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In this study, investigators compared genome sequencing with cytogenetic analysis in 263 patients with acute myeloid leukemia or myelodysplastic syndromes. Prospective sequencing detected new genetic information that was not revealed by cytogenetic analysis in nearly 25% of the patients, which altered the risk category for most of these patients.

Homeostatic mechanisms can eliminate abnormal cells to prevent diseases such as cancer. However, the underlying mechanisms of this surveillance are poorly understood. Here we investigated how clones of cells mutant for the neoplastic tumor suppressor gene scribble (scrib) are eliminated from Drosophila imaginal discs. When all cells in imaginal discs are mutant for scrib, they hyperactivate the Hippo pathway effector Yorkie (Yki), which drives growth of the discs into large neoplastic masses. Strikingly, when discs also contain normal cells, the scrib– cells do not overproliferate and eventually undergo apoptosis through JNK-dependent mechanisms. However, induction of apoptosis does not explain how scrib– cells are prevented from overproliferating. We report that cell competition between scrib– and wild-type cells prevents hyperproliferation by suppressing Yki activity in scrib– cells. Suppressing Yki activation is critical for scrib– clone elimination by cell competition, and experimental elevation of Yki activity in scrib– cells is sufficient to fuel their neoplastic growth. Thus, cell competition acts as a tumor-suppressing mechanism by regulating the Hippo pathway in scrib– cells.

Background Genome sequencing (GS) of individuals without a medical indication, known as elective GS, is now available at a number of centers around the United States. Here we report the results of elective GS and pharmacogenetic panel testing in 52 individuals at a private genomics clinic in Alabama. Methods Individuals seeking elective genomic testing and pharmacogenetic testing were recruited through a private genomics clinic in Huntsville, AL. Individuals underwent clinical genome sequencing with a separate pharmacogenetic testing panel. Results Six participants (11.5%) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history. Ten participants (19%) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential. Forty‐four participants (85%) were carriers of a recessive or X‐linked disorder. All individuals with pharmacogenetic testing had variants that affected current and/or future medications. Conclusion Our study highlights the importance of collecting detailed phenotype information to interpret results in elective GS. Genome sequencing (GS) of individuals without a medical indication is referred to as elective GS. Among 52 individuals undergoing elective GS, 11.5% (6/52) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history, 19% (10/52) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential, 85% (44/52) were carriers of a recessive or X‐linked disorder, and 100% of individuals with pharmacogenetic testing had variants that affected current and/or future medications.

Purpose Exome and genome sequencing (ES/GS) are performed frequently in patients with congenital anomalies, developmental delay, or intellectual disability (CA/DD/ID), but the impact of results from ES/GS on clinical management and patient outcomes is not well characterized. A systematic evidence review (SER) can support future evidence-based guideline development for use of ES/GS in this patient population. Methods We undertook an SER to identify primary literature from January 2007 to March 2019 describing health, clinical, reproductive, and psychosocial outcomes resulting from ES/GS in patients with CA/DD/ID. A narrative synthesis of results was performed. Results We retrieved 2654 publications for full-text review from 7178 articles. Only 167 articles met our inclusion criteria, and these were primarily case reports or small case series of fewer than 20 patients. The most frequently reported outcomes from ES/GS were changes to clinical management or reproductive decision-making. Two studies reported on the reduction of mortality or morbidity or impact on quality of life following ES/GS. Conclusion There is evidence that ES/GS for patients with CA/DD/ID informs clinical and reproductive decision-making, which could lead to improved outcomes for patients and their family members. Further research is needed to generate evidence regarding health outcomes to inform robust guidelines regarding ES/GS in the care of patients with CA/DD/ID.

To the Editor: Duncavage et al. (March 11 issue) 1 describe the use of whole-genome sequencing as an alternative to cytogenetic analysis in myeloid cancers. We confirmed the investigators’ findings by performing whole-genome sequencing of 440 samples obtained from patients with acute myeloid leukemia (AML) with each base sequenced 100 times (i.e., 100× coverage), along with reviewing orthogonal data of targeted next-generation sequencing and cytogenetic analysis. However, the minimum coverage needed for tumor sequencing is still under debate. Thus, we performed a down-sampling experiment that included 466 small variants (variant allele frequency [VAF], 1 to 98%), as identified by targeted next-generation . . .

Wambach et al discuss how homozygous intragenic tandem duplication of SFTPB causes neonatal respiratory failure. This study reports a case of neonatal respiratory failure caused by a homozygous intragenic tandem duplication of the SFTPB gene. The duplication was identified in a term infant male proband and his female full siblings who underwent lung transplantation or died due to progressive respiratory failure. Functional studies on lung tissue from the proband confirmed the pathogenicity of the duplication. The duplication was flanked by Alu elements, which are repetitive DNA sequences that can mediate nonallelic chromosomal rearrangements. This is the first report of a homozygous pathogenic partial gene copy number gain in SFTPB. The study highlights the importance of genetic testing in infants with persistent respiratory failure and the potential of long-read sequencing to detect structural variants that may be missed by short-read sequencing.

Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies.

Behavioral weight loss programs typically enroll 12-40 people into groups that then suffer from declining engagement over time. Web-based patient communities, on the other hand, typically offer no limits on capacity and membership is fluid. This model may be useful for boosting engagement in behavioral weight loss interventions, which could lead to better outcomes. In this study, we aimed to examine the feasibility and acceptability of continuously enrolling participants into a Facebook-delivered weight loss intervention for the first 8 of 16 weeks relative to the same intervention where no new participants were enrolled after randomization. We conducted a randomized pilot trial to compare a Facebook weight loss group that used open enrollment with a group that used closed enrollment on feasibility and acceptability in adults with BMI 27-45 kg/m . The feasibility outcomes included retention, engagement, and diet tracking adherence. We described the percentage loss of ≥5% weight in both groups as an exploratory outcome. We also explored the relationship between total volume of activity in the group and weight loss. The participants provided feedback via web-based surveys and focus groups. Randomized participants (68/80, 85% women) were on average, aged 40.2 (SD 11.2) years with a mean BMI of 34.4 (SD 4.98) kg/m . We enrolled an additional 54 participants (50/54, 93% female) in the open enrollment condition between weeks 1 and 8, resulting in a total group size of 94. Retention was 88% and 98% under the open and closed conditions, respectively. Randomized participants across conditions did not differ in engagement (P=.72), or diet tracking adherence (P=.42). Participant feedback in both conditions revealed that sense of community was what they liked most about the program and not enough individualized feedback was what they liked the least. Weight loss of ≥5% was achieved by 30% (12/40) of the participants randomized to the open enrollment condition and 18% (7/40) of the participants in the closed enrollment condition. Exploratory analyses revealed that the open condition (median 385, IQR 228-536.5) had a greater volume of engagement than the closed condition (median 215, IQR 145.5-292; P=.007). Furthermore, an increase of 100 in the total volume of engagement in the Facebook group each week was associated with an additional 0.1% weekly weight loss among the randomized participants (P=.02), which was independent of time, individual participant engagement, and sociodemographic characteristics. Open enrollment was as feasible and acceptable as closed enrollment. A greater volume of engagement in the Facebook group was associated with weight loss, suggesting that larger groups that produce more engagement overall may be beneficial. Future research should examine the efficacy of the open enrollment approach for weight loss in a fully powered randomized trial. ClinicalTrials.gov NCT02656680; https://clinicaltrials.gov/ct2/show/NCT02656680.

Fundamentals of hand surgery in a compact high-yield resource! Hand surgery emerged as a specialty due to advances in treatment of hand injuries incurred during World War II. Synopsis of Hand Surgery by distinguished hand surgeon Dawn LaPorte reflects the approach championed by the late American surgeons Sterling Bunnell and Norman Kirk: multidisciplinary care is key to optimal treatment of bone and soft tissue conditions in the hand and wrist. The book features contributions from an impressive group of hand and upper extremity surgeons and radiologists. Anatomy, surgical approaches, clinical exams, radiographic anatomy, advanced imaging, and electrodynamic studies are introduced in the first five chapters and emphasized throughout, providing a solid foundation. Twenty condition-specific chapters cover a wide array of hand disorders including fractures, arthritis, tendinitis, tendinosis, and injuries, as well as less common pathologies such as Kienbock's Disease, compartment syndrome, tumors, and congenital conditions. The final chapter discusses hand fractures in children. Key Highlights * Insightful guidance on necessary evaluation and tests enables accurate diagnosis of common and uncommon hand injuries and conditions * Firsthand recommendations on conservative to operative treatment options enhance the ability to achieve optimal results * Richly illustrated chapters in an easy-to-read bulleted format augment learning and retention of knowledge This compact book provides a go-to reference for medical students, junior residents in orthopedic and plastic surgery, as well as emergency medicine, family practice, internal medicine, and pediatric physicians.