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Accessing vulnerable and hard-to-reach populations is a significant challenge for nurse researchers. Adaptive sampling is a procedure that has been used effectively in community-based research to recruit rare or hidden populations. Structured community assessment, as practiced by community health nurses, can be used to enhance adaptive sampling procedures to recruit research participants. This article describes adaptive sampling techniques, discusses how the techniques can be enhanced with a structured nursing community assessment, and describes how adaptive sampling was used successfully by nurse researchers to obtain a diverse and vulnerable community sample for a grounded-theory study of women's and men's responses to sexual violence. [ABSTRACT FROM AUTHOR]

Abstract Background Exaggerated male ornaments and displays often evolve in species where males only provide females with ejaculates during reproduction. Although "good genes" arguments are typically invoked to explain this phenomenon, a simpler alternative is possible if variation in male reproductive quality (e.g. sperm number, ejaculate content, mating rate) is an important determinant of female reproductive success. The "phenotype-linked fertility hypothesis" states that female preference for male ornaments or displays has been selected to ensure higher levels of fertility and has driven the evolution of exaggerated male traits. Females of the stalk-eyed fly Teleopsis dalmanni must mate frequently to maintain high levels of fertility and prefer to mate with males exhibiting large eyespan, a condition-dependent sexual ornament. If eyespan indicates male reproductive quality, females could directly increase their reproductive success by mating with males with large eyespan. Here we investigate whether male eyespan indicates accessory gland and testis length, and then ask whether mating with large eyespan males affects female fertility. Results Male eyespan was a better predictor of two key male reproductive traits – accessory gland and testis length – than was body size alone. This positive relationship held true over three levels of increasing environmental stress during the maturation of the adult accessory glands and testes. Furthermore, females housed with a large eyespan male exhibited higher levels of fertility than those with small eyespan males. Conclusion Male eyespan in stalk-eyed flies is subject to strong directional mate preference and is a reliable indicator of male reproductive quality – both because males with larger eyespan have bigger accessory glands and testes, and also as they confer higher fertility on females. Fertility enhancement may have arisen because males with larger eyespan mated more often and/or because they transferred more sperm or other substances per ejaculate. The need to ensure high levels of fertility could thus have been an important selective force in the coevolution of female preference and male eyespan in stalk-eyed flies. Our results support the phenotype-linked fertility hypothesis and suggest that it might be of general importance in explaining the evolution of exaggerated male ornaments and displays in species where males only provide females with ejaculates during reproduction.

Abstract Background When females mate with different males, competition for fertilizations occurs after insemination. Such sperm competition is usually summarized at the level of the population or species by the parameter, P2, defined as the proportion of offspring sired by the second male in double mating trials. However, considerable variation in P2 may occur within populations, and such variation limits the utility of population-wide or species P2 estimates as descriptors of sperm usage. To fully understand the causes and consequences of sperm competition requires estimates of not only mean P2, but also intra-specific variation in P2. Here we investigate within-population quantitative variation in P2 using a controlled mating experiment and microsatellite profiling of progeny in the multiply mating stalk-eyed fly, Teleopsis dalmanni. Results We genotyped 381 offspring from 22 dam-sire pair families at four microsatellite loci. The mean population-wide P2 value of 0.40 was not significantly different from that expected under random sperm mixing (i.e. P2 = 0.5). However, patterns of paternity were highly variable between individual families; almost half of families displayed extreme second male biases resulting in zero or complete paternity, whereas only about one third of families had P2 values of 0.5, the remainder had significant, but moderate, paternity skew. Conclusion Our data suggest that all modes of ejaculate competition, from extreme sperm precedence to complete sperm mixing, occur in T. dalmanni. Thus the population mean P2 value does not reflect the high underlying variance in familial P2. We discuss some of the potential causes and consequences of post-copulatory sexual selection in this important model species.

Abstract Background Internal reproductive organ size is an important determinant of male reproductive success. While the response of testis length to variation in the intensity of sperm competition is well documented across many taxa, few studies address the importance of testis size in determining other components of male reproductive success (such as mating frequency) or the significance of size variation in accessory reproductive organs. Accessory gland length, but not testis length, is both phenotypically and genetically correlated with male mating frequency in the stalk-eyed fly Cyrtodiopsis dalmanni. Here we directly manipulate male mating status to investigate the effect of copulation on the size of both the testes and the accessory glands of C. dalmanni. Results Accessory gland length was positively correlated with male mating frequency. Copulation induced a significant decrease in accessory gland size. The size of the accessory glands then recovered slowly over the next 8–48 hours. Neither testis length nor testis area was altered by copulation. Conclusion These results reveal that the time course of accessory gland recovery corresponds to field observations of mating behaviour and suggest that accessory gland size may limit male mating frequency in C. dalmanni.

Purpose: The purpose of this study was to provide updated data on oncologic outcomes following definitive surgical treatment of soft tissue sarcoma of the hand in a cohort of 109 patients, as well as to characterize risk factors for poor oncologic and functional outcomes., Methods: We analyzed data from 109 consecutive patients who had definitive surgical treatment for soft tissue sarcoma of the hand performed between 1996 and 2019 by a single surgeon at a sarcoma center. Primary outcomes included functional outcome (assessed by Musculoskeletal Tumor Society scores), disease-free survival (DFS), and overall survival (OS). We compiled descriptive data and used a multivariable linear model to identify factors associated with functional outcomes. Kaplan-Meier methods were used to estimate 5- and 10-year DFS and OS., Results: Patients had a median age of 36 years at presentation. Median follow-up was 6.1 years among patients alive at the end of follow-up. The median Musculoskeletal Tumor Society score was 29; functional outcome was worse among patients with high-grade tumors or complications. Among the 107 patients who became disease-free, there were four local recurrences (one with metastasis), six distant recurrences, and one death without recurrence. All local recurrences were deep tumors (two myxofibrosarcoma and two myxoinflammatory fibrosarcoma). Estimated 5- and 10-year DFS rates were 89% (95% confidence interval [CI]: 83% to 96%) and 88% (95% CI: 80% to 95%). There were seven deaths, and the estimated 5- and 10-year OS rates were 95% (95% CI: 90% to 100%) and 92% (95% CI: 84% to 100%). Larger tumor size and higher stage at diagnosis were associated with shorter DFS and OS in univariable analyses; low event rates precluded multivariable analysis of survival., Conclusions: Aggressive disease-specific surgical and multidisciplinary treatment can yield long DFS and OS, and good functional outcomes. However, complications and high-grade tumors are associated with worse functional scores., Type of Study/level of Evidence: Prognostic II., Competing Interests: Conflicts of Interest Drs Chapman, Nolan, and Athanasian have nothing to disclose. Ms Lavery reports salary support, unrelated to the submitted work, that was paid to her institution by the American Association of Cancer Research Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background: Limb salvage has better functional outcomes than amputation in the upper extremity. This can however be challenging after bony tumor resections., Methods: This is a retrospective case series of patients who underwent humerus, ulna, or radius reconstruction with a fibula free flap. Data were collected on demographics, oncologic history, surgical details, and complications. Functional outcome measures included the patient's ability to perform activities of daily living (ADL), presence of pain, and musculoskeletal tumor society (MSTS) score., Results: Over a 25-year period, 38 reconstructions were performed. The flap success rate was 97.5%. Bony union was obtained in 19 of 19 (100%) forearm reconstructions and in 15 of 19 (79%) humerus reconstructions (p = 0.10). All 19 forearm reconstruction patients and 18/19 humerus reconstruction patients were able to perform ADLs with no pain or only occasional pain. The MSTS scores were not significantly different between the humerus and forearm cohorts (27.1 vs. 27.3, p = 0.68). Functional outcomes were significantly better in limbs that achieved union (p < 0.001). Recipient and donor site complications occurred in 10 (26.3%) and 5 (13%) patients, respectively., Conclusions: Oncologic upper-extremity reconstruction with fibula free flaps has excellent functional outcomes. Bone union is a predictor of superior limb function., (© 2023 Wiley Periodicals LLC.)

The past decade has seen a rapid acceleration in the discovery of new genetic causes of ALS, with more than 20 putative ALS-causing genes now cited. These genes encode proteins that cover a diverse range of molecular functions, including free radical scavenging (e.g., SOD1), regulation of RNA homeostasis (e.g., TDP-43 and FUS), and protein degradation through the ubiquitin-proteasome system (e.g., ubiquilin-2 and cyclin F) and autophagy (TBK1 and sequestosome-1/p62). It is likely that the various initial triggers of disease (either genetic, environmental and/or gene-environment interaction) must converge upon a common set of molecular pathways that underlie ALS pathogenesis. Given the complexity, it is not surprising that a catalog of molecular pathways and proteostasis dysfunctions have been linked to ALS. One of the challenges in ALS research is determining, at the early stage of discovery, whether a new gene mutation is indeed disease-specific, and if it is linked to signaling pathways that trigger neuronal cell death. We have established a proof-of-concept proteogenomic workflow to assess new gene mutations, using CCNF (cyclin F) as an example, in cell culture models to screen whether potential gene candidates fit the criteria of activating apoptosis. This can provide an informative and time-efficient output that can be extended further for validation in a variety of in vitro and in vivo models and/or for mechanistic studies. As a proof-of-concept, we expressed cyclin F mutations (K97R, S195R, S509P, R574Q, S621G) in HEK293 cells for label-free quantitative proteomics that bioinformatically predicted activation of the neuronal cell death pathways, which was validated by immunoblot analysis. Proteomic analysis of induced pluripotent stem cells (iPSCs) derived from patient fibroblasts bearing the S621G mutation showed the same activation of these pathways providing compelling evidence for these candidate gene mutations to be strong candidates for further validation and mechanistic studies (such as E3 enzymatic activity assays, protein-protein and protein-substrate studies, and neuronal apoptosis and aberrant branching measurements in zebrafish). Our proteogenomics approach has great utility and provides a relatively high-throughput screening platform to explore candidate gene mutations for their propensity to cause neuronal cell death, which will guide a researcher for further experimental studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cheng, De Luca, Hogan, Rayner, Davidson, Watchon, Stevens, Muñoz, Ooi, Yerbury, Don, Fifita, Villalva, Suddull, Chapman, Hedl, Walker, Yang, Morsch, Shi, Blair, Laird, Chung and Lee.)

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas is a rare and potentially aggressive variant of pancreatic ductal adenocarcinoma. Data on this disease are sparse, and despite genetic similarities to pancreatic ductal adenocarcinoma, UCOGC clinical outcomes can be markedly different. We report on a female patient aged 62 years who presented with UCOGC with pulmonary metastases initially treated with 2 lines of cytotoxic chemotherapy. After rapid disease progression with both cytotoxic treatments, the patient's tissue was sent for next-generation sequencing, which revealed a high tumor mutation burden (32 mutations per megabase), as well as somatic mutations in BRAF, NF1, PIK3CA, CDKN2A, TERT, and TP53. Pancreatic cancers have previously demonstrated suboptimal responses to immunotherapeutic approaches. However, given the high tumor mutation burden and distinctiveness of the tumor class, the patient began third-line pembrolizumab monotherapy after palliative radiation to the rapidly progressing and painful abdominal mass from her primary tumor. She had a marked response in her primary UCOGC tumor and metastatic sites, and she remains on pembrolizumab monotherapy with ongoing response after 32 months of therapy. Recent evidence showing significant PD-L1 enrichment on neoplastic cells of undifferentiated carcinomas (including UCOGC) may indicate a role for immunotherapeutic approaches in these patients. Rare cancers such as UCOGC and other undifferentiated carcinomas may benefit from next-generation sequencing to inform treatment decisions when standards of care are absent, as in this report.

Histone methylation is central to the regulation of eukaryotic transcription. In Saccharomyces cerevisiae, it is controlled by a system of four methyltransferases (Set1p, Set2p, Set5p, and Dot1p) and four demethylases (Jhd1p, Jhd2p, Rph1p, and Gis1p). While the histone targets for these enzymes are well characterized, the connection of the enzymes with the intracellular signaling network and thus their regulation is poorly understood; this also applies to all other eukaryotes. Here we report the detailed characterization of the eight S. cerevisiae enzymes and show that they carry a total of 75 phosphorylation sites, 92 acetylation sites, and two ubiquitination sites. All enzymes are subject to phosphorylation, although demethylases Jhd1p and Jhd2p contained one and five sites respectively, whereas other enzymes carried 14 to 36 sites. Phosphorylation was absent or underrepresented on catalytic and other domains but strongly enriched for regions of disorder on methyltransferases, suggesting a role in the modulation of protein-protein interactions. Through mutagenesis studies, we show that phosphosites within the acidic and disordered N-terminus of Set2p affect H3K36 methylation levels in vivo, illustrating the functional importance of such sites. While most kinases upstream of the yeast histone methylation enzymes remain unknown, we model the possible connections between the cellular signaling network and the histone-based gene regulatory system and propose an integrated regulatory structure. Our results provide a foundation for future, detailed exploration of the role of specific kinases and phosphosites in the regulation of histone methylation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Recent studies in general surgery and internal medicine have shown that female physicians may have improved morbidity and mortality compared with their male counterparts. In the field of orthopaedic surgery, little is known about the influence of surgeon gender on patient complications. This study investigates patient complications after hip and knee arthroplasty based on the gender of the treating surgeon., Methods: Using a risk-adjusted outcomes database of 100% Medicare data from a third party, an analysis of outcomes after primary hip and knee arthroplasty based on surgeon gender was performed. This data set, which provided risk-adjusted complication rates for each surgeon performing at least 20 primary knee or hip arthroplasties from 2009 to 2013, was matched with publically available Medicare data sets to determine surgeon gender, year of graduation, area of practice, and surgical volume. Confounding variables were controlled for in multivariate analysis., Results: Of the 8,965 surgeons with identified gender, 187 (2.0%; 187 of 8,965) were identified as women and performed 21,216 arthroplasties (1.4%; 21,216 of 1,518,419). Overall, female surgeons averaged fewer arthroplasties (total knee arthroplasty: 87.0 versus 124.9 [P < 0.001]; total hip arthroplasty [THA]: 62.8 versus 78.8 [P = 0.02]) and were earlier in their practice (20.6 versus 25.0 years; P < 0.001) compared with their male counterparts. Male and female surgeons had similar adjusted complication rates for THA (2.78% versus 2.84%) and total knee arthroplasty (2.24% versus 2.26%). Multivariate analysis found that the predictors of increased complications were decreased surgeon volume, THA, increased surgeons' years in practice, and geographic region., Discussion: Overall, female orthopaedic surgeons performed fewer arthroplasties and were earlier in their career. This, however, did not a have a negative impact on their surgical outcomes. Rather, complication rates were dependent on surgeon volume, surgeon experience, and region., Level of Evidence: Level III-prognostic retrospective case-control study.

Background: Orthopaedic surgery has a shortage of women surgeons. An even geographic distribution of women orthopaedic surgeons may provide more uniform care to patients. However, little is known about the geographical distribution of women orthopaedic surgeons., Questions/purposes: (1) Is there substantial geographic variation in the distribution of orthopaedic surgeons who are women? (2) How does the geographic distribution of women orthopaedic surgeons compare with that of other physicians? (3) What are the variables associated with increased region-based proportions of orthopaedic surgeons who are women?, Methods: To obtain a national snapshot of orthopaedic providers, two Medicare databases were used (Medicare Provider Utilization and Payment Data and Medicare's current and archived Physician Compare Data). These databases were used to identify physicians with self-reported specialties of "Orthopedic Surgeon," "Hand Surgeon," or "Sports Medicine" with at least 11 Medicare claims in 1 year for a single procedure type between 2012 and 2014. These databases are the only databases known to specifically report surgeon gender on a national scale and include physician demographics and education. The Dartmouth Atlas's hospital referral regions and United States Census Bureau divisions were used to group physicians by geographic region. The Gini coefficient, a measure of statistical dispersion, was used to quantify the regional distribution of orthopaedic surgeons. This was compared with the dispersion of non-orthopaedic physicians within the same Medicare databases. Surgeon and regional characteristics were correlated with the proportion of women orthopaedic surgeons in the region., Results: There is substantial geographic variation in the distribution of orthopaedic surgeons who are women, ranging from 0% to 15%. There was a greater prevalence of women orthopaedic surgeons in New England (7.3%, 107 of 1469 surgeons) and the Pacific region (6.5%, 208 of 3196 surgeons) than in the South Atlantic (4.5%, 210 of 4618 surgeons) and East South Central regions (3.5%, 50 of 1442 surgeons). This represents a greater level of variation (Gini coefficient = 0.37) compared with other specialties (0.30 and 0.37) and compared with men orthopaedic surgeons (0.16). Variables independently associated with an increased prevalence of women orthopaedic surgeons based on hospital referral region were an increased proportion of currently practicing women physicians who graduated from medical schools in that region (beta = 0.03; p = 0.01), increased proportion of Medicaid-eligible patients (beta = 0.12; p = 0.002), increased proportion of regional population is black (beta = -0.06; p = 0.03), and increased regional supply of women physicians (beta = 0.26; p < 0.0001)., Conclusions: Despite the recent increase in women orthopaedic surgeons nationally, gains have not been equally distributed throughout the United States., Clinical Relevance: In other medical fields, gender diversity has been proven to be beneficial for patients. If this holds true in the field of orthopaedic surgery, we should be mindful of the geographic distribution of women orthopaedic surgeons as the percentage of these surgeons increases.

Purpose: Soft tissue sarcomas (STS) represent a heterogeneous group of diseases, and selection of individualized treatments remains a challenge. The goal of this study was to determine whether radiomic features extracted from magnetic resonance (MR) images are independently associated with overall survival (OS) in STS., Methods and Materials: This study analyzed 2 independent cohorts of adult patients with stage II-III STS treated at center 1 (N = 165) and center 2 (N = 61). Thirty radiomic features were extracted from pretreatment T1-weighted contrast-enhanced MR images. Prognostic models for OS were derived on the center 1 cohort and validated on the center 2 cohort. Clinical-only (C), radiomics-only (R), and clinical and radiomics (C+R) penalized Cox models were constructed. Model performance was assessed using Harrell's concordance index., Results: In the R model, tumor volume (hazard ratio [HR], 1.5) and 4 texture features (HR, 1.1-1.5) were selected. In the C+R model, both age (HR, 1.4) and grade (HR, 1.7) were selected along with 5 radiomic features. The adjusted c-indices of the 3 models ranged from 0.68 (C) to 0.74 (C+R) in the derivation cohort and 0.68 (R) to 0.78 (C+R) in the validation cohort. The radiomic features were independently associated with OS in the validation cohort after accounting for age and grade (HR, 2.4; P  = .009)., Conclusions: This study found that radiomic features extracted from MR images are independently associated with OS when accounting for age and tumor grade. The overall predictive performance of 3-year OS using a model based on clinical and radiomic features was replicated in an independent cohort. Optimal models using clinical and radiomic features could improve personalized selection of therapy in patients with STS.

Purpose: Hepatotoxicity risk in patients with hepatocellular carcinoma (HCC) is modulated by radiation dose delivered to normal liver tissue, but reported dose-response data are limited. Our prior work established baseline [ 99m Tc]sulfur colloid (SC) single-photon emission computed tomography (SPECT)/computed tomography (CT) liver function imaging biomarkers that predict clinical outcomes. We conducted a proof-of-concept investigation with longitudinal SC SPECT/CT to characterize patient-specific radiation dose-response relationships as surrogates for liver radiosensitivity., Methods and Materials: SC SPECT/CT images of 15 patients with HCC with variable Child-Pugh (CP) status (8 CP-A, 7 CP-B/C) were acquired in treatment position before and 1 month (nominal) after stereotactic body radiation therapy (n = 6) or proton therapy (n = 9). Localized rigid registrations between pre/posttreatment CT to planning CT scans were performed, and transformations were applied to pre/posttreatment SC SPECT images. Radiation therapy doses were converted to EQD2 and Gy RBE (relative biological effectiveness) and binned in 5 GyEQD2 increments within tumor-subtracted livers. Mean dose and percent change (%ΔSC) between pre- and posttreatment SPECT uptake, normalized to regions receiving <5 GyEQD2, were calculated in each binned dose region. Dose-response data were parameterized by sigmoid functions (double exponential) consisting of maximum reduction (%ΔSC max ), dose midpoint (D mid ), and dose-response slope (α mid ) parameters., Results: Individual patient sigmoid dose-response curves had high goodness-of-fit (median R 2  = 0.96, range 0.76-0.99). Large interpatient variability was observed, with median (range) in %ΔSC max of 44% (20%-75%), D mid of 13 Gy (4-27 GyEQD2), and α mid of 0.11 GyEQD2 -1 (0.04-0.29 GyEQD2 -1 ), respectively. Eight of 15 patients had %ΔSC max of 20% to 45%, whereas 7 of 15 had %ΔSC max of 60% to 75%, with subgroups made up of variable baseline liver function status and radiation treatment modality. Fatal hepatotoxicity occurred in patients (2 of 15) with low total liver funcation (<0.12) and low D mid (<7 GyEQD2)., Conclusions: Longitudinal SC SPECT/CT imaging revealed patient-specific variations in dose-response and may identify patients with poor baseline liver function and increased sensitivity to radiation therapy. Validation of this regional liver dose-response modeling concept as a surrogate for patient-specific radiosensitivity has potential to guide HCC therapy regimen selection and planning constraints., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Mitigating radiation-induced liver disease (RILD) is an ongoing need in patients with hepatocellular carcinoma. We hypothesize that [ 99m Tc]-sulfur colloid (SC) single photon emission computed tomography (SPECT)/computed tomography (CT) scans can provide global functional liver metrics and functional liver dosimetric parameters that are predictive of hepatotoxicity risk in patients with primary liver cancer with cirrhosis., Materials and Methods: We retrospectively reviewed 47 patients (n = 26 proton, n = 21 stereotactic body radiation therapy) with Child-Pugh (CP)-A (62%) or CP-B (38%) cirrhosis who underwent SC SPECT/CT scans for radiation therapy planning. SC SPECT scans were mined for image intensity threshold-based functional liver volumes (FLV), mean liver-spleen uptake ratio (L/S mean ), and total liver function (TLF = FLV*L/S mean ). Radiation therapy doses were voxel-wise converted to the biologically equivalent dose (EQD2 a/b=3 ) and relative biological effectiveness (GyRBE). Normal liver (liver minus gross tumor volume [GTV]) and FLV mean doses, absolute and relative dose-volumes (V Gy [cc], V Gy [%]), and relative dose-function histogram quantiles in 10 GyEQD2 increments were calculated. Logistic regression was performed for correlation to CP score increase of 2 or higher (CP+2). Cox regression was performed for correlation to RILD-specific survival (RILD-SS) and overall survival., Results: The strongest predictors of RILD-SS were FLV V20 and liver-GTV F20. FLV mean dose, but not CT-derived anatomic mean dose, was predictive of RILD-SS. TLF and L/S mean were the only parameters that were associated with CP+2 after adjusting for baseline CP score. Optimal cutoffs to mitigate risk RILD-SS were identified: FLV mean dose <23 GyEQD2, liver-GTV V20 <36%, FLV V20 <36%, liver-GTV F20 <36%, FLV <32% (350 cc), L/S mean >0.75, TLF >0.60, tumor volume <40 cm 3 , and CP score A5-6 versus B7-C10. A narrower therapeutic window was observed in CP-B/C patients. The discriminatory power for RILD-SS within CP-B/C classes was improved with the addition of a functional dosimetric constraint, resulting in low- and high-risk subgroups (P = 3 × 10 -6 )., Conclusions: Functional liver metrics and dosimetric parameters derived from pretreatment SC SPECT/CT scans were complementary predictors of hepatotoxicity and may provide useful clinical decision support in the management of cirrhotic patients with primary liver cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Normal liver-sparing with proton beam therapy (PBT) allows for dose escalation in the treatment of liver malignancies, but it may result in high doses to the chest wall (CW). CW toxicity (CWT) data after PBT for liver malignancies are limited, with most published reports describing toxicity after a combination of hypofractionated proton and photon radiation therapy. We examined the incidence and associated factors for CWT after hypofractionated PBT for liver malignancies., Methods and Materials: We retrospectively reviewed the charts of 37 consecutive patients with liver malignancies (30 hepatocellular carcinoma, 6 intrahepatic cholangiocarcinoma, and 1 metastasis) treated with hypofractionated PBT. CWT was scored using Common Terminology Criteria for Adverse Events, version 4. Receiver-operating characteristic curves were used to identify patient and dosimetric factors associated with CWT and to determine optimal dose-volume histogram parameters/cutoffs. Cox regression univariate analysis was used to associate factors to time-dependent onset of CWT., Results: Thirty-nine liver lesions were treated with a median dose of 60 GyE (range, 35-67.5) in 15 fractions (range, 13-20). Median follow-up was 11 months (range, 2-44). Grade ≥2 and 3 CW pain occurred in 7 (19%) and 4 (11%) patients, respectively. Median time to onset of pain was 6 months (range, 1-14). No patients had radiographic rib fracture. On univariate analysis, CW equivalent 2 Gy dose with an α/β = 3 Gy (EQD2 α/β=3 ), V57 >20 cm 3 (hazard ratio [HR], 2.7; P = .004), V63 >17 cm 3 (HR, 2.7; P = .003), and V78 >8 cm 3 (HR, 2.6; P = .003) had the strongest association with grade ≥2 CW pain, as did tumor dose of >75 Gy EQD2 α/β=10 (HR, 8.7; P = .03). No other patient factors were associated with CWT., Conclusions: CWT after hypofractionated PBT for liver malignancies is clinically relevant. For a 15-fraction regimen, V47 >20 cm 3 , V50 >17 cm 3 , and V58 >8 cm 3 were associated with higher rates of CWT. Further investigation of PBT techniques to reduce CW dose are warranted., (Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: The increase in the percentage of women in orthopaedics in the United States over the last half century has been substantially slower than in every other surgical specialty. While this percentage has improved recently, the current demographic and practice characteristics of female orthopaedic surgeons are not well known. This study defines the landscape of practicing female orthopaedic surgeons caring for Medicare patients., Methods: Publicly available Medicare billing data sets from 2012 to 2014 were utilized to identify practicing orthopaedic surgeons. We analyzed demographics, medical training, practice characteristics, case volume, specialization, and procedure profiles of orthopaedic surgeons. Representative Current Procedural Terminology (CPT) codes were utilized for each subspecialty. Multivariate analysis was performed to confirm the independent characteristics that were associated with female orthopaedic surgeons after identification by univariate statistics., Results: The percentage of practicing female orthopaedic surgeons caring for Medicare patients increased significantly from 4.7% (1,043 of 22,038) in 2012 to 5.2% (1,179 of 22,510) in 2014. Women had graduated from medical school in more recent years than men (mean, 14.9 versus 22.5 years, respectively; p < 0.001), and were more likely to have attended a top-25 medical school (27.5% versus 24.5%, respectively; p = 0.01). Women were more likely to be part of larger practices (median, 49.5 versus 24 partners, respectively; p < 0.001), and were more likely to leave practice (4.4% versus 3.1% in 2013, respectively; p = 0.02). Women submitted fewer claims for billing per year (median, 528 versus 1,193, respectively; p < 0.001), and performed 6.8% (9,852 of 144,492) of hand procedures compared with 1.5% (10,043 of 651,856) of all other common procedures (p < 0.001). Multivariate analysis demonstrated that despite confounders, gender was an independent predictor of number of claims, the likelihood of leaving clinical practice, and Medicare reimbursement., Conclusions: There are significant differences between female and male orthopaedic surgeons caring for Medicare patients in terms of subspecialty choices, education, billing practices, and attrition rates. Despite the recent increase in the number of female orthopaedic surgeons, there are significant gender differences within the specialty.

Background: Our purpose was to define the most clinically relevant "nonclassic" radiation-induced liver disease (RILD) endpoints in cirrhotic patients receiving stereotactic body radiation therapy or proton beam therapy for primary liver cancer., Methods and Materials: We retrospectively collected pretreatment, detailed toxicity (≤6 months posttreatment), and outcomes data from 48 patients. Deaths were examined for association with RILD. Univariate and multivariate Cox models defined significant predictors of overall survival (OS)/RILD-specific survival (RILD-SS)., Results: With median follow-up of 13 months, 23 patients (48%) had an increase in Child-Pugh (CP) score (≥2, 25%) and 3 (6%) had ≥G3 transaminase elevation. Of 18 deaths, 6 were potentially ascribed to RILD. Univariate analysis showed that CP score increases of ≥1 and ≥2 and CP class change predicted OS, as did ≥G3 aspartate transaminase (AST) elevation and ≥1 Common Terminology Criteria for Adverse Events (CTCAE) AST toxicity grade change. On multivariate analysis, CP score increase of ≥2 and ≥1 CTCAE AST toxicity grade change were the strongest independent nonclassic RILD predictors of OS. For RILD-SS, CP score increases of ≥2, ≥grade 3 CTCAE alanine transaminase, and ≥grade 2 bilirubin elevations were predictive., Conclusions: Increased CP score ≥2 strongly predicts for both OS and RILD-SS and should be reported in future studies along with transaminase elevations, which are also predictive of outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Ulnar nerve dysfunction following distal humerus fractures is a well-recognized phenomenon. There is no consensus regarding optimal handling of the ulnar nerve during surgical management of these fractures between in situ management and transposition. Using an electronic database to identify retrospective studies involving surgical fixation of distal humerus fractures yielded 46 studies, 5 trials meeting the authors' inclusion criteria, totaling 362 patients. An overall incidence of 19.3% for ulnar neuropathy was identified. Of those patients undergoing in situ release, the incidence was 15.3%. Of those who underwent transposition, there was a 23.5% incidence of ulnar neuropathy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Open fractures of the hand are thought to be less susceptible to infection than other open fractures because of the increased blood supply to the area. Current evidence for all open fractures shows that antibiotic use and the extent of contamination are predictive of infection risk, but time to debridement is not. We reviewed in a systematic review the available literature on open fractures of the hand and upper extremity to determine infection rates based on the timing of debridement and antibiotic administration. We continue to recommend prompt debridement and treatment of most open fractures of the upper extremity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Radiation therapy is an effective treatment option for hepatocellular carcinoma (HCC) patients. However, radiotherapy for HCC still has limited recognition as a standard treatment option in international consensus guidelines due to a paucity of randomized controlled trials and the risk of hepatotoxicity, which is primarily mediated by baseline liver function and dose delivered to non-tumor liver cells. Proton beam therapy (PBT) may offer advantages over photon-based radiation treatments through its dosimetric characteristic of sparing more liver volume at low to moderate doses. PBT has the potential to reduce radiation-related hepatotoxicity and allow for tumor dose escalation. Areas covered: This article reviews the clinical rationale for using PBT for HCC patients and clinical outcome and toxicity data from retrospective and prospective studies. PBT-specific technical challenges for these tumors and appropriate selection of patients to be treated with PBT are discussed. Expert commentary: Local control, overall survival, and toxicity results are promising for liver PBT. Future studies, including ongoing randomized cooperative group trials, will aim to determine the incremental benefit of PBT over photons and which patients are most suitable for PBT.

Purpose: A semiquantitative assessment of hepatic reticuloendothelial system function using colloidal particles scintigraphy has been proposed previously as a surrogate for liver function evaluation. In this article, we present an updated method for the overall assessment of technetium-99m (Tc)-sulfur colloid (SC) biodistribution that combines information from planar and attenuation-corrected Tc-SC single-photon emission computed tomography (SPECT) images. The imaging protocol described here was developed as an easy-to-implement method to assess overall and regional liver function changes associated with chronic liver disease., Patients and Methods: Thirty patients with chronic liver disease and primary liver cancers underwent Tc-SC whole-body planar imaging and upper-abdomen SPECT/computed tomography (CT) imaging before external beam radiation therapy. Liver plus spleen and bone marrow counts as a fraction of whole-body total counts were calculated from SC planar imaging. Attenuation correction Tc-SC images were rigidly coregistered with treatment planning CT images that contained liver and spleen regions-of-interest. Ratios of total liver counts to total spleen counts were obtained from the aligned Tc-SC SPECT and CT images, and were subsequently used to separate liver plus spleen counts obtained on the planar images. This hybrid SPECT/CT and planar scintigraphy approach yielded an updated estimation of whole-body SC distribution. These biodistribution estimates were compared with historical data for reference. Statistical associations of Tc-SC biodistribution to liver function parameters and liver disease scoring systems (Child-Pugh) were evaluated by Spearman rank correlation., Results: Percentages of Tc-SC uptake ranged from 19.3 to 77.3% for the liver; 3.4 to 40.7% for the spleen; and 19.0 to 56.7% for the bone marrow. Spearman's correlation coefficient showed a significant statistical association between Child-Pugh score and bone marrow uptake at 0.55 (P≤0.05), liver uptake at 0.71 (P≤0.001), spleen uptake at 0.56 (P≤0.05), and spleen plus bone marrow uptake at 0.71 (P≤0.001). There was also a good correlation of SC uptake percentages with individual quantitative liver function components such as albumin and total bilirubin, and qualitative liver function components (varices, portal hypertension, ascites). For albumin: r=0.64 (P<0.001) compared with liver uptake percentage from the whole-body counts, r=0.49 (P<0.001) compared with splenic uptake percentage, and r=0.45 (P≤0.05) compared with bone marrow uptake percentage., Conclusion: We describe a novel liver function quantitative assessment method that combines whole-body planar images and SPECT/CT attenuation-corrected images of Tc-SC distribution. Attenuation-corrected SC images provide valuable regional liver function information, which is a unique feature compared with other imaging methods available. The results of our study indicate that the Tc-SC uptake by the liver, spleen, and bone marrow correlates with liver function parameters in patients with diffuse liver disease and the correlation with liver disease severity is slightly better for liver uptake percentages than for individual values of bone marrow and spleen uptake percentages.

Purpose: The delivery of safe and effective radiation therapy relies on accurate target delineation, particularly in the era of highly conformal treatment techniques. Current contouring resources are fragmented and can be cumbersome to use. The present study reports on the efficacy and usability of a web-based contouring atlas compared with those of existing contouring resources in a randomized trial., Methods and Materials: We enrolled radiation oncology residents into a 2-phase contouring study. All residents contoured a T1N1 nasopharyngeal cancer case using the currently available resources. The participants were then randomized to recontour the case with access to existing resources or an interactive web-based contouring atlas (eContour.org). Contour analysis was performed using conformation number and simultaneous truth and performance level estimation. At completion of the second contouring session, the residents completed a multiple choice question knowledge test and a 10-item System Usability Scale., Results: Twenty-four residents from 5 institutions completed the study. Compared with the residents using currently available resources, the residents using eContour had improved contour agreement with both the consensus (0.63 vs 0.52; P=.02) and the expert (0.58 vs 0.50; P=.01) contours for the high-risk clinical target volume and greater agreement with the expert contour for the contralateral parotid gland (0.44 ± 0.12 vs 0.56 ± 0.08; P=.003). The residents using eContour demonstrated greater knowledge of contour delineation and radiographic anatomy on a multiple-choice knowledge-based test (89% vs 77%; P=.03). Usability (89 vs 66; P<.0001) and satisfaction (4.1 vs 3.0; P=.002) were greater for eContour than for the existing resources., Conclusions: This study demonstrates the capacity of an interactive 3-dimensional contouring atlas to improve quality of resident target delineation in radiation oncology. Further research is needed to define the utility of easily accessible interactive educational reference tool to improve adherence to contouring-based guidelines and quality of care in routine clinical practice., (Published by Elsevier Inc.)

Background: Assessment of liver function is critical in hepatocellular carcinoma (HCC) patient management. We evaluated parameters of [(99m)Tc] sulfur colloid (SC) SPECT/CT liver uptake for association with clinical measures of liver function and outcome in HCC patients., Methods: Thirty patients with HCC and variable Child-Turcotte-Pugh scores (CTP A5-C10) underwent [(99m)Tc]SC SPECT/CT scans for radiotherapy planning. Gross tumor volume (GTV), anatomic liver volume (ALV), and spleen were contoured on CT. SC SPECT image parameters include threshold-based functional liver volumes (FLV) relative to ALV, mean liver-to-spleen uptake ratio (L/Smean), and total liver function (TLF) ratio derived from the product of FLV and L/Smean. Optimal SC uptake thresholds were determined by ROC analysis for maximizing CTP classification accuracy. Image metrics were tested for rank correlation to composite scores and clinical liver function parameters. Image parameters of liver function were tested for association to overall survival with Cox proportional hazard regression., Results: Optimized thresholds on SC SPECT were 58 % of maximum uptake for FLV, 38 % for L/Smean, and 58 % for TLF. TLF produced the highest CTP classification accuracy (AUC = 0.93) at threshold of 0.35 (sensitivity = 0.88, specificity = 0.86). Higher TLF was associated with lower CTP score: TLFA = 0.6 (0.4-0.8) versus TLFB = 0.2 (0.1-0.3), p < 10(-4). TLF was rank correlated to albumin and bilirubin (|R| > 0.63). Only TLF >0.30 was independently associated with overall survival when adjusting for CTP class (HR = 0.12, 95 % CI = 0.02-0.58, p = 0.008)., Conclusions: SC SPECT/CT liver uptake correlated with differential liver function. TLF was associated with improved overall survival and may aid in personalized oncologic management of HCC patients.

Purpose: The aim of this study was to review institutional outcomes for advanced thyroid cancers treated with fast neutron radiation therapy (FNRT) and photon radiation therapy (RT)., Methods and Materials: In all, 62 consecutive patients were analyzed. Fifty-nine had stage IV disease. Twenty-three were treated with FNRT and 39 with photon RT. Median follow-up was 14 months. The primary endpoint was overall survival (OS)., Results: There was no significant difference in median OS between FNRT and photon RT (26 vs 16 months; P = .49). Patients with well-differentiated histologies had superior median OS with photon RT (17 vs 69 months; P = .04). There was a nonsignificant trend toward improved OS with FNRT for medullary and anaplastic histologies., Conclusions: Outcomes in this study are in line with historical results. There is an apparent detriment in OS with FNRT for well-differentiated histologies and a trend toward improved OS with medullary and anaplastic histologies that warrants further investigation.

Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Radiation therapy (RT) is increasingly being utilized as a treatment modality for the treatment of primary and metastatic liver malignancies. Accurate assessment of liver function and prediction of radiation induced liver disease (RILD) remains a challenge with conventional laboratory tests and imaging. Imaging-pathology correlation of hepatic injury after RT has been described with computer tomography (CT) imaging that depicts perfusion changes. However, these imaging changes may not directly characterize the functional capacity of the liver., Case Presentation: This case report describes a patient that received preoperative chemoradiation and surgical resection for a liver metastasis from endometrial cancer. Sulfur colloid (SC) single photon emission computed tomography (SPECT/CT) was obtained post-chemoradiation and prior to surgery. Imaging-pathology correlation between radiation changes depicted on functional imaging using SC SPECT/CT and corresponding histopathology is described., Discussion: Quantitative SC SPECT/CT may allow non-invasive assessment of global and spatial liver function before treatment and enable personalized treatment approaches for liver-directed therapies.

Purpose: To evaluate the feasibility of a novel planning concept that differentially redistributes RT dose away from functional liver regions as defined by (99m)Tc-sulphur colloid (SC) uptake on patient SPECT/CT images., Materials and Methods: Ten HCC patients with different Child-Turcotte-Pugh scores (A5-B9) underwent SC SPECT/CT scans in treatment position prior to RT that were registered to planning CT scans. Proton pencil beam scanning (PBS) therapy plans were optimized to deliver 37.5-60.0Gy (RBE) over 5-15 fractions using single field uniform dose technique robust to range and setup uncertainty. Photon volumetrically modulated arc therapy (VMAT) plans were optimized to the same prescribed dose and minimum target coverage. For both treatment modalities, differential hepatic avoidance RT (DHART) plans were generated to decrease dose to functional liver volumes (FLV) defined by a range of thresholds relative to maximum SC uptake (43-90%) in the tumor-subtracted liver. Radiation dose was redistributed away from regions of increased SC uptake in each FLV by linearly scaling mean dose objectives during PBS or VMAT optimization. DHART planning feasibility was assessed by a significantly negative Spearman's rank correlation (RS) between dose difference and SC uptake. Patient, tumor, and treatment planning characteristics were tested for association to DHART planning feasibility using non-parametric Kruskal-Wallis ANOVA., Results: Compared to conventional plans, DHART plans achieved a 3% FLV dose reduction for every 10% SC uptake increase. DHART planning was feasible in the majority of patients with 60% of patients having RS<-0.5 (p<0.01, range -1.0 to 0.2) and was particularly effective in 30% of patients (RS<-0.9). Mean dose to FLV was reduced by up to 20% in these patients. Only fractionation regimen was associated with DHART planning feasibility: 15 fraction courses were more feasible than 5-6 fraction courses (RS<-0.93 vs. RS>-0.60, p<0.02)., Conclusion: Differential avoidance of functional liver regions defined on sulphur colloid SPECT/CT is achievable with either photon VMAT or proton PBS therapy. Further investigation with phantom studies and in a larger cohort of patients may validate the utility of DHART planning for HCC radiotherapy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)