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As germline genetic testing is increasingly integrated into the clinical care of patients with hematologic malignancies, it is important for hematologists to effectively communicate with patients and families about the genetic testing process and to relay the results in a concise and understandable manner. Effective communication facilitates trust between patients and providers and allows patients to feel empowered to ask questions and actively participate in their healthcare. Especially for inherited conditions, patient understanding of germline genetic information is critical as it enables them to share this information with at-risk relatives, thereby promoting cascade testing and providing potentially life-saving information to family members who may be similarly affected. Accordingly, a hematologist's skills in understanding the importance and implications of germline genetic information and the ability to convey this information in patient-friendly language is a critical first step and can have a far-reaching impact. In this "How I Treat" article, we outline a straightforward approach to discussing genetic information and provide the reader with practical tips that can be used when consenting patients to germline genetic testing and disclosing subsequent test results. We also review special considerations and ethical concerns arising when offering genetic evaluation and germline testing to patients and related donors for allogeneic hematopoietic stem cell transplantation.

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Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor–normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers.Significance:Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers.This article is highlighted in the In This Issue feature, p. 2945

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).

PURPOSEFor the advances of pediatric oncology next-generation sequencing (NGS) research to equitably benefit all children, a diverse and representative sample of participants is needed. However, little is known about demographic and clinical characteristics that differentiate families who decline enrollment in pediatric oncology NGS research.METHODSDemographic and clinical data were retrospectively extracted for 363 pediatric patients (0-21 years) with cancer approached for enrollment in Genomes for Kids (G4K), a study examining the feasibility of comprehensive clinical genomic analysis of tumors and paired normal samples. Demographic and clinical factors that significantly differentiated which families declined were subsequently compared, for 348 families, with enrollment in Clinical Implementation of Pharmacogenetics (PG4KDS), a pharmacogenomics study with more explicit therapeutic benefit examining genes affecting drug responses and metabolism.RESULTSFifty-three families (14.6%) declined enrollment in G4K. Race/ethnicity was the only variable that significantly differentiated study refusal according to multivariable logistic regression, with families of black children more likely to decline enrollment compared with families of non-Hispanic or Hispanic white children. Reasons for declining G4K were generally consistent with other pediatric genomics research: feeling overwhelmed and insurance discrimination fears were most frequently cited. Families of black children were also more likely to decline enrollment in PG4KDS. Thirteen (3.7%) of the 348 families approached for both studies declined PG4KDS.CONCLUSIONRace/ethnicity differentiated study declination across two different pediatric oncology genomics studies, suggesting enrollment disparities in the context of pediatric oncology genomics research. Genomics research participant samples that do not fully represent racial and ethnic minorities risk further exacerbating health disparities. Additional work is needed to understand the nuances of parental decision making in genomic research and facilitate enrollment of diverse patient populations.

Visceral artery pseudoaneurysms (PSAs) are relatively rare, and cases associated with distal vasculature of the superior mesenteric artery are largely unreported. Visceral artery PSAs, without intervention, can lead to morbidity or mortality from rupture or mesenteric ischemia. Historically, open aneurysmectomy is the gold standard; however, endovascular modalities have emerged as the first-line treatment in patients who are poor surgical candidates and/or have unfavorable anatomy. Herein, we describe a case of a symptomatic PSA of the distal superior mesenteric artery treated via the transradial approach with endovascular coil embolization, showing successful aneurysmal exclusion and preservation of enteric collateral flow.

Exciting the imaginations of doctors and patients for millennia, transplantation has struggled to overcome significant technical and biological barriers. Over the course of the last 150 years, physicians have worked in laboratories and operatories to find solutions to these problems. A generation of surgeons led by Alexis Carrel solved the technical problem of implanting organs, highlighting the potential of this therapy. Yet, these men consistently failed when exchanging organs between animals, rejected by hosts’ immune systems. After World War II, scientists like Peter Medawar uncovered some of the mysteries of rejection by elucidating the underlying immunology. Their discoveries focused attention on combatting this process, initially through agents like steroids and azathioprine, which allowed for limited success. It also opened searing questions over the definition of death. The introduction of calcineurin inhibitors transformed the field into a clinical reality and expanded the repertoire of possible organs to implant. It simultaneously created new problems of fairly distributing an extremely limited resource. Recent efforts have worked to solve both of these problems, with increased usage of biologics, organ perfusion systems, and ongoing experimentation into xenotransplantation. No straight line of progress, the field has swerved in as many incorrect directions as right ones, but through a combination of meticulous investigation and empirical forays, transplantation has transformed from a hope into a realistic cure for thousands of patients.

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor–normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. Significance: Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers. This article is highlighted in the In This Issue feature, p. 2945

Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses(1,2) and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients(3). Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MB(SHH) cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MB(SHH). Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHα subtype(4) and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNA modifications at the wobble (U(34)) position(5,6). Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MB(SHH) are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA wobble modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems(7–9). Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide a strong rationale for further investigating the role of protein homeostasis in other cancer types and potential opportunities for novel therapeutic interference.

The XAF1-E134* variant increases the cancer risk for carriers of the TP53-R337H allele., Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

Charles V. Hamilton is the Wallace Sayre Professor Emeritus of Political Science and Government at Columbia University. He is the author of several important books on the study of race and politics, focusing primarily on the African-American experience. He is the coauthor of Black Power: A Politics of Liberation with the late Stokely Carmichael (Kwame Ture), as well as The Black Preacher in America; Bench and the Ballot: Southern Federal Judges and Black Voters; Adam Clayton Powell, Jr.: The Political Biography of an American Dilemma; and coauthor with Dona Cooper Hamilton of The Dual Agenda: Race and the Social Welfare Policies of Civil Rights Organizations. He was interviewed by Fredrick C. Harris, Dean of Social Science and Professor of Political Science at Columbia University, on July 13, 2017, at the University of Chicago. This is an edited transcript; a video of the entire interview can be viewed below or at http://www.annualreviews.org/r/charlesvhamilton .

Objective: This study explores the experiences of adolescents and young adults with craniofacial microsomia, including the impact of growing up with this craniofacial condition on daily life and sense of self. The results may guide future research on optimally supporting individuals with craniofacial microsomia during this critical life phase. Design and Setting: Participants were recruited through a craniofacial center, online patient support groups, and social media sites. Eleven individual semistructured interviews with participants between 12 and 22 years old were conducted by a single interviewer, transcribed, iteratively coded, and thematically analyzed. Results: Five themes were evident in the data: (1) impact on personal growth and character development, (2) negative psychosocial impact, (3) deciding to hide or reveal the condition, (4) desire to make personal surgical decisions, and (5) struggles with hearing loss. Conclusions: We identified both medical and psychosocial concerns prevalent among adolescents with craniofacial microsomia. Although adolescents with craniofacial microsomia exhibit considerable resilience, the challenges they face impact their sense of self and should be addressed through psychosocial support and counseling. Further research should investigate the potential benefit of the wider use of hearing aids, as well as the involvement of patients in decision-making about reconstructive ear surgery.

The influence of igneous intrusions and their associated vent complexes on hydrocarbon migration is poorly understood, yet may be significant in the exploration of petroleum basins located on passive margins. A regional review of the northeasternmost frontier sector of the UK Continental Shelf (UKCS) encompassing the southern extent of the More Basin has revealed evidence of extensive vent formation during the Late Paleocene. Anomalous seismic amplitude events that have not been previously described in this area are identified above and clearly related to several of the vent complexes, and a number of scenarios are postulated to explain their presence. Integrating existing geological studies and regional seismic interpretation with a new 3D seismic dataset reveals a close relationship between sills, vents and seismic anomalies which may be related to the presence of gas/fluid. Recognition of the vent complexes as potential fluid conduits long after initial formation may be important in focusing migration to younger stratigraphic levels. Important observations are made regarding a link to possible hydrocarbon migration mechanisms within the study area and the associated implications for hydrocarbon exploration and risking within this petroleum basin are investigated.

We propose a 3D-printable soft, stretchable, and transparent hydrogel-elastomer device that is able to detect simulated ‘nerve’ signals. The signal is passed to a conductive hydrogel electrode through a non-contact method of capacitive coupling through polydimethylsiloxane (PDMS). We demonstrate that the device is able to detect sinusoidal waveforms passed through a simulated ‘nerve’ made from conductive hydrogel over a range of frequencies (1 kHz – 1 MHz). Analysis of signal detection showed a correlation to the electrode contact area and a Vin/Vout of larger than 10%. This provides the framework for the future development of a soft, 3D-printable, capacitive coupling device that can be used as a cuff electrode for detecting peripheral nerve signals.

Clinical genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. In the Genomes for Kids study (NCT02530658) we used a three-platform sequencing approach, including whole genome (WGS), whole exome (WES) and RNA sequencing, to examine tumor and paired germline genomes from prospectively identified children with cancer. The goal of the study was to assess the potential of comprehensive next generation sequencing to elucidate the molecular mechanisms underlying tumor formation and investigate the potential of this information to influence clinical decision-making.The cohort, with a median age of 6 yrs, range 0 - 26 yrs, included 301 patients with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type or stage. Patients with hematologic malignancies accounted for 41% of cases, 31% had CNS tumors, and 28% had other non-CNS solid tumors. This cohort also included 18 patients with very rare tumor types, defined here as occurring in less than 2 cases per million person per year.Two hundred fifty three patients (84%) had sufficient tumor for three-platform sequencing and all 301 had adequate paired germline samples. Following analysis, 86% of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer predisposing (18%) variants. The inclusion of WGS enabled detection of oncogenic gene fusions, as well as 22 cases in which oncogenes were activated through enhancer hijacking, a particularly frequent occurrence in hematologic malignancies. In addition, WGS effectively detected clinically relevant small intragenic deletions (15% of tumors) and a variety of mutational signatures, which were not detectable through analysis of whole exome data. Evaluation of 56 pathogenic germline variants in the context of paired tumor sequence data helped establish the disease relevance of several genes that are not typically associated with the cancer type in question, providing critical insights on a case-by-case basis. Examples include a pathogenic germline variant in MUTYH in a patient with retinoblastoma whose tumor exhibited a mutation signature associated with reactive oxygen species indicative of loss of MUTYH function; and conversely, a likely pathogenic variant in PMS2 in a rare brain cancer, which did not exhibit a mutation signature associated with microsatellite instability. This study successfully demonstrated the power of this three-platform approach to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. As a result of these findings, we have incorporated this three-platform approach into our routine real-time clinical service at St. Jude Children's Hospital. Citation Format: David A. Wheeler, Scott Newman, Joy Nakitandwe, Chimene A. Kesserwan, Elizabeth M. Azzato, Michael C. Rusch, Sheila Shurtleff, Armita Bahrami, Brent Orr, Jeffery M. Klco, Dale J. Hedges, Kayla V. Hamilton, Scott G. Foy, Michael N. Edmonson, Andrew Thrasher, Jiali Gu, Lynn W. Harrison, Lu Wang, Roya Mostafavi, Manish Kubal, Jamie Maciaszek, Michael Clay, Annastasia Ouma, Antonina Silkov, Yanling Liu, Zhaojie Zhang, Yu Liu, Samuel W. Brady, Xin Zhou, Mark Wilkinson, Delaram Rahbarinia, Jay Knight, Jian Wang, Charles G. Mullighan, Rose B. McGee, Emily A. Quinn, Elsie L. Gerhardt, Leslie M. Taylor, Regina Nuccio, Jessica M. Valdez, Stacy J. Hines-Dowell, Alberto Pappo, Giles Robinson, Liza-Marie Johnson, Ching-Hon Pui, David W. Ellison, James R. Downing, Jinghui Zhang, Kim E. Nichols. Genomes for Kids: Comprehensive DNA and RNA sequencing defining the scope of actionable mutations in pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 642.

Interest in planting mixtures of cover crop species has grown in recent years as farmers seek to increase the breadth of ecosystem services cover crops provide. As part of a multidisciplinary project, we quantified the degree to which monocultures and mixtures of cover crops suppress weeds during the fall-to-spring cover crop growing period. Weed-suppressive cover crop stands can limit weed seed rain from summer- and winter-annual species, reducing weed population growth and ultimately weed pressure in future cash crop stands. We established monocultures and mixtures of two legumes (medium red clover and Austrian winter pea), two grasses (cereal rye and oats), and two brassicas (forage radish and canola) in a long fall growing window following winter wheat harvest and in a shorter window following silage corn harvest. In fall of the long window, grass cover crops and mixtures were the most weed suppressive, whereas legume cover crops were the least weed suppressive. All mixtures also effectively suppressed weeds. This was likely primarily due to the presence of fast-growing grass species, which were effective even when they were seeded at only 20% of their monoculture rate. In spring, weed biomass was low in all treatments due to winter kill of summer-annual weeds and low germination of winter annuals. In the short window following silage corn, biomass accumulation by cover crops and weeds in the fall was more than an order of magnitude lower than in the longer window. However, there was substantial weed seed production in the spring in all treatments not containing cereal rye (monoculture or mixture). Our results suggest that cover crop mixtures require only low seeding rates of aggressive grass species to provide weed suppression. This creates an opportunity for other species to deliver additional ecosystem services, though careful species selection may be required to maintain mixture diversity and avoid dominance of winter-hardy cover crop grasses in the spring.Nomenclature: Austrian winter pea, Pisum sativum L.; canola, Brassica napus L.; cereal rye, Secale cereale L., corn, Zea mays L., forage radish, Raphanus sativus L., medium red clover, Trifolium pratense L.; oats, Avena sativa L.; wheat, Triticum aestivum L.

C over cropping is a conservation practice that has captured the enthusiasm of farmers and conservation professionals alike over the past decade. The practice, planting crops primarily “to manage soil fertility, soil quality, water, weeds, pests, diseases, or wildlife,” (USDA NASS 2012) has grown in popularity over the last 10 years to a level not seen since the advent of widespread adoption of synthetic fertilizers following WWII (Craven 1926; White 2015; Magdoff and Van Es 2009). Many federal agencies and farming and environmental stewardship groups have ambitious targets for increased adoption of the practice. In 2012, the National Wildlife Federation called for cover cropping 4 million (12%) of the 33.6 million ha (10 million of 83 million ac) of cropland in the Mississippi River Basin by 2015 and 40 million cover cropped ha (100 million ac) nationwide by 2025 (Bryant et al. 2013). In 2014, the USDA Natural Resource Conservation Service called for a doubling of cover cropped land from 4 to 8 million ha (10 to 20 million ac) by 2020 at the National Conference for Cover Crops and Soil Health in Omaha, Nebraska (SARE 2014). These cover crop goals are stated in the format of land area in a…

BACKGROUND Our previous analysis of established cancer predisposition genes in medulloblastoma (MB) identified pathogenic germline variants in ~5% of all patients. Here, we extended our analysis to include all protein-coding genes. METHODS Case-control analysis performed on 795 MB patients against >118,000 cancer-free children and adults was performed to identify an association between rare germline variants and MB. RESULTS Germline loss-of-function variants of Elongator Complex Protein 1 (ELP1; 9q31.3) were strongly associated with SHH subgroup (MBSHH). ELP1-associated-MBs accounted for ~15% (29/202) of pediatric MBSHH cases and were restricted to the SHHα subtype. ELP1-associated-MBs demonstrated biallelic inactivation of ELP1 due to somatic chromosome 9q loss and most tumors exhibited co-occurring somatic PTCH1 (9q22.32) alterations. Inheritance was verified by parent-offspring sequencing (n=3) and pedigree analysis identified two families with a history of pediatric MB. ELP1-associated-MBSHH were characterized by desmoplastic/nodular histology (76%; 13/17) and demonstrated a favorable clinical outcome when compared to TP53-associated-MBSHH (5-yr OS 92% vs 20%; p-value=1.3e-6) despite both belonging to the SHHα subtype. ELP1 is a subunit of the Elongator complex, that promotes efficient translational elongation through tRNA modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed ELP1-associated-MBs exhibit destabilization of the core Elongator complex, loss of tRNA wobble modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response. CONCLUSIONS We identified ELP1 as the most common MB predisposition gene, increasing the total genetic predisposition for pediatric MBSHH to 40%. These results mark MBSHH as an overwhelmingly genetically-predisposed disease and implicate disruption of protein homeostasis in MBSHH development.

Summary Background Surgical, anaesthetic, and obstetric (SAO) health-care system strengthening is needed to address the emergency and essential surgical care that approximately 5 billion individuals lack globally. To our knowledge, a complete, non-modelled national situational analysis based on the Lancet Commission on Global Surgery surgical indicators has not been done. We aimed to undertake a complete situation analysis of SAO system preparedness, service delivery, and financial risk protection using the core surgical indicators proposed by the Commission in Colombia, an upper-middle-income country. Methods Data to inform the six core surgical system indicators were abstracted from the Colombian national health information system and the most recent national health survey done in 2007. Geographical access to a Bellwether hospital (defined as a hospital capable of providing essential and emergency surgery) within 2 h was assessed by determining 2 h drive time boundaries around Bellwether facilities and the population within and outside these boundaries. Physical 2 h access to a Bellwether was determined by the presence of a motor vehicle suitable for individual transportation. The Department Administrativo Nacional de Estadistica population projection for 2016 and 2018 was used to calculate the SAO provider density. Total operative volume was calculated for 2016 and expressed nationally per 100 000 population. The total number of postoperative deaths that occurred within 30 days of a procedure was divided by the total operative volume to calculate the all-cause, non-risk-adjusted postoperative mortality. The proportion of the population subject to impoverishing costs was calculated by subtracting the baseline number of impoverished individuals from those who fell below the poverty line once out-of-pocket payments were accounted for. Individuals who incurred out-of-pocket payments that were more than 10% of their annual household income were considered to have experienced catastrophic expenditure. Using GIS mapping, SAO system preparedness, service delivery, and cost protection were also contextualised by socioeconomic status. Findings In 2016, at least 7·1 million people (15·1% of the population) in Colombia did not have geographical access to SAO services within a 2 h driving distance. SAO provider density falls short of the Commission's minimum target of 20 providers per 100 000 population, at an estimated density of 13·7 essential SAO health-care providers per 100 000 population in 2018. Lower socioeconomic status of a municipality, as indicated by proportion of people enrolled in the subsidised insurance regime, was associated with a smaller proportion of the population in the municipality being within 2 h of a Bellwether facility, and the most socioeconomically disadvantaged municipalities often had no SAO providers. Furthermore, Colombian providers appear to be working at or beyond capacity, doing 2690–3090 procedures per 100 000 population annually, but they have maintained a relatively low median postoperative mortality of 0·74% (IQR 0·48–0·84). Finally, out-of-pocket expenses for indirect health-care costs were a key barrier to accessing surgical care, prompting 3·1 million (6·4% of the population) individuals to become impoverished and 9·5 million (19·4% of the population) individuals to incur catastrophic expenditures in 2007. Interpretation We did a non-modelled, indicator-based situation analysis of the Colombian SAO system, finding that it has not yet met, but is working towards achieving, the targets set by the Lancet Commission on Global Surgery. The observed interdependence of these indicators and correlation with socioeconomic status are consistent with well recognised factors and outcomes of social, health, and health-care inequity. The internal consistency observed in Colombia's situation analysis validates the use of the indicators and has now informed development of an early national SAO plan in Colombia, to set a data-informed stage for implementation and evaluation of timely, safe, and affordable SAO health care, within the National Public Health Decennial Plan, which is due in 2022. Funding Zoll Medical.

Patients harboring germline pathogenic biallelic variants in genes involved in the recognition and repair of DNA damage are known to have a substantially increased cancer risk. Emerging evidence suggests that individuals harboring heterozygous variants in these same genes may also be at heightened, albeit lesser, risk for cancer. Herein, we sought to determine whether heterozygous variants in RECQL4, the gene encoding an essential DNA helicase that is defective in children with the autosomal recessive cancer-predisposing condition Rothmund–Thomson syndrome (RTS), are associated with increased risk for childhood cancer. To address this question, we interrogated germline sequence data from 4435 pediatric cancer patients at St. Jude Children's Research Hospital and 1127 from the National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and identified 24 (0.43%) who harbored loss-of-function (LOF) RECQL4 variants, including five of 249 (2.0%) with osteosarcoma (OS). These RECQL4 variants were significantly overrepresented in children with OS, the cancer most frequently observed in patients with RTS, as compared to 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; P = 0.00087, odds ratio [OR] = 7.1, 95% CI, 2.9–17). Nine of the 24 (38%) individuals possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis. Altogether these data expand our understanding of the genetic factors predisposing to childhood cancer and reveal a novel association between heterozygous RECQL4 LOF variants and development of pediatric OS.

Introduction Leiomyosarcoma of the Inferior Vena Cava (IVC) is a rare smooth muscle neoplasm typically presenting in the fifth to sixth decades of life with both intraluminal and extraluminal growth patterns. Surgical resection remains the gold standard for non-metastatic disease and often requires vascular reconstruction. We present an atypical case of leiomyosarcoma involving both the IVC and infrarenal abdominal aorta necessitating reconstruction with intraoperative veno-venous bypass. Methods A 63-year-old man initially presenting with back pain was found to have a large mass adjacent to the IVC on MRI, subsequently confirmed to be leiomyosarcoma by biopsy. After six months of neo-adjuvant chemotherapy the patient was taken for resection. However, intra-operatively the tumor was found to involve the aorta necessitating combined aorto-caval reconstruction. To facilitate en-bloc resection of the tumor, the aorta was reconstructed first followed by the inferior vena cava using veno-venous bypass. Results Post-operatively, the patient was taken to the intensive care unit for resuscitation and had an uncomplicated hospital course. He was discharged to rehab six days post-operatively and at one year remains free of significant tumor burden with patent aorto-caval bypass grafts. Conclusion Primary leiomyosarcoma of the IVC is estimated to have aortic involvement in

BACKGROUND Patients with cancer are increasingly offered genomic sequencing, including germline testing for cancer predisposition or other disorders. Such testing is unfamiliar to patients and families, and clear communication is needed to introduce genomic concepts and convey risk and benefit information. METHODS Parents of children with cancer were offered the opportunity to have their children's tumor and germline examined with clinical genomic sequencing. Families were introduced to the study with a 2-visit informed consent model. Baseline genetic knowledge and self-reported literacy/numeracy were collected before a study introduction visit, during which basic concepts related to genomic sequencing were discussed. Information was reinforced during a second visit, during which informed consent was obtained and a posttest was administered. RESULTS As reflected by the percentage of correct answers on the pretest and posttest assessments, this model increased genetic knowledge by 11.1% (from 77.8% to 88.9%; P

The mechanisms involved in anthelmintic resistance (AR) are complex but a greater understanding of AR management is essential for effective and sustainable control of parasitic helminth worms in livestock. Current tests to measure AR are time consuming and can be technically problematic, gold standard diagnostics are therefore urgently required to assist in combatting the threat from drug resistant parasites. For anthelmintics such as ivermectin (IVM), target proteins may be present in the cellular membrane. As proteins usually act in complexes and not in isolation, AR may develop and be measurable in the target associated proteins present in the parasite membrane. The model nematode Caenorhabditis elegans was used to develop a sub-proteomic assay to measure protein expression differences, between IVM resistant and IVM susceptible isolates in the presence and absence of drug challenge. Evaluation of detergents including CHAPS, ASB-14, C7BzO, Triton ×100 and TBP (tributyl phosphine) determined optimal conditions for the resolution of membrane proteins in Two Dimensional Gel Electrophoresis (2DE). These sub-proteomic methodologies were then translated and evaluated using IVM-susceptible and IVM-resistant Haemonchus contortus; a pathogenic blood feeding parasitic nematode which is of global importance in livestock health, welfare and productivity. We have demonstrated the successful resolution of membrane associated proteins from both C. elegans and H. contortus isolates, using a combination of CHAPS and the zwitterionic amphiphilic surfactant ASB-14 to further support the detection of markers for AR.

The advent of next-generation sequencing (NGS) has introduced an exciting new era in biomedical research. NGS forms the foundation of current genetic testing approaches, including targeted gene panel testing, as well as more comprehensive whole-exome and whole-genome sequencing. Together, these approaches promise to provide critical insights into the understanding of health and disease. However, with NGS testing come many ethical questions and concerns, particularly when testing involves children. These concerns are especially relevant for children with cancer, where the testing of tumor and germline tissues is increasingly being incorporated into clinical care. Areas covered: In this manuscript, we explore the key ethical considerations related to conducting germline NGS testing in pediatric oncology, focusing on the four main principles of beneficence, non-maleficence, autonomy and justice. Expert commentary: The ethical issues surrounding germline NGS testing are complex and result in part from our limited understanding of the medical relevance of many of the results obtained and poor knowledge of the impacts of testing, both beneficial and detrimental, on patients and their families. In this article we discuss the risks and benefits of germline NGS testing and the arguments for and against such testing in children with cancer.

RECQL4 encodes an essential helicase that repairs DNA damage and maintains genomic stability. Biallelic pathogenic germline mutations in RECQL4 cause the autosomal recessive (AR) Rothmund-Thomson, Baller-Gerold, and RAPADILINO syndromes. Predisposition to cancer has been observed in all three syndromes, with osteosarcoma (OS) representing the greatest risk. Monoallelic pathogenic variants in DNA damage response genes (e.g., ATM, NBN) are associated with a moderate increase in cancer risk. Building upon this notion, we sought to determine whether monoallelic RECQL4 loss of function (LOF) variants contribute to childhood cancer, particularly OS. Here, LOF variants were defined as nonsense, frameshift, or canonical splice altering variants that are classified as pathogenic or likely pathogenic based on the 2015 ACMG Guidelines. Among 4,436 pediatric cancer patients at St. Jude and 1,127 in the National Cancer Institute TARGET database (total: 5,563 patients), we identified 20 individuals (0.36%; tumor types in Table) harboring germline monoallelic RECQL4 LOF variants. Compared to reference controls in the Genome Aggregation Database (gnomAD), we observed an enrichment of RECQL4 LOF variants in pediatric cancer patients (P = 0.046, prevalence ratio [PR] = 1.51). We next assessed for enrichment of RECQL4 LOF variants across tumor types (Table). This examination revealed a significant association between monoallelic RECQL4 mutations and leukemia (P = 0.032, PR = 1.91) and more notably, with OS (P = 0.0028, PR = 7.03) where 1.7% of pediatric OS patients carried monoallelic RECQL4 LOF variants. No evidence of association was observed for the other tumor types examined. Our data provide the first evidence of an association linking germline monoallelic RECQL4 LOF variants to childhood cancer, especially OS. Examination of larger cohorts are warranted to elucidate the extent to which these mutations increase the risk for leukemia and OS and the mechanisms by which they promote tumor formation. Pediatric Cancer PatientsgnomAD ControlsCancer Risk (Fisher’s Exact Test)Average age at cancer diagnosis (range)Carriers, RECQL4mut/wtTotal Patients, RECQL4wt/wtCarriers, RECQL4mut/wtTotal Controls, RECQL4wt/wtPrevalence Ratio (95% CI)P ValueAll cancers7 (0.3 - 18)2055632811206591.51 (0.99, 2.30)0.046OS10 (6 - 16)42432811206597.03 (2.65, 18.69)0.0028CNS tumor515792811206590.74 (0.10, 5.26)0.74GCT0.31752811206595.74 (0.81, 40.88)0.16Leukemia4 (3 - 11)1124312811206591.91 (1.07, 3.41)0.032Lymphoma10 (7 - 18)35862811206592.19 (0.71, 6.76)0.16OS = osteosarcoma; CNS tumor = central nervous system tumor; GCT = germ cell tumor Citation Format: Jamie L. Maciaszek, Gang Wu, Kayla Hamilton, Rose B. McGee, Zhaoming Wang, Regina Nuccio, Stacy Hines-Dowell, Lynn Harrison, Elsie L. Gerhardt, Annastasia Ouma, Scott Newman, Aman Patel, Joy Nakitandwe, Elizabeth Azzato, Alberto S. Pappo, Sheila A. Shurtleff, David W. Ellison, James R. Downing, Melissa M. Hudson, Leslie L. Robison, Victor Santana, Jinghui Zhang, Kim E. Nichols, Chimene A. Kesserwan. Increased prevalence of germline monoallelic RECQL4 mutations in children with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3651.

We present single-shot images of a laser-driven shock wave interacting with micron-scale materials heterogeneities taken with an X-ray free electron laser. We observed an evolution from an elastic to plastic shock wave in uniaxially loaded LiF and PETN.

Sexual sadism disorder is a condition associated with sexual arousal resulting from the suffering of another person. Formulating a precise definition of the disorder has proved challenging through the years on a number of fronts: not being overly inclusive so as to pathologize or stigmatize consensual sexual activity, yet constructing diagnostic criteria that are sensitive enough to allow for study and treatment in both forensic and non-forensic populations. Sexual Sadism has been difficult to identify, and has challenges associated in treating it through both pharmacologic and psychotherapeutic avenues. Studies have noted that the diagnosis has serious and long-term consequences for the patient (Psychiatr Clin North Am 37:215–230, 2014), so it is important to draw a distinction between pathology and variants of normal sexual behavior. How the disorder is defined also has a large role in how we identify the disorder; the definition should provide clinical utility in linking the disorder with people who are prone to sexual offending and recidivism (Severe sexual sadism: its features and treatment, Sex and sexuality, Sexual deviation and sexual offenses, Westport, 227–250). Much of the literature on the subject is in forensic populations alone. There is a paucity of research outside of the forensic population. Moreover, there is scant research on treatments, either pharmacologic or psychotherapeutic, specifically with regard to sexual sadism. However, given the damages the disorder can cause when a patient does offend, intervention is mandated. As we shall demonstrate, the available treatment modalities are limited and have been largely appropriated from the extant research on the treatment of paraphilias in general.

RATIONALE There are relatively few cross-section measurements for negatively charged ions. Available calibrants provide sufficient cross-section coverage for the 390 A(2) to 641 A(2) and 1174 A(2) to 3395 A(2) ranges. This is not particularly well suited for determining the collision cross-sections of smaller ions, such as small peptides. METHODS Molecular mechanics/molecular dynamics (MM/MD) simulations, coupled with simulated annealing, were used to find the low-energy molecular conformations of polystyrene (PS) oligomers of length 3-9 (singly deprotonated) and 5-13 (doubly deprotonated). The trajectory method in MOBCAL was employed to derive their respective collision cross-sections, Ω. A calibration plot relating corrected Ω values to drift times in a Waters Synapt G2 mass spectrometer was used to predict the Ω values for the -2 to -6 charge states of dT(10) DNA. RESULTS The in silico design of a reliable negative ion calibration set for ion mobility spectrometry successfully resulted in the use of α,ω-carboxy-terminated PS oligomers to determine the collision cross-sections of negatively charged ions in the range 132-388 A(2). All charge states of dT(10) DNA were predicted to within 3% of the referenced values for these ions. CONCLUSIONS α,ω-Carboxy-terminated PS oligomers were found to be an excellent choice to calibrate ion mobility spectrometers to obtain cross-sections for moderately sized ions. Oligomers with fewer, or weaker, interactions among the internal side chains (like poly(ethylene glycol) oligomers) tend to have a wide range of low-energy molecular conformations resulting in large standard deviations in their theoretically predicted collision cross-sections.