Locoregional Management of Multiple Ipsilateral Breast Cancers: A Review.

The incidence of preoperatively diagnosed multiple ipsilateral breast cancer (MIBC) is increasing due to improved sensitivity of screening and preoperative staging modalities including digital breast tomosynthesis (3D breast mammography) and magnetic resonance imaging (MRI). The surgical management of MIBC remains controversial. Many surgeons continue to recommend mastectomy due to high local recurrence rates in patients with MIBC undergoing breast conservation therapy reported in historic, retrospective studies. More recent retrospective studies report acceptable rates of local recurrence. Yet concerns persist due to a paucity of prospective data regarding recurrence as well as concerns for margin positivity, cosmetic outcomes and the feasibility of adequate and safe delivery of radiation following breast conserving surgery. Breast conservation has emerged as the preferred surgical strategy for eligible patients with unifocal disease. Benefits include improved quality of life, body image and sexual function and lower surgical complication rates. A recent prospective clinical trial has corroborated a large body of retrospective data confirming the safety of breast conserving therapy and adjuvant radiation in women with MIBC with good oncologic control, low rates of conversion to mastectomy and satisfactory patient-reported cosmetic outcomes. With the current rise in MIBC diagnoses, it is imperative that surgeons understand the existent evidence in order to guide shared decision-making conversations with patients diagnosed with MIBC. This comprehensive review synthesizes the best available data and offers current recommendations for management of both the primary sites of disease as well as management of the axilla in patients with MIBC.

Over-the-Counter Medications Encountered in the Postmortem Pediatric Population from 2010-2020.

In forensic toxicology, the pediatric population requires special focus when evaluating positive findings because of the many toxicokinetic and toxicodynamic differences (e.g., metabolic capabilities, body size, etc.) between the pediatric and adult populations. In particular, the administration of over-the-counter (OTC) medications needs careful consideration, as dosages given to the pediatric population (0 days - 18 years), particularly those given to individuals less than five years of age, tend to be lower than those given to individuals closer to adulthood. Postmortem pediatric data from eleven years (2010-2020) was compiled. A total of 1413 positive cases contained one or more of the following common OTC medications: antihistamines (brompheniramine, chlorpheniramine, diphenhydramine, doxylamine, and pheniramine), pain relievers (acetaminophen, naproxen, ibuprofen, and salicylates), cold/flu medications (dextro/levomethorphan, guaifenesin, ephedrine, and pseudoephedrine), gastrointestinal (GI) aids (dicyclomine and loperamide), and/or sleep aids (melatonin). Antihistamines, cold/flu medications, and pain relievers are the most common classes of drugs encountered in the postmortem pediatric population. To evaluate trends, three main age groups were created: ≤5 years old (5U, birth-5 years old), middle childhood (MC, 6-11 years old), and early adolescence (EA, 12-18 years old). When considering the data, it must be noted that many of these drugs may be co-administered in single and/or multi-drug formulations. In addition, some drugs may have a variety of uses, e.g., antihistamines may also be used as sleep aids. Of note, the prevalence of cases involving those aged 6-11 years old was far less than their younger and older pediatric counterparts. With the widespread availability of OTC medications, unintentional overdoses, recreational misuse, and suicidal overdoses can occur in the vulnerable, pediatric population.

Feeding Management and Palate Repair Timing in Infants with Cleft Palate with and without Pierre Robin Sequence: A Multisite Study.

OBJECTIVES: Compare the feeding management practices in infants with cleft palate with and without Pierre Robin sequence (PRS) and determine if specific feeding difficulties or interventions predict delayed palate repair. DESIGN: Retrospective cross-sectional study. SETTING: Seventeen cleft palate teams contributed data. PATIENTS: 414 infants were included in this study: 268 infants with cleft palate only and 146 infants with cleft palate and PRS. PROCEDURES: Data were collected via parent interview and electronic health records. MAIN OUTCOME MEASURES: Outcomes for the primary objective included categorical data for: history of poor growth, feeding therapy, milk fortification, use of enteral feeding, and feeding difficulties. The outcome for the secondary objective was age in months at primary palate repair. RESULTS: Infants with PRS had a significantly higher prevalence of feeding difficulties (81% versus 61%) and poor growth (29% versus 15%) compared to infants with cleft palate only. Infants with PRS received all feeding interventions-including feeding therapy, milk fortification, and enteral feeding-at a significantly higher frequency. Infants with PRS underwent primary palate repair at a mean age of 13.55 months (SD = 3.29) which was significantly (P < .00001) later than infants with cleft palate only who underwent palate repair at a mean age of 12.05 months (SD = 2.36). Predictors of delayed palate repair included diagnosis of PRS as well as Hispanic ethnicity and a history of poor growth. CONCLUSIONS: These findings can be used to establish clinical directives focused on providing early, multimodal feeding interventions to promote optimal growth and timely palate repair for infants with PRS.

A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development.

Craniofacial abnormalities account for approximately one third of birth defects. The regulatory programs that build the face require precisely controlled spatiotemporal gene expression, achieved through tissue-specific enhancers. Clusters of coactivated enhancers and their target genes, known as superenhancers, are important in determining cell identity but have been largely unexplored in development. In this study we identified superenhancer regions unique to human embryonic craniofacial tissue. To demonstrate the importance of such regions in craniofacial development and disease, we focused on an ~600 kb noncoding region located between NPVF and NFE2L3. We identified long range interactions with this region in both human and mouse embryonic craniofacial tissue with the anterior portion of the HOXA gene cluster. Mice lacking this superenhancer exhibit perinatal lethality, and present with highly penetrant skull defects and orofacial clefts phenocopying Hoxa2-/- mice. Moreover, we identified two cases of de novo copy number changes of the superenhancer in humans both with severe craniofacial abnormalities. This evidence suggests we have identified a critical noncoding locus control region that specifically regulates anterior HOXA genes and copy number changes are pathogenic in human patients.

Enhanced milieu teaching with phonological emphasis: A pilot, telepractice study for parent training in early intervention.

PURPOSE: This pilot study evaluated enhanced milieu teaching with phonological emphasis (EMT + PE) parent training intervention delivered through telepractice and its impact on parent implementation, child speech outcomes, and child language outcomes. METHOD: A multiple baseline design across behaviours was used to assess response to parent training and child outcomes. The intervention was delivered to four parents and their young children with repaired cleft palate. Speech production, receptive language, and expressive language were assessed prior to intervention. EMT + PE strategies including matched turns, modelling and expansions, and prompting/speech recasting were taught to parents using the teach-model-coach-review model. Social validity questionnaires were administered pre- and post-intervention to assess parents' rating of competence and confidence for managing their child's early development. Reliability and procedural fidelity were conducted. RESULT: All parents increased their use of modelling and expansions, and prompting and speech recasting in response to training, as evidenced by large effect sizes. Children also responded positively to these strategies by increasing percentage of consonants correct (PCC) and target vocabulary, although PCC gains were less than observed in a prior hybrid telepractice and face-to-face intervention. Social validity measures indicated parents increased their confidence to provide intervention for their children. CONCLUSION: This pilot study indicated that effective parent training in EMT + PE strategies can be delivered through telepractice.

Umbilical Cord Tissue: From Antemortem Monitoring to Postmortem Possibilities.

ABSTRACT: Umbilical cord tissue (UCT) traditionally has been used as an antemortem matrix for identifying and monitoring fetal exposure to drugs suspected to have been used during pregnancy. The specimen offers several advantages as a testable tissue, including accessibility and ease of collection, ample sample volume, a long window of detection, and ability to detect for a wide range of drugs. Despite these advantages, little to no research exists on the use of UCT as a postmortem forensic toxicology specimen. This article aims to provide insights into UCT toxicological testing and infer potential applications for postmortem use, such as investigations into stillbirths and infant abandonment. Umbilical cord tissue offers several benefits as a postmortem toxicological specimen. Importantly, it can be collected with or without an autopsy being performed and may help explain factors that contribute to the underdevelopment and death of the neonate. With the limited sample volumes present in infant investigations, toxicological analysis of UCT could become a valuable tool for neonatal medicolegal death investigations.

Comparison of Fixed Dosing vs Train of Four Titration of Cisatracurium in COVID-19 ARDS Patients.

Background: Early neuromuscular blockade with cisatracurium has been associated with improved outcomes in moderate-severe acute respiratory distress syndrome (ARDS). Previous studies have demonstrated increased drug utilization without benefits in oxygenation using fixed dose cisatracurium compared to train-of-four (TOF) titration. Objective: We sought to compare a novel, lower fixed dose cisatracurium protocol to TOF titration evaluating the impact on PaO2:FiO2 ratio (P/F). Methods: We conducted a single-center retrospective cohort study comparing fixed dose cisatracurium to TOF titration. We included patients aged 18-89 treated for COVID-19 ARDS with a baseline P/F≤200 who received a cisatracurium infusion for ≥12 h. The primary outcome was change in P/F at 48 h from baseline. Secondary outcomes included change in P/F at 24 h and 7 days, need for mechanical ventilation at day 28, and cisatracurium utilization. Results: Analyses included 125 patients (fixed dose = 65, TOF = 60). Severe ARDS was common with a baseline median P/F of 73.7 vs 79.5, P = .133. The change in P/F at 48 h was larger in the TOF cohort in the adjusted analysis (24.9 vs 70.8, P < .005). The rate and total cumulative dose of cisatracurium were higher in the fixed dose cohort (5 vs 3 mcg/kg/min, P < .001; 1034 vs 612 mg, P < .001) despite similar infusion durations (44.1 h vs 48.5 h, P = .642). Conclusions: Patients in the TOF cisatracurium cohort had improved P/F at 48 h compared to the fixed dose cohort, while also using only 60% of the cumulative dose. Future directions should include analysis of the implications of increased cisatracurium exposure on patient outcomes.

Uterine Fibroid-Induced Compressive Neuropathy of Lumbar Plexus and Obturator Nerve.

Introduction: Uterine fibroids are the most common gynecologic tumors in reproductive-aged women with a prevalence of up to 80%. Symptoms can range from heavy vaginal bleeding and bulk symptoms to, less frequently, deep vein thrombosis and bowel obstruction. Case Description: A 32-year-old female patient presented with acute-onset of right groin and knee pain, and difficulty ambulating. A large posterior uterine fibroid was found to be compressing branches of the lumbar plexus, including the obturator nerve. The patient underwent gynecologic evaluation and an urgent laparoscopic myomectomy. Postoperatively, she had significant improvement in neurologic symptoms. She continued physical therapy for residual mild paresthesia and pain with prolonged ambulation. Discussion: Large pelvic masses such as uterine fibroids should be considered on the differential diagnosis for acute-onset non-gynecologic symptoms such as compressive neuropathy, which require urgent evaluation and possible surgical management.

Standardization of Videorecorded Speech Samples for Children with Cleft Palate: Methods to Facilitate High-Quality Speech Outcomes Data Collection.

BACKGROUND: Collection of high-quality videorecorded speech samples is essential for speech outcomes research. SOLUTION: Cleft palate team SLPs were trained to collect standard videorecorded speech samples in the clinic setting across 20 sites in North America. Standard training and equipment was provided. WHAT WE DID THAT IS NEW: Quality management procedures were developed and utilized to verify video quality and protocol adherence. Over 97% of speech samples collected by trained SLPs met defined quality standards.

Capitojoppa, a new genus of Ichneumoninae (Hymenoptera, Ichneumonidae) from Peruvian Amazonia.

A new monotypic genus of ichneumonine parasitoid wasps (Hymenoptera, Ichneumonidae, Ichneumoninae) is described from Peru; Capitojoppagen. nov. is described to accommodate Capitojoppaamazonicasp. nov. The new genus is morphologically very distinctive and can be easily separated from all known ichneumonine genera. By describing Capitojoppa from the lowland rain forests of Peru, we aim to draw attention to the considerable diversity and morphological variation of the Amazonian ichneumonine fauna.

Exploring the Impact of Dawn Phenomenon on Glucose-Guided Eating Thresholds in Individuals With Type 2 Diabetes Using Continuous Glucose Monitoring: Observational Study.

BACKGROUND: Glucose-guided eating (GGE) improves metabolic markers of chronic disease risk, including insulin resistance, in adults without diabetes. GGE is a timed eating paradigm that relies on experiencing feelings of hunger and having a preprandial glucose level below a personalized threshold computed from 2 consecutive morning fasting glucose levels. The dawn phenomenon (DP), which results in elevated morning preprandial glucose levels, could cause typically derived GGE thresholds to be unacceptable or ineffective among people with type 2 diabetes (T2DM). OBJECTIVE: The aim of this study is to quantify the incidence and day-to-day variability in the magnitude of DP and examine its effect on morning preprandial glucose levels as a preliminary test of the feasibility of GGE in adults with T2DM. METHODS: Study participants wore a single-blinded Dexcom G6 Pro continuous glucose monitoring (CGM) system for up to 10 days. First and last eating times and any overnight eating were reported using daily surveys over the study duration. DP was expressed as a dichotomous variable at the day level (DP day vs non-DP day) and as a continuous variable reflecting the percent of days DP was experienced on a valid day. A valid day was defined as having no reported overnight eating (between midnight and 6 AM). ∂ Glucose was computed as the difference in nocturnal glucose nadir (between midnight and 6 AM) to morning preprandial glucose levels. ∂ Glucose ≥20 mg/dL constituted a DP day. Using multilevel modeling, we examined the between- and within-person effects of DP on morning preprandial glucose and the effect of evening eating times on DP. RESULTS: In total, 21 adults (59% female; 13/21, 62%) with non-insulin-treated T2DM wore a CGM for an average of 10.5 (SD 1.1) days. Twenty out of 21 participants (95%) experienced DP for at least 1 day, with an average of 51% of days (SD 27.2; range 0%-100%). The mean ∂ glucose was 23.7 (SD 13.2) mg/dL. People who experience DP more frequently had a morning preprandial glucose level that was 54.1 (95% CI 17.0-83.9; P<.001) mg/dL higher than those who experienced DP less frequently. For within-person effect, morning preprandial glucose levels were 12.1 (95% CI 6.3-17.8; P=.008) mg/dL higher on a DP day than on a non-DP day. The association between ∂ glucose and preprandial glucose levels was 0.50 (95% CI 0.37-0.60; P<.001). There was no effect of the last eating time on DP. CONCLUSIONS: DP was experienced by most study participants regardless of last eating times. The magnitude of the within-person effect of DP on morning preprandial glucose levels was meaningful in the context of GGE. Alternative approaches for determining acceptable and effective GGE thresholds for people with T2DM should be explored and evaluated.

Screening of attention and executive functions in pediatric patients at a tertiary epilepsy center.

OBJECTIVE: Executive dysfunction is prevalent in children with epilepsy, and associated with poor psychosocial outcome. Sensitive and time effective tools are needed, which capture executive dysfunction across a wide range of impairment. The present study evaluates the applicability of EpiTrack Junior® (EpiTrackJr) as a screening tool at a tertiary epilepsy center, and explore how EpiTrackJr in combination with a subjective measure of everyday attention and executive functions (EFs) may provide clinically important information. METHODS: Retrospective study including 235 pediatric patients admitted to the Norwegian National Centre for Epilepsy. EpiTrackJr and Behavioral Rating Inventory of Executive Functioning (BRIEF) were used to assess attention and EFs. RESULTS: 27,7% obtained a score categorized as "average/unimpaired", 23% as "mildly impaired", and 47.7% as "significantly impaired" on EpiTrackJr. The distribution of age-corrected EpiTrackJr scores was satisfactory. Performance was related to numbers of anti-seizure medication (ASM load), comorbidity and IQ. We found a significant, but weak correlation between EpiTrackJr performance and the BRIEF Metacognitive Index (r = -0.236, n = 108, p=.014), but no significant correlation with the Behavioral Regulation Index (r = -0.178, n = 108, p=.065). SIGNIFICANCE: Our results indicate that EpiTrackJr is applicable as a screening tool for attention and EFs in pediatric patients at a tertiary epilepsy center. Impaired test performance was associated with greater ASM load, comorbidity and lower IQ. Performance based measures and behavior ratings likely capture different aspects of EFs. In combination, the two provide important and nonredundant information about the child's EFs in different settings.

Implementing shared decision making for early-stage breast cancer treatment using a coproduction learning collaborative: the SHAIR Collaborative protocol.

BACKGROUND: Shared decision making (SDM) in breast cancer care improves outcomes, but it is not routinely implemented. Results from the What Matters Most trial demonstrated that early-stage breast cancer surgery conversation aids, when used by surgeons after brief training, improved SDM and patient-reported outcomes. Trial surgeons and patients both encouraged using the conversation aids in routine care. We will develop and evaluate an online learning collaborative, called the SHared decision making Adoption Implementation Resource (SHAIR) Collaborative, to promote early-stage breast cancer surgery SDM by implementing the conversation aids into routine preoperative care. Learning collaboratives are known to be effective for quality improvement in clinical care, but no breast cancer learning collaborative currently exists. Our specific aims are to (1) provide the SHAIR Collaborative resources to clinical sites to use with eligible patients, (2) examine the relationship between the use of the SHAIR Collaborative resources and patient reach, and (3) promote the emergence of a sustained learning collaborative in this clinical field, building on a partnership with the American Society of Breast Surgeons (ASBrS). METHODS: We will conduct a two-phased implementation project: phase 1 pilot at five sites and phase 2 scale up at up to an additional 32 clinical sites across North America. The SHAIR Collaborative online platform will offer free access to conversation aids, training videos, electronic health record and patient portal integration guidance, a feedback dashboard, webinars, support center, and forum. We will use RE-AIM for data collection and evaluation. Our primary outcome is patient reach. Secondary data will include (1) patient-reported data from an optional, anonymous online survey, (2) number of active sites and interviews with site champions, (3) Normalization MeAsure Development questionnaire data from phase 1 sites, adaptations data utilizing the Framework for Reporting Adaptations and Modifications-Extended/-Implementation Strategies, and tracking implementation facilitating factors, and (4) progress on sustainability strategy and plans with ASBrS. DISCUSSION: The SHAIR Collaborative will reach early-stage breast cancer patients across North America, evaluate patient-reported outcomes, engage up to 37 active sites, and potentially inform engagement factors affecting implementation success and may be sustained by ASBrS.

Barriers and facilitators of the return-to-school process affecting adolescent recipients of allogeneic hematopoietic cell transplantation: A qualitative interview study of caregivers.

BACKGROUND: Adolescent hematopoietic cell transplant (HCT) recipients remain out of school for a prolonged period of time; navigating their return to school after completion of therapy can be challenging for caregivers. METHODS: Between August 2020 and June 2021, we conducted individual semi-structured interviews of 19 caregivers of adolescent HCT recipients (10-18 years of age at HCT; 1-7 years post HCT) to understand the challenges faced at the time of their child's return to in-person school post HCT. Conventional content analysis was used to analyze interview transcripts, and thematic analysis was used to identify and organize emerging themes. RESULTS: Three themes emerged from the caregivers' experiences. First, caregivers reported facing several challenges related to lack of communication between their child's healthcare and school teams, which was burdensome for them. Second, some caregivers reported receiving support from school and healthcare professionals, as well as their child's peers, which helped reduce the burden of return to school. Caregivers also reported providing motivational, emotional, and spiritual support to patients. Lastly, caregivers made several recommendations regarding the need for better communication between family, healthcare professionals, and school professionals and availability of supportive care such as mental health counseling and neuropsychological testing. Notably, the need for a return-to-school navigator emerged as a key finding from our analysis. CONCLUSIONS: Caregivers of adolescent HCT recipients face several challenges supporting their children's return to school post HCT, which are related to lack of communication between patients' healthcare and school teams. While some reported receiving support from school and healthcare professionals and their child's peers, the need to coordinate the return-to-school process was burdensome for several caregivers. Additional work is needed to optimize support for HCT recipients and their caregivers during their return-to-school process to minimize burden. Our study findings have the potential to serve as a framework for developing and testing supportive care interventions to improve the return-to-school experience of HCT survivors and ultimately their quality of life.

How Did We Get Here and Where Are We Going? Career Trajectories of United States General Surgery Residency Program Directors.

OBJECTIVE: To develop the future of United States (US) surgical education leadership, surgical trainees and early career faculty who aspire to become program directors (PDs) must understand the potential career pathways and requisite skills and experience to become a general surgery residency PD. The objective of this study was to understand the demographics, career experiences, and professional satisfaction of US PDs in general surgery. DESIGN: An anonymous, cross-sectional survey utilizing a novel instrument. SETTING: An electronic survey distributed to US general surgery PDs between June and November 2022 PARTICIPANTS: PDs of US general surgery residency programs. A list of the Accrediting Council for Graduate Medical Education (ACGME)-accredited general surgery PDs was created from the ACGME list from the 2022 to 23 academic year. RESULTS: The survey achieved a response rate of 46.2% (159/344). Only 32.1% of PDs identified as female and 67.3% identified as male with 1 respondent preferring not to identify their gender. PDs were White or Caucasian (68.6%), Asian (13.8%), and Black (3.7%); 4.4% were Hispanic or Latino. Only 83.7% of PDs completed fellowship training. PDs have been in the role for an average of 5.5 ± 4.9 years. The PDs were compensated for an average of 54.7% (±14.9% SD, 0%-100% range) of their time towards clinical duties. They were compensated on average for 35.7% (±12.6%, 0%-100%) of effort for residency-related administrative duties. Only 5% of PDs had obtained or were enrolled in an education-related degree. Only 55.4% of PDs had received formal surgical education training in teaching and assessment. 54.1% of PDs were interested in obtaining a more senior leadership position in the future. Most PDs (38.4%) expect to serve as PD for 5 to 8 years in total. Overall, the majority of PDs were very satisfied (29.6%) or satisfied (51.6%) professionally; similarly 28.9% were very satisfied and 48.4% satisfied personally. CONCLUSIONS: This study represents the most up-to-date characterization of the personal, academic, and career-related features of current surgical residency PDs across the US. PDs enjoy a high degree of professional and personal satisfaction and most aspire to increasing leadership within their organizations. Compared to prior data, PDs have become more diverse in terms of both gender and race over time. Opportunities exist for increased mentorship of aspiring and current PDs as well as increased training in teaching and assessment.

Coordinating science during an eruption: lessons from the 2020-2021 Kilauea volcanic eruption.

Data collected during well-observed eruptions can lead to dramatic increases in our understanding of volcanic processes. However, the necessary prioritization of public safety and hazard mitigation during a crisis means that scientific opportunities may be sacrificed. Thus, maximizing the scientific gains from eruptions requires improved planning and coordinating science activities among governmental organizations and academia before and during volcanic eruptions. One tool to facilitate this coordination is a Scientific Advisory Committee (SAC). In the USA, the Community Network for Volcanic Eruption Response (CONVERSE) has been developing and testing this concept during workshops and scenario-based activities. The December 2020 eruption of Kilauea volcano, Hawaii, provided an opportunity to test and refine this model in real-time and in a real-world setting. We present here the working model of a SAC developed during this eruption. Successes of the Kilauea SAC (K-SAC) included broadening the pool of scientists involved in eruption response and developing and codifying procedures that may form the basis of operation for future SACs. Challenges encountered by the K-SAC included a process of review and facilitation of research proposals that was too slow to include outside participation in the early parts of the eruption and a decision process that fell on a small number of individuals at the responding volcano observatory. Possible ways to address these challenges include (1) supporting community-building activities between eruptions that make connections among scientists within and outside formal observatories, (2) identifying key science questions and pre-planning science activities, which would facilitate more rapid implementation across a broader scientific group, and (3) continued dialog among observatory scientists, emergency responders, and non-observatory scientists about the role of SACs. The SAC model holds promise to become an integral part of future efforts, leading in the short and longer term to more effective hazard response and greater scientific discovery and understanding.

Analysis of umbilical cord tissue as an indicator of in utero exposure to toxic adulterating substances.

In utero drug exposure is a significant public health threat to the well-being and normal development of the neonate. Recently, testing of umbilical cord tissue (UCT) has been employed to measure illicit drug exposure, as drugs used by the mother during the third trimester may be retained in the UCT. Focus has also been given to potential adverse health effects among drug users, resulting from exposure to pharmacologically active adulterants and cutting agents in the street drug supply. The in utero effects of these substances have not been well studied in humans, nor has their presence been demonstrated as a means for assessing adverse health effects in the neonate. Here, we describe the application of a novel test method to analyze UCT for the presence of more than 20 common adulterating/cutting substances via LC/Q-TOF. In total, 300 de-identified UCT samples were analyzed-all had previously tested positive for cocaine or opiates. Generally, the positivity rates of individual compounds were similar between the Cocaine and Opiates Subgroups, apart from levamisole, xylazine, dipyrone (metabolites), and promethazine. Many of the adulterants used in the street drug supply do have legitimate medicinal/therapeutic uses, including several of the compounds most frequently detected in this study. Caffeine and lidocaine were the most frequently identified compounds both individually (>70% each) and in combination with each other. Alternatively, levamisole, an adulterant with no legitimate therapeutic use, was present in 12% of cases. Importantly, this data demonstrates that the detection of traditional drugs of abuse may serve as indicators of potential in utero exposure to toxic adulterating substances during gestation. While there is cause for concern with respect to any unintentional drug exposure, illicit drug use during pregnancy, including uncontrolled dosing, poly-adulterant consumption, and the interactions of these drug mixtures, produces a significant public health threat to the neonate which warrants further study.

Outcomes of the 2021-2022 APDS General Surgery Recruitment Process Recommendations.

BACKGROUND: In recent years, mounting challenges for applicants and programs in resident recruitment have catapulted this topic into a top priority in medical education. These challenges span all aspects of recruitment-from the time an applicant applies until the time of the Match-and have widespread implications on cost, applicant stress, compromise of value alignment, and holistic review, and equity. In 2021-2022, the Association of Program Directors in Surgery (APDS) set forth recommendations to guide processes for General Surgery residency recruitment. OBJECTIVES: This work summarizes the APDS 2021-2022 resident recruitment process recommendations, along with their justification and program end-of-cycle program feedback and compliance. This work also outlines the impact of these data on the subsequent 2022-2023 recommendations. METHODS: After a comprehensive review of the available literature and data about resident recruitment, the APDS Task Force proposed recommendations to guide 2021-2022 General Surgery resident recruitment. Following cycle completion, programs participating in the categorical General Surgery Match were surveyed for feedback and compliance. RESULTS: About 122 of the 342 programs (35.7%) participating in the 2022 categorical General Surgery Match responded. Based on available data in advance of the cycle, recommendations around firm application and interview numbers could not be made. About 62% of programs participated in the first round interview offer period with 86% of programs limiting offers to the number of slots available; 95% conducted virtual-only interviews. Programs responded they would consider or strongly consider the following components in future cycles: holistic review (90%), transparency around firm requirements (88%), de-emphasis of standardized test scores (54%), participation in the ERAS Supplemental application (58%), single first round interview release period (69%), interview offers limited to the number of available slots (93%), 48-hour minimum interview offer response time (98%), operationalization of applicant expectations (88%), and virtual interviews (80%). There was variability in terms of the feedback regarding the timing of the single first round offer period as well as support for a voluntary, live site visit for applicants following program rank list certification. CONCLUSIONS: The majority of programs would consider implementing similar recommendations in 2022-2023. The greatest variability around compliance revolved around single interview release and the format of interviews. Future innovation is contingent upon the ongoing collection of data as well as unification of data sources involved in the recruitment process.

Precision-activated T-cell engagers targeting HER2 or EGFR and CD3 mitigate on-target, off-tumor toxicity for immunotherapy in solid tumors.

To enhance the therapeutic index of T-cell engagers (TCEs), we engineered masked, precision-activated TCEs (XPAT proteins), targeting a tumor antigen (human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR)) and CD3. Unstructured XTEN polypeptide masks flank the N and C termini of the TCE and are designed to be released by proteases in the tumor microenvironment. In vitro, unmasked HER2-XPAT (uTCE) demonstrates potent cytotoxicity, with XTEN polypeptide masking providing up to 4-log-fold protection. In vivo, HER2-XPAT protein induces protease-dependent antitumor activity and is proteolytically stable in healthy tissues. In non-human primates, HER2-XPAT protein demonstrates a strong safety margin (>400-fold increase in tolerated maximum concentration versus uTCE). HER2-XPAT protein cleavage is low and similar in plasma samples from healthy and diseased humans and non-human primates, supporting translatability of stability to patients. EGFR-XPAT protein confirmed the utility of XPAT technology for tumor targets more widely expressed in healthy tissues.

Local Recurrence After Breast-Conserving Therapy in Patients With Multiple Ipsilateral Breast Cancer: Results From ACOSOG Z11102 (Alliance).

PURPOSE: Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC. PATIENTS AND METHODS: Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%. RESULTS: Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy-proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002). CONCLUSION: The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.