaucoma. Accordingly, a trabeculectomy was performed in the left eye achieving consistent IOPs in the range of 7 to 10 mm Hg without medications, rending the left eye stable since the filtration surgery nearly 2 years previously. The right eye continued to progress both subjectively and objectively, and on recent examination, the IOP measured 20 mm Hg and 09 mm Hg in the right and left eyes, respectively (Figure 2JOURNAL/jcrs/04.03/02158034-202401000-00017/figure2/v/2023-12-22T124801Z/r/image-tiff). Medications included timolol and latanoprostene bunod in the right eye only. Central corneal thickness was 526 µm and 527 µm in the right and left eyes, respectively. The visual acuity now measured 20/25 in the right eye and 20/250 in the left eye. The vertical cup-to-disc ratio was 0.9 in the right eye and 1.0 in the left eye. Gonioscopy revealed a wide open angle in each eye with a patent sclerostomy superiorly in the left eye. The conjunctiva and sclera were healthy and without scarring in the right eye. The bleb in the left eye was diffuse, lightly vascularized, and seidel negative. Axial length (AL) was 26.88 µm in the right eye and 26.77 µm in the left eye. The patient was in good health and was not anticoagulated. An extensive discussion ensued about the best course of action for the right eye. How would you proceed in managing definite progression in this individual's right eye, knowing that he had lost fixation in his left eye at similar pressures?

Too Much of a Good Thing: Extended Duration of Gut Microbiota Depletion Reverses Protection From Experimental Autoimmune Uveitis.

Purpose: Using the model of experimental autoimmune uveitis (EAU) induced by immunization with a retinal antigen, two studies have reported contradictory results on disease development following oral antibiotic treatment (ABX). We showed that long-term ABX did not affect EAU, but another study showed that short-term ABX was protective. We therefore studied the effects of ABX on EAU, gut microbiota, and host immune responses as a function of treatment duration. Methods: EAU-susceptible mice were treated orally with broad-spectrum antibiotics starting at least 10 weeks (long-term) or 1 week (short-term) before immunization until termination of the experiment. Gut microbiota were characterized by 16S amplicon sequencing, and host gut immune elements were studied phenotypically and functionally. Results: Long-term ABX had no effect, whereas short-term ABX delayed EAU, as previously reported by us and others, respectively. Microbial sequencing revealed progressive reduction of gut microbiota that showed some differences in the two ABX groups. Interestingly, duration of ABX was associated with a gradual disappearance of the CD4+ and CD4+CD8+ subset of gut intraepithelial lymphocytes (IELs). This IEL subset is microbiota dependent and is absent in germ-free mice. Relative abundance of Lactobacillus reuteri correlated with the frequencies of CD4+CD8+ IELs. IELs suppressed antigen-specific activation of autoreactive T cells in culture. Conclusions: Gut microbiota may play dual roles in uveitis development: They promote EAU development but also help maintain IEL populations that have regulatory function against autoreactive T cells. We propose that the progressive loss of this population during long-term ABX reverses the EAU-ameliorating effects of microbiota depletion.

Diabetes-associated breast cancer is molecularly distinct and shows a DNA damage repair deficiency.

Diabetes commonly affects patients with cancer. We investigated the influence of diabetes on breast cancer biology using a 3-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.

Improved Elastic Recovery from ABC Triblock Terpolymers.

The promise of ABC triblock terpolymers for improving the mechanical properties of thermoplastic elastomers is demonstrated by comparison with symmetric ABA/CBC analogs having similar molecular weights and volume fraction of B and A/C domains. The ABC architecture enhances elasticity (up to 98% recovery over 10 cycles) in part through essentially full chain bridging between discrete hard domains leading to the minimization of mechanically unproductive loops. In addition, the unique phase space of ABC triblocks also enables the fraction of hard-block domains to be higher (fhard ≈ 0.4) while maintaining elasticity, which is traditionally only possible with non-linear architectures or highly asymmetric ABA triblock copolymers. These advantages of ABC triblock terpolymers provide a tunable platform to create materials with practical applications while improving our fundamental understanding of chain conformation and structure-property relationships in block copolymers.

Fungal panophthalmitis presenting as severe posterior scleritis.

Purpose: To report a highly unusual and fulminant case of infectious fungal panophthalmitis that initially presented as angle closure in the setting of posterior scleritis, culminating in the loss of the affected eye. Observations: A 57-year-old woman with a history of poorly controlled diabetes mellitus and autoimmune disease presented with a unilateral flat anterior chamber, highly elevated intraocular pressure (50-65 mmHg) and severe chemosis of the right eye. Initial VA was NLP in the affected eye. An ultrasound B-scan revealed a very pronounced T-sign and severely thickened posterior sclera and choroid indicative of posterior scleritis. Bloodwork showed elevation of WBC count to 18 K/µL and broad spectrum antibiotics were initiated. However, a comprehensive infectious workup including fungal cultures were persistently negative. After three days of IV NSAIDs and antibiotics, WBC count normalized and pain had mildly improved. After consultation with a multidisciplinary team that included the Glaucoma, Retina/Uveitis, Infectious Disease, Rheumatology and Internal Medicine services, high dose IV methylprednisolone was started. Despite the initial improvement, corneoscleral decompensation and paralimbal perforation of the globe occurred. The eye was enucleated, and pathologic examination revealed a dense focus of budding yeast in the vitreous cavity. Conclusions and importance: Scleritis is a rare entity, with posterior scleritis, infectious scleritis, and fungal scleritis representing increasingly rare subtypes. However, fungal scleritis may be underdiagnosed due to a number of factors including culture negativity, a lack of clinical suspicion, as well as the disease's propensity to masquerade as other pathologies such as angle closure or malignant glaucoma. Fungal scleritis should be considered in cases that present with possible infectious etiology, worsen with systemic corticosteroid treatment, or worsen despite broad-spectrum antibiotic coverage. When treating patients with underlying risk factors such as uncontrolled diabetes mellitus, recent antibiotic use, use of total parenteral nutrition, or immunosuppression, a higher level of suspicion for fungal etiology is also appropriate. In the outpatient setting, fungal eye infections do not always present with critical systemic illness or culture positivity. If there is suspicion for fungal involvement, early aqueous or vitreous tap may improve diagnostic yield.

Utilizing the Social Determinants of Health Model to Explore Factors Affecting Nurses' Job Satisfaction in Saudi Arabian Hospitals: A Systematic Review.

The purpose of this systematic review was to explore factors affecting nurses' job satisfaction in Saudi Arabian hospitals by utilizing the social determinants of a health model. We conducted a systematic review using three databases (PubMed, PsychINFO, and CINAHL) following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. A total of 235 studies were screened. Of these studies, nine met the inclusion criteria. The studies were appraised using the Joanna Briggs Institute checklist tool. The majority of studies reported that salary, years of experience, nationality, and marital status were factors affecting nurses' job satisfaction. Gender and educational level did not impact job satisfaction for male and female nurses. Overall, the review highlighted some knowledge gaps in the assessment of the impact of social determinants of health regarding gender and educational level on nurses' job satisfaction. Further research is needed to address this knowledge gap.

Utilizing Social Determinants of Health Model to Understand Barriers to Medication Adherence in Patients with Ischemic Stroke: A Systematic Review.

Introduction: Ischemic strokes and their recurrence create an immense disease burden globally. Therefore, preventing recurrent strokes by promoting medication adherence is crucial to reduce morbidity and mortality. In addition, understanding the barriers to medication adherence related to the social determinants of health (SDoH) could promote equity among persons with ischemic stroke. Objective: To explore the barriers to medication adherence among patients with ischemic stroke through the SDoH. Methods: This systematic review included studies published between January 2018 and December 2022 identified through PubMed, MEDLINE, Web of Science, and CINAHL Plus Full Text. The descriptions of the studies were systematically summarized and discussed based on the SDoH from the US Healthy People 2030 initiative. Results: Eight studies met the inclusion criteria and were included in this review. The most common barrier to adherence was inappropriate medication beliefs, medication side effects, and patient-physician relationship, which relate to the dimensions of healthcare access and quality. Health literacy and health perception, dependent on education access and quality, frequently influenced adherence. Other social determinants, such as financial strain and social and community context, were found to alter adherence behaviors. No study addressed the neighborhood and built environment domain. We found that cognitive impairment is another factor that impacts adherence outcomes among stroke patients. Conclusion: Multifaceted approaches are needed to address the SDoH to improve medication adherence among patients with ischemic stroke. This review emphasized strategies, including patient education, provider-patient communication, social support, health literacy, technology, and policy advocacy to enhance adherence.

Diagnoses and medications associated with delayed ejaculation.

Background: Delayed ejaculation (DE) is a disorder that can cause significant distress for sexually active men. The etiology of DE is largely idiopathic, with even less being known about clinical factors associated with the condition. Aim: We sought to use data mining techniques to examine a broad group of health conditions and pharmaceutical treatments to identify factors associated with DE. Methods: Using an insurance claims database, we evaluated all men with a diagnosis of DE and matched them to a cohort (1:1) of men with other male sexual disorders of urologic origin (ie, erectile dysfunction [ED] and Peyronie's disease [PD]). Given the low prevalence of DE, we incorporated the random forest approach for classification of DE vs controls, with a plethora of predictors and cross-validation with the least absolute shrinkage and selection operator (LASSO). We used both a high-performance generalized linear model and a multivariate logistic model. The area under the curve was reported to demonstrate classifier performance, and odds ratios were used to indicate risks of each predictor. We also evaluated for differences in the prevalence of conditions in DE by race/ethnicity. Outcomes: Clinical factors (ie, diagnoses and medications) associated with DE were identified. Results: In total, 11 602 men with DE were matched to a cohort of men with PD and ED. We focused on the 20 factors with the strongest association with DE across all models. The factors demonstrating positive associations with DE compared to other disorders of male sexual dysfunction (ie, ED and PD) included male infertility, testicular dysfunction, anxiety, disorders of lipid metabolism, alpha adrenergic blocker use, anemia, antidepressant use, and psychoses such as schizophrenia or schizoaffective disorder. In addition, the prevalence of several conditions varied by race/ethnicity. For example, male infertility was present in 5% of Asian men compared to <2% of men of other races. Clinical Implications: Several medical conditions and pharmacologic treatments are associated with DE, findings that may provide insight into the etiology of DE and offer treatment options. Strengths and Limitations: This study is to our knowledge the first to use using data mining techniques to investigate the association between medical conditions/pharmacologic agents and the development of subsequent DE. The generalizability of our findings is limited given that all men were commercially insured. Conclusion: DE is associated with multiple medical conditions, a finding that may help identify the etiology for this disorder.

Chemokine expression predicts T cell-inflammation and improved survival with checkpoint inhibition across solid cancers.

Immune checkpoint inhibitors (ICI) are highly effective in specific cancers where canonical markers of antitumor immunity are used for patient selection. Improved predictors of T cell-inflammation are needed to identify ICI-responsive tumor subsets in additional cancer types. We investigated associations of a 4-chemokine expression signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) with metrics of antitumor immunity across tumor types. Across cancer entities from The Cancer Genome Atlas, subgroups of tumors displayed high expression of the c-Score (c-Scorehi) with increased expression of immune checkpoint (IC) genes and transcriptional hallmarks of the cancer-immunity cycle. There was an incomplete association of the c-Score with high tumor mutation burden (TMB), with only 15% of c-Scorehi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Scorehi tumors had a longer median time to progression (103 versus 72 days, P = 0.012) and overall survival (382 versus 196 days, P = 0.038) following ICI therapy initiation, compared to patients with low c-Score expression. We also found c-Score stratification to outperform TMB assignment for overall survival prediction (HR = 0.42 [0.22-0.79], P = 0.008 versus HR = 0.60 [0.29-1.27], P = 0.18, respectively). Assessment of the c-Score using the TIDE and PredictIO databases, which include ICI treatment outcomes from 10 tumor types, provided further support for the c-Score as a predictive ICI therapeutic biomarker. In summary, the c-Score identifies patients with hallmarks of T cell-inflammation and potential response to ICI treatment across cancer types, which is missed by TMB assignment.

Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA-Associated Pancreatic Cancer in the Clinical and Preclinical Setting.

Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions. SIGNIFICANCE: glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.