Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein's C-Terminal Helix.

The cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to drive cell proliferation. A well-known target of cyclin D-Cdk4,6 is the retinoblastoma protein Rb, which inhibits cell-cycle progression until its inactivation by phosphorylation. However, the role of Rb phosphorylation by cyclin D-Cdk4,6 in cell-cycle progression is unclear because Rb can be phosphorylated by other cyclin-Cdks, and cyclin D-Cdk4,6 has other targets involved in cell division. Here, we show that cyclin D-Cdk4,6 docks one side of an alpha-helix in the Rb C terminus, which is not recognized by cyclins E, A, and B. This helix-based docking mechanism is shared by the p107 and p130 Rb-family members across metazoans. Mutation of the Rb C-terminal helix prevents its phosphorylation, promotes G1 arrest, and enhances Rb's tumor suppressive function. Our work conclusively demonstrates that the cyclin D-Rb interaction drives cell division and expands the diversity of known cyclin-based protein docking mechanisms.

BREAST-Q REACT: Qualitative Assessment of the Design, Functionality, and Clinical Utility of a New Score Interpretation Tool.

BACKGROUND: The BREAST-Q real-time engagement and communication tool (REACT) was developed to aid with BREAST-Q score interpretation and guide patient-centered care. OBJECTIVE: The purpose of this qualitative study was to examine the perspectives of patients and providers on the design, functionality, and clinical utility of REACT and refine the REACT based on their recommendations. METHODS: We conducted three patient focus groups with women who were at least 6 postoperative months from their postmastectomy breast reconstruction, and two provider focus groups with plastic surgeons, breast surgeons, and advanced practice providers. Focus groups were audio-taped, transcribed verbatim, and analyzed thematically. RESULTS: A total of 18 breast reconstruction patients and 14 providers participated in the focus groups. Themes identified by thematic analysis were organized into two categories: (1) design and functionality, and (2) clinical utility. On the design and functionality of REACT, four major themes were identified: visual appeal and usefulness; contextualizing results; ability to normalize patients' experiences, noting participants' concerns; and suggested modifications. On the clinical utility of REACT, three major themes were identified: potential to empower patients to communicate with their providers; increase patient and provider motivation to engage with the BREAST-Q; and effective integration into clinical workflow. CONCLUSION: Patients and providers in this qualitative study indicated that with some modifications, REACT has a great potential to elevate the clinical utility of the BREAST-Q by enhancing patient-provider communication that can lead to patient-centered, clinically relevant action recommendations based on longitudinal BREAST-Q scores.

Remote Symptom Monitoring with Clinical Alerts Following Mastectomy: Do Early Symptoms Predict 30-Day Surgical Complications.

BACKGROUND: Electronic patient-reported outcome measures (ePROMs) for real-time remote symptom monitoring facilitate early recognition of postoperative complications. We sought to determine whether remote, electronic, patient-reported symptom-monitoring with Recovery Tracker predicts 30-day readmission or reoperation in outpatient mastectomy patients. METHODS: We conducted a retrospective review of breast cancer patients who underwent outpatient (< 24-h stay) mastectomy with or without reconstruction from April 2017 to January 2022 and who received the Recovery Tracker on Days 1-10 postoperatively. Of 5,130 patients, 3,888 met the inclusion criteria (2,880 mastectomy with immediate reconstruction and 1,008 mastectomy only). We focused on symptoms concerning for surgical complications and assessed if symptoms reaching prespecified alert levels-prompting a nursing call-predicted risk of 30-day readmission or reoperation. RESULTS: Daily Recovery Tracker response rates ranged from 45% to 70%. Overall, 1,461 of 3,888 patients (38%) triggered at least one alert. Most red (urgent) alerts were triggered by pain and fever; most yellow (less urgent) alerts were triggered by wound redness and pain severity. The 30-day readmission and reoperation rates were low at 3.8% and 2.4%, respectively. There was no statistically significant association between symptom alerts and 30-day reoperation or readmission, and a clinically relevant increase in risk can be excluded (odds ratio 1.08; 95% confidence interval 0.8-1.46; p = 0.6). CONCLUSIONS: Breast cancer patients undergoing mastectomy with or without reconstruction in the ambulatory setting have a low burden of concerning symptoms, even in the first few days after surgery. Patients can be reassured that symptoms that do present resolve quickly thereafter.

Early Complications in Prepectoral Tissue Expander-Based Breast Reconstruction.

BACKGROUND: Prepectoral implant placement for postmastectomy breast reconstruction has increased in recent years. Benefits of prepectoral reconstruction may include lack of animation deformities and reduced postoperative pain, but its complication profile is currently unclear. This study aimed to examine the complication profile of prepectoral tissue expanders (TEs) to determine factors associated with TE loss. METHODS: A retrospective review was performed to identify all patients who underwent immediate prepectoral TE reconstruction from January 2018 to June 2021. The decision to use the prepectoral technique was based on mastectomy skin quality and patient comorbidities. Patient demographics, comorbidities, and operative details were evaluated. Outcomes of interest included TE loss, seroma, hematoma, infection/cellulitis, mastectomy skin flap necrosis requiring revision, and TE exposure. Logistic regression analysis was performed to identify factors associated with TE loss. RESULTS: The study identified 1225 TEs. The most frequent complications were seroma (8.7%, n = 106), infection/cellulitis (8.2%, n = 101), and TE loss (4.2%, n = 51). Factors associated with TE loss in the univariate analysis included ethnicity, history of smoking, body mass index, mastectomy weight, and neoadjuvant chemotherapy. In the multivariate regression analysis, only mastectomy weight had a positive association with TE loss (odds ratio, 1.001; p = 0.016). CONCLUSION: Prepectoral two-stage breast reconstruction can be performed safely with an acceptable early complication profile. The study data suggest that increasing mastectomy weight is the most significant factor associated with TE loss. Further research examining the quality of the soft tissue envelope and assessing patient-reported outcomes would prove beneficial.

A guide for addressing sexual health in breast cancer patients.

PURPOSE: Sexual health concerns are common in breast cancer surgery but often overlooked. Yet, breast cancer patients want more sexual health information from their providers. We aimed to share ways for providers to address sexual health concerns with their breast cancer patients at different stages of the treatment process. METHODS: Experts in breast cancer treatments, surgeries, and sexual health at Memorial Sloan Kettering Cancer Center assembled to review the literature and to develop the recommendations. RESULTS: Providers should provide sexual health information for their breast cancer patients throughout the continuum of care. Conversations should be initiated by the providers and can be brief and informative. Whenever appropriate, patients should be referred to Sexual Medicine experts and/or psychosocial support. There are various recommendations and tools that can be utilized at diagnosis, endocrine and chemotherapy, and breast surgery to identify patients with sexual health concerns and to improve their sexual functioning. CONCLUSION: In this paper, we sought to provide providers with some insights, suggestions, and tools to address sexual health concerns. We encourage healthcare providers to initiate the conversation throughout the continuum of care beginning as early as diagnosis and refer patients to additional services if available.

Nonresponse data in sexual well-being among breast reconstruction patients-who are we overlooking?

BACKGROUND: Missing data can affect the representativeness and accuracy of survey results, and sexual health-related surveys are especially at a higher risk of nonresponse due to their sensitive nature and stigma. The purpose of this study was to evaluate the proportion of patients who do not complete the BREAST-Q Sexual Well-being relative to other BREAST-Q modules and compare responders versus nonresponders of Sexual Well-being. We secondarily examined variables associated with Sexual Well-being at 1-year. METHODS: A retrospective analysis of patients who underwent breast reconstruction from January 2018 to December 2021 and completed any of the BREAST-Q modules postoperatively at 1-year was performed. RESULTS: The 2941 patients were included. Of the four BREAST-Q domains, Sexual Well-being had the highest rate of nonresponse (47%). Patients who were separated (vs. married, OR = 0.69), whose primary language was not English (vs. English, OR = 0.60), and had Medicaid insurance (vs. commercial, OR = 0.67) were significantly less likely to complete the Sexual Well-being. Postmenopausal patients were significantly more likely to complete the survey than premenopausal patients. Lastly, autologous reconstruction patients were 2.93 times more likely to respond than implant-based reconstruction patients (p < 0.001) while delayed (vs. immediate, OR = 0.70, p = 0.022) and unilateral (vs. bilateral, OR = 0.80, p = 0.008) reconstruction patients were less likely to respond. History of psychiatric diagnosis, aromatase inhibitors, and immediate breast reconstruction were significantly associated with lower Sexual Well-being at 1-year. CONCLUSION: Sexual Well-being is the least frequently completed BREAST-Q domain, and there are demographic and clinical differences between responders and nonresponders. We encourage providers to recognize patterns in nonresponse data for Sexual-Well-being to ensure that certain patient population's sexual health concerns are not overlooked.

Prolactin: A hormone with diverse functions from mammary gland development to cancer metastasis.

Prolactin has a rich mechanistic set of actions and signaling in order to elicit developmental effects in mammals. Historically, prolactin has been appreciated as an endocrine peptide hormone that is responsible for final, functional mammary gland development and lactation. Multiple signaling pathways impacted upon by the microenvironment contribute to cell function and differentiation. Endocrine, autocrine and paracrine signaling are now apparent in not only mammary development, but also in cancer, and involve multiple cell types including those of the immune system. Multiple ligands agonists are capable of binding to the prolactin receptor, potentially expanding receptor function. Prolactin has an important role not only in tumorigenesis of the breast, but also in a number of hormonally responsive cancers such as prostate, ovarian and endometrial cancer, as well as pancreatic and lung cancer. Although pituitary and extra-pituitary sources of prolactin such as the epithelium are important, stromal sourced prolactin is now also being recognized as an important factor in tumor progression, all of which potentially signal to multiple cell types in the tumor microenvironment. While prolactin has important roles in milk production including calcium and bone homeostasis, in the disease state it can also affect bone homeostasis. Prolactin also impacts metastatic cancer of the breast to modulate the bone microenvironment and promote bone damage. Prolactin has a fascinating contribution in both physiologic and pathologic settings of mammals.

Anti-HER2 therapy in metastatic breast cancer: many choices and future directions.

Metastatic HER2 + breast cancer is an expanding area of drug development and research, with three new drugs approved in 2020 alone. While first-line therapy is well-established for metastatic HER2 + breast cancer, the standard of care for second-line therapy will likely be changing soon based on the results of the DESTINY-Breast03 trial. In the third-line setting, many options are available. Considerations in choosing between regimens in the third-line include resistance to trastuzumab, the presence of brain metastases, and tolerability. High rates of resistance exist in this setting particularly due to expression of p95, a truncated form of HER2 that constitutively activates downstream signaling pathways. We suggest a tyrosine kinase inhibitor (TKI)-based regimen because of the activity of TKIs in brain metastases and in p95-expressing tumors. Attempts to overcome resistance to anti-HER2 therapies with PI3K inhibitors, mTOR inhibitors, and CDK 4/6 inhibitors are an active area of research. In the future, biomarkers are needed to help predict which therapies patients may benefit from the most. We review the many new drugs in development, including those with novel mechanisms of action.

Breast Surgical Oncology Epidemiologic Research: A Guide and Comparison of Four National Databases.

BACKGROUND: National databases are a rich source of epidemiologic data for breast surgical oncology research. However, these databases differ in the demographic, surgical, and oncologic variables provided. This study aimed to compare the strengths and limitations of four national databases in the context of breast surgical oncology research. METHODS: The study comprised a descriptive analysis of four national databases (the National Surgical Quality Improvement Program [NSQIP], the Nationwide Inpatient Sample [NIS], the Surveillance, Epidemiology and End Results [SEER] program, and the National Cancer Database [NCDB]) to assess their strengths and limitations in the context of breast surgical oncology. The study assessed the data available in each database for female patients with a breast cancer diagnosis between 2007 and 2017, and compared patient age, ethnicity, and race distributions. RESULTS: Data from 3.9 million female patients were examined, with most patients being between 60 and 69 years of age, non-Hispanic, and white. Age, ethnicity, and race distributions were similar in the databases. The NSQIP includes data on operative details, comorbidities, and postoperative outcomes. The NIS provides health services and inpatient utilization information, but does not evaluate outpatient procedures. The SEER program provides population-based oncologic detail including stage, histology, and neoadjuvant/adjuvant treatment. The NCDB offers hospital-based oncologic information and the largest population in the study period, with approximately 2.5 million breast cancer patients. CONCLUSION: Epidemiologic datasets offer tremendous potential for the examination of oncologic breast surgery, with each database providing unique data useful for addressing different epidemiologic questions. Understanding the strengths and limitations of each database creates a more efficient and productive research environment.

An updated analysis of hominin phylogeny with an emphasis on re-evaluating the phylogenetic relationships of Australopithecus sediba.

The discovery and description of Australopithecus sediba has reignited the debate over the evolutionary history of the australopiths and the genus Homo. It has been suggested that A. sediba may be an ancestor of Homo because it possesses a mosaic of derived Homo-like and primitive australopith-like traits. However, an alternative hypothesis proposes that the majority of the purported Homo-like craniodental characters can be attributed to the juvenile status of the type specimen, MH1. We conducted an independent character assessment of the craniodental morphology of A. sediba, with particular emphasis on evaluating whether the ontogenetic status of MH1 may have affected its purported Homo-like characteristics. In doing so, we have also expanded fossil hypodigms to incorporate the new Australopithecus anamensis cranium from Woranso-Mille (MRD-VP-1/1), as well as recently described Paranthropus robustus cranial remains from Drimolen (DNH 7, DNH 155). Morphological character data were analyzed using both standard parsimony and Bayesian techniques. In addition, we conducted a series of Bayesian analyses constrained to evaluate the hypothesis that Australopithecus africanus and A. sediba are sister taxa. Based on the results of the parsimony and Bayesian analyses, we could not reject the hypothesis that A. sediba shares its closest phylogenetic affinities with the genus Homo. Therefore, based on currently available craniodental evidence, we conclude that A. sediba is plausibly the terminal end of a lineage that shared a common ancestor with the earliest representatives of Homo. We caution, however, that the discovery of new A. sediba fossils preserving adult cranial morphology or the inclusion of postcranial characters may ultimately necessitate a re-evaluation of this hypothesis.

Implications of outgroup selection in the phylogenetic inference of hominoids and fossil hominins.

Understanding the phylogenetic relationships among hominins and other hominoid species is critical to the study of human origins. However, phylogenetic inferences are dependent on both the character data and taxon sampling used. Previous studies of hominin phylogenetics have used Papio and Colobus as outgroups in their analyses; however, these extant monkeys possess many derived traits that may confound the polarities of morphological changes among living apes and hominins. Here, we consider Victoriapithecus and Ekembo as more suitable outgroups. Both Victoriapithecus and Ekembo are anatomically well known and are widely accepted as morphologically primitive stem cercopithecoid and hominoid taxa, respectively, making them more appropriate for inferring polarity for later-occurring hominoid- and hominin-focused analyses. Craniodental characters for both taxa were scored and then added to a previously published matrix of fossil hominin and extant hominoid taxa, replacing outgroups Papio and Colobus over a series of iterative analyses using both parsimony and Bayesian inference methods. Neither the addition nor replacement of outgroup taxa changed tree topology in any analysis. Importantly, however, bootstrap support values and posterior probabilities for nodes supporting their relationships generally increased compared to previous analyses. These increases were the highest at extant hominoid and basal hominin nodes, recovering the molecular ape phylogeny with considerably higher support and strengthening the inferred relationships among basal hominins. Interestingly, however, the inclusion of both extant and fossil outgroups reduced support for the crown hominid node. Our findings suggest that, in addition to improving character polarity estimation, including fossil outgroups generally strengthens confidence in relationships among extant hominoid and basal hominins.

Taxonomic attribution of the KNM-ER 1500 partial skeleton from the Burgi Member of the Koobi Fora Formation, Kenya.

Paranthropus boisei is well represented in the eastern African fossil record by craniodental remains, but very few postcranial fossils can be securely attributed to this taxon. For this reason, KNM-ER 1500 from East Turkana, Kenya, is especially important. KNM-ER 1500 is a badly weathered and fragmented postcranial skeleton associated with a small piece of mandibular corpus. It derives from the Burgi Member, which has yielded diagnostic craniodental fossils attributable to P. boisei, Homo habilis, Homo rudolfensis and Homo erectus. Although it has been proposed that KNM-ER 1500 may be attributable to P. boisei based on the small mandibular fragment, this hypothesis remained challenging to test. Here we re-examine the preserved portions of KNM-ER 1500 and reassess support for its taxonomic attribution. There are compelling features of the mandible, proximal femur, and especially the proximal radius that support attribution of KNM-ER 1500 to P. boisei. These features include the absolute width of the mandible and its lack of a lateral intertoral sulcus, an anteroposteriorly compressed femoral neck with a distinctive posteroinferior marginal ridge, the rim of the radial head that is proximodistally uniform in thickness around its circumference, and a long radial neck that is elliptical in cross section. No feature serves to align KNM-ER 1500 with Homo to the exclusion of Paranthropus. KNM-ER 1500 was a small-bodied individual and attributing this specimen to P. boisei confirms that significant postcranial-size dimorphism was present in this species.

Increasing rates of general anesthesia use in lumpectomy procedures: A 15-year trends analysis.

BACKGROUND: Anesthesia methods in oncologic breast surgery have evolved with less invasive practices. The aims of this study were primarily to examine trends in anesthesia type used during lumpectomy. METHODS: We analyzed lumpectomy procedures from 2005 to 2019 using the NSQIP database. Upon defining the nadir in general anesthesia (GA) and peak in monitored anesthesia care (MAC) use as 2007, we compared patient characteristics and complications in the 2007 versus 2019 GA and MAC cohorts. Multivariable logistic regression was used to examine associations with receipt of GA. RESULTS: Of 253 545 lumpectomy patients, 191 773 (75.6%) received GA and 61 772 (24.4%) received MAC. From 2005 to 2019, GA rates increased from 66.7% to 82.5%, while MAC rates decreased from 33.3% to 17.5%. More GA patients were obese and American Society of Anesthesiologists class 3. Over time, age and body mass index (BMI) increased in both GA and MAC cohorts. Odds of receiving GA increased over time, and predictors included concurrent axillary lymph node dissection (p < 0.0001) or sentinel lymph node biopsy (p < 0.0001). CONCLUSIONS: We demonstrate increasing use of GA over time for lumpectomy, which may be related to aging lumpectomy patient population with higher BMIs. We also find a strong association between use of GA and concurrent lymph node procedures.

Decreasing length of stay in breast reconstruction patients: A national analysis of 2019-2020.

BACKGROUND: The effects of COVID-19 on breast reconstruction included shifts toward alloplastic reconstruction methods to preserve hospital resources and minimize COVID exposures. We examined the effects of COVID-19 on breast reconstruction hospital length of stay (LOS) and subsequent early postoperative complication rates. METHODS: Using the National Surgical Quality Improvement Program, we examined female patients who underwent mastectomy with immediate breast reconstruction from 2019 to 2020. We compared postoperative complications across 2019-2020 for alloplastic and autologous reconstruction patients. We further performed subanalysis of 2020 patients based on LOS. RESULTS: Both alloplastic and autologous reconstruction patients had shorter inpatient stays. Regarding the alloplastic 2019 versus 2020 cohorts, complication rates did not differ (p > 0.05 in all cases). Alloplastic patients in 2020 with longer LOS had more unplanned reoperations (p < 0.001). Regarding autologous patients in 2019 versus 2020, the only complication increasing from 2019 to 2020 was deep surgical site infection (SSI) (2.0% vs. 3.6%, p = 0.024). Autologous patients in 2020 with longer LOS had more unplanned reoperations (p = 0.007). CONCLUSIONS: In 2020, hospital LOS decreased for all breast reconstruction patients with no complication differences in alloplastic patients and a slight increase in SSIs in autologous patients. Shorter LOS may lead to improved satisfaction and lower healthcare costs with low complication risk, and future research should examine the potential relationship between LOS and these outcomes.

BREAST-Q REACT: Clinical Reference Values for the BREAST-Q in Post-mastectomy Breast Reconstruction Patients.

BACKGROUND: The BREAST-Q is the most commonly used patient-reported outcome measure (PROM) for breast reconstruction research. However, clinical implementation of this PROM has been impeded by a lack of context for score interpretation. The aim of this study was to define reference values for the BREAST-Q at discrete timepoints following surgery, generating a tool for real-time score interpretation. METHODS: BREAST-Q scores were prospectively obtained in women who underwent implant or autologous post-mastectomy breast reconstruction preoperatively and for 2 years following surgery at Memorial Sloan Kettering Cancer Center (MSK). Descriptive statistics were used to create reference values for BREAST-Q satisfaction and quality-of-life subscales. Reference values were externally validated by comparing patient characteristics and BREAST-Q scores between the MSK and the Mastectomy Reconstruction Outcomes Consortium (MROC) study cohorts. RESULTS: Overall, 3268 MSK patients and 2814 MROC patients were included for analysis. When MSK and MROC cohorts were compared for validation, there were some statistical differences in BREAST-Q scores; however, most of these differences did not meet the minimal clinically important difference of 4 points. Reference values were used to create the BREAST-Q Real-time Engagement and Communication Tool (REACT). CONCLUSIONS: Using a large cohort of patients, we have defined BREAST-Q reference values for post-mastectomy breast reconstruction patients for use in clinical practice. The BREAST-Q REACT will help breast reconstruction providers gauge patient wellbeing and satisfaction relative to the "average" breast reconstruction patient and determine which patients may benefit from additional intervention.

The taxonomic attribution of African hominin postcrania from the Miocene through the Pleistocene: Associations and assumptions.

Postcranial bones may provide valuable information about fossil taxa relating to their locomotor habits, manipulative abilities and body sizes. Distinctive features of the postcranial skeleton are sometimes noted in species diagnoses. Although numerous isolated postcranial fossils have become accepted by many workers as belonging to a particular species, it is worthwhile revisiting the evidence for each attribution before including them in comparative samples in relation to the descriptions of new fossils, functional analyses in relation to particular taxa, or in evolutionary contexts. Although some workers eschew the taxonomic attribution of postcranial fossils as being less important (or interesting) than interpreting their functional morphology, it is impossible to consider the evolution of functional anatomy in a taxonomic and phylogenetic vacuum. There are 21 widely recognized hominin taxa that have been described from sites in Africa dated from the Late Miocene to the Middle Pleistocene; postcranial elements have been attributed to 17 of these. The bones that have been thus assigned range from many parts of a skeleton to isolated elements. However, the extent to which postcranial material can be reliably attributed to a specific taxon varies considerably from site to site and species to species, and is often the subject of considerable debate. Here, we review the postcranial remains attributed to African hominin taxa from the Late Miocene to the Middle and Late Pleistocene and place these assignations into categories of reliability. The catalog of attributions presented here may serve as a guide for making taxonomic decisions in the future.

Effects of COVID-19 on mastectomy and breast reconstruction rates: A national surgical sample.

BACKGROUND: The COVID-19 pandemic profoundly impacted breast cancer treatment in 2020. Guidelines initially halted elective procedures, subsequently encouraging less invasive surgeries and restricting breast reconstruction options. We examined the effects of COVID-19 on oncologic breast surgery and reconstruction rates during the first year of the pandemic. METHODS: Using the National Surgical Quality Improvement Program, we performed an observational examination of female surgical breast cancer patients from 2017 to 2020. We analyzed annual rates of lumpectomy, mastectomy (unilateral/contralateral prophylactic/bilateral prophylactic), and breast reconstruction (alloplastic/autologous) and compared 2019 and 2020 reconstruction cohorts to evaluate the effect of COVID-19. RESULTS: From 2017 to 2020, 175 949 patients underwent lumpectomy or mastectomy with or without reconstruction. From 2019 to 2020, patient volume declined by 10.7%, unilateral mastectomy rates increased (70.5% to 71.9%, p = 0.003), and contralateral prophylactic mastectomy rates decreased. While overall reconstruction rates were unchanged, tissue expander reconstruction increased (64.0% to 68.4%, p < 0.001) and direct-to-implant and autologous reconstruction decreased. Outpatient alloplastic reconstruction increased (65.7% to 73.8%, p < 0.0001), and length of hospital stay decreased for all reconstruction patients (p < 0.0001). CONCLUSIONS: In 2020, there was a nearly 11% decline in breast cancer surgeries, comparable mastectomy and reconstruction rates, increased use of outpatient alloplastic reconstruction, and significantly reduced in-hospital time across all reconstruction types.

Assessing Population Structure and Genetic Diversity in US Suffolk Sheep to Define a Framework for Genomic Selection.

Long-term sustainability of breeds depends on having sufficient genetic diversity for adaptability to change, whether driven by climatic conditions or by priorities in breeding programs. Genetic diversity in Suffolk sheep in the United States was evaluated in four ways: 1) using genetic relationships from pedigree data [(n = 64 310 animals recorded in the US National Sheep Improvement Program (NSIP)]; 2) using molecular data (n = 304 Suffolk genotyped with the OvineHD BeadChip); 3) comparing Australian (n = 109) and Irish (n = 55) Suffolk sheep to those in the United States using molecular data; and 4) assessing genetic relationships (connectedness) among active Suffolk flocks (n = 18) in NSIP. By characterizing genetic diversity, a goal was to define the structure of a reference population for use for genomic selection strategies in this breed. Pedigree-based mean inbreeding level for the most recent year of available data was 5.5%. Ten animals defined 22.8% of the current gene pool. The effective population size (Ne) ranged from 27.5 to 244.2 based on pedigree and was 79.5 based on molecular data. Expected (HE) and observed (HO) heterozygosity were 0.317 and 0.306, respectively. Model-based population structure included 7 subpopulations. From Principal Component Analysis, countries separated into distinct populations. Within the US population, flocks formed genetically disconnected clusters. A decline in genetic diversity over time was observed from both pedigree and genomic-based derived measures with evidence of population substructure as measured by FST. Using these measures of genetic diversity, a framework for establishing a genomic reference population in US Suffolk sheep engaged in NSIP was proposed.

Assessment of Karnofsky (KPS) and WHO (WHO-PS) performance scores in brain tumour patients: the role of clinician bias.

PURPOSE: Inclusion of brain tumour patients in oncological protocols may be hampered by their neurological impairment. The goal of this study was to assess the reliability of Karnofsky Performance Scale (KPS) and WHO Performance Scale (WHO-PS) scores in this population. METHODS: A cross-sectional survey was conducted through the Association des Neuro-Oncologues d'Expression Française (ANOCEF) and European Neuro-Oncology Association (EANO) networks. Clinicians were asked to write a text defining their operative definition of a patient with ≥ 70 KPS and to assess KPS and WHO-PS in six different clinical case vignettes. RESULTS: Two hundred seventy-six clinicians sent a response. The operative definition mentioned a normal life (89%), what patients were able (26%) or unable (29%) to do, normal cognitive processing (8%) and caregivers (6%). Older physicians mentioned more often what patients were unable to do (p = 0.005). The two scales were homogeneous in less severely handicapped patients only. More patients were excluded for hemiplegia than for expressive aphasia. Older physicians significantly excluded more patients for KPS and WHO-PS. Speciality of the physician significantly influenced scoring. On multivariable analysis, age and speciality of the physicians were correlated with KPS and WHO-PS rating even if adjusted on cases. Discordant scoring increased with severity of the deficit: in nearly all cases, the KPS would have denied, while WHO-PS would have allowed, access to a trial. CONCLUSION: Performance scores assigned to brain tumour patients are clinician and score dependant. WHO-PS would allow more access to a trial. Specific criteria should be developed for patients with neurological deficits to facilitate their access to trials.

The effect of data provenance on estimates of gestation length in African and Asian colobines.

OBJECTIVES: It seems to be commonly accepted that gestation length within the subfamily Colobinae lasts several weeks longer in the African tribe (Colobini) than in the Asian tribe (Presbytini) even though closely related taxa of similar body mass should have similar life histories. Suspecting problems with data provenance to cause the difference, we revisited the published records expecting similar gestation lengths in both tribes if based on vetted, accurate data. MATERIALS AND METHODS: We compiled published gestation length data for Colobini and Presbytini, labeling them as "unspecified" (n = 16) if the primary reference could not be located, methods were not described, and/or conceptions, the beginning of gestation, were determined based on sporadic observations of mating. If conceptions were determined based on changing hormone levels or patterns of daily mating records, we labeled the data as "accurate" (n = 12). We analyzed the ln transformed data in a phylogenetic framework in relation to adult female body mass. RESULTS: In the unspecified dataset, gestation length in the two tribes overlapped extensively and did not differ significantly. However, in the accurate dataset, gestation length was significantly shorter in Colobini (not longer, as previously assumed). DISCUSSION: Data provenance had a strong impact on the comparison, reversing the relationship in gestation length in the two sister tribes. It remains to be determined why gestation lengths differ, whether, relative to the other primates, Colobini have a shortened gestation or Presbytini a lengthened gestation, and whether similar differences exist in other closely related taxa. Addressing these questions will require additional, broader, comparative analyses.