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Pain control is important after penile surgery, and opioid use should be minimized as able. We sought to describe our experience performing complex penile surgeries with vs without post-operative opioids.A retrospective review of penile surgeries, including 3998 between 2009 and 2019. We identified patients8 years who underwent outpatient penile surgery requiring either penile degloving or hypospadias repair. Patients who were or were not prescribed opioids were matched 1:1 by age and type of penile surgery. Primary outcomes of interest were pain-related encounters, delayed opioid prescription, and predictors of pain.200 children were identified, 100 per group, with mean age 1.3 ± 0.8 years. 48% were penile degloving procedures, 31% hypospadias repairs with catheters, and the remaining 21% hypospadias repairs without catheters. Perioperative features were comparable between groups(p 0.05). 59% of patients without opioids had an impromptu post-operative encounter vs 41%, and 20% had an associated pain complaint vs 9%(p = 0.026). Two patients in both groups received delayed opioid prescription(p = 1.00). The presence of a catheter (OR 2.9) and no opioid prescription (OR 2.6) were independent predictors for pain complaint.Patients discharged without an opioid were more likely to contact a provider postoperatively and were more likely to endorse pain complaint (number needed to treat: 9).

Objective The investigators aimed to assess predictive factors of novel oppositional defiant disorder (ODD) among children and adolescents in the first 6 months following traumatic brain injury (TBI). Methods Children ages 5-14 years who experienced a TBI were recruited from consecutive admissions to five hospitals. Testing of a biopsychosocial model that may elucidate the development of novel ODD included assessment soon after injury (baseline) of preinjury characteristics, including psychiatric disorders, adaptive function, family function, psychosocial adversity, family psychiatric history, socioeconomic status, injury severity, and postinjury processing speed (which may be a proxy for brain injury). MRI analyses were also conducted to examine potential brain lesions. Psychiatric outcome, including that of novel ODD, was assessed 6 months after the injury. Results A total of 177 children and adolescents were recruited for the study, and 134 who were without preinjury ODD, conduct disorder, or disruptive behavior disorder not otherwise specified (DBD NOS) returned for the 6-month assessment. Of those who returned 6 months postinjury, 11 (8.2%) developed novel ODD, and none developed novel conduct disorder or DBD NOS. Novel ODD was significantly associated with socioeconomic status, preinjury family functioning, psychosocial adversity, and processing speed. Conclusions These findings show that an important minority of children with TBI developed ODD. Psychosocial and injury-related variables, including socioeconomic status, lower family function, psychosocial adversity, and processing speed, significantly increase risk for this outcome.

In this study, hospital discharge data from the 2016–2017 Healthcare Cost and Utilization Project were analyzed to describe national and, where data were available, state-specific prevalences of chronic hypertension and pregnancy-associated hypertension at delivery hospitalization. In 2016–2017, the prevalence of chronic hypertension was 216 per 10,000 delivery hospitalizations nationwide, ranging from 125 to 400 per 10,000 delivery hospitalizations in individual states. The prevalence of pregnancy-associated hypertension was 1021 per 10,000 delivery hospitalizations nationwide, ranging from 693 to 1382 per 10,000 delivery hospitalizations in individual states. The burden of hypertensive disorders in pregnancy remains high and varies considerably by jurisdiction.

Highlights • This feasibility study showed thyroid sparing in head and neck cancer patients. • Thyroid sparing with acceptable target volume coverage was possible with IMRT. • Average mean dose to thyroid was significantly reduced with thyroid optimization. • Thyroid optimized plans had relatively unchanged doses to surrounding OARs., Background Radiation-induced hypothyroidism is a common toxicity of head and neck radiation. Our re-planning study aimed to reduce thyroid dose while maintaining target coverage with IMRT. Methods We retrospectively identified patients with oral-cavity (n = 5) and oropharyngeal cancer (n = 5). Treatment plans were re-optimized with 45 Gy thyroid mean dose constraint, then we cropped the thyroid out of PTVs and further reduced thyroid dose. Target coverage was delivering 100% dose to ≥ 93% of PTV and 95% of dose to > 99% of PTV. Results Originally, average mean dose to thyroid was 5580 cGy. In model I, this dropped to 4325 cGy (p

Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors.

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms ‘graduate’ in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome., HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.

Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, and it's linked to a higher risk of academic failure, interpersonal issues, mental illness, and criminality. Despite several of the comparative and detailed reviews on the effects of ADHD interventions on core symptoms, there is no data summarizing the effects of aerobic exercise (AE) on executive functions (EFs). Therefore, this study aimed to systematically review and determine the relationship between AE (acute and chronic) dosage and EFs (attention, inhibition, set-shifting, and working memory) in youth with ADHD. The consideration of how AE dosage impacts aspects of EFs has not been investigated in detail previously. The study adhered to PRISMA guideline. Sixdatabases were searched without any date restrictions, up to February 2021, for articles relating to AE interventions to influence EFs in youth with ADHD ≤ 18 years old. Quality assessment of the reviewed papers was addressed. Thirteen studies met the inclusion criteria. Improvements in all aspects of EFs were reported after children with ADHD engaged in acute AE lasting 20-30 minutes with at least moderate intensity (65% ≤ 80% HRmax).Furthermore, chronic exercise that lasts at least 45 minutes and in the range of moderate tohigh intensity (i.e., 60% ≤ 75% HRmax), 3 days/week for 6-12, elicits additional benefits in inhibition and set-shifting.Different dosage of AE might differently influence aspects of EFs; however, this finding rests on preliminary evidence at this stage and thus should be treated with caution.It is necessary to establish suitable interventions with regard to the dosage of AE types to improve EFs in young people with ADHD.

Funder: Marie Curie; FundRef: https://doi.org/10.13039/501100000654, OBJECTIVES: To understand how people with Chronic Obstructive Pulmonary Disease (COPD) disavow their support needs and the impact on care. METHODS: Two stage mixed-method design. Stage 1 involved sub-analyses of data from a mixed-method population-based longitudinal study exploring the needs of patients with advanced COPD. Using adapted criteria from mental health research, we identified 21 patients who disavowed their needs from the 235 patient cohort. Qualitative interview transcripts and self-report measures were analysed to compare these patients with the remaining cohort. In stage 2 focus groups (n = 2) with primary healthcare practitioners (n = 9) explored the implications of Stage 1 findings. RESULTS: Patients who disavowed their support needs described non-compliance with symptom management and avoidance of future care planning (qualitative data). Analysis of self-report measures of mental and physical health found this group reported fewer needs than the remaining sample yet wanted more GP contact. The link between risk factors and healthcare professional involvement present in the rest of the sample was missing for these patients. Focus group data suggested practitioners found these patients challenging. DISCUSSION: This study identified patients with COPD who disavow their support needs, but who also desire more GP contact. GPs report finding these patients challenging to engage.

A biphasic computational model of a growing, vascularized glioma within brain tissue was developed to account for unique features of gliomas, including soft surrounding brain tissue, their low stiffness relative to brain tissue, and a lack of draining lymphatics. This model is the first to couple non-linear tissue deformation with porosity and tissue hydraulic conductivity to study the mechanical interaction of leaky vasculature and solid growth in an embedded glioma. The present model showed that leaky vasculature and elevated interstitial fluid pressure produces tensile stress within the tumor in opposition to the compressive stress produced by tumor growth. This tensile effect was more pronounced in softer tissue and resulted in a compressive stress concentration at the tumor rim that increased when tumor was softer than host. Aside from generating solid stress, fluid pressure driven tissue deformation decreased the effective stiffness of the tumor while growth increased it, potentially leading to elevated stiffness in the tumor rim. A novel prediction of reduced porosity at the tumor rim was corroborated by direct comparison with estimates from our in vivo imaging studies. Antiangiogenic and radiation therapy were simulated by varying vascular leakiness and tissue hydraulic conductivity. These led to greater solid compression and interstitial pressure in the tumor, respectively, the former of which may promote tumor infiltration of the host. Our findings suggest that vascular leakiness has an important influence on in vivo solid stress, stiffness, and porosity fields in gliomas given their unique mechanical microenvironment.

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. Registration: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.

Background Unilateral coronal craniosynostosis (UCS) is the third most prevalent form of craniosynostosis. Traditional treatment of UCS has been achieved with fronto-orbital advancement and cranial vault remodeling (FOAR), but utilization of cranial distraction osteogenesis (DO) techniques has increased. This study aims to compare perioperative complications and reoperation trends in FOAR versus DO techniques at a single institution. Methods An Institutional Review Board-approved retrospective review was performed from January 1999 to November 2018 at a single institution. Patients were those that have undergone FOAR or DO with an anterior rotational flap technique as previously described. Indications for secondary procedures included: contour deformities, relapse, surgical site infection, and persistent cranial defects. Results Eighty-one patients with UCS were identified, 64 patients underwent FOAR and 17 patients underwent DO. When perioperative characteristics were compared, patients who underwent DO were younger in age, however, there was no significant difference in transfusion requirement or length of stay between patient cohorts. Surgery time was increased in DO patients. When perioperative complications were compared, more intraoperative dural tears were observed in the FOAR cohort. When unplanned reoperation rates were compared, patients who had undergone FOAR had a statistically significant higher reoperation rates at 5 years of follow up. When including routine distractor removal as a reoperation, reoperative rate was increased in the DO cohort. No difference in reoperation rates was noted at 5 years following index operation. Conclusions The safety profile of DO is similar to that of traditional FOAR techniques for treatment of UCS. Longer-term follow-up studies are needed to elucidate whether outcomes are durable, but the unplanned reoperation rate in DO is less than that of FOAR at 5 years and presents several advantages that warrants its use in patients with UCS.

PURPOSE: Studies based on administrative databases show that infant pyeloplasty is associated with minority race/ethnicity but lack clinical data that may influence treatment. Our objective was to identify clinical and demographic factors associated with pyeloplasty in infants from three large tertiary centers. METHODS: We reviewed infants with unilateral Society for Fetal Urology (SFU) grade 3-4 hydronephrosis seen at three tertiary centers from 2/1/2018-9/30/2019. Patients were excluded if > 6 months old or treated surgically prior to the initial visit. Outcomes were: pyeloplasty < age 1 year and SFU grade on most recent ultrasound (US) within the first year. Covariables included: age at the initial visit, race/ethnicity, treating site, insurance type, febrile UTI, and initial imaging findings. Univariable and multivariable analyses were performed using log-rank tests and Cox proportional hazards models, respectively. RESULTS: 197 patients met study criteria; 19.3% underwent pyeloplasty. Pyeloplasty was associated with: treating site (p=0.03), SFU 4 on initial US (p =0.001), MAG-3 (p 20 minutes (p < 0.001) in patients undergoing a MAG-3 (n=107). MAG-3 (p

Introduction Black women are at disproportionately greater risk for HIV and sexually transmitted infections than women of other ethnic/racial backgrounds. Alcohol use may further elevate the risk of HIV/sexually transmitted infection acquisition and transmission. Study Design A random-assignment parallel-group comparative treatment efficacy trial was conducted with random assignment to 1 of 3 conditions. Setting/participants The sample comprised 560 Black or African American women aged 18–24 years who reported recent unprotected vaginal or anal sex and recent alcohol use. Participants were recruited from community settings in Atlanta, Georgia, from January 2012 to February 2014. Intervention A Group Motivational Enhancement Therapy module was designed to complement a Centers for Disease Control and Prevention–designated evidence-based intervention (Horizons) to reduce sexual risk behaviors, alcohol use, and sexually transmitted infections, with 3 comparison groups: (1) Horizons + Group Motivational Enhancement Therapy intervention, (2) Horizons + General Health Promotion intervention, and (3) enhanced standard of care. Main outcome measures Outcome measures included safe sex (abstinence or 100% condom use); condom nonuse; proportion of condom use during sexual episodes; incident chlamydia, gonorrhea, and trichomonas infections; and problematic alcohol use measured by Alcohol Use Disorders Identification Test score. Treatment effects were estimated using an intention-to-treat protocol‒generalized estimating equations with logistic regression for binomial outcomes and Poisson regression for count outcomes. Analyses were conducted between October 2018 and October 2019. Results Participants assigned to Horizons + Group Motivational Enhancement Therapy had greater odds of safe sex (AOR=1.45, 95% CI=1.04, 2.02, p=0.03), greater proportion of condom use (AOR=1.68, 95% CI=1.18, 2.41, p=0.004), and lower odds of condom nonuse (AOR=0.57, 95% CI=0.38, 0.83, p=0.004). Both interventions had lower odds of problematic alcohol use (Horizons: AOR=0.57, 95% CI=0.39, 0.85, p=0.006; Horizons + Group Motivational Enhancement Therapy: AOR=0.61, 95% CI=0.41, 0.90, p=0.01). Conclusions Complementing an evidence-based HIV prevention intervention with Group Motivational Enhancement Therapy may increase safer sexual behaviors and concomitantly reduce alcohol use among young Black women who consume alcohol. Trial registration This study is registered at www.clinicaltrials.gov NCT01553682.

Background Structural brain abnormalities in newborn animals after prolonged exposure to all routinely used general anaesthetics have raised substantial concerns for similar effects occurring in millions of children undergoing surgeries annually. Combining a general anaesthetic with non-injurious sedatives may provide a safer anaesthetic technique. We tested dexmedetomidine as a mitigating therapy in a sevoflurane dose-sparing approach. Methods Neonatal rats were randomised to 6 h of sevoflurane 2.5%, sevoflurane 1% with or without three injections of dexmedetomidine every 2 h (resulting in 2.5, 5, 10, 25, 37.5, or 50 μg kg−1 h−1), or fasting in room air. Heart rate, oxygen saturation, level of hypnosis, and response to pain were measured during exposure. Neuronal cell death was quantified histologically after exposure. Results Sevoflurane at 2.5% was more injurious than at 1% in the hippocampal cornu ammonis (CA)1 and CA2/3 subfields; ventral posterior and lateral dorsal thalamic nuclei; prefrontal, retrosplenial, and somatosensory cortices; and subiculum. Although sevoflurane 1% did not provide complete anaesthesia, supplementation with dexmedetomidine dose dependently increased depth of anaesthesia and diminished responses to pain. The combination of sevoflurane 1% and dexmedetomidine did not reliably reduce neuronal apoptosis relative to an equianaesthetic dose of sevoflurane 2.5%. Conclusions A sub-anaesthetic dose of sevoflurane combined with dexmedetomidine achieved a level of anaesthesia comparable with that of sevoflurane 2.5%. Similar levels of anaesthesia caused comparable programmed cell death in several developing brain regions. Depth of anaesthesia may be an important factor when comparing the neurotoxic effects of different anaesthetic regimens.

Objective To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls. Methods Peak aerobic capacity (VO2peak) and workload (Wpeak) were measured by cardiopulmonary exercise test (CPET) in 19 ambulatory SMA patients and 16 healthy controls. Submaximal exercise (SME) at 40% Wpeak was performed for 10 minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near‐infrared spectroscopy, determined muscle oxygen uptake (ΔHHb) at rest and during CPET and SME. Dual energy X‐ray absorptiometry assessed fat‐free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (FatigueSME) and six‐minute walk test (Fatigue6MWT), respectively. Results ΔHHb‐PEAK, ΔHHb‐SME, VO2peak, Wpeak, FFM%, and 6MWT distance were lower (P

Neoadjuvant therapy in breast cancer can downstage axillary lymph nodes and reduce extent of axillary surgery. As such, accurate determination of nodal status after neoadjuvant therapy and before surgery impacts surgical management. There are scarce data on the diagnostic accuracy of breast magnetic resonance imaging (MRI) for nodal evaluation after neoadjuvant therapy in patients with invasive lobular carcinoma (ILC), a diffusely growing tumor type. We retrospectively analyzed patients with stage 1–3 ILC who underwent pre-operative breast MRI after either neoadjuvant chemotherapy or endocrine therapy at our institution between 2006 and 2019. Two breast radiologists reviewed MRIs and evaluated axillary nodes for suspicious features. All patients underwent either sentinel node biopsy or axillary dissection. We evaluated sensitivity, specificity, negative and positive predictive values, and overall accuracy of the post-treatment breast MRI in predicting pathologic nodal status. Of 79 patients, 58.2% received neoadjuvant chemotherapy and 41.8% neoadjuvant endocrine therapy. The sensitivity and negative predictive value of MRI were significantly higher in the neoadjuvant endocrine therapy cohort than in the neoadjuvant chemotherapy cohort (66.7 vs. 37.9%, p = 0.012 and 70.6 vs. 40%, p = 0.007, respectively), while overall accuracy was similar. Upstaging from clinically node negative to pathologically node positive occurred in 28.0 and 41.7%, respectively. In clinically node positive patients, those with an abnormal post-treatment MRI had a significantly higher proportion of patients with ≥4 positive nodes on pathology compared to those with a normal MRI (61.1 versus 16.7%, p = 0.034). Overall, accuracy of breast MRI for predicting nodal status after neoadjuvant therapy in ILC was low in both chemotherapy and endocrine therapy cohorts. However, post-treatment breast MRI may help identify patients with a high burden of nodal disease (≥4 positive nodes), which could impact pre-operative systemic therapy decisions. Further studies are needed to assess other imaging modalities to evaluate for nodal disease following neoadjuvant therapy and to improve clinical staging in patients with ILC.

Objective: In the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC)

Posterior cruciate ligament (PCL) injuries commonly occur in association with participation in sporting or recreational activities or due to a direct trauma. Cartilage and meniscal lesions are prevalent in PCL-injured knees with increasing likelihood and severity based on extent and duration of trauma to the knee. As such, comprehensive diagnostics should be performed to ascertain all related pathology, and patients should be thoroughly educated regarding treatment options, likely sequelae including posttraumatic osteoarthritis, and associated outcomes. Treatments should address the joint as an organ, ensuring stability, alignment, and functional tissue restoration are optimized by the most efficient and effective means possible. Compliance with patient- and procedure-specific postoperative management protocols is critical for optimizing successful outcomes for these complex cases. The objectives of this review article are to highlight the likelihood and importance of osteochondral and meniscal pathology in the PCL-injured knee, and to provide the best current evidence regarding comprehensive evaluation and management for PCL-injured knees with cartilage and/or meniscal comorbidities.

INTRODUCTION The primary outcome metric in patients with craniosynostosis are changes in intracranial volumes (ICVs). In patients who undergo distraction osteogenesis (DO) to treat craniosynostosis, changes are also dependent on the length of distraction. Virtual surgical planning (VSP) has been used to predict anticipated changes in ICV during cranial vault reconstruction. The purpose of this study is to analyze the actual versus predicted ICV changes using VSP in patients who undergo DO for craniosynostosis management. METHODS All patients with craniosynostosis treated with DO at a single institution, Rady Children's Hospital, between December 2013 and May 2019 were identified. Inclusion criteria are as follows: VSP planning with predicted postoperative ICV values and preoperative and postdistraction CT scans to quantify ICV. Postoperative ICV and VSP-estimated ICV were adjusted for age-related ICV growth. The primary outcome measure calculated was age-adjusted percent volume change per millimeter distraction (PVCPD), and results were analyzed using paired Wilcoxon signed rank tests. RESULTS Twenty-seven patients underwent DO for cranial vault remodeling. Nineteen patients were nonsyndromic, and 8 patients were syndromic. The median postoperative PVCPD was 0.30%/mm, and the median VSP-estimated PVCPD was 0.36% per millimeter (P < 0.001). A subanalysis of nonsyndromic patients showed a median postoperative PVCPD of 0.29%/mm in nonsyndromic patients that differed significantly from the VSP estimate of 0.34%/mm (P = 0.003). There was also a significant difference in syndromic patients' observed PVCPD of 0.41%/mm versus VSP estimate of 0.79%/mm (P = 0.012). CONCLUSIONS Virtual surgical planning overestimates the change in ICV attributable to DO in both syndromic and nonsyndromic patients.

Missing data is common in electronic health records (EHR)-based obesity research. To avoid bias, it is critical to understand mechanisms that underpin missingness. We conducted a survey among bariatric surgery patients in three integrated health systems to (i) investigate predictors of disenrollment and (ii) examine differences in weight between disenrollees and enrollees at 5 years. We identified 2883 patients who had bariatric surgery between 11/2013 and 08/2014. Patients who disenrolled before their 5-year anniversary were invited to participate in a survey to ascertain reasons for disenrollment and current weight. Logistic regression was used to investigate predictors of disenrollment. Five-year percent weight change distributions were estimated using inverse-probability weighting to adjust for (un)availability of EHR weight data at 5 years among enrollees and survey (non-)response among disenrollees. Among 536 disenrolled patients, 104 (19%) completed the survey. Among 2347 patients who maintained enrollment, 384 (16%) had no weight measurement in the EHR near 5 years. Insurance, age, Hispanic ethnicity, and site predicted disenrollment. Disenrollees had slightly greater weight loss than enrollees. We found little evidence of weight loss differences by enrollment status. Collecting information through surveys can be an effective tool to investigate and adjust for missingness in EHR-based studies.

Rationale: Weight loss is recommended to treat obstructive sleep apnea (OSA).Objectives: To determine whether the initial benefit of intensive lifestyle intervention (ILI) for weight loss on OSA se...

Background There is no consensus on the treatment of blunt vertebral artery injuries, and studies are limited to small case series. We assessed the natural history and current management of these injuries. Methods We performed a retrospective study of a prospectively collected registry at a level I trauma center over a 5-year period. Additional information was gathered from patient charts and imaging review from electronic medical records. We analyzed demographics, mechanism of injury, Glasgow Coma Score, mortality, length of stay, associated injuries, Denver grading scale, neurological findings, level and laterality of injury, delay in diagnosis, treatment, and follow-up imaging. Results There were 13,080 trauma admissions during this time period yielding 141 patients with blunt vertebral artery injuries from 2013 to 2018 (1.1% incidence). Mean injury severity score (ISS) was 22 with a 30-day mortality of 14 (9.9%). An ISS of greater than 15 is associated with polytrauma and increased mortality. There were 112 (79.4%) associated cervical fractures. C6 and C7 were both equally the most common locations. There was one symptomatic injury manifesting as a cerebellar ischemic infarct. The degree of arterial injury was classified by the Denver grading scale. There were 61 (43.3%) instances of Denver grade I injuries, followed by grade IV at 36 (25.5%), grade II at 34 (24.1%), grade III at 8 (5.7%), and grade V at 1 (0.7%). The level of injury was recorded as follows: V2 = 67 (47.5%), V3 = 56 (39.7%), V1 = 48 (34%), V4 = 14 (9.9%). Medical therapy included aspirin in 93 patients (66%), 31 patients (22%) received systemic anticoagulation with heparin drip, and 2 patients (1%) were administered therapeutic Lovenox. A total of 15 patients (11%) received no medical treatment. There was one intervention in our series. Our only grade V injury was coil embolized. A total of 118 patients (84%) had follow-up imaging. Seventy-eight patients (96%) with grade I and grade II injuries did not worsen, and complete radiographic resolution was found in 50 patients (62%). Grade IV injuries persisted in 22 patients (75.9%). Median time to resolution for grade I and grade II injuries was 7 and 8 days, respectively. Most follow-up scans for grade I and II injuries occurred within 50 days. Conclusions Posterior circulation stroke due to blunt vertebral artery injury is rare. In our experience, the natural course of blunt vertebral artery injury was benign and neither delay in medical treatment nor choice of antithrombotic had a significant impact on outcomes. In our series, only 3 (3.7%) grade I and II injuries worsened and were without any clinical sequelae. We suggest that routine serial imaging in grade I and II blunt vertebral injuries is not warranted.

Traumatic brain injury (TBI) produces microstructural damage to white matter pathways connecting neural structures in pre-frontal and striatal regions involved in self-regulation (SR). Dorsal and ventral frontostriatal pathways have been linked to cognitive (“cool”) and emotional (“hot”) SR, respectively. We evaluated the relation of frontostriatal pathway fractional anisotropy (FA) 2 months post-TBI on cool and hot SR assessed 7 months post-TBI. Participants were 8–15 years of age, including children with uncomplicated mild TBI (mTBI; n = 24), more severe TBI (complicated-mild, moderate, severe [cms]TBI; n = 60), and typically developing (TD) children (n = 55). Diffusion tensor tractography was used to map frontostriatal pathways. Cool SR included focused and sustained attention performance, and parent-reported attention, whereas hot SR included risk-taking performance and parent-reported emotional control. Multivariate general linear models showed that children with cmsTBI had greater parent-reported cool and hot SR difficulties and lower dorsal and ventral FA than TD children. Focused attention, risk taking, and emotional control correlated with FA of specific dorsal and ventral pathways; however, only the effect of TBI on focused attention was mediated by integrity of dorsal pathways. Results suggest that frontostriatal FA may serve as a biomarker of risk for SR difficulties or to assess response to interventions targeting SR in pediatric TBI and in broader neurodevelopmental populations.

This study investigated patterns of cortical organization in adolescents who had sustained a traumatic brain injury (TBI) during early childhood to determine ways in which early head injury may alter typical brain development. Increased gyrification in other patient populations is associated with polymicrogyria and aberrant development, but this has not been investigated in TBI. Seventeen adolescents (mean age = 14.1 ± 2.4) who sustained a TBI between 1–8 years of age, and 17 demographically-matched typically developing children (TDC) underwent a high-resolution, T1-weighted 3-Tesla magnetic resonance imaging (MRI) at 6–15 years post-injury. Cortical white matter volume and organization was measured using FreeSurfer's Local Gyrification Index (LGI). Despite a lack of significant difference in white matter volume, participants with TBI demonstrated significantly increased LGI in several cortical regions that are among those latest to mature in normal development, including left parietal association areas, bilateral dorsolateral and medial frontal areas, and the right posterior temporal gyrus, relative to the TDC group. Additionally, there was no evidence of increased surface area in the regions that demonstrated increased LGI. Higher Vineland-II Socialization scores were associated with decreased LGI in right frontal and temporal regions. The present results suggest an altered pattern of expected development in cortical gyrification in the TBI group, with changes in late-developing frontal and parietal association areas. Such changes in brain structure may underlie cognitive and behavioral deficits associated with pediatric TBI. Alternatively, increased gyrification following TBI may represent a compensatory mechanism that allows for typical development of cortical surface area, despite reduced brain volume.

Background Student-run free clinics (SRFCs) provide medical care to uninsured, and surgical issues are often outside the normal scope of care of these clinics. The Shade Tree Clinic (STC) is an SRFC serving 300 patients with complex medical conditions. This study describes the implementation and efficacy of a General Surgery Specialty Clinic in this setting. Methods This descriptive study examines the demographics and referral patterns of patients seen in two pilot Specialty Clinics and other patients evaluated for general surgical issues from December 2017 to January 2020. Providers were surveyed regarding their experience in clinic. Results Twenty patients were evaluated by six general surgeons during 22 separate encounters (n = 20). Nine patients were seen in two pilot Specialty Clinics for biliary colic, hernia, hemorrhoids, anal mass, toenail lesion, surgical weight loss, and venous insufficiency. Referrals from these clinics to affiliated Vanderbilt University Medical Center included six ultrasounds; referrals to vascular surgery and podiatry clinics; and referrals for laparoscopic cholecystectomy and anal mass excision. STC also directly referred eight patients for colonoscopies and five patients for major operations through primary care clinic. Hundred percent of care was cost-free to patients. Providers reported a median satisfaction score of five with the Specialty Clinics (Very Satisfied; [4, 5]). Hundred percent of providers felt that the concerns of patients were addressed. Conclusions A surgery specialty clinic in the setting of an SRFC is an effective way to provide surgical care to underserved populations with the potential to reduce unplanned hospital utilization.

Although rates of total skin-sparing (nipple-sparing) mastectomies are increasing, the oncologic safety of this procedure has not been evaluated in invasive lobular carcinoma (ILC). ILC is the second most common type of breast cancer, and its diffuse growth pattern and high positive margin rates potentially increase the risk of poor outcomes from less extensive surgical resection. We compared time to local recurrence and positive margin rates in a cohort of 300 patients with ILC undergoing either total skin-sparing mastectomy (TSSM), skin-sparing mastectomy, or simple mastectomy between the years 2000–2020. Data were obtained from a prospectively maintained institutional database and were analyzed by using univariate statistics, the log-rank test, and multivariate Cox proportional hazards models. Of 300 cases, mastectomy type was TSSM in 119 (39.7%), skin-sparing mastectomy in 52 (17.3%), and simple mastectomy in 129 (43%). The rate of TSSM increased significantly with time (p

Ponatinib (Pon) is a multi-tyrosine kinase inhibitor that demonstrated high efficiency for treating cancer. However, severe side effects caused by Pon off-targeting effects prevent its extensive use. Using our understanding into the mechanisms by which Pon is transported by bovine serum albumin in the blood, we have successfully encapsulated Pon into a biomimetic nanoparticle (NP). This lipid NP (i.e., "leukosomes") incorporates membrane proteins purified from activated leukocytes that enable immune evasion, and enhanced targeting of inflamed endothelium NPs have been characterized for their size, charge, and encapsulation efficiency. Membrane proteins enriched on the NP surface enabled modulation of Pon release. These NP formulations showed promising dose-response results on two different murine osteosarcoma cell lines, F420 and RF379. Our results indicate that our fabrication method is reproducible, nonuser-dependent, efficient in loading Pon, and applicable toward repurposing numerous therapeutic agents previously shelved due to toxicity profiles.

Background: Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population.Methods: AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921.Findings: Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [Interpretation: Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke.Funding: National Health and Medical Research Council of Australia.

We developed and tested the feasibility of computational fluid modeling (CFM) based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for quantitative estimation of interstitial fluid pressure (IFP) and velocity (IFV) in patients with head and neck (HN) cancer with locoregional lymph node metastases. Twenty-two patients with HN cancer, with 38 lymph nodes, underwent pretreatment standard MRI, including DCE-MRI, on a 3-Tesla scanner. CFM simulation was performed with the finite element method in COMSOL Multiphysics software. The model consisted of a partial differential equation (PDE) module to generate 3D parametric IFP and IFV maps, using the Darcy equation and Ktrans values (min−1, estimated from the extended Tofts model) to reflect fluid influx into tissue from the capillary microvasculature. The Spearman correlation (ρ) was calculated between total tumor volumes and CFM estimates of mean tumor IFP and IFV. CFM-estimated tumor IFP and IFV mean ± standard deviation for the neck nodal metastases were 1.73 ± 0.39 (kPa) and 1.82 ± 0.9 × (10−7 m/s), respectively. High IFP estimates corresponds to very low IFV throughout the tumor core, but IFV rises rapidly near the tumor boundary where the drop in IFP is precipitous. A significant correlation was found between pretreatment total tumor volume and CFM estimates of mean tumor IFP (ρ = 0.50, P = 0.004). Future studies can validate these initial findings in larger patients with HN cancer cohorts using CFM of the tumor in concert with DCE characterization, which holds promise in radiation oncology and drug-therapy clinical trials.

Introduction and background A tetravalent DNA vaccine for Dengue virus is under development but has not yet achieved optimal immunogenicity. Salivary glands vaccination has been reported efficacious in rodents and dogs. We report on a pilot study testing the salivary gland as a platform for a Dengue DNA vaccine in a non-human primate model. Materials and methods Four cynomolgus macaques were used in this study. Each macaque was pre-medicated with atropine and sedated with ketamine. Stensen’s duct papilla was cannulated with a P10 polyethylene tube, linked to a 500ul syringe. On the first two infusions, all macaques were infused with 300ul of TVDV mixed with 2 mg of zinc. For the 3rd infusion, to increase transfection into salivary tissue, two animals received 100uL TVDV mixed with 400uL polyethylenimine 1μg/ml (PEI) and the other two animals received 500uL TVDV with zinc. Antibody titers were assessed 4 weeks following the second and third infusion. Results and conclusions SGRI through Stensen’s duct is a well-tolerated, simple and easy to reproduce procedure. TVDV infused into macaques salivary glands elicited a significantly weaker antibody response than with different delivery methods.

Qualification for bariatric surgery is based upon strict medical guidelines, but individual insurance companies may introduce additional requirements for approval and coverage as they deem necessary. A mandatory preoperative medical weight loss management (MWM) program is commonly such a requirement. The primary objective of this study is to assess the effect of MWM programs on weight loss outcomes. A retrospective review of all sleeve gastrectomies performed between 2012 and 2016 at our institution was conducted. Patients were divided into two groups: those who required a preoperative MWM program, and those who did not. A 1:1 greedy nearest-neighbor method matching algorithm was used to match patients based on age, BMI, smoking, gender, race, sleep apnea, and diabetes. Total weight loss and percent excess weight loss at 1 year for each group were compared. A total of 3059 sleeve gastrectomy patients were reviewed. Of these, 941 patients had adequate data points to be evaluated. The matching algorithm resulted in 530 patients for the final analysis, 265 patients in each group. There were no significant differences between the groups in terms of age, BMI, smoking, gender, race, sleep apnea, or diabetes. A paired t test found no significant differences between the MWM group and the control group at 1 year in both total weight loss (36.7 kg vs 36.2 kg) and in percent excess weight loss (56.5% vs 55.8%, p = 0.24). There was no significant difference in weight loss outcomes after 1 year in patients required by insurance to participate in MWM programs compared to those who were not. The necessity of these programs should be questioned.

Mitochondria play a variety of roles in the cell, far beyond their widely recognized role in ATP generation. One such role is the regulation and sequestration of calcium, which is done with the help of the mitochondrial calcium uniporter (MCU) and its regulators, MICU1 and MICU2. Genetic variations in MICU1 and MICU2 have been reported to cause myopathy, developmental disability and neurological symptoms typical of mitochondrial disorders. The symptoms of MICU1/2 deficiency have generally been attributed to calcium regulation in the metabolic and biochemical roles of mitochondria. Here, we report a female child with heterozygous MICU1 variants and multiple congenital brain malformations on MRI. Specifically, she shows anterior perisylvian polymicrogyria, dysmorphic basal ganglia, and cerebellar dysplasia in addition to white matter abnormalities. These novel findings suggest that MICU1 is necessary for proper neurodevelopment through a variety of potential mechanisms, including calcium‐mediated regulation of the neuronal cytoskeleton, Miro1‐MCU complex‐mediated mitochondrial movement, or enhancing ATP production. This case provides new insight into the molecular pathogenesis of MCU dysfunction and may represent a novel diagnostic feature of calcium‐based mitochondrial disease.

Objective: This study evaluated weight changes after cessation of the 10-year intensive lifestyle intervention (ILI) in the Look AHEAD (Action for Health in Diabetes) study. It was hypothesized that ILI participants would be more likely to gain weight during the 2-year observational period following termination of weight-loss-maintenance counseling than would participants in the diabetes support and education (DSE) control group. Methods: Look AHEAD was a randomized controlled trial that compared the effects of ILI and DSE on cardiovascular morbidity and mortality in participants with overweight/obesity and type 2 diabetes. Look AHEAD was converted to an observational study in September 2012. Results: Two years after the end of the intervention (EOI), ILI and DSE participants lost a mean (SE) of 1.2 (0.2) kg and 1.8 (0.2) kg, respectively (P = 0.003). In addition, 31% of ILI and 23.9% of DSE participants gained ≥ 2% (P < 0.001) of EOI weight, whereas 36.3% and 45.9% of the respective groups lost ≥ 2% of EOI weight (P = 0.001). Two years after the EOI, ILI participants reported greater use of weight-control behaviors than DSE participants. Conclusions: Both groups lost weight during the 2-year follow-up period, but more ILI than DSE participants gained ≥ 2% of EOI weight. Further understanding is needed of factors that affected long-term weight change in both groups.

Introduction Currently, the need for additional myofascial release (AMR) in addition to retromuscular dissection during open Rives-Stoppa hernia repair is determined intraoperatively based on the discretion of the surgeon. We developed a novel method to objectively predict the need for AMR preoperatively using computed tomography (CT)-measured rectus width to hernia width ratio (RDR). Methods A retrospective chart review of all patients who underwent open retro-muscular mesh repair of midline ventral hernia between August 1, 2007 and February 1, 2018, who had a preoperative CT scan within 1 year prior to their operation. The primary endpoint was the ability of the defect ratio to predict the need for AMR in pursuit of fascial closure. The secondary endpoint was the ability of Component Separation Index (CSI) to predict the need for AMR to obtain fascial closure. Results Of 342 patients, 208 repaired with rectus abdominis release alone (RM group), while 134 required AMR (RM + group). An RDR of > 1.34 on area under the curve analysis predicted the need for AMR with 77.6% accuracy. There was a linear decrease in the need for AMR with increasing RDR: RDR 2 in just 10.8%. Similarly, CSI > 0.146 predicted the need for AMR with 76.3% accuracy on area under the curve analysis. Conclusion The RDR is a practical and reliable tool to predict the ability to close the defect during open Rives-Stoppa ventral hernia repair without AMR. An RDR of > 2 portends fascial closure with rectus abdominis myofascial release alone in 90% of cases.

Pleomorphic invasive lobular carcinoma (ILC) has long been thought to have worse outcomes than classic ILC and is therefore often treated with chemotherapy. However, recent data question the utility of the pleomorphic designation, as the poor outcomes seen may be related to other associated high-risk features. Importantly, mitotic count may better define a subset of ILC with high risk of recurrence. We sought to determine the impact of pleomorphic histology versus mitotic count on disease-free survival (DFS) in pure ILC. Additionally, we evaluated whether pleomorphic histology was associated with receipt of chemotherapy when adjusting for other factors. We analyzed a cohort of 475 patients with stage I–III pure ILC. We used Kaplan–Meier estimates, and Cox proportional hazards and logistic regression for multivariate analyses. Pleomorphic histology was confirmed by central pathology review. In a multivariate model, pleomorphic histology was not associated with reduced DFS. Only mitotic score, receptor subtype, and pathologic stage were independently and significantly associated with DFS. Patients with pleomorphic ILC were significantly more likely to receive chemotherapy than patients with classic ILC (adjusted odds ratio 2.96, p = 0.026). The pleomorphic designation in ILC does not have clinical utility and should not be used to determine therapy. Rather, mitotic count identified clear prognostic groups in this cohort of pure ILC.

The apoptosis-stimulating protein of p53 (ASPP) family of proteins can regulate apoptosis by interacting with the p53 family and have been identified to play an important role in cancer progression. Previously, we have demonstrated that ASPP2 downregulation can promote invasion and migration by controlling β-catenin- dependent regulation of ZEB1, however, the role of ASPP1 in colorectal cancer (CRC) remains unclear. We analyzed data from The Cancer Genome Atlas (TCGA) and coupled this to in vitro experiments in CRC cell lines as well as to experimental pulmonary metastasis in vivo. Tissue microarrays of CRC patients with information of clinical-pathological parameters were also used to investigate the expression and function of ASPP1 in CRC. Here, we report that loss of ASPP1 is capable of enhancing migration and invasion in CRC, both in vivo and in vitro. We demonstrate that depletion of ASPP1 could activate expression of Snail2 via the NF-κB pathway and in turn, induce EMT; and this process is further exacerbated in RAS-mutated CRC. ASPP1 could be a prognostic factor in CRC, and the use of NF-κB inhibitors may provide new strategies for therapy against metastasis in ASPP1-depleted CRC patients.

Dengue fever, caused by dengue viruses (DENV 1-4) is a leading cause of illness and death in the tropics and subtropics. Therefore, an effective vaccine is urgently needed. Currently, the only available licensed dengue vaccine is a chimeric live attenuated vaccine that shows varying efficacy depending on serotype, age and baseline DENV serostatus. Accordingly, a dengue vaccine that is effective in seronegative adults, children of all ages and in immunocompromised individuals is still needed. We are currently researching the use of psoralen to develop an inactivated tetravalent dengue vaccine. Unlike traditional formalin inactivation, psoralen inactivates pathogens at the nucleic acid level, potentially preserving envelope protein epitopes important for protective anti-dengue immune responses. We prepared highly purified monovalent vaccine lots of formalin- and psoralen-inactivated DENV 1-4, using Capto DeVirS and Capto Core 700 resin based column chromatography. Tetravalent psoralen-inactivated vaccines (PsIV) and formalin-inactivated vaccines (FIV) were prepared by combining the four monovalent vaccines. Mice were immunized with either a low or high dose of PsIV or FIV to evaluate the immunogenicity of monovalent as well as tetravalent formulations of each inactivation method. In general, the monovalent and tetravalent PsIVs elicited equivalent or higher titers of neutralizing antibodies to DENV than the FIV dengue vaccines and this response was dose dependent. The immunogenicity of tetravalent dengue PsIVs and FIVs were also evaluated in nonhuman primates (NHPs). Consistent with what was observed in mice, significantly higher neutralizing antibody titers for each dengue serotype were observed in the NHPs vaccinated with the tetravalent dengue PsIV compared to those vaccinated with the tetravalent dengue FIV, indicative of the importance of envelope protein epitope preservation during psoralen inactivation of DENV.

Problem, research strategy, and findings: The literature widely reports a statistical association between the built environment and obesity. What is less clear is the reason for the association. Is...

Background: Patients who achieve a pathological complete response (pCR- defined as no invasive cancer) after neoadjuvant chemotherapy (NAC) for breast cancer (BC) have improved outcomes, but there is still controversy about the significance of residual ductal carcinoma in situ (DCIS) on local recurrence rate (LRR). The I-SPY 2 TRIAL is an adaptive neoadjuvant platform trial evaluating novel experimental regimens in comparison to standard chemotherapy in women with high-risk breast cancer. The purpose of this study is to determine if residual DCIS after NAC in early BC affects LRR in patients with or without residual invasive disease in the I-SPY 2 TRIAL. Methods: 933 I-SPY 2 patients with residual cancer burden (RCB) and follow-up data were included in this analysis. Residual DCIS was defined as any carcinoma in situ > 0% on RCB evaluation. Local recurrence was defined as recurrence in breast, chest wall or locoregional nodes and/or skin and subcutaneous tissue. We stratified our cohort into four groups: those without residual invasive disease (defined as RCB0) ± residual DCIS, and those with residual invasive disease (RCB>0) ± residual DCIS. We estimated LRR within each group using the Kaplan Meier method; and used Cox proportional hazards models to assess LRR differences between groups, with: patients with no residual disease (invasive or in situ) as reference group. Results: Among 933 patients assessed, median follow up time was 3.9 years. RCB 0 status was achieved in 337 patients (36%). Of these, 267 (29%) had no residual DCIS, which represents our reference group, and 70 (7%) had residual DCIS. Among 596 (64%) patients who had RCB>0, 296 (32%) had residual DCIS. For patients with RCB0 without DCIS and RCB0 with DCIS, the LRR at 3 years were similar: 2% vs 3% respectively (Hazard ratio: 1.29 [0.26-6.39]). Results were also similar in the RCB>0 group, with a LRR of 10% at 3 years in those without residual DCIS, and 11% in those with residual DCIS. Both RCB>0 groups had significantly higher LRR when compared to the patients with RCB0 without DCIS (Hazard ratio: 5.25 [2.20-12.5]) and HR 5.85 [2.47-13.9] respectively). Conclusion: There was no association between residual DCIS and LRR after neoadjuvant chemotherapy, regardless of resolution of invasive disease. Further work is needed to determine whether residual DCIS should drive locoregional therapy decisions after neoadjuvant chemotherapy for invasive breast cancer. Citation Format: Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Smita M. Asare, Ron Balassanian, Jodi M. Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Gretchen Ahrendt, Akiko Chiba, Cheryl Ewing, Constantine Godellas, Nora Jaskowiak, Brigid Killelea, Helen Krontiras, Rachael Lancaster, Julie Lang, M. Catherine Lee, Arpana Naik, Roshni Rao, Julia Tchou, Shannon Tierney, Eleni Tousimis, Tod Tuttle, Anne Wallace, I-SPY 2 TRIAL Consortium, Bev Parker, Laura J. Esserman, Rita A. Mukhtar. The impact of residual ductal carcinoma in situ on breast cancer recurrence in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-16.

Background: Ductal carcinoma in situ (DCIS) now represents nearly a quarter of newly diagnosed breast cancers in the United States. Standard-of-care treatment for DCIS is aggressive local therapy consisting of either mastectomy or breast conserving surgery with radiation. However, DCIS mortality is low regardless of initial treatment, suggesting opportunities to explore a spectrum of treatment options. With these treatment options, there is the potential to create risk-adapted treatment plans, but the question of how to assess risk remains. Molecular tests can help to personalize treatment by stratifying disease sub-types and providing prognosis. One such tool is the Oncotype DX® Breast DCIS Score, a risk measure which was validated in a meta-analysis of 773 patients from the E5194 and Ontario DCIS Cohort studies. Along with calculating a Breast DCIS Score™ from the expression levels of 12 genes, the test provides a predicted 10-year risk of local recurrence from the score result, age, and tumor size for patients who receive breast conserving surgery alone. Understanding how such a tool might impact decision-making will inform its implementation. Eligibility & trial design: The ATHENA Breast Health Network is a consortium of the five University of California Medical centers. Through ATHENA, patients with histologically confirmed DCIS and no concurrent invasive cancer are approached to participate in the Athena DCIS Registry. Patients in the registry facing an active management decision are eligible to participate in the Oncotype DX® DCIS prospective study. Specific aims: The primary aim of the study is to determine whether the additional diagnostic information (i.e. the DCIS Score™) impacts patient treatment decisions and physician recommendation. Additional goals are to correlate the DCIS Score™ with mammographic findings, pathological variables, and treatment recommendations, and to estimate risk within each DCIS Score™ group. Participants and their physicians answer survey questions both before and after receiving the score to evaluate the impact of the DCIS Score™ on treatment recommendations and decisions. Statistical methods: The study will assess the percentage of patients who thought the DCIS risk score influenced their treatment decision. The study will also assess whether a significant proportion of physicians changed their recommendations after considering the DCIS Score™ using the chi-square test. Similarly, the patients’ preferred treatment option pre- and post- test surveys will be evaluated. In addition, the concordance between physicians’ and patients’ choices will be assessed by the Kappa statistic before and after the score. The patients’ and physicians’ confidence levels in their treatment recommendation and decision pre- and post- test will be compared using a Wilcoxon signed-rank test, as well as the percentage of patients and physicians who are glad they used the test. In addition, the study will assess whether the DCIS test influences a patient’s perception of their recurrence risk by comparing the self-reported 10-year breast cancer recurrence risk in their pre- and post- test questionnaires using a Wilcoxon signed-rank test. Current and target accrual: The current accrual across all sites in the Oncotype study is 94 patients. The target accrual for the initial pilot phase data is defined as the first 100 patients accrued. If interested in learning more about the study, please contact Rita Mukhtar, MD (Rita.Mukhtar@ucsf.edu). Citation Format: Jane M Wei, Paul Kim, Cheryl Ewing, Jasmine Wong, Laura J Esserman, Michael D Alvarado, Abimbola O Olusanya, Skye Stewart, Ashley Tydon, Parima Daroui, Jeffrey V Kuo, Hannah L Park, Karen T Lane, Eliza Jeong, Kelsey Brown, Ava Hosseini, Barbara A Parker, Sarah L Blair, Athena Breast Health Network Investigators, Frederick Baehner, Olivier Harismendy, Antonia Petruse, Carlie K Thompson, Helena R Chang, Alexander D Borowsky, Christina Yau, Gillian L Hirst, Richard J Bold, Rita A Mukhtar. Use of Oncotype DX DCIS for disease management in a prospective DCIS registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-09-01.

To determine the impact of pathology review on the management of patients with cervical carcinoma, 264 reports of pathology review from 230 patients referred to Erasmus MC (2010–2012) were studied retrospectively. Discrepancies between pathologic diagnoses were classified as ‘major’ if they led to changes in treatment, and as ‘minor’ where there was no change. Patient and tumor characteristics were analyzed to identify the factors influencing these discrepancies. Fifty-eight (25.2%) discrepancies were identified; 28 (12.2%) were major, these resulted frequently from missing essential information, or discordant assessment of tumor invasion. Pathology review prevented under-treatment of 3.5%, over-treatment of 1.3%, treatment for incorrect malignancy of 1.3%, and enabled definitive treatment of 6.1% of patients. This highlights the importance of pathology review for appropriate management. Major discrepancies were rare (1%) for patients with macroscopic tumor and histologic diagnosis of squamous cell carcinoma (n = 100). For these patients, yield of pathology review may be limited.

Summary Genital lichen sclerosus (LS), a chronic noninfectious dermatosis, is not rare in pediatric dermatology. The histopathological diagnosis in children and adults in both genital and nongenital LS is considered to be the same and encompasses a broad range of possible characteristics. Clinical manifestations and treatment options of genital LS in children are different depending on gender. The vast majority of boys are treated with circumcision, making for a larger amount of information on the histopathology of genital LS in boys, whereas substantial information on the histopathology of juvenile vulvar LS is lacking. In girls, vulvar LS almost always persists beyond puberty and, therefore, presents a particular challenge to clinicians and cause for concern for the patient. Vulvar LS in childhood and adolescence (juveniles) is underreported, and there are uncertainties with regard to the long-term course of the disease when it occurs at an age when the vulva is still developing. The present study investigates biopsies of 100 juvenile cases of vulvar LS and analyzes the presence or absence of the most salient histopathological characteristics of LS that are described in the literature. We found that the range of histopathological characteristics known for adult LS are also present in juvenile vulvar LS, even at very young ages, including histopathological features associated with autoimmune disease, in support of the idea of a similar pathogenesis.

Cannabis use peaks during adolescence and emerging adulthood, and cannabis use disorder (CUD) is associated with a wide range of adverse outcomes. This is particularly pertinent in youth, because the developing brain may be more vulnerable to adverse effects of frequent cannabis use. Combining evidence-based psychosocial interventions with safe and effective pharmacotherapy is a potential avenue to improve youth outcomes, but we lack approved CUD pharmacotherapies. Here, we review new potential avenues for helping youth with CUD, with a particular focus on cannabinoid-based treatments. Evidence from placebo-controlled RCTs suggests synthetic delta-9-tetrahydrocannabinol (THC) decreases withdrawal symptoms, but not cannabis use, in adults with daily cannabis use/CUD, while findings regarding formulations containing THC combined with cannabidiol (CBD) are mixed. Preliminary evidence from two placebo-controlled RCTs in adults with CUD suggests that both Fatty Acid Amide Hydrolase inhibitors and CBD can reduce cannabis use. However, larger trials are needed to strengthen the evidence. Findings from adults point to cannabinoid-based treatments as a potential strategy that should be examined in youth with CUD.

Reports linking prenatal testosterone exposure to autistic traits and to a masculinized face structure have motivated research investigating whether autism is associated with facial masculinization. This association has been reported with greater consistency for females than for males, in studies comparing groups with high and low levels of autistic traits. In the present study, we conducted two experiments to examine facial masculinity/femininity in 151 neurotypical adults selected for either low, mid-range, or high levels of autistic traits. In the first experiment, their three-dimensional facial photographs were subjectively rated by 41 raters for masculinity/femininity and were objectively analysed. In the second experiment, we generated 6-face composite images, which were rated by another 36 raters. Across both experiments, findings were consistent for ratings of photographs and composite images. For females, a linear relationship was observed where femininity ratings decreased as a function of higher levels of autistic traits. For males, we found a U-shaped function where males with mid-range levels of traits were rated lowest on masculinity. Objective facial analyses revealed that higher levels of autistic traits were associated with less feminine facial structures in females and less masculine structures in males. These results suggest sex-specific relationships between autistic traits and facial masculinity/femininity.

Introduction\ud \ud Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction.\ud \ud \ud \ud Methods\ud \ud A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori.\ud \ud \ud \ud Results\ud \ud 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity.\ud \ud \ud \ud Conclusions\ud \ud Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups.

Children who experience a traumatic brain injury (TBI) are at elevated risk for a range of negative cognitive and neuropsychological outcomes. Identifying which children are at greatest risk for negative outcomes can be difficult due to the heterogeneity of TBI. To address this barrier, the current study applied a novel method of characterizing brain connectivity networks, Bayesian multi-subject vector autoregressive modelling (BVAR-connect), which used white matter integrity as priors to evaluate effective connectivity-the time-dependent relationship in functional magnetic resonance imaging (fMRI) activity between two brain regions-within the default mode network (DMN). In a prospective longitudinal study, children ages 8-15 years with mild to severe TBI underwent diffusion tensor imaging and resting state fMRI 7 weeks after injury; post-concussion and anxiety symptoms were assessed 7 months after injury. The goals of this study were to (1) characterize differences in positive effective connectivity of resting-state DMN circuitry between healthy controls and children with TBI, (2) determine if severity of TBI was associated with differences in DMN connectivity and (3) evaluate whether patterns of DMN effective connectivity predicted persistent post-concussion symptoms and anxiety. Healthy controls had unique positive connectivity that mostly emerged from the inferior temporal lobes. In contrast, children with TBI had unique effective connectivity among orbitofrontal and parietal regions. These positive orbitofrontal-parietal DMN effective connectivity patterns also differed by TBI severity and were associated with persisting behavioural outcomes. Effective connectivity may be a sensitive neuroimaging marker of TBI severity as well as a predictor of chronic post-concussion symptoms and anxiety.

Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non–BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.

Laser interstitial thermal therapy (LITT) is a minimally invasive tumor cytoreductive treatment for recurrent gliomas, brain tumors in eloquent regions and/or otherwise inaccessible. Following reports of persistent peri-ablation blood-brain barrier (BBB) opening in humans, we examined this phenomenon using a rat glioblastoma model. Athymic female rats were implanted with U251 tumor cells in one brain hemisphere. Tumor growth was monitored using magnetic resonance imaging (MRI) and dynamic contrast enhanced (DCE)-MRI. When tumors reached about 4 mm in diameter, they were ablated under supervision of diffusion-weighted MRI using Visualase®, a clinical LITT system. Four rats were used as controls. Longitudinal MRI data were obtained before LITT, and at post-LITT 2 (n=9), 3 (n=3) and 4 (n=9) weeks. After the terminal MRI at each time point, rats were injected intravenously with fluorescent isothiocyanate dextran (FITC-dextran; 2000 kDa) and Evans Blue (68 kDa after binding to plasma albumin) and the brains immersion fixed in 10% paraformaldehyde. The brains were cut into 100 μM thick slices in a vibratome and examined for the distribution of the two fluorophores. All rats survived the LITT procedure. The sham controls showed increased tumor burden by 2 weeks and were sacrificed. DCE-MRI data and fluorescent data showed elevated BBB permeability in peri-ablation regions, with leakage of a gadolinium contrast on DCE-MRI and of Evans Blue, but not of FITC-dextran. Histology showed little tumor tissue at 2 weeks, but evidence of recurrence at ablation margins at later times. These data demonstrate that LITT is adaptable to rat glioma models and can be performed under MRI monitoring. Peri-ablation regions showed selective increase in BBB permeability acutely due to sublethal heating, but later increases in permeability may be due to tumor recurrence. We suggest this model is useful for examining the temporal and spatial development of peri-ablation BBB opening following LITT.

PURPOSE In patients with advanced non–small-cell lung cancer (aNSCLC), tumor mutational burden (TMB) may vary by genomic ancestry; however, its impact on treatment outcomes is unclear. This retrospective, observational study describes treatment patterns of patients with aNSCLC by genomic ancestry and electronic health record (EHR)-reported race and/or ethnicity and evaluates differences in TMB, cancer immunotherapy (CIT) access, and treatment outcomes across racial and ancestral groups. METHODS Patients diagnosed with aNSCLC after January 1, 2011, were selected from a real-world deidentified clinicogenomics database and EHR-derived database; continuously enrolled patients were evaluated. Race and/or ethnicity was recorded using variables from the EHR database; genomic ancestry was classified by single-nucleotide polymorphisms on a next-generation sequencing panel. A threshold of 16 mutations per megabase was used to categorize TMB status. RESULTS Of 59,559 patients in the EHR-derived database and 7,548 patients in the clinicogenomics database, 35,016 (58.8%) and 4,392 (58.2%) were continuously enrolled, respectively. CIT use was similar across EHR-reported race groups, ranging from 34.4% to 37.3% for non-Hispanic Asian and non-Hispanic Black patients, respectively. TMB levels varied significantly across ancestry groups ( P < .001); patients of African ancestry had the highest median TMB (8.75 mutations per megabase; interquartile range, 4.35-14.79). In patients who had received CIT, high TMB was associated with improved overall survival compared with low TMB (20.89 v 11.83 months; hazard ratio, 0.60; 95% CI, 0.51 to 0.70) across genomic ancestral groups. CONCLUSION These results suggest that equitable access to next-generation sequencing may improve aNSCLC outcome disparities in racially and ancestrally diverse populations.