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BACKGROUND Treatment of tubo-ovarian high-grade serous carcinoma (HGSC) includes cytoreductive surgery, platinum-based chemotherapy, and often poly(ADP-ribose) polymerase (PARP) inhibitors. While homologous recombination (HR) deficiency is a well-established predictor of therapy sensitivity, over 50% of HR-proficient HGSCs also exhibit sensitivity. Currently, there are no biomarkers to identify which HR-proficient HGSCs will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response. METHODS We evaluated phospho–RPA2-T21 (p-RPA2) foci via immunofluorescence as a biomarker of replication stress in formalin-fixed, paraffin-embedded HGSC samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort, n = 31; validation cohort, n = 244) or PARP inhibitors ( n = 63). Recurrent HGSCs ( n = 38) were also analyzed. p-RPA2 score was calculated using automated imaging analysis. RESULTS Samples were defined as p-RPA2-high if more than 16% of cells had ≥2 p-RPA2 foci on automated analysis. In the discovery cohort, HR-proficient, p-RPA2-high HGSCs demonstrated significantly higher rates of a chemotherapy response score of 3 to platinum chemotherapy than HR-proficient, p-RPA2-low HGSCs. In the validation cohort, patients with HR-proficient, p-RPA2-high HGSCs had significantly longer survival after platinum treatment than those with HR-proficient, p-RPA2-low HGSCs. Additionally, the p-RPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent HGSC samples. CONCLUSION Our study underscores the importance of considering replication stress markers, such as p-RPA2, alongside HR status in therapeutic planning. This approach has the potential to increase the number of patients receiving effective therapy while reducing unnecessary toxicity. FUNDING The Reproductive Scientist Development Program, GOG Foundation, Pilot Translational and Clinical Studies function of the Washington University Institute of Clinical and Translational Sciences, the Foundation for Barnes-Jewish Hospital, Washington University School of Medicine Dean’s Scholar Program, The Cancer Biology Pathway Training Grant (5T32CA113275-17), The Lucy, Anarcha, and Betsey (L.A.B.) Award from the Department of Obstetrics and Gynecology at Washington University School of Medicine, and Veterans Affairs Office of Research and Development (I01BX006020).

ObjectiveThe objective is to provide evidence‐based and expert guidance for the screening, treatment, and management of lupus nephritis.MethodsThe Core Team developed clinical questions for screening, treatment, and management of lupus nephritis using the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were completed for each PICO question, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the quality of evidence and to formulate recommendations. The Voting Panel achieved a consensus ≥70% on the direction (for or against) and strength (strong or conditional) of each recommendation.ResultsWe present 28 graded recommendations (7 strong, 21 conditional) and 13 ungraded, consensus‐based good practice statements for the screening and management of lupus nephritis. Our recommendations focus on the unifying principle that lupus nephritis therapy is continuous and ongoing, rather than consisting of discrete induction/initial and maintenance/subsequent therapies. Therapy should include pulse glucocorticoids followed by oral glucocorticoid taper and two additional immunosuppressive agents for 3–5 years for those achieving complete renal response.ConclusionThis guideline provides direction for clinicians regarding screening and treatment decisions for management of lupus nephritis. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each individual patient.

AbstractObjectiveNeuromodulation for pediatric refractory epilepsy (PRE) is preferred when the seizure onset zone is not amenable to surgical resection, due to multifocal onset or involvement of eloquent cortex. Given its rapidly evolving landscape, we describe our institutional experience with neurostimulation therapies including deep brain stimulation (DBS) of the anterior nucleus (DBS‐ANT), the centromedian nucleus (DBS‐CM), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS) to treat PRE.MethodsA retrospective chart review was conducted to identify pediatric patients (≤18 years of age) who presented to our institution with PRE. Patients were included who had at least 1 year of follow‐up after neurostimulation was started. Patients with ≥50% seizure frequency reduction at last follow‐up compared to baseline were classified as responders.ResultsA total of 35 patients (21 females) were included in the series. Nine patients underwent DBS‐ANT, 9 underwent DBS‐CM (+ ANT in 7 patients), 5 underwent RNS, and 12 underwent CSS. The median age at seizure onset and surgery was 8 and 16 years, respectively. Structural lesions were the most common etiology of epilepsy (54%). Eighteen patients had prior interventions and 13 received invasive EEG. Post‐operative complications following neurostimulation implantation were noted in three patients (9%). However, no permanent deficits were noted. Median follow‐up time was 46 months (range 13–162 months). Twenty‐three patients (59%) were responders (3/9 DBS‐ANT; 7/9 DBS‐CM; 4/5 RNS; 9/12 CSS). Further, median seizure reduction was 25% (DBS‐ANT), 89% (DBS‐CM), 87% (RNS), and 88% (CSS) across the cohort. Six patients (17%) had improved subjective neurocognitive outcomes while the other 29 had stable neurocognitive outcomes.SignificanceDBS, RNS, and CSS are safe and effective options for PRE. An understanding of treatment approaches can optimize results by tailoring therapy to individual patients.Plain Language SummaryThis study investigates the use of various neurostimulation therapies for treating pediatric refractory epilepsy (PRE) including deep brain stimulation (DBS), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS). Overall, neuromodulation was found to be effective in reducing seizures in most patients, with 59% of patients showing at least a 50% reduction in seizure frequency. Additionally, the treatments were generally safe, with few complications and no instances of permanent deficits.

Objective The objective is to provide evidence‐based and expert guidance for the screening, treatment, and management of lupus nephritis. Methods The Core Team developed clinical questions for screening, treatment, and management of lupus nephritis using the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were completed for each PICO question, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the quality of evidence and to formulate recommendations. The Voting Panel achieved a consensus ≥70% on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present 28 graded recommendations (7 strong, 21 conditional) and 13 ungraded, consensus‐based good practice statements for the screening and management of lupus nephritis. Our recommendations focus on the unifying principle that lupus nephritis therapy is continuous and ongoing, rather than consisting of discrete induction/initial and maintenance/subsequent therapies. Therapy should include pulse glucocorticoids followed by oral glucocorticoid taper and two additional immunosuppressive agents for 3–5 years for those achieving complete renal response. Conclusion This guideline provides direction for clinicians regarding screening and treatment decisions for management of lupus nephritis. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each individual patient.

Abstract Background Cadaveric dissection remains a preferred and irreplaceable learning modality among neurosurgery residents. We aimed to develop and describe a tiered, quantifiable, and practical curriculum for cranial neurosurgical anatomy education. We report the structure and evaluation of our 2-year pilot study to serve as a suggested guide for other neurosurgery programs. Methods Our Complex Cranial Dissection Program is tailored to the needs of junior-level neurosurgery residents based on their postgraduation years 1 to 4. Dissections are performed in a sequential manner, each of which emphasize a particular set of manual skills and neuroanatomical knowledge. Dissections are scored on a scale of 10 points. The grading was based on specific landmarks and anatomical structures, which need to be exposed, explored, and preserved. Results Out of 16 residents, 14 individuals (87.5%) attended the dissections in the first iteration of the program and 16 individuals (100%) attended the dissections in the second iteration. A total of 17 dissections were performed across all years. In survey feedback about the program, 100% (Year 1) and 94% (Year 2) of residents considered the assigned dissections to be appropriate for their respective training levels. Further, 100% (Year 1) and 94% (Year 2) of residents endorsed that the dissections were important and helpful for their practice prior to similar operating room experiences. Conclusion The development and implementation of structured dissection programs within residency training, along with dedicated staff, and objective feedback serve a crucial role in neurosurgical education to further develop and enhance surgical skills in the operative setting.

AbstractHemifacial spasm is a neuromuscular disorder caused by compression of the facial nerve at the nerve root entry zone, often due to ectatic or aberrant vasculature. Pathologic compression of the nerve–brainstem interface results in involuntary, paroxysmal contractions of ipsilateral facial muscles that may cause considerable impairments in quality of life. For those with severe symptoms, have positive imaging demonstrating vascular compression, or who fail other management modalities,1 2 3 4 microvascular decompression offers potential definitive treatment.5 6 Traditionally, nonabsorbable packing agent is used to pack between the nerve and offending vascular structure. However, for large and more complex arterial structures, simple nonabsorbable padding is often not sufficient.In this operative video, we demonstrate microvascular decompression for intractable hemifacial spasm in a 52-year-old female using a specialized sling tacked to the petrous dura for management of a large, ectatic vertebral artery. Following a standard left retrosigmoid craniotomy, an atheromatous ectatic vertebral artery was identified. We fashioned a bovine pericardium sling around the vessel and used a permanent aneurysm clip to secure it to an incision portion of petrous dura. We subsequently identified potential additional facial nerve root compression by anterior inferior cerebellar artery (AICA) and posterior inferior cerebellar artery (PICA) branches, which were elevated and secured using Teflon felt packing. Following elevation of all three vessels, the lateral spread response resolved. At 2 weeks postoperatively, the patient reported substantial relief in her hemifacial spasms and endorsed highly improved quality of life.

Objective This study aimed to characterize implicit bias (IB) and health disparities (HD) education in neonatal–perinatal medicine (NPM), including current educational opportunities, resources, and barriers. Study Design A national web-based survey was sent to NPM fellows, neonatologists, and frontline providers after iterative review by education experts from the National Neonatology Curriculum Committee. Quantitative data were analyzed with chi-square and Fisher's exact tests. Qualitative data were evaluated using thematic analysis. Results Of the 452 NPM survey respondents, most desired additional IB (76%) and HD (83%) education. A greater proportion of neonatologists than fellows received IB (83 vs. 57%) and HD (87 vs. 74%) education. Only 41% of neonatologists reported that their institution requires IB training. A greater proportion of fellows than neonatologists expressed dissatisfaction with the current approaches for IB (51 vs. 25%, p < 0.001) and HD (43 vs. 25%, p = 0.015) education. The leading drivers of dissatisfaction included insufficient time spent on the topics, lack of specificity to NPM, inadequate curricular scope or depth, and lack of local educator expertise. A minority of faculty who were tasked to educate others have received specific educator training on IB (21%) and HD (16%). Thematic analysis of survey free-text responses identified three main themes on the facilitators and barriers to successful IB and HD education: individual, environmental, and curricular design variables. Conclusion NPM trainees and neonatologists desire tailored, active, and expert-guided IB and HD education. Identified barriers are important to address in developing an effective IB/HD curriculum for the NPM community. Key Points

ImportanceTumor necrosis factor α (TNF) inhibitor–induced psoriasiform eruption is well recognized in adults, but few reports document this paradoxical effect in children.ObjectiveTo characterize the clinical features and the clinical time course of TNF inhibitor–induced psoriasiform eruptions in children.Design, Setting, and ParticipantsA multicenter retrospective case series of children younger than 18 years seen between January 1, 2000, and December 31, 2016, who developed a new-onset psoriasiform eruption while taking a TNF inhibitor for a nondermatologic disorder. Participating sites were members of the Pediatric Dermatology Research Alliance. Data were entered into a Research Electronic Data Capture database at the Mayo Clinic (ie, the coordinating center).ResultsPsoriasiform eruptions were identified in 103 TNF inhibitor–treated patients (median age, 13.8 years [IQR, 11.7-16.4 years]; 52 female patients [50%]; 57 White patients [55%]), with 67 patients (65%) treated with infliximab, 35 (34%) with adalimumab, and 1 (1%) with certolizumab pegol. Most patients had no personal history (101 [98%]) or family history of psoriasis (60 patients [58%]). Inflammatory bowel disease was the most common indication for treatment with TNF inhibitor (94 patients [91%]). The primary extracutaneous disease was under control in 95 patients (92%) who developed the eruption. Most patients (n = 85 [83%]) developed psoriasiform eruptions at multiple anatomic sites, with scalp involvement being most common (65 patients [63%]). Skin disease developed at a median of 14.5 months (IQR, 9-24 months) after TNF inhibitor initiation. To treat the psoriasiform eruption, topical steroidal and nonsteroidal medication was prescribed for all patients. Systemic therapy was added for 30 patients (29%): methotrexate for 24 patients (23%), oral corticosteroids for 8 patients (8%), and azathioprine for 1 patient (1%). For 26 patients (25%), suboptimal effectiveness with topical medications alone prompted discontinuation of the initial TNF inhibitor and a change to a second-line TNF inhibitor with cutaneous improvement in 23 patients (88%) by a median of 3 months (IQR, 2-4 months). Eight patients (31%) who started a second-line TNF inhibitor developed a subsequent TNF inhibitor–induced psoriasiform eruption at a median of 6 months (IQR, 4-8 months). Persistent skin disease in 18 patients (17%) prompted discontinuation of all TNF inhibitors; 11 patients changed to a non-TNF inhibitor systemic therapy, and 7 discontinued all systemic therapy.Conclusions and RelevanceIn this case series, paradoxical TNF inhibitor–induced psoriasiform eruptions were seen in children treated with TNF inhibitors for any indication, and there appears to be a class effect among the varying TNF inhibitors. The majority of these children were able to continue TNF inhibitor therapy with adequate skin-directed and other adjuvant therapies.