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Data comparing radical prostatectomy and external beam radiation therapy with low dose rate brachytherapy boost are lacking. To better guide shared decision making regarding treatment, we compared patient reported outcomes through 5 years following radical prostatectomy or external beam radiation therapy with low dose rate brachytherapy boost for localized prostate cancer.From 2011-2012, men aged80 years with localized prostate adenocarcinoma were enrolled and followed longitudinally. Patient reported outcomes included the Expanded Prostate Index Composite. Regression models adjusted for baseline scores and covariates were constructed.The study population included 112 men treated with external beam radiation therapy with low dose rate brachytherapy boost and 1,553 treated with radical prostatectomy. Compared to radical prostatectomy, external beam radiation therapy with low dose rate brachytherapy boost was associated with clinically meaningful worse urinary irritative/obstructive (adjusted mean score difference [95% confidence interval]: 5.0 [-8.7, -1.3];Compared to radical prostatectomy, external beam radiation therapy with low dose rate brachytherapy boost was associated with clinically meaningful worse urinary irritative/obstructive and bowel functions but better urinary incontinence function through 5 years after treatment. These patient-reported functional outcomes may clarify treatment expectations and help inform treatment choices for localized prostate cancer.

Extracranial carotid artery aneurysms (ECAA) are rare. Open surgery has traditionally been the treatment of choice, and endovascular management has recently been increasingly described. However, operative guidelines have not been defined.A systematic review following PRISMA guidelines was performed to identify articles related to the symptoms, treatments, and outcomes of ECAAs. Included studies were further evaluated to identify distribution of treatment strategy based on anatomical location by Attigah classification (Type I-V) and aneurysmal type (true versus pseudoaneurysm).Twenty-eight retrospective reviews were included. A total of 906 patients (63% male) with 959 ECAAS were identified. The most common presenting symptoms included neck mass (45%) and neurological deficits (26%), while 218 (23%) were asymptomatic. True aneurysms accounted for 52% and pseudoaneurysms for 45% of cases. Of the 959 ECAAs, 750 were treated with open surgery, 85 with an endovascular procedure, and 124 conservatively. Perioperative complications of open surgery included cranial nerve injuries (CNI) in 9% (68), strokes in 4% (27), and death in 2% (18) of cases. There were no CNI, perioperative stroke, or perioperative mortality associated with 85 endovascular procedures; however, there was 1 case of restenosis (1%). Of the 124 patients treated conservatively, 3% (4) died as a result of the aneurysm. Twenty-two of 28 studies (688 ECAAs) reported anatomical location according to Attigah classification. The distribution of ECAAs were Type I (296/688; 43%), Type II (19/688; 3%), Type III (195/688; 28%), Type IV (76/688: 11%), and Type V (102/688; 15%). Eleven of 28 studies (241 ECAAs) reported treatment choice according to Attigah classification and revealed that the majority of Type I (82%), Type II (81%), Type III (91%), and Type IV (100%) ECAAs were treated via open surgery, while Type V ECAAs were evenly treated by open surgery and endovascular surgery. Twenty-three of 28 studies (780 ECAAs) reported treatment choice stratified by aneurysmal type. Of 417 true ECAAs, 88% were treated open surgically, 4% were treated endovascularly, and 8% were treated conservatively. Of 357 pseudoaneurysms, 67% were treated open surgically, 14% were treated endovascularly, and 19% were treated conservatively.Most reported patients with ECAAs are symptomatic. Type I and III account for more than two-thirds of ECAAs, while true aneurysms account for roughly half. The vast majority of ECAAs have been treated surgically with results comparable to reoperative carotid endarterectomy. In selected patients, endovascular treatment has been very successful with no reported morbidity or mortality.

Background Diurnal rhythms in gene expression have been detected in the human brain. Previous studies found that males and females exhibit 24-hour rhythms in known circadian genes, with earlier peak expression in females. Whether there are sex differences in large-scale transcriptional rhythms in the cortex that align with observed sex differences in physiological and behavioral rhythms is currently unknown. Methods Diurnal rhythmicity of gene expression was determined for males and females using RNA sequencing data from human postmortem dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Sex differences among rhythmic genes were determined using significance cutoffs, threshold-free analyses, and R2 difference. Phase concordance was assessed across the DLPFC and ACC for males and females. Pathway and transcription factor analyses were also conducted on significantly rhythmic genes. Results Canonical circadian genes had diurnal rhythms in both sexes with similar amplitude and phase. When analyses were expanded to the entire transcriptome, significant sex differences in transcriptional rhythms emerged. There were nearly twice as many rhythmic transcripts in the DLPFC in males and nearly 4 times as many rhythmic transcripts in the ACC in females. Results suggest a diurnal rhythm in synaptic transmission specific to the ACC in females (e.g., GABAergic [gamma-aminobutyric acidergic] and cholinergic neurotransmission). For males, there was phase concordance between the DLPFC and ACC, while phase asynchrony was found in females. Conclusions There are robust sex differences in molecular rhythms of genes in the DLPFC and ACC, providing potential mechanistic insights into how neurotransmission and synaptic function are modulated in a circadian-dependent and sex-specific manner.

OBJECTIVE Venous thromboembolism (VTE) can cause significant morbidity and mortality in hospitalized patients, and may disproportionately occur in patients with limited mobility following spinal trauma. The authors aimed to characterize the epidemiology and clinical predictors of VTE in pediatric patients following traumatic spinal injuries (TSIs). METHODS The authors conducted a retrospective cohort analysis of children who experienced TSI, including spinal fractures and spinal cord injuries, encoded within the National Trauma Data Bank from 2011 to 2014. RESULTS Of the 22,752 pediatric patients with TSI, 192 (0.8%) experienced VTE during initial hospitalization. Proportionally, more patients in the VTE group (77%) than in the non-VTE group (68%) presented following a motor vehicle accident. Patients developing VTE had greater odds of presenting with moderate (adjusted odds ratio [aOR] 2.6, 95% confidence interval [CI] 1.4–4.8) or severe Glasgow Coma Scale scores (aOR 4.3, 95% CI 3.0–6.1), epidural hematoma (aOR 2.8, 95% CI 1.4–5.7), and concomitant abdominal (aOR 2.4, 95% CI 1.8–3.3) and/or lower extremity (aOR 1.5, 95% CI 1.1–2.0) injuries. They also had greater odds of being obese (aOR 2.9, 95% CI 1.6–5.5). Neither cervical, thoracic, nor lumbar spine injuries were significantly associated with VTE. However, involvement of more than one spinal level was predictive of VTE (aOR 1.3, 95% CI 1.0–1.7). Spinal cord injury at any level was also significantly associated with developing VTE (aOR 2.5, 95% CI 1.8–3.5). Patients with VTE stayed in the hospital an adjusted average of 19 days longer than non-VTE patients. They also had greater odds of discharge to a rehabilitative facility or home with rehabilitative services (aOR 2.6, 95% CI 1.8–3.6). CONCLUSIONS VTE occurs in a low percentage of hospitalized pediatric patients with TSI. Injury severity is broadly associated with increased odds of developing VTE; specific risk factors include concomitant injuries such as cranial epidural hematoma, spinal cord injury, and lower extremity injury. Patients with VTE also require hospital-based and rehabilitative care at greater rates than other patients with TSI.

Advances in radiotherapy technology and technique over the last 3 decades have revolutionized radiation treatment options for genitourinary malignancies. The development of more focused and accurate radiation treatment has facilitated safe delivery of dose-escalated treatment that improves disease control and the development of shorter-duration hypofractionated treatment regimens that are more convenient for patients and improve access to treatment. The management of oligometastatic disease is evolving with ablative treatment of oligometastasis and the primary for select patients and shorter-duration palliative treatment regimens. Work is ongoing to personalize radiation treatment regimens for genitourinary malignancies based on molecular biomarkers.

Sexual dysfunction, including erectile dysfunction and loss of libido, are common among men undergoing treatment for localized prostate cancer. Both local treatments and systemic androgen deprivation therapy may contribute to these outcomes and are differentially indicated based on disease characteristics. We sought to compare sexual function through 5 years after radiation treatment with and without androgen deprivation therapy in men with good baseline sexual function to better understand long-term effects in this understudied subset of patients. We retrospectively reviewed a prospectively assembled population-based cohort of men who underwent radiation with and without androgen deprivation therapy for intermediate or high-risk localized prostate cancer. Sexual function was assessed longitudinally over 5 years. Men with erections sufficient for intercourse at baseline were selected for inclusion. Out of 167 patients included, 73 underwent radiation alone and 94 received androgen deprivation therapy plus radiation (51 with intermediate and 43 with high-risk disease). Androgen deprivation therapy use was associated with worse sexual function through 1 year regardless of disease risk. This difference was no longer statistically significant at 3 years in the intermediate-risk group. Compared to radiation alone, androgen deprivation therapy in high-risk disease was associated with worse sexual function at 3 years (effect: −20.3 points, CI [−31.8, −8.8], p

Contemporary treatment modalities for localized prostate cancer provide comparable overall and cancer-specific survival. However, the degree of financial burden imposed by treatment, the factors contributing to that burden, and how different treatments compare with regard to financial toxicity remain poorly understood.The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study enrolled men with localized prostate cancer from 2011 to 2012. Questionnaires were collected at 6, 12, 36, and 60 months after enrollment. Differences in patient-reported financial burden were compared between active surveillance, radical prostatectomy, and external beam radiotherapy using multivariable logistic regression.Among 2,121 patients meeting inclusion criteria, 15% reported large or very large burden of treatment costs within 6 months, declining to 3% by year 5. When controlling for age, education, income and other covariates, external beam radiotherapy was associated with greater financial burden than active surveillance and radical prostatectomy at 1 year (OR 2.2, 95% CI 1.2-4.1 and OR 1.5, 95% CI 1.0-2.3, respectively) and 3 years (OR 3.1 95% CI 1.1-8.8 and OR 2.1, 95% CI 1.2-3.7, respectively). Radical prostatectomy and active surveillance had similar rates of financial burden at all time points. Age, race, education, and D'Amico risk group were associated with financial burden.External beam radiotherapy was associated with the highest financial burden, even when controlling for age, education and income. Prospective studies that directly measure out-of-pocket and indirect costs and account more thoroughly for baseline socioeconomic differences are warranted in order to identify those most at risk.

Purpose Definitive radiation therapy (RT), with or without concurrent chemotherapy, is an alternative to radical cystectomy for patients with localized, muscle-invasive bladder cancer (MIBC) who are either not surgical candidates or prefer organ preservation. We aim to synthesize an evidence-based guideline regarding the appropriate use of RT. Methods and Materials We performed a Preferred Reporting Items for Systematic Reviews and Meta-analyses literature review using the PubMed and Embase databases. Based on the literature review, critical management topics were identified and reformulated into consensus questions. An expert panel was assembled to address key areas of both consensus and controversy using the modified Delphi framework. Results A total of 761 articles were screened, of which 61 were published between 1975 and 2019 and included for full review. There were 7 well-designed studies, 20 good quality studies, 28 quality studies with design limitations, and 6 references not suited as primary evidence. Adjuvant radiation therapy after cystectomy was not included owing to lack of high-quality data or clinical use. An expert panel consisting of 14 radiation oncologists, 1 medical oncologist, and 1 urologist was assembled. We identified 4 clinical variants of MIBC: surgically fit patients who wish to pursue organ preservation, patients surgically unfit for cystectomy, patients medically unfit for cisplatin-based chemotherapy, and borderline cystectomy candidates based on age with unilateral hydronephrosis and normal renal function. We identified key areas of controversy, including use of definitive radiation therapy for patients with negative prognostic factors, appropriate radiation therapy dose, fractionation, fields and technique when used, and chemotherapy sequencing and choice of agent. Conclusions There is limited level-one evidence to guide appropriate treatment of MIBC. Studies vary significantly with regards to patient selection, chemotherapy use, and radiation therapy technique. A consensus guideline on the appropriateness of RT for MIBC may aid practicing oncologists in bridging the gap between data and clinical practice.

Purpose MRI-assisted radiosurgery (MARS) is a modern technique for prostate brachytherapy that provides superior soft tissue contrast. The purpose of this analysis was to evaluate treatment planning factors associated with urinary toxicity, particularly damage to the membranous urethra (MUL) and external urethral sphincter (EUS), after MARS. Material and Methods We retrospectively reviewed 227 patients treated with MARS. Comparisons were made between several factors including preimplantation length of the MUL and EUS dosimetric characteristics after implantation with longitudinal changes in American Urological Association (AUA) urinary symptom score. Results Rates of grade 3 urinary incontinence and obstructive urinary symptoms were 4% and 2%. A piecewise mixed univariate model revealed that MUL and V200, V150, V125, and D5 to the EUS were all associated with increased rates of urinary toxicity over time. On univariate logistic regression, MUL >14.2 mm (odds ratio [OR] 2.03 per cm3, 95% confidence interval [CI] 1.10–3.77, p = 0.025), V125 to the EUS (OR 3.21 cm3, 95% CI 1.18–8.71, p = 0.022), and use of the I-125 isotope (OR 3.45, 95% CI 1.55–7.70, p = 0.001) were associated with subacute urinary toxicity (i.e., that occurring at 4–8 months). Optimal dose-constraint limits to the EUS were determined to be V200 Conclusions MARS brachytherapy provides detailed anatomic information for treatment planning, implantation, and quality assurance. Overall rates of urinary toxicity are low; however, several dosimetric variables associated with the EUS were found to correlate with urinary toxicity.

Patients with prostate cancer presenting with advanced T stage, mainly T4, might have a unique pattern of nodal failure and disease involvement that is not typically covered when local therapy is offered. We attempted to identify common sites of nodal disease presentation and failure for patients presenting with cT4 prostate cancer.All patients with treatment-naïve cT4 prostate cancer were retrospectively identified. All patients were required to have a confirmed diagnosis reviewed by our genitourinary pathologist and completed baseline staging. Lymph node (LN) involvement and location at diagnosis were reviewed by a genitourinary radiologist. All patients' follow-up scans were also reviewed; based on LN size, imaging characteristics, and progression/regression characteristics on systemic therapy, the locations of sites of LN failure were recorded. For patients who underwent surgery, any pathologically involved LNs and their anatomic locations were recorded. A total of 103 patients met these criteria, with a median follow-up of 8 years (range, 0.5-14 years).Rectal involvement by the primary disease was associated with a higher risk of perirectal and mesorectal LN involvement (45%) relative to no rectal involvement (26%) (P.05). These echelons are typically not covered with conventional pelvic external beam radiation therapy and are not routinely part of pelvic LN dissection in patients treated surgically. Conversely, bladder or pelvic side wall invasion did not correlate with increased frequency of involvement of perirectal/mesorectal LNs (P.05).When offering local therapy, target modification to include the perirectal and mesorectal LNs should be considered for patients presenting with T4 prostate cancer with rectal involvement.

PURPOSE: Recent trends in payer and patient preferences increasingly incentivize time-efficient (≤2-week treatment time) prostate cancer treatments. METHODS AND MATERIALS: National Medicare claims from January 1, 2011, through December 31, 2014, were analyzed to identify newly diagnosed prostate cancers. Three “radical treatment” cohorts were identified (prostatectomy, brachytherapy, and stereotactic body radiation therapy [SBRT]) and matched to an active surveillance (AS) cohort by using inverse probability treatment weighting via propensity score. Total costs at 1 year after biopsy were calculated for each cohort, and treatment-specific costs were estimated by subtracting total 1-year costs in each radical treatment group from those in the AS group. RESULTS: Mean 1-year adjusted costs were highest among patients receiving SBRT ($26,895), lower for prostatectomy ($23,632), and lowest for brachytherapy ($19,980), whereas those for AS were $9687. Costs of radical modalities varied significantly by region, with the Mid-Atlantic and New England regions having the highest cost ranges (>$10,000) and the West South Central and Mountain regions the lowest range in costs (

Soft tissue sarcoma (STS) of the sella is exceptionally rare. We conducted a case series, literature review, and nationwide analysis of primary and iatrogenic (radiation-associated) STS of the sella to define the clinical course of this entity. This study employed a multi-institutional retrospective case review, literature review, and nationwide analysis using the National Cancer Database (NCDB). We report five patients who were diagnosed at three institutions with malignant STS of the sella. All patients presented with symptoms related to mass effect in the sellar region. All tumors extended to the suprasellar space, with the majority displaying extension into the cavernous sinus. All patients underwent an operation via a transsphenoidal approach with a goal of maximal safe tumor resection in four patients and biopsy for 1 patient. Histopathologic evaluation demonstrated STS in all patients. Post-operative adjuvant radiotherapy and chemotherapy were given to 2 and 1 out of 4 patients with known post-operative clinical course, respectively. The 1-year and 5-year overall survival rates were 100% (5/5) and 25% (1/4). Twenty-two additional reports of primary, non-iatrogenic STS of the sella were identified in the literature. Including the three cases from our series, treatment included resection in all cases, and adjuvant radiotherapy and chemotherapy were utilized in 50% (12/24) and 17% (4/24) of cases, respectively. The national prevalence of malignant STS is estimated to be 0.01% among all pituitary and sellar tumors within the NCDB. We report the prevalence and survival rates of STS of the sella. Multimodal therapy, including maximal safe resection, chemotherapy, and radiotherapy are necessary to optimize outcomes for this uncommon pathology.

Structural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs., Structural variants (SVs) contribute to the genetic architecture of many brain-related disorders. Here, the authors integrate SV calls from genome sequencing (n = 755) with RNA-seq data (n = 629) from post-mortem dorsal lateral prefrontal cortex to annotate the gene regulatory effects of SVs in the human brain and their potential to contribute to disease.

Background Financial toxicity is emerging as an important patient-centered outcome and is understudied in prostate cancer patients. We sought to understand the association between financial burden and treatment regret in men with localized prostate cancer to better evaluate the role of financial discussions in patient counseling. Methods Utilizing the Comparative Effectiveness Analysis of Surgery and Radiation dataset, we identified all men accrued between 2011 and 2012 who underwent surgery, radiation, or active surveillance for localized prostate cancer. Financial burden and treatment regret were assessed at 3- and 5-year follow-up. The association between financial burden and regret was assessed using multivariable longitudinal logistic regression controlling for demographic and disease characteristics, treatment, functional outcomes, and patient expectations. Results Of the 2924 eligible patients, regret and financial burden assessments for 3- and/or 5-year follow-up were available for 81% (n = 2359). After adjustment for relevant covariates, financial burden from “finances in general” was associated with treatment regret at 3 years (odds ratio [OR] = 2.47, 95% confidence interval [CI] = 1.33 to 4.57; P = .004); however, this association was no longer statistically significant at 5-year follow-up (OR = 1.19, 95% CI = 0.56 to 2.54; P = .7). Conclusions In this population-based sample of men with localized prostate cancer, we observed associations between financial burden and treatment regret. Our findings suggest indirect treatment costs, especially during the first 3 years after diagnosis, may impact patients more profoundly than direct costs and are important for inclusion in shared decision making.

PURPOSE: We aim to compare patient-reported mental health outcomes for men undergoing treatment for localized prostate cancer, longitudinally over 5 years. MATERIALS & METHODS: We conducted a prospective population-based analysis using the Comparative Effectiveness Analysis of Surgery and Radiation study (CEASAR) study. Patient-reported depressive symptoms (Centers for Epidemiologic Studies Depression, CES-D) and domains of the Medical Outcomes Study 36-item short form survey evaluating emotional well-being and energy/fatigue, were assessed through 5 years after treatment with surgery, radiotherapy (with or without androgen deprivation therapy) and active surveillance. Regression models were adjusted for outcome-specific baseline function, demographic and clinicopathologic characteristics, and treatment approach. RESULTS: 2742 men (median [quartiles] age 64 [59–70]) met inclusion criteria. Baseline depressive symptoms, as measured by the CES-D, were low (median 4, quartiles 1–8) without differences between groups. We found no effect of treatment modality on depressive symptoms (p= 0.78), though older age, poorer health, being unmarried, and baseline CES-D score were associated with declines in mental health. There was no clinically meaningful association between treatment modality and scores for either emotional well-being (p=0.81) or energy/fatigue (p=0.054). CONCLUSIONS: This prospective, population-based cohort study of men with localized prostate cancer showed no clinically important differences in mental health outcomes including depressive symptoms, emotional well-being, and energy/fatigue according to the treatment received (surgery, radiotherapy, or surveillance). However, we identified a number of characteristics associated with worse mental health outcomes including: older age, poorer health, being unmarried, and baseline CES-D score which may allow for early identification of patients most at risk of these outcomes following treatment.

Importance Treatment-related regret is an integrative, patient-centered measure that accounts for morbidity, oncologic outcomes, and anxiety associated with prostate cancer diagnosis and treatment. Objective To assess the association between treatment approach, functional outcomes, and patient expectations and treatment-related regret among patients with localized prostate cancer. Design, setting, and participants This population-based, prospective cohort study used 5 Surveillance, Epidemiology, and End Results (SEER)-based registries in the Comparative Effectiveness Analysis of Surgery and Radiation cohort. Participants included men with clinically localized prostate cancer from January 1, 2011, to December 31, 2012. Data were analyzed from August 2, 2020, to March 1, 2021. Exposures Prostate cancer treatments included surgery, radiotherapy, and active surveillance. Main outcomes and measures Patient-reported treatment-related regret using validated metrics. Regression models were adjusted for demographic and clinicopathologic characteristics, treatment approach, and patient-reported functional outcomes. Results Among the 2072 men included in the analysis (median age, 64 [IQR, 59-69] years), treatment-related regret at 5 years after diagnosis was reported in 183 patients (16%) undergoing surgery, 76 (11%) undergoing radiotherapy, and 20 (7%) undergoing active surveillance. Compared with active surveillance and adjusting for baseline differences, active treatment was associated with an increased likelihood of regret for those undergoing surgery (adjusted odds ratio [aOR], 2.40 [95% CI, 1.44-4.01]) but not radiotherapy (aOR, 1.53 [95% CI, 0.88-2.66]). When mediation by patient-reported functional outcomes was considered, treatment modality was not independently associated with regret. Sexual dysfunction, but not other patient-reported functional outcomes, was significantly associated with regret (aOR for change in sexual function from baseline, 0.65 [95% CI, 0.52-0.81]). Subjective patient-perceived treatment efficacy (aOR, 5.40 [95% CI, 2.15-13.56]) and adverse effects (aOR, 5.83 [95% CI, 3.97-8.58]), compared with patient expectations before treatment, were associated with treatment-related regret. Other patient characteristics at the time of treatment decision-making, including participatory decision-making tool scores (aOR, 0.80 [95% CI, 0.69-0.92]), social support (aOR, 0.78 [95% CI, 0.67-0.90]), and age (aOR, 0.78 [95% CI, 0.62-0.97]), were significantly associated with regret. Results were comparable when assessing regret at 3 years rather than 5 years. Conclusions and relevance The findings of this cohort study suggest that more than 1 in 10 patients with localized prostate cancer experience treatment-related regret. The rates of regret appear to differ between treatment approaches in a manner that is mediated by functional outcomes and patient expectations. Treatment preparedness that focuses on expectations and treatment toxicity and is delivered in the context of shared decision-making should be the subject of future research to examine whether it can reduce regret.

ObjectiveLittle is known about clinicians’ decision-making about decreasing active surveillance (AS) testing/converting patients to watchful waiting (WW), nor are there any guidelines. The objective of this study was to identify factors that clinicians consider when decreasing AS testing/converting to WW for men with prostate cancer.DesignExploratory qualitative study.SettingAll participants practiced in various institutions in the USA.ParticipantsEligible clinicians had to provide clinical care for patients with prostate cancer in the USA and speak English. Clinicians could be either urologists or radiation oncologists. Of the 24 clinicians, 83% were urologists representing 11 states, 92% were men and 62% were white.MethodsThis qualitative study used data from semi-structured interviews. Purposive sampling was used to ensure geographical variation in the USA. Data collection continued until thematic saturation was achieved. Framework analysis guided coding and identification of themes. Two researchers coded all transcripts independently, met to discuss and reached consensus.ResultsInterviews with clinicians demonstrated that testing or monitoring for AS or transitioning to WW is happening in practice, whether intentionally or unintentionally. Decisions to decrease AS were personalised and tailored to patients’ health status. Life expectancy was the dominant factor that influenced decision, but clinicians were generally hesitant to specify an age when they would decrease AS or transition to WW. Fear that poor adherence could lead to missed progression and concerns about the medico-legal issue of not doing enough were cited as barriers to decreasing AS.ConclusionsThese findings suggest that in certain situations, AS frequency is reduced or transitioned to WW, yet decisions appear to be inconsistent and there are no significant barriers. These findings could inform further areas to explore when drafting recommendations that consider patients’ values and preferences when making decisions about decreasing AS/converting to WW.

Background Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy – Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM. Methods FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders. Results Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores. Conclusion The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach. Trial registration This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.

PurposeThe EPIC-26 (Expanded Prostate Cancer Index Composite-Short Form) is a validated questionnaire for measuring health related quality of life. However, the relationship between domain scores and functional outcomes remains unclear, leading to potential confusion about expectations after treatment. For instance, does a sexual function domain score of 80 mean that a patient can achieve erection sufficient for intercourse? Consequently we sought to determine the relationship between the domain score and the response to obtaining the best possible outcome for each question.Materials and methodsUsing data from the CEASAR (Comparative Effectiveness Analysis of Surgery and Radiation) study, a multicenter, prospective study of men diagnosed with localized prostate cancer, we analyzed 11,464 EPIC-26 questionnaires from a total of 2,563 men at baseline through 60 months of followup who were treated with robotic prostatectomy, radiotherapy or active surveillance. We dichotomized every item into its best possible outcome and assessed the percent of men at each domain score who achieved the best result.ResultsFor every EPIC-26 item the frequency of the best possible outcome was reported by domain score category. For example, a score of 80 to 100 on sexual function corresponded to 97% of men reporting erections sufficient for intercourse while at a score of 40 to 60 only 28% reported adequate erections. Also, at a score of 80 to 100 on the urinary incontinence domain 93% of men reported rarely or never leaking vs 6% at a score of 61 to 80.ConclusionsOur findings indicate a novel way to interpret EPIC-26 domain scores, demonstrating large variations in the percent of respondents reporting the best possible outcomes over narrow domain score differences. This information may be valuable when counseling men on treatment options.

BACKGROUND The purpose of this study was to assess treatment choices among men with prostate cancer who presented at The University of Texas MD Anderson Cancer Center multidisciplinary (MultiD) clinic compared with nationwide trends. METHODS In total, 4451 men with prostate cancer who presented at the MultiD clinic from 2004 to 2016 were analyzed. To assess nationwide trends, the authors analyzed 392,710 men with prostate cancer who were diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. The primary endpoint was treatment choice as a function of pretreatment demographics. RESULTS Univariate analyses revealed similar treatment trends in the MultiD and SEER cohorts. The use of procedural forms of definitive therapy decreased with age, including brachytherapy and prostatectomy (all P

Light is a potent biologic force that profoundly influences circadian, neuroendocrine, and neurobehavioral regulation in animals. Previously we examined the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit more light in the blue-appearing portion of the visible spectrum (465 to 485 nm) than do broad-spectrum cool white fluorescent (CWF) light, on the nighttime melatonin amplitude and circadian regulation of metabolism and physiology. In the current studies, we tested the hypothesis that exposure to blue-enriched LED light at day (bLAD), compared with CWF, promotes the circadian regulation of neuroendocrine, metabolic, and physiologic parameters that are associated with optimizing homeostatic regulation of health and wellbeing in 3 mouse strains commonly used in biomedical research (C3H [melatonin-producing], C57BL/6, and BALB/c [melatonin-non-producing]). Compared with male and female mice housed for 12 wk under 12:12-h light:dark (LD) cycles in CWF light, C3H mice in bLAD evinced 6-fold higher peak plasma melatonin levels at the middark phase; in addition, high melatonin levels were prolonged 2 to 3 h into the light phase. C57BL/6 and BALB/c strains did not produce nighttime pineal melatonin. Body growth rates; dietary and water intakes; circadian rhythms of arterial blood corticosterone, insulin, leptin, glucose, and lactic acid; pO2 and pCO2; fatty acids; and metabolic indicators (cAMP, DNA, tissue DNA 3H-thymidine incorporation, fat content) in major organ systems were significantly lower and activation of major metabolic signaling pathways (mTOR, GSK3β, and SIRT1) in skeletal muscle and liver were higher only in C3H mice in bLAD compared with CWF. These data show that exposure of C3H mice to bLAD compared with CWF has a marked positive effect on the circadian regulation of neuroendocrine, metabolic, and physiologic parameters associated with the promotion of animal health and wellbeing that may influence scientific outcomes. The absence of enhancement in amelatonic strains suggests hyperproduction of nighttime melatonin may be a key component of the physiology.

The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders remain unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells (hiPSCs), to evaluate the effects of schizophrenia-associated common variants predicted to function as brain expression quantitative trait loci (SZ-eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ-eQTL (FURIN rs4702) and four top-ranked SZ-eQTL genes (FURIN, SNAP91, TSNARE1, CLCN3), our platform resolves pre- and post-synaptic neuronal deficits, recapitulates genotype-dependent gene expression differences, and identifies convergence downstream of SZ-eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ-eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.

Purpose Optimal treatment of patients diagnosed with de novo metastatic breast cancer limited to the mediastinum or sternum has never been delineated. Herein, we sought to determine the efficacy of multimodality treatment, including metastasis-directed radiation therapy, in curing patients with this presentation. Methods and Materials This is a single-institution retrospective cohort study of patients with de novo metastatic breast cancer treated from 2005 to 2014, with a 50-month median follow-up for the primary cohort. The primary patient cohort had metastasis limited to the mediastinum/sternum treated with curative intent (n = 35). We also included a cohort of patients with stage IIIC disease treated with curative intent (n = 244). Additional groups included a mediastinal/sternal palliative cohort (treatment did not include metastasis-directed radiation therapy; n = 14) and all other patients with de novo stage IV disease (palliative cohort; n = 1185). The primary study outcomes included locoregional recurrence-free survival (LRRFS), recurrence-free survival (RFS), and overall survival (OS), which were calculated using the Kaplan-Meier method. Cox multivariable models compared survival outcomes across treatment cohorts adjusted for molecular subtype, age, and race. Results For the mediastinal/sternal curative-intent cohort, 5-year LRRFS was 85%, RFS was 52%, and OS was 63%. After adjustment, there was no statistically significant difference in LRRFS (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.13-1.13; P = .08), RFS (HR, 0.87; 95% CI 0.50-1.49; P = .61), or OS (HR, 0.79; 95% CI 0.44-1.43; P = .44) between the stage IIIC cohort and the mediastinal/sternal curative-intent cohort (referent). In contrast, RFS was worse for the mediastinal/sternal palliative cohort (HR, 2.29; 95% CI 1.05-5.00; P = .04). OS was worst for the de novo stage IV palliative cohort (HR, 2.61; 95% CI 1.50-4.53; P Conclusions For select patients presenting with breast cancer metastatic to the sternum and/or mediastinum, curative-intent treatment with chemotherapy, surgery, and radiation yields outcomes similar to those of stage IIIC disease and superior to de novo stage IV breast cancer treated with palliative intent.

Purpose To determine the long-term outcomes for prostate adenocarcinoma when escalating radiation dose from 70 Gy to 78 Gy. Methods and Materials Between 1993 and 1998, 301 patients with biopsy-proven clinical stage T1b-T3 prostate adenocarcinoma, any prostate-specific antigen level, and any Gleason score were randomized to 70 Gy in 35 fractions versus 78 Gy in 39 fractions of photon radiation therapy using a 4-field box technique without hormone deprivation therapy. The primary outcome was powered to detect a 15% difference in biochemical or clinical failure. Secondary outcomes included survival, prostate cancer mortality, biochemical failure, local failure, nodal failure, distant failure, and secondary malignancy rates. Results With a median follow-up of 14.3 years, the cumulative incidence of 15-year biochemical or clinical failure was 18.9% versus 12.0% in the 70 Gy versus 78 Gy arms, respectively (subhazard ratio [sHR], 0.61; 95% confidence interval [CI], 0.38-0.98; Fine-Gray P = .042). The 15-year cumulative incidence of distant metastasis was 3.4% versus 1.1%, respectively (sHR, 0.33; 95% CI, 0.13-0.82; Fine-Gray P = .018). The 15-year cumulative incidence of prostate cancer-specific mortality was 6.2% versus 3.2%, respectively, (sHR, 0.52; 95% CI, 0.27-0.98; Fine-Gray P = .045). There were no differences in overall survival (HR, 1.10; 95% CI, 0.84-1.45; log rank P = .469) or other-cause survival (sHR, 1.33; 95% CI, 0.99-1.79; Fine-Gray P = .061). Salvage therapy was more common in the 70 Gy arm, at 38.7% versus 21.9% in the 78 Gy arm (P = .002). There was a 2.3% secondary solid malignancy rate (1 bladder, 6 rectal) within the radiation treatment field, which was not significantly different between treatment arms. Conclusions Dose escalation by 8 Gy (78 Gy vs 70 Gy) provided a sustained improvement in biochemical and clinical failure, which translated into lower salvage rates and improved prostate cancer-specific mortality, but not overall survival. Long-term follow-up demonstrated a low incidence of potential solid tumor secondary malignancies.

Subcellular RNAseq promises to dissect transcriptional dynamics but is not well characterized. Furthermore, FACS may introduce bias but has not been benchmarked genome-wide. Finally, D1 and D2 dopamine receptor-expressing medium spiny neurons (MSNs) of the nucleus accumbens (NAc) are fundamental to neuropsychiatric traits but have only a short list of canonical surface markers. We address these gaps by systematically comparing nuclear-FACS, whole cell-FACS, and RiboTag affinity purification from D1- and D2-MSNs. Using differential expression, variance partitioning, and co-expression, we identify the following trade-offs for each method. RiboTag-seq best distinguishes D1- and D2-MSNs but has the lowest transcriptome coverage. Nuclear-FACS-seq generates the most differentially expressed genes and overlaps significantly with neuropsychiatric genetic risk loci, but un-annotated genes hamper interpretation. Whole cell-FACS is more similar to nuclear-FACS than RiboTag, but captures aspects of both. Using pan-method approaches, we discover that transcriptional regulation is predominant in D1-MSNs, while D2-MSNs tend towards cytosolic regulation. We are also the first to find evidence for moderate sexual dimorphism in these cell types at baseline. As these results are from 49 mice (nmale = 39, nfemale = 10), they represent generalizable ground-truths. Together, these results guide RNAseq methods selection, define MSN transcriptomes, highlight neuronal sex differences, and provide a baseline for D1- and D2-MSNs.

Background: A limited pool of nurse faculty has affected enrollment of nursing students and the ability to produce the nursing workforce needed for the evolving health care system. The experiences clinical nurses face as they transition to the faculty role may contribute to the faculty shortage. Method: A qualitative descriptive study was conducted to explore the lived experiences of clinical nurses as they entered the nurse faculty role. A purposive sample was recruited from two higher learning institutions in the midwestern United States. Data analysis was performed using Colaizzi's method. Results: Four themes emerged: Perpetual Novice, Faculty as a Resource, Teaching Ambiguity, and Student as My Patient. The prominent theme surrounded the idea that the faculty were in a state of constant change as a perpetual novice. Conclusion: Implications exist for academic nursing program administration to invest in developing nurse faculty skill level and ease the transition to the role. [ J Nurs Educ. 2019;58(5):260–265.]

PURPOSE: To evaluate trends in fractionation and cost of radiation for bone metastasis during a time period of multiple national quality improvement initiatives that focused on reducing the number of fractions per radiation episode. METHODS: Using nationwide Medicare claims from 2011 to 2014, we identified radiation episodes for bone metastasis from prostate, lung, and breast cancer. Details regarding fractionation, radiation therapy (RT) modality, and sociodemographic characteristics were abstracted from claims. Time trends in use of 10 or fewer RT fractions per episode were evaluated using the Cochran-Armitage test. Total cost per episode was calculated from a payer’s perspective and reported in 2017 dollars; time trends in cost were assessed using linear regression. Generalized linear models identified predictors of treatment with 10 or fewer fractions. RESULTS: Of 51,533 episodes identified, 46,326 used 2D/3D RT, 3,199 used intensity-modulated RT, and 2,008 used stereotactic body RT. The proportion of 2D/3D RT episodes using 10 or fewer fractions increased from 65.5% to 79.7% ( Ptrend < .001), and mean total cost per episode decreased from $6,742 to $6,067 ( Ptrend < .001). Use of single-fraction radiation increased modestly for 2D/3D treatment (6.5% to 8.1%; Ptrend < .001). Predictors of 10 or fewer fractions included treatment in recent years, advanced age (≥ 85 years), and higher comorbidity score. Variation was noted based on geographic region and primary cancer. CONCLUSION: During a period with quality initiatives launched by the American Society for Radiation Oncology, American Board of Internal Medicine, and National Quality Forum, use of 10 or fewer fractions for bone metastasis increased by 14.2%, but single-fraction regimens increased by only 1.6%, highlighting opportunities for quality improvement.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C., Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

Background While schizophrenia differs between males and females in the age of onset, symptomatology, and disease course, the molecular mechanisms underlying these differences remain uncharacterized. Methods To address questions about the sex-specific effects of schizophrenia, we performed a large-scale transcriptome analysis of RNA sequencing data from 437 controls and 341 cases from two distinct cohorts from the CommonMind Consortium. Results Analysis across the cohorts identified a reproducible gene expression signature of schizophrenia that was highly concordant with previous work. Differential expression across sex was reproducible across cohorts and identified X- and Y-linked genes, as well as those involved in dosage compensation. Intriguingly, the sex expression signature was also enriched for genes involved in neurexin family protein binding and synaptic organization. Differential expression analysis testing a sex-by-diagnosis interaction effect did not identify any genome-wide signature after multiple testing corrections. Gene coexpression network analysis was performed to reduce dimensionality from thousands of genes to dozens of modules and elucidate interactions among genes. We found enrichment of coexpression modules for sex-by-diagnosis differential expression signatures, which were highly reproducible across the two cohorts and involved a number of diverse pathways, including neural nucleus development, neuron projection morphogenesis, and regulation of neural precursor cell proliferation. Conclusions Overall, our results indicate that the effect size of sex differences in schizophrenia gene expression signatures is small and underscore the challenge of identifying robust sex-by-diagnosis signatures, which will require future analyses in larger cohorts.

OBJECTIVE The coronavirus disease 2019 (COVID-19) pandemic disrupted the landscape of traditional neurosurgical subinternships, ramifications of which persist to this day. The outright cancellation of in-person subinternships in 2020 presented not only a challenge to both applicants and programs, but also an opportunity to establish an effective and efficient platform for virtual neurosurgical training. To address this need, the authors designed and trialed a novel virtual neurosurgical subinternship (Virtual Sub-I). METHODS The weeklong, case-based Virtual Sub-I program combined flipped-classroom and active learning approaches. Students worked in small groups to discuss neurosurgical cases. Faculty and residents offered personalized mentorship sessions to participants. Surveys were used to assess students’ experience with the authors’ subinternship program, consistent with level 1 of the Kirkpatrick model. RESULTS A total of 132 students applied from both international and American medical schools. The final cohort comprised 27 students, of whom 8 (30%) were female and 19 (70%) were male. Students characterized the subinternship as “interactive,” “educational,” and “engaging.” One hundred percent of survey respondents were “very likely” to recommend the Virtual Sub-I to their peers. Faculty involved in the Virtual Sub-I stated that the program allowed them to determine the fit of participating medical students for their neurosurgery residency program, and that information gathered from the Virtual Sub-I had the potential to influence their ranking decisions. CONCLUSIONS The Virtual Sub-I recapitulates the educational and interpersonal benefits of the traditional subinternship experience and can serve as a prototype for future virtual surgical education endeavors. Furthermore, the Virtual Sub-I presents a more equitable platform for introducing medical students across the undergraduate medical education spectrum to neurosurgical education and mentorship.

BackgroundThe role of pelvic irradiation in men receiving external beam radiotherapy (EBRT) for prostate cancer is unclear, in part due to a lack of data on patient-reported outcomes. We sought to compare functional outcomes for men receiving prostate and pelvic versus prostate-only radiotherapy, longitudinally over 5 years.Materials and methodsWe performed a population-based, prospective cohort study of men with clinically-localized prostate cancer undergoing EBRT. We examined the effect of prostate and pelvic (n = 102) versus prostate-only (n = 485) radiotherapy on patient-reported disease-specific (using the Expanded Prostate Cancer Index Composite[EPIC]-26) and general health-related (using the SF-36) function, over 5 years. Regression models were adjusted for outcome-specific baseline function, clinicopathologic characteristics, and androgen deprivation therapy (ADT).Results587 men (median [quartiles] age 69 [64-73] years) met inclusion criteria and completed ≥1 post-treatment survey. More men treated with prostate and pelvic radiotherapy had high-risk disease (58% vs. 18%, P < 0.01) and received ADT (75% vs. 41%, P < 0.01). These men reported worse sexual (6 months-5 years), hormonal (at 6 months), and physical (6 months-5 years) function. Accounting for baseline function, patient and tumor characteristics, and use of ADT, pelvic irradiation was not associated with statistically or clinically significant differences in bowel function, urinary incontinence, irritative voiding symptoms or sexual function through 5-years (all P > 0.05). Marginally clinically important differences were noted in hormonal function at 3-years (adjusted mean difference 4.7, 95% confidence interval [1.2-8.3]; minimally clinically important difference (MCID) 4 to 6) and 5-years (4.2, [0.4-8.0]) following treatment. After adjustment, there was a transient statistically significant, but not clinically important, difference in emotional well-being at 6 months (3.0, [0.19-5.8]; MCID 6) that resolved by 1 year and no differences in physical functioning or energy and fatigue.ConclusionThis prospective, population-based cohort study of men with localized prostate cancer treated with EBRT, showed no clinically important differences in disease-specific or general health-related quality of life with the addition of pelvic irradiation to prostate radiotherapy, supporting the use of pelvic radiotherapy when it may be of clinical benefit, such as men with increased risk of nodal involvement.

Major changes in the field of prostate cancer over the last 25 years include the implementation of prostate specific antigen screening and the recognition that BRCA confers hereditary risk of prostate cancer. Quality of life and survivorship have driven risk stratification for localized prostate cancer, facilitated by molecular signatures and leading to increased acceptance of active surveillance as a mainstream treatment option. Advances in technology have improved efficacy and reduced toxicity in both radical prostatectomy and radiation therapy for localized prostate cancer. Improved understanding of the androgen receptor has yielded substantially more effective therapies. Future growth areas include personalized treatment based on genomic and genetic information, theranostics radiopharmaceuticals, and more aggressive treatment of metastatic disease to include focal therapy. Multidisciplinary management between specialized urologists, radiation oncologists, and medical oncologists remains central to maximizing patient outcomes.

To provide the status of women neurosurgeons (WNS) in academic faculty and/or leadership positions in neurosurgery in the United States.Neurosurgery academic programs were defined as having an Accreditation Council for Graduate Medical Education (ACGME) neurosurgery residency program (NSRP). Using a Google search, gender, academic rank, postgraduate degrees, academic and clinical titles, and subspecialty were recorded for each neurosurgery faculty. Officer gender was recorded for the top 7 neurosurgery U.S. organizations, 7 subspecialty sections, and 50 state neurosurgical societies.WNS were faculty at 77% (89/115) of ACGME NSRPs and constituted 10% of the workforce (186/1773). WNS residents were in 92% of ACGME NSRPs and constituted 19% of the workforce (293/1515). Two NSRPs (8%) had neither WNS faculty nor WNS residents. Of NSRPs without WNS faculty, 52% (13/25) had a faculty size10. WNS accounted for 3% of NSRP chair positions. Academic rank of WNS faculty was lower than academic rank of men neurosurgeons faculty (P0.05). WNS faculty had a higher number of postgraduate degrees (P0.05). Pediatrics was the most common subspecialty (30%) among WNS. Over time, WNS held 1% of the leadership positions within the top 7 U.S. neurosurgery organizations and 7% within the 7 subspecialty sections. Over the past 20 years, 28% (14/50) of U.S. state neurosurgical societies had WNS serve as president.In 2020, the gender gap for U.S. WNS faculty and residents still exists. By providing informed benchmarks, our study might help neurosurgery organizations, medical school leadership, hiring committees, editors, and conference speakers to plan their next steps.

BACKGROUND To inform patients who are in the process of selecting prostate cancer treatment, the authors compared disease-specific function after external-beam radiotherapy (EBRT) alone versus EBRT plus a low-dose-rate (LDR) brachytherapy boost (EBRT-LDR). METHODS For this prospective study, men who had localized prostate cancer in 2011 and 2012 were enrolled. Assessments at baseline, 0.5, 1, 3, and 5 years included the patient-reported Expanded Prostate Index Composite, the 36-item Medical Outcomes Study Short-Form Health Survey, and treatment-related regret. Regression models were adjusted for baseline function and for patient and treatment characteristics. The minimum clinically important difference in scores on the Expanded Prostate Index Composite 26-item instrument was from 5 to 7 for urinary irritation and from 4 to 6 for bowel function. RESULTS Six-hundred ninety-five men met inclusion criteria and received either EBRT (n = 583) or EBRT-LDR (n = 112). Patients in the EBRT-LDR group were younger (median age, 66 years [interquartile range [IQR], 60-71 years] vs 69 years [IQR, 64-74 years]; P < .001), were less likely to receive pelvic radiotherapy (10% vs 18%; P = .040), and had higher baseline 36-item Medical Outcomes Study Short-Form Health Survey physical function scores (median score, 95 [IQR, 86-100] vs 90 [IQR, 70-100]; P < .001). Over a 3-year period, compared with EBRT, EBRT-LDR was associated with worse urinary irritative scores (adjusted mean difference at 3 years, -5.4; 95% CI, -9.3, -1.6) and bowel function scores (-4.1; 95% CI, -7.6, -0.5). The differences were no longer clinically meaningful at 5 years (difference in urinary irritative scores: -4.5; 95% CI, -8.4, -0.5; difference in bowel function scores: -2.1; 95% CI, -5.7, -1.4). However, men who received EBRT-LDR were more likely to report moderate or big problems with urinary function bother (adjusted odds ratio, 3.5; 95% CI, 1.5-8.2) and frequent urination (adjusted odds ratio, 2.6; 95% CI, 1.2-5.6) through 5 years. There were no differences in survival or treatment-related regret between treatment groups. CONCLUSIONS Compared with EBRT alone, EBRT-LDR was associated with clinically meaningful worse urinary irritative and bowel function over 3 years after treatment and more urinary bother at 5 years. LAY SUMMARY In men with prostate cancer who received external-beam radiation therapy (EBRT) with or without a brachytherapy boost (EBRT-LDR), EBRT-LDR was associated with clinically worse urinary irritation and bowel function through 3 years but resolved after 5 years. Men who received EBRT-LDR continued to report moderate-to-big problems with urinary function bother and frequent urination through 5 years. There was no difference in treatment-related regret or survival between patients who received EBRT and those who received EBRT-LDR. These intermediate-term estimates of function may facilitate counseling for men who are selecting treatment.

Purpose Several definitive treatment options are available for prostate cancer, but geographic access to those options is not uniform. We created maps illustrating provider practice patterns relation to patients and assessed the influence of distance to treatment receipt. Methods and Materials The patient cohort was created by searching the National Medicare Database for patients diagnosed and treated for prostate cancer from 2011 to 2014. The provider cohort was created by querying the American Medical Association Physician Masterfile to identify physicians who had treated patients with prostatectomy, intensity modulated radiation therapy (IMRT), brachytherapy, stereotactic body radiation therapy (SBRT), or proton therapy. Maps detailing the location of providers were created for each modality. Multivariate multinomial logistic regressions were used to assess the association between patient-provider distance and probability of treatment. Results Cohorts consisted of 89,902 patients treated by 5518 physicians. Substantial numbers of providers practicing established modalities (IMRT, prostatectomy, and brachytherapy) were noted in major urban centers, whereas provider numbers were reduced in rural areas, most notably for brachytherapy. Ninety percent of prostate cancer patients lived within 35.1, 28.9, and 55.6 miles of a practitioner of prostatectomy, IMRT, and brachytherapy, respectively. Practitioners of emerging modalities (SBRT and proton therapy) were predominantly concentrated in urban locations, with 90% of patients living within 128 miles (SBRT) and 374.5 miles (proton). Greater distance was associated with decreased probability of treatment (IMRT –3.8% per 10 miles; prostatectomy –2.1%; brachytherapy –2%; proton therapy –1.6%; and SBRT –1.1%). Conclusions Geographic disparities were noted for analyzed treatment modalities, and these disparities influenced delivery.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C., Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder., Epigenetic mechanisms have emerged as contributors to the molecular impairments caused by exposure to environmental factors such as abused substances. Here the authors perform epigenetic profiling of the striatum and identify the tyrosine kinase FYN is an important driver of neurodegenerative-like pathology and drug-taking behaviour.

Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiation therapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate- or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control.This prospective phase 2 single-arm trial enrolled men with low-volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone (AAP) once daily and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable prostate-specific antigen (PSA) at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual and hormonal quality of life.We enrolled 37 men between January 2014 and August 2016, 45% of whom were high risk. All patients had T1-2 disease and PSA20 ng/mL. Median follow-up is 37 months (95% confidence interval [CI], 35.7-39.1). Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no toxicities ≥G4. The rate of undetectable PSA at 12 months was 55% (95% CI, 36%-72%). With 46 months of median follow-up, 2 of 37 patients developed PSA progression (36-month PFS = 96%; 95% CI, 76%-99%), and 81% of patients recovered testosterone with a median time to recovery of 9.2 months. Hormonal or sexual function declined at 6 months with subsequent improvement by 24 months.The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of quality of life and excellent disease control in men with low-volume, intermediate- or high-risk localized prostate cancer. Prospective comparative studies are justified.

Prior studies suggest that nationally endorsed quality measures for prostate cancer care are not linked closely with outcomes. Using a prospective, population based cohort we measured clinically relevant variation in structure, process and outcome measures in men undergoing radical prostatectomy.The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) Study enrolled men with clinically localized prostate cancer diagnosed from 2011 to 2012 with 1,069 meeting the final inclusion criteria. Quality of life was assessed using the Expanded Prostate Index Composite (EPIC-26) and clinical data by chart review. Six quality measures were assessed, including pelvic lymphadenectomy with risk of lymph node involvement 2% or greater, appropriate nerve sparing, negative surgical margins, urinary and sexual function, treatment by high volume surgeon, and 30-day and 1-year complications. Receipt of high quality care was compared across categories of race, age, surgeon volume and surgical approach via multivariable analysis.There were no significant differences in quality across race, age or surgeon volume strata, except for worse urinary incontinence in Black men. However, robotic surgery patients experienced fewer complications (3% vs 9.3% short-term and 11% vs 16% long-term), were more likely to be treated by a high volume surgeon (47% vs 25%) and demonstrated better sexual function.In this cohort we did not identify meaningful variation in quality of care across racial groups, age groups and surgeon volume strata, suggesting that men are receiving comparable quality of care across these strata. However, we did find variation between open and robotic surgery with fewer complications, improved sexual function and increased use of high volume surgeons in the robotic group, possibly reflecting differences in quality between approaches, differences in practice patterns and/or biases in patient selection.

Background While the addition of androgen deprivation therapy (ADT) to external beam radiation therapy (EBRT) is known to improve overall survival (OS) in Gleason 8–10 (Grade Group 4–5) prostate cancer (PCa), it has been hypothesized that Gleason 9–10 disease, which is less differentiated than Gleason 8 disease, may be less sensitive to ADT. Objective To examine the association between ADT and OS for Gleason 8 versus Gleason 9–10 PCa. Design, setting, and participants A retrospective cohort study of 20 139 men from the National Cancer Database with localized or locally advanced, Gleason 8–10 PCa who received EBRT. Data were collected from 2004 to 2012. Intervention ADT. Outcome measurements and statistical analysis Cox proportional hazards regression was used to examine the association between ADT and OS. Results and limitations Overall, 9509 (78%) of the 12 160 men with Gleason 8 disease and 6908 (87%) of the 7979 men with Gleason 9–10 disease received ADT. On multivariable analysis, ADT was associated with a significant improvement in OS for Gleason 8 patients (adjusted hazard ratio 0.78, 95% confidence interval 0.70–0.87, p Conclusions In contrast to the significant survival advantage of ADT for Gleason 8 disease, our results suggest that Gleason 9–10 disease derives less survival benefit from ADT and that a higher Gleason score predicts lesser benefit. Consideration should be given to treatment intensification for Gleason 9–10 patients through enrollment in clinical trials or potentially adding novel antiandrogens or docetaxel, which have shown efficacy in both castration-resistant and castration-sensitive settings. Patient summary In this study, we examined the effect of androgen deprivation therapy (ADT) for Gleason 8 (Grade Group 4) versus Gleason 9–10 (Grade Group 5) prostate cancer. We found that Gleason 9–10 disease may derive a smaller survival benefit from ADT than Gleason 8 disease.

Introduction and objectiveThe timing of radiotherapy (RT) after prostatectomy is controversial, and its effect on sexual, urinary, and bowel function is unknown. This study seeks to compare patient-reported functional outcomes after radical prostatectomy (RP) and postprostatectomy radiation as well as elucidate the timing of radiation to allow optimal recovery of function.MethodsThe Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study is a prospective, population-based, observational study of men with localized prostate cancer. Patient-reported sexual, urinary, and bowel functional outcomes were measured using the 26-item Expanded Prostate Index Composite at baseline and at 6, 12, 36, and 60 months after enrollment. Functional outcomes were compared among men undergoing RP alone, post-RP adjuvant radiation (RP + aRT), and post-RP salvage radiation (RP + sRT) using multivariable models controlling for baseline clinical, demographic, and functional characteristics.ResultsAmong 1,482 CEASAR participants initially treated with RP for clinically localized prostate cancer, 11.5% (N = 170) received adjuvant (aRT, N = 57) or salvage (sRT, N = 113) radiation. Men who received post-RP RT had worse scores in all domains (sexual function [-9.0, 95% confidence interval {-14.5, -3.6}, P < 0.001], incontinence [-8.8, {-14.0, -3.6}, P < 0.001], irritative voiding [-5.9, {-9.0, -2.8}, P < 0.001], bowel irritative [-3.5, {-5.8, -1.2}, P = 0.002], and hormonal function [-4.5, {-7.2, -1.7}, P = 0.001]) compared to RP alone at 5 years of follow-up. Compared to men treated with RP alone in an adjusted linear model, sRT was associated with significantly worse scores in all functional domains. aRT was associated with significantly worse incontinence, urinary irritation, and hormonal function domain scores compared to RP alone at 5 years of follow-up. On multivariable modeling, RT administered approximately 24 months after RP was associated with the smallest decline in sexual domain score, with an adjusted mean decrease of 8.85 points (95% confidence interval [-19.8, 2.1]) from post-RP, pre-RT baseline.ConclusionsIn men with localized prostate cancer, post-RP RT was associated with significantly worse sexual, urinary, and bowel function domain scores at 5 years compared to RP alone. Radiation delayed for approximately 24 months after RP may be optimal for preserving erectile function compared to radiation administered closer to the time of RP.

Racial disparities are apparent in the management and outcomes for prostate cancer; however, disparities in compliance to quality measures for radiation therapy for prostate cancer have not been previously studied. Therefore, the goal of the study was to characterize disparities in the compliance rates with quality measures. The comparative effectiveness analysis of radiation therapy and surgery study is a population-based, prospective cohort study that enrolled 3708 men with clinically localized prostate cancer from 2011 to 2012. Compliance with 5 radiation-specific quality measures endorsed by national consortia as of 2011 was assessed, and compliance was compared by race using logistic regression. Overall, 604 men received definitive external beam radiation therapy (EBRT) of which 20% were self-reported black, 74% non-Hispanic white, and 6% Hispanic. Less than two-thirds of black and Hispanic men received EBRT that was compliant with all available quality measures (p = 0.012). Compared to white men, black men were less likely to receive dose-escalated EBRT (95% vs. 87%, p = 0.011) and less likely to avoid unnecessary pelvic radiation for low-risk disease (99% vs. 20%, p

Current diagnostic criteria for noncompaction cardiomyopathy (NCC) lack specificity, and the disease lacks prognostic indicators. Reverse apical rotation (RAR) with abnormal rotation of the cardiac apex in the same clockwise direction as the base has been described in adults with NCC. The aim of this study was to test the hypothesis that RAR might differentiate between symptomatic NCC and benign hypertrabeculations and might be associated with ventricular dysfunction.Echocardiograms from 28 children with NCC without cardiac malformations were prospectively compared with those from 29 age-matched normal control subjects. A chart review was performed to identify the patients' histories and clinical characteristics. Speckle-tracking was used to measure longitudinal strain, circumferential strain, and rotation.RAR occurred in 39% of patients with NCC. History of left ventricular (LV) dysfunction or arrhythmia was universal in, but not exclusive to, patients with RAR. Patients with RAR had lower LV longitudinal strain but similar ejection fractions compared with patients without RAR (median, -15.6% [interquartile range, -12.9% to -19.3%] vs -19% [interquartile range, -14.5% to -21.9%], P.01; 53% [interquartile range, 43% to 68%] vs 61% [interquartile range, 58% to 67%], P = .08). Only a pattern of contraction with RAR, early arrest of twisting by mid-systole, and premature untwisting was associated with lower ejection fraction (46%; interquartile range, 43% to 52%; P = .006).RAR is not a sensitive but is a specific indicator of complications in children with NCC. Therefore, RAR may have prognostic rather than diagnostic value. Premature untwisting of the left ventricle during ejection may be an even more worrisome indicator of LV dysfunction.

Hypofractionated prostate radiotherapy may increase biologically effective dose delivered while shortening treatment duration, but information on patient-reported urinary, bowel, and sexual function after dose-escalated hypofractionated radiotherapy is limited. We report patient-reported outcomes (PROs) from a randomized trial comparing hypofractionated and conventional prostate radiotherapy.Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity-modulated radiation therapy (CIMRT, 75.6 Gy in 1.8 Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4 Gy fractions). Questionnaires assessing urinary, bowel, and sexual function were completed pretreatment and at 2, 3, 4, and 5 years after treatment.Of 203 eligible patients, 185 were evaluable for PROs. A total of 173 completed the pretreatment questionnaire (82 CIMRT, 91 HIMRT) and 102 completed the 2-year questionnaire (46 CIMRT, 56 HIMRT). Patients who completed PROs were similar to those who did not complete PROs (all P0.05). Patient characteristics, clinical characteristics, and baseline symptoms were well balanced between the treatment arms (all P0.05). There was no difference in patient-reported bowel (urgency, control, frequency, or blood per rectum), urinary (dysuria, hematuria, nocturia, leakage), or sexual symptoms (erections firm enough for intercourse) between treatment arms at 2, 3, 4, and 5 years after treatment (all P0.01). Concordance between physician-assessed toxicity and PROs varied across urinary and bowel domains.We did not detect an increase in patient-reported urinary, bowel, and sexual symptom burden after dose-escalated intensity-modulated prostate radiation therapy using a moderate hypofractionation regimen (72 Gy in 2.4 Gy fractions) compared with conventionally fractionated radiation.

Nerve sparing contributes to the recovery of sexual and urinary function after radical prostatectomy but it may be ineffective in some patients or carry the risk of a positive surgical margin. We evaluated sexual and urinary function outcomes according to the degree of nerve sparing in patients with prostate cancer treated with radical prostatectomy.The CEASAR (Comparative Effectiveness Analysis of Surgery and Radiation) study is a prospective, population based, observational study of men diagnosed with localized prostate cancer in 2011 to 2012. Patient reported sexual and urinary functions were measured using the 26-item Expanded Prostate Index Composite at baseline within 6 months after diagnosis, and 6, 12 and 36 months after enrollment. Study inclusion criteria included radical prostatectomy as primary treatment, documentation of nerve sparing status and absent androgen deprivation therapy. Nerve sparing status was defined as none, unilateral or bilateral according to the operative report.The final analytical cohort included 991 men. The 11 men treated with unilateral nerve sparing and the 75 treated with a nonnerve sparing procedure were grouped together. In the multivariable model there was a significant difference in the sexual function score 3 years after radical prostatectomy in the bilateral nerve sparing group compared with the unilateral and nonnerve sparing group (6.1 points, 95% CI 2.0-10.3, p = 0.004). This was more pronounced in men with high baseline sexual function (8.23 points, 95% CI 1.6-14.8, p = 0.014) but not in those with low baseline function (4.0 points, 95% CI -0.6-8.7, p = 0.090). Similar effects were demonstrated on urinary incontinence scores.Bilateral nerve sparing resulted in better sexual and urinary function outcomes than unilateral or nonnerve sparing but the difference was not significant in men with low baseline sexual function.

Schizophrenia is a severe global health problem, with over half of such patients experiencing auditory verbal hallucinations (AVHs). A better understanding of the neural correlates differentiating patients experiencing AVHs from patients not experiencing AVHs and healthy controls may identify targets that lead to better treatment strategies for AVHs. Employing 2 data-driven, voxel-based measure of functional connectivity, we studied 46 patients with schizophrenia or schizoaffective disorder (28 experiencing AVHs and 18 not experiencing AVHs). Twenty healthy controls matched for age, gender, ethnicity, education level, handedness, and estimated verbal intelligence were included for comparison. The intrinsic connectivity distribution (ICD) was used to model each voxel’s connectivity to the rest of the brain using a Weibull distribution. To investigate lateralization of connectivity, we used cross-hemisphere ICD, a method that separates the contribution of each hemisphere to interrogate connectivity laterality. Patients with AVHs compared with patients without AVHs exhibited significantly decreased whole-brain connectivity in the medial prefrontal cortex and posterior cingulate cortex, less lateralized connectivity in left putamen, and more lateralized connectivity in left interior frontal gyrus. Correlations with Auditory Hallucination Rating Scale (AHRS) and post hoc seed connectivity analyses revealed significantly altered network connectivity. Using the results from all analyses comparing the patient groups and correlations with AHRS, we identified a potential AVH network, consisting of 25 nodes, showing substantial overlap with the default mode network and language processing networks. This network as a whole, instead of individual nodes, may represent actionable targets for interventions.

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Background: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Methods: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. Results: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44–0.79]; P P =0.05) and wild-type transthyretin amyloidosis (0.61 [0.43–0.87]; P =0.006); and baseline New York Heart Association class I and II (0.56 [0.38–0.82]; P =0.003) and class III (0.65 [0.41–1.01]; P =0.06). Conclusions: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01994889 and NCT02791230.

Mechanisms driving acute food allergic reactions have not been fully characterized. We profile the dynamic transcriptome of acute peanut allergic reactions using serial peripheral blood samples obtained from 19 children before, during, and after randomized, double-blind, placebo-controlled oral challenges to peanut. We identify genes with changes in expression triggered by peanut, but not placebo, during acute peanut allergic reactions. Network analysis reveals that these genes comprise coexpression networks for acute-phase response and pro-inflammatory processes. Key driver analysis identifies six genes (LTB4R, PADI4, IL1R2, PPP1R3D, KLHL2, and ECHDC3) predicted to causally modulate the state of coregulated networks in response to peanut. Leukocyte deconvolution analysis identifies changes in neutrophil, naive CD4+ T cell, and macrophage populations during peanut challenge. Analyses in 21 additional peanut allergic subjects replicate major findings. These results highlight key genes, biological processes, and cell types that can be targeted for mechanistic study and therapeutic targeting of peanut allergy., Rising rates of peanut allergy pose a public health problem. Here, the authors profile blood transcriptomes during double-blind, placebo-controlled oral challenge in peanut-allergic children to identify gene and cell composition changes, and construct causal networks to detect key allergic reaction drivers.

Background Relatively little is known about the relationship between race/ethnicity and patient-reported outcomes after contemporary treatments for localized prostate cancer. Objective To test the hypothesis that treatment-related changes in urinary, bowel, sexual, and hormonal function vary by race/ethnicity. Design, setting, and participants The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study is a prospective, population-based, observational study that enrolled 3708 men diagnosed with localized prostate cancer in 2011–2012. Outcome measurements and statistical analysis Patient-reported disease-specific function was measured using the 26-item Expanded Prostate Index Composite (EPIC) at baseline and 6 and 12 mo after enrollment. Mean treatment differences in function were compared by race using risk-adjusted generalized estimating equations. Results and limitations While all race/ethnic groups reported considerable declines in scores for urinary incontinence after radical prostatectomy (RP) when compared to active surveillance, African-American men reported a greater difference than white men did (adjusted difference-in-differences 8.4 points, 95% confidence interval 2.0–14.8; p =0.01). No difference in bother scores was noted and the overall proportion of explained variation attributable to race/ethnicity was relatively small in comparison to primary treatment and baseline function. No clinically significant racial variation was noted for the sexual, bowel, irritative voiding, or hormone domains. Limitations include the lack of well-established thresholds for clinical significance using the EPIC instrument. Conclusion While these data demonstrate that incontinence at 1 yr after RP may be worse for African-American compared to white men, the difference appears to be modest overall. Treatment selection and baseline function explain a much greater proportion of the variation in function after treatment. Patient summary We observed that the effect of treatment for prostate cancer on patient-reported function did not vary dramatically by race/ethnicity. Compared to white men, African-American men experienced a somewhat more pronounced decline in urinary continence after radical prostatectomy, but the corresponding changes in bother scores were not significantly different between the two groups.