Cultural competency and ethical behavior for collaboration in limited-resource settings: Guidelines from the Society of University Surgeons Academic Global Surgery Committee and the Association for Academic Global Surgery.

BACKGROUND: There are an increasing number of global surgery activities worldwide. With such tremendous growth, there is a potential risk for untoward interactions between high-income country members and low-middle income country members, leading to programmatic failure, poor results, and/or low impact. METHODS: Key concepts for cultural competency and ethical behavior were generated by the Academic Global Surgery Committee of the Society for University Surgeons in collaboration with the Association for Academic Global Surgery. Both societies ensured active participation from high-income countries and low-middle income countries. RESULTS: The guidelines provide a framework for cultural competency and ethical behavior for high-income country members when collaborating with low-middle income country partners by offering recommendations for: (1) preparation for work with low-middle income countries; (2) process standardization; (3) working with the local community; (4) limits of practice; (5) patient autonomy and consent; (6) trainees; (7) potential pitfalls; and (8) gray areas. CONCLUSION: The article provides an actionable framework to address potential cultural competency and ethical behavior issues in high-income country - low-middle income country global surgery collaborations.

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

Programming memristor arrays with arbitrarily high precision for analog computing.

In-memory computing represents an effective method for modeling complex physical systems that are typically challenging for conventional computing architectures but has been hindered by issues such as reading noise and writing variability that restrict scalability, accuracy, and precision in high-performance computations. We propose and demonstrate a circuit architecture and programming protocol that converts the analog computing result to digital at the last step and enables low-precision analog devices to perform high-precision computing. We use a weighted sum of multiple devices to represent one number, in which subsequently programmed devices are used to compensate for preceding programming errors. With a memristor system-on-chip, we experimentally demonstrate high-precision solutions for multiple scientific computing tasks while maintaining a substantial power efficiency advantage over conventional digital approaches.

Intestinal Atresias: A Ten-Year Evaluation of Outcomes.

INTRODUCTION: Intestinal atresia is a common cause of neonatal bowel obstruction. Atresias are often associated with other congenital anomalies. The purpose of the study was to evaluate associated anomalies, operative management, and postoperative outcomes of infants with intestinal atresia. METHODS: A review of patients presenting to a single free-standing children's hospital from March 2012 through February 2022 was performed. The variables examined were type of atresia, additional congenital anomalies, type of operative intervention, and postoperative outcomes. Standard statistical methods were utilized. RESULTS: A total of 75 patients with intestinal atresia were identified and several of these patients had multiple atresias. Isolated duodenal atresia patients were the most common (49.3%), followed by jejunal (32%) and ileal (12%). Mixed atresias were rare at 4%, with isolated pyloric and colonic also rare at 1.3% each. Malrotation was associated with 13% of patients and equally associated with duodenal and jejunoileal atresias. A low percentage (3%) of intestinal atresias was seen in conjunction with gastroschisis and concomitant malrotation. A majority of infants with duodenal atresia underwent standard duodenoduodenostomy (19% laparoscopic, 81% open). In infants with jejunoileal atresia, most underwent resection with primary anastomosis. A tapering enteroplasty was performed primarily in 13% of atresias. There were no significant differences noted in time to first feed or length of stay between those with and without tapering enteroplasty. Eleven percent of patients required subsequent intervention for stricture or small bowel obstruction. There was one death in this series. CONCLUSIONS: Consistent with other literature, duodenal atresia was the most common type of intestinal atresia. However, we demonstrated that malrotation was equally associated with duodenal and jejunoileal atresias while prior reports had shown a higher association with duodenal atresia. In our patient population, the use of tapering enteroplasty did not appear to be associated with outcomes. Overall, these infants have a low morbidity and mortality rate with a rare need for reoperation.

Tamoxifen retinopathy: A comprehensive review.

Tamoxifen is a selective estrogen receptor modulator used mainly for the treatment of breast cancer. Based on the case reports and studies performed to date on the retinal toxicity of tamoxifen, retinopathy appears to occur in as many as 12% of patients taking 20 mg tamoxifen a day for over 2 years. Of this 12%, as many as half develop symptomatic changes in visual acuity. Retinal changes consist primarily of crystalline deposits, cystoid macular edema, hyperreflective deposits in the inner retinal layers, and telangiectasia. Tamoxifen retinopathy is currently managed by discontinuing tamoxifen therapy as the cancer prognosis permits; however, discontinuing therapy demonstrates little to no improvement in visual acuity once visual changes have taken place. Intravitreal injections of steroids or antivascular endothelial growth factor therapy have been performed, but require further studying before conclusions can be made. Until then, optical coherence tomography screening for retinal changes should be performed every 6 months for patients who have been on tamoxifen therapy for 2 years or more. This way, patients can become aware of retinal changes, and their physicians can consider adjusting tamoxifen therapy before they risk developing changes in visual acuity.

Impact of allele-specific anti-human leukocyte antigen class I antibodies on organ allocation.

Technological advances in the field of histocompatibility have allowed us to define anti-human leukocyte antigen (HLA) antibody specificity at the allelic level. However, how allele-specific antibodies affect organ allocation is poorly studied. We examined allelic specificities of class I HLA antibodies in 6726 consecutive serum samples from 2953 transplant candidates and evaluated their impact on the corresponding crossmatch and organ allocation. Out of 17 class I HLA antigens represented by >1 allele in the LABScreen single antigen bead assay, 12 had potential allele-specific reactivity. Taking advantage of our unbiased cohort of deceased donor-candidate testing (123,135 complement-dependent cytotoxicity crossmatches between 2014 and 2017), we estimated that the presence of allele-specific antibody detected using a single antigen bead assay (median fluorescence intensity, >3000) against only the rare allele was a poor predictor of a positive complement-dependent cytotoxicity crossmatch, with a positive predictive value of 0% to 7%, compared with 52.5% in allele-concordant class I HLA antibodies against A or B locus antigens. Further, we confirmed allele-specific reactivity using flow crossmatch in 3 scenarios: A11:01/A11:02, A68:01/A68:02, and B44:02/B44:03. Our results suggest that allele-specific antibodies may unnecessarily exclude transplant candidates (up to 10%) from organ offers by overcalling unacceptable antigens; incorporation of selective reactivity pattern in allocation may promote precision matching and more equitable allocation.

In Vitro and in Vivo Study of the Effect of Osteogenic Pulsed Electromagnetic Fields on Breast and Lung Cancer Cells.

Introduction: Although there have been significant advances in research and treatments over the past decades, cancer remains a leading cause of morbidity and mortality, mostly due to resistance to standard therapies. Pulsed electromagnetic field (PEMF), a newly emerged therapeutic strategy, has been highly regarded as less invasive and almost safe to patients, is now a clinically accepted form to treat diseases including cancer. Breast and lung cancer are the most prevalent forms of human cancers, yet reported investigations on exploring regimes including PEMF are limited. Methods: Intended to examine the anti-tumor effects of a clinically accepted osteogenic PEMF and the possibility of including PEMF in breast and lung cancer treatments, we studied the effects of 2 PEMF signals (PMF1 and PMF2) on breast and lung cancer cell growth and proliferation, as well as the possible underline mechanisms in vitro and in vivo. Results: We found that both signals caused modest but significant growth inhibition (∼5%) in MCF-7 and A549 cancer cells. Interestingly, mice xenograft tumors with A549 cells treated by PEMF were smaller in sizes than controls. However, for mice with MCF-7 tumor implants, treatment with PMF1 resulted in a slight increase (2.8%) in mean tumor size, while PMF2 treated tumors showed a 9% reduction in average size. Furthermore, PEMF increased caspase 3/7 expression levels and percentage of annexin stained cells, indicating the induction of apoptosis. It also increased G0 by 8.5%, caused changes in the expression of genes associated with cell growth suppression, DNA damage, cell cycle arrest, and apoptosis. When cancer cells or xenograft tumors treated with combined PEMF and chemotherapy drugs, PEMF showed growth inhibition effect independent of cisplatin in A549 cells, but with added effect by pemetrexed for the inhibition of MCF-7 growth. Conclusion: Together, our data suggested that clinically used osteogenic PEMF signals moderately suppressed cancer cell growth and proliferation both in vitro and in vivo.

A Proposed Brain-, Spine-, and Mental- Health Screening Methodology (NEUROSCREEN) for Healthcare Systems: Position of the Society for Brain Mapping and Therapeutics.

The COVID-19 pandemic has accelerated neurological, mental health disorders, and neurocognitive issues. However, there is a lack of inexpensive and efficient brain evaluation and screening systems. As a result, a considerable fraction of patients with neurocognitive or psychobehavioral predicaments either do not get timely diagnosed or fail to receive personalized treatment plans. This is especially true in the elderly populations, wherein only 16% of seniors say they receive regular cognitive evaluations. Therefore, there is a great need for development of an optimized clinical brain screening workflow methodology like what is already in existence for prostate and breast exams. Such a methodology should be designed to facilitate objective early detection and cost-effective treatment of such disorders. In this paper we have reviewed the existing clinical protocols, recent technological advances and suggested reliable clinical workflows for brain screening. Such protocols range from questionnaires and smartphone apps to multi-modality brain mapping and advanced imaging where applicable. To that end, the Society for Brain Mapping and Therapeutics (SBMT) proposes the Brain, Spine and Mental Health Screening (NEUROSCREEN) as a multi-faceted approach. Beside other assessment tools, NEUROSCREEN employs smartphone guided cognitive assessments and quantitative electroencephalography (qEEG) as well as potential genetic testing for cognitive decline risk as inexpensive and effective screening tools to facilitate objective diagnosis, monitor disease progression, and guide personalized treatment interventions. Operationalizing NEUROSCREEN is expected to result in reduced healthcare costs and improving quality of life at national and later, global scales.

Who manages burn injuries in children? A program director survey evaluating burn training during pediatric surgery fellowship.

PURPOSE: Burn is one of the leading causes of injury and death in children. Currently, the Residency Review Committee does not require general surgery residents to rotate on a burn service. With many trainees no longer receiving burn training during residency, we sought to evaluate the exposure to burn management in pediatric surgery training programs. MATERIAL AND METHODS: An electronic survey was sent to program directors at accredited pediatric surgery training programs (56) during the 2020 academic year. Case log reviews were performed for 2005-2019. Descriptive statistical analysis was performed. RESULTS: Thirty-six program directors participated in the survey (64%), and 56% reported having an inpatient and outpatient component for burn management. Nearly 20% of program directors reported having no burn management at their institution. Fifty-four percent of responding programs had fellow participation in burn management. Over a fifteen-year period, case logs identified a median of 0-2 burn cases logged each year for graduating fellows. Logistically, 65% of burn centers relied on general pediatric surgeons for management. CONCLUSION: Pediatric surgery trainee involvement in burn management varies with many programs offering no designated burn training. Increasing exposure to pediatric burn management during training is needed to provide improved care for this patient population. LEVEL OF EVIDENCE: III, Retrospective Review.

Bilateral simultaneous postoperative endophthalmitis: review of cases reported over the past 50 years.

A detailed retrospective analysis and literature review were conducted for all previously published reports of bilateral simultaneous postoperative endophthalmitis (BSPOE) since 1970. There have been 7 (9, with 2 currently being reported elsewhere) cases of BSPOE after immediately sequential bilateral cataract surgery (ISBCS) reported over 50 years. Generally, in these cases, the surgical protocol recommended by the International Society of Bilateral Cataract Surgeons ( i SBCS) was breached or uncertain. Bacterial causes were Pseudomonas aeruginosa (3), Staphylococcus epidermidis (3), and Burkholderia cepacia complex (1). One case showed negative results for bacterial infection and 1 was not determined. Visual recovery was light perception, or worse, for Pseudomonas cases, generally good for Staphylococcus and Burkholderia cases, and mixed in cases of unknown etiology. Therefore, BSPOE is rare and causes vary. Strict adherence to the i SBCS General Principles of Excellence in ISBCS 2009 surgical protocol and care with operating room construction seem to considerably lessen the risk.

Human induced pluripotent stem cell-derived platelets loaded with lapatinib effectively target HER2+ breast cancer metastasis to the brain.

Prognosis of patients with HER2+ breast-to-brain-metastasis (BBM) is dismal even after current standard-of-care treatments, including surgical resection, whole-brain radiation, and systemic chemotherapy. Radiation and systemic chemotherapies can also induce cytotoxicity, leading to significant side effects. Studies indicate that donor-derived platelets can serve as immune-compatible drug carriers that interact with and deliver drugs to cancer cells with fewer side effects, making them a promising therapeutic option with enhanced antitumor activity. Moreover, human induced pluripotent stem cells (hiPSCs) provide a potentially renewable source of clinical-grade transfusable platelets that can be drug-loaded to complement the supply of donor-derived platelets. Here, we describe methods for ex vivo generation of megakaryocytes (MKs) and functional platelets from hiPSCs (hiPSC-platelets) in a scalable fashion. We then loaded hiPSC-platelets with lapatinib and infused them into BBM tumor-bearing NOD/SCID mouse models. Such treatment significantly increased intracellular lapatinib accumulation in BBMs in vivo, potentially via tumor cell-induced activation/aggregation. Lapatinib-loaded hiPSC-platelets exhibited normal morphology and function and released lapatinib pH-dependently. Importantly, lapatinib delivery to BBM cells via hiPSC-platelets inhibited tumor growth and prolonged survival of tumor-bearing mice. Overall, use of lapatinib-loaded hiPSC-platelets effectively reduced adverse effects of free lapatinib and enhanced its therapeutic efficacy, suggesting that they represent a novel means to deliver chemotherapeutic drugs as treatment for BBM.

Reconfigurable Stochastic neurons based on tin oxide/MoS2 hetero-memristors for simulated annealing and the Boltzmann machine.

Neuromorphic hardware implementation of Boltzmann Machine using a network of stochastic neurons can allow non-deterministic polynomial-time (NP) hard combinatorial optimization problems to be efficiently solved. Efficient implementation of such Boltzmann Machine with simulated annealing desires the statistical parameters of the stochastic neurons to be dynamically tunable, however, there has been limited research on stochastic semiconductor devices with controllable statistical distributions. Here, we demonstrate a reconfigurable tin oxide (SnOx)/molybdenum disulfide (MoS2) heterogeneous memristive device that can realize tunable stochastic dynamics in its output sampling characteristics. The device can sample exponential-class sigmoidal distributions analogous to the Fermi-Dirac distribution of physical systems with quantitatively defined tunable "temperature" effect. A BM composed of these tunable stochastic neuron devices, which can enable simulated annealing with designed "cooling" strategies, is conducted to solve the MAX-SAT, a representative in NP-hard combinatorial optimization problems. Quantitative insights into the effect of different "cooling" strategies on improving the BM optimization process efficiency are also provided.

Perforated Appendicitis During a Pandemic: The Downstream Effect of COVID-19 in Children.

INTRODUCTION: Coronavirus Disease-19 (COVID-19) was declared a pandemic in March 2020. States issued stay-at-home orders and hospitals cancelled non-emergent surgeries. During this time, we anecdotally noticed more admissions for perforated appendicitis. Therefore, we hypothesized that during the months following the COVID-19 pandemic declaration, more children were presenting with perforated appendicitis. MATERIALS AND METHODS: This is a retrospective cohort study reviewing pediatric patients admitted at a single institution with acute and/or perforated appendicitis between October 2019 to May 2020. Interval appendectomies were excluded. COVID-19 months were designated as March, April, and May 2020. Additional analysis of March, April, and May 2019 was performed for comparison purposes. Analyzed data included demographics, symptoms, white blood cell count, imaging findings, procedures performed, and perforation status. Statistical analysis was performed. RESULTS: During the study period, 285 patients were admitted with the diagnosis of acute appendicitis with 95 patients being perforated. We identified a significant increase in perforated appendicitis cases in the three COVID-19 months compared with the preceding five months (45.6% vs 26.4%; P <0.001). In addition, a similar significant increase was identified when comparing to the same months a year prior (P = 0.003). No significant difference in duration of pain was identified (P=0.926). CONCLUSION: The COVID-19 pandemic and its associated stay-at-home orders have had downstream effects on healthcare. Our review has demonstrated a significant increase in the number of children presenting with perforated appendicitis following these stay-at-home ordinances. These results demonstrate that further investigations into the issues surrounding access to healthcare, especially during this pandemic, are warranted.

Inhibition of Jumonji Histone Demethylases Selectively Suppresses HER2+ Breast Leptomeningeal Carcinomatosis Growth via Inhibition of GMCSF Expression.

HER2+ breast leptomeningeal carcinomatosis (HER2+ LC) occurs when tumor cells spread to cerebrospinal fluid-containing leptomeninges surrounding the brain and spinal cord, a complication with a dire prognosis. HER2+ LC remains incurable, with few treatment options. Currently, much effort is devoted toward development of therapies that target mutations. However, targeting epigenetic or transcriptional states of HER2+ LC tumors might efficiently target HER2+ LC growth via inhibition of oncogenic signaling; this approach remains promising but is less explored. To test this possibility, we established primary HER2+ LC (Lepto) cell lines from nodular HER2+ LC tissues. These lines are phenotypically CD326+CD49f-, confirming that they are derived from HER2+ LC tumors, and express surface CD44+CD24-, a cancer stem cell (CSC) phenotype. Like CSCs, Lepto lines showed greater drug resistance and more aggressive behavior compared with other HER2+ breast cancer lines in vitro and in vivo. Interestingly, the three Lepto lines overexpressed Jumonji domain-containing histone lysine demethylases KDM4A/4C. Treatment with JIB04, a selective inhibitor of Jumonji demethylases, or genetic loss of function of KDM4A/4C induced apoptosis and cell-cycle arrest and reduced Lepto cell viability, tumorsphere formation, regrowth, and invasion in vitro. JIB04 treatment of patient-derived xenograft mouse models in vivo reduced HER2+ LC tumor growth and prolonged animal survival. Mechanistically, KDM4A/4C inhibition downregulated GMCSF expression and prevented GMCSF-dependent Lepto cell proliferation. Collectively, these results establish KDM4A/4C as a viable therapeutic target in HER2+ LC and spotlight the benefits of targeting the tumorigenic transcriptional network. SIGNIFICANCE: HER2+ LC tumors overexpress KDM4A/4C and are sensitive to the Jumonji demethylase inhibitor JIB04, which reduces the viability of primary HER2+ LC cells and increases survival in mouse models.

The diminishing experience in pediatric surgery for general surgery residents in the United States.

PURPOSE: The Accreditation Council for Graduate Medical Education (ACGME) regulates the general surgery residency curriculum. Case volume remains a priority as recent concerns surrounding a lack of proficiency for certain surgical cases have circulated. We hypothesize that there is a significant decrease in pediatric surgery case numbers during general surgery residency despite residents meeting the minimum case requirements. METHODS: We reviewed publicly available ACGME case reports for general surgery residency from 1999 to 2018. Cases are classified as Surgeon Chief or Surgeon Junior. Analyzed data included case classifications, number of residents, and number of residency programs. Simple linear regression analysis was performed. RESULTS: We identified a significant decrease in total number of logged pediatric surgery cases over the past 20 years (p<0.001). Nearly 60% of cases were logged under a single category - inguinal/umbilical hernia. From the past five years, pyloric stenosis was the only other category with an average of greater than two cases logged (range 2.1-2.8). CONCLUSION: We identified a significant decrease in total pediatric surgery case numbers during general surgery residency from 1999 to 2018. Though meeting set requirements, overall case variety was limited. With minimal number of cases required by the ACGME, graduating general surgery residents may lack proficiency in simple pediatric surgery cases.

Trending diversity: Reviewing four-decades of graduating fellows and the current leadership in pediatric surgery.

PURPOSE: Diversity in the physician workforce remains a priority in healthcare as it has been shown to improve outcomes. Decisions for choosing specific fields in medicine are partly influenced by mentors, which tend to be the same sex or ethnicity. Females are starting to outnumber males in medical school and minorities are targeted for recruitment. We hypothesized that diversity in pediatric surgery has increased over time. METHODS: The recently published A Genealogy of North American Pediatric Surgery was utilized to identify graduating pediatric surgery fellows from 1981 to 2018. Organization websites were used to identify past and current leaders. A web-based analysis, including online facial recognition software, was performed. A year-to-year and decade-to-decade demographic comparison was completed. RESULTS: 1217 pediatric surgery fellows graduated between 1981 and 2018. When comparing graduates from the first and last decades, an increase from 16.9% to 39.5% for female graduates was observed (p = 0.046). A significant increase in nonwhite graduates was seen for all races (p < 0.05). Representation in leadership was White and male dominant. CONCLUSION: There was a significant increase in diversity in pediatric surgery fellowship graduates. There were increasing trends in female graduates and all nonwhite racial groups. Focusing on enhancing the pipeline and mentoring underrepresented minorities will continue to enhance this trend for the field of pediatric surgery. LEVEL OF EVIDENCE: III; Retrospective Review.