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The Big Five Inventory - 2 (BFI-2) is a commonly used self-report assessment of normal personality trait domains (Extraversion, Agreeableness, Conscientiousness, Negative Emotionality, Open-Mindedness) and facets. To date, however, no direct measures of response distortion have been developed for it to identify potentially invalid responses. Such distortions (e.g., careless or random responding) can adversely impact data quality. The current study developed and provided initial validation data for an inconsistent responding scale within the BFI-2 to identify careless responders using two large undergraduate samples and a community sample. To create the scale, we first identified highly correlated BFI-2 item pairs in one undergraduate sample ( N  = 1,461) and then computed a total score by summing the absolute differences of these item pairs. This scale, the Detection of Response Inconsistency Procedure (DRIP), differentiated randomly generated and genuine data and generally correlated as expected with personality domains and other inconsistent responding scales across samples. The DRIP also incrementally predicted random data beyond a composite of items with exceptionally high or low base rates of endorsement from the Comprehensive Infrequency/Frequency Item Repository. We provide recommendations for DRIP cut scores that can detect careless responding while balancing sensitivity and specificity.

Background: We hypothesize that creation of a structured curriculum in neuro-ophthalmology principles might improve self-rated learner satisfaction and knowledge base of National Football League (NFL) game officials. Our initial objective is to create the said curriculum in coordination with game official experts and staff at the NFL to increase levels of understanding of neuro-ophthalmology principles. We reviewed the prior published literature on applicable neuro-ophthalmic principles in professional sports. Major neuro-ophthalmic principles reviewed include both the efferent (e.g., saccadic and pursuit eye movements and vestibulo-ocular reflex) and afferent (visual field, dynamic visual acuity during body movement, and selective attention deficits)., Methods: A 6-question survey pertaining to levels of understanding, future applicability, relevance, satisfaction, and interest in additional training was then given to 26 individuals before and after a lecture given by Dr. Andrew Lee in Plano, TX. The primary outcome measure was the creation of the curriculum followed by real-world testing for face and content validity and ending with a self-rated assessment., Results: Twenty-one individuals completed the prelecture and postlecture survey out of 26 individuals who attended. Prelecture means for the level of understanding of oculomotor terms and the likelihood of using said terms were 3.4 and 3.2, respectively. Postlecture means were 8.9 and 8.8, respectively. The lecture was rated 9.2 of 10 for relevance to coaching and teaching officials, and individuals rated their interest in further content as 9.4 of 10., Conclusions: This study found that NFL game officials are interested in learning more about the science behind play-calling in terms of neuro-ophthalmology principles and practices. In addition, from our pilot survey, it is evident that even one lecture can improve participants' level of understanding and likelihood of learning more about neuro-ophthalmic principles., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

Background and Aims: This study assesses the attitudes of healthcare practitioners toward Living Donation Prior to Planned Withdrawal of Care (LD-PPW): the recovery of a living donor organ before withdrawal of life-sustaining measures in a patient who does not meet criteria for brain death, but for whom medical care toward meaningful recovery is deemed futile., Methods: An electronic survey was administered to 1735 members of the American Society of Transplant Surgeons mailing list with 187 responses (10.8%)., Results: Data from this study revealed that 70% of responding practitioners agreed with LD-PPW due to principles of beneficence and autonomy. Also, 65% of participants felt confident in their ability to declare the futility of care and 70% felt that LD-PPW should be added as an option when registering to become an organ donor., Conclusion: Currently, nearly half of all donation after circulatory determination of death do not proceed to donation. LD-PPW has been proposed as an alternative procedure targeted at increasing the quality and quantity of transplantable organs while respecting the donor's right to donate, though its implementation has been hindered by concerns over public and provider perception. This study revealed support for LD-PPW among healthcare practitioners as an alternative procedure to increase the quality and quantity of transplantable organs while respecting the donor's right to donate., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The incidence of young-onset colorectal cancer (YOCRC; defined as patients who are diagnosed with CRC before age 50 years) is rising rapidly, and CRC is predicted to be the leading cause of cancer death in this age group by 2030. Yet, there has been limited research into the experiences and needs of patients with YOCRC and their caregivers. The goal of this study was to better understand the experiences and needs of patients with YOCRC and their caregivers., Patients and Methods: Semistructured focus groups were conducted with patients with YOCRC, caregivers of patients with YOCRC, and bereaved caregivers of patients with YOCRC. Focus group discussion guides addressed the experience and impact of diagnosis and treatment of YOCRC. Results were analyzed using a thematic analysis informed by framework analysis., Results: Twenty patients and caregivers participated in three focus groups (eight patients, seven caregivers, and five bereaved caregivers). Four primary themes were identified: (1) feeling overwhelmed by the health care system and desiring patient navigation; (2) feeling isolated and wanting opportunities for peer support; (3) life disruption because of difficulty juggling multiple roles and desiring psychosocial support; and (4) enthusiasm about participation in research and genetic testing., Conclusion: This study identified and described the unique experiences and care needs of patients with YOCRC and their caregivers. The findings provide evidence that specialized models of care are needed. The results of this study informed the development of a center dedicated to the care of patients with YOCRC.

We evaluated how the number of response options affects the psychometric properties of the Big Five Inventory-2 (BFI-2). Using two large samples collected from a market research company ( N s = 893 and 1,213), we tested how different response options of the BFI-2 influenced scale score distributions, internal consistency estimates, convergent validity correlations, and criterion validity correlations. Results suggest that score distributions were impacted by the number of response options such that ceiling and floor effects were more common when using two or three response options than when using more options. Estimates of Cronbach's alpha were generally lower with fewer scale points as compared with more scale points, but these effects disappeared when ordinal alpha was used. There were no systematic effects of response options on convergent validity and criterion validity correlations. Given these results, there seems to be few psychometric reasons for deciding whether to administer personality items with five, six, or seven scale points., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Secukinumab and Dead Sea treatment result in clear skin for many psoriasis patients, through distinct mechanisms. However, recurrence in the same areas after treatments suggests the existence of a molecular scar. We aimed to compare the molecular and genetic differences in psoriasis patients who achieved complete response from secukinumab and Dead Sea climatotherapy treatments. We performed quantitative immunohistochemical and transcriptomic analysis, in addition to digital spatial profiling of skin punch biopsies. Histologically, both treatments resulted in a normalization of the lesional skin to a level resembling nonlesional skin. Interestingly, the transcriptome was not normalized by either treatments. We revealed 479 differentially expressed genes between secukinumab and Dead Sea climatotherapy at the end of treatment, with a psoriasis panel identifying SERPINB4 , SERPINB13 , IL36G , IL36RN , and AKR1B10 as upregulated in Dead Sea climatotherapy compared with secukinumab. Using digital spatial profiling, pan-RAS was observed to be differentially expressed in the microenvironment surrounding CD103 + cells, and IDO1 was differentially expressed in the dermis when comparing the two treatments. The differences observed between secukinumab and Dead Sea climatotherapy suggest the presence of a molecular scar, which may stem from mechanistically different pathways and potentially contribute to disease recurrence. This may be important for determining treatment response duration and disease memory.

Objective: Self-focused language use has been frequently assumed to reflect narcissism; however, research indicates that the association between first-person singular pronouns (i.e., "I-talk") and grandiose narcissism is negligible., Method: To extend this literature, we progressively identify vulnerable narcissism and rumination as positive correlates of I-talk in five studies (valid Ns = 211, 475, 1253, 289, 1113)., Results: The first study revealed positive correlates of I-talk suggestive of vulnerable narcissism. The second study showed more directly that vulnerable narcissism was a positive correlate but that this association was attributable to shared variance with neuroticism. The third study, a preregistered effort, replicated and extended the results of the second study. The fourth and fifth studies focused on rumination in a preregistered manner., Conclusions: All the studies point to a clear distinction: While grandiose narcissism is negligibly related to I-talk, vulnerable narcissism is positively related to I-talk; moreover, rumination is a robust predictor of I-talk. A research synthesis revealed the following constructs significantly capture I-talk: depression (r = 0.10), neuroticism (r = 0.15), rumination (r = 0.14), and vulnerable narcissism (r = 0.12). The association between I-talk and neuroticism was partially mediated by rumination, providing a testable candidate mechanism for neuroticism interventions., (© 2024 Wiley Periodicals LLC.)

The skull roof, or calvaria, is comprised of interlocking plates of bones that encase the brain. Separating these bones are fibrous sutures that permit growth. Currently, we do not understand the instructions for directional growth of the calvaria, a process which is error-prone and can lead to skeletal deficiencies or premature suture fusion (craniosynostosis, CS). Here, we identify graded expression of fibronectin (FN1) in the mouse embryonic cranial mesenchyme (CM) that precedes the apical expansion of calvaria. Conditional deletion of Fn1 or Wasl leads to diminished frontal bone expansion by altering cell shape and focal actin enrichment, respectively, suggesting defective migration of calvarial progenitors. Interestingly, Fn1 mutants have premature fusion of coronal sutures. Consistently, syndromic forms of CS in humans exhibit dysregulated FN1 expression, and we also find FN1 expression altered in a mouse CS model of Apert syndrome. These data support a model of FN1 as a directional substrate for calvarial osteoblast migration that may be a common mechanism underlying many cranial disorders of disparate genetic etiologies., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Sports participation and the risk of osteoarthritis (OA) have been a concern for decades. Few research efforts have been dedicated to clarify this issue for females, although they are considered at greater risk of developing OA than males. In contrast, several reviews have established an association between sports participation and OA for males. The aim of the systematic review was to assess the association between OA and participation in popular sports for females. PubMed, Embase, and Google Scholar were searched and yielded 578 articles. Nine eligible studies were included and covered ballet (age range: 19-54 years), running or tennis (age range: 40-65 years), Olympic sports (age range: not specified), volleyball (age range: 16.0 ± 0.8 to 46.8 ± 5.1 years), and cross-country skiing (age range: 15 to ≥60 years). For females, participating in sports at an elite level was associated with a higher risk of OA and an increased need for surgical treatment. At non-elite level, it was associated with a higher risk of OA, but it did not materialize to an increased risk for surgical treatment. Few studies compared females and males, and these studies suggested that sex did not affect the risk of developing OA from participating in sports. Nevertheless, to isolate the precise effect of sports participation on the development of OA remains difficult as injuries are common among athletes and are independently associated with an increased risk of OA.

Inconsistent or careless responding is a significant threat to the validity of self-reported personality data. Using archival samples of undergraduate and community participants, we developed an inconsistent responding scale using items that appear on both the 60- and 100-item versions of the HEXACO Personality Inventory-Revised-two widely used measures of the HEXACO model of personality trait structure. We identified pairs of correlated HEXACO items in Sample 1 and created a total inconsistent responding score by summing absolute differences between each item pair. The Brief Response Inconsistency Evaluation (BRIE) for the HEXACO effectively differentiated between genuine and randomly generated responses across samples. The BRIE also correlated as expected with other measures of careless responding and relevant personality traits (e.g., conscientiousness). Tentative cut scores for the BRIE that appear to provide a reasonable balance between sensitivity and specificity in Sample 1 were investigated. Future research should examine the BRIE with different populations and translations of the HEXACO inventories and further investigate the effectiveness of the recommended cut scores., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The Rosenberg Self-Esteem Scale is the most frequently used measure of self-esteem in the social sciences. These items are often administered with a different number of response options, but it is unclear how the number of response options impacts the psychometric properties of this measure. Across three experiments ( N s = 739, 2,358, and 1,461), we evaluated how different response options of the Rosenberg influenced (a) coefficient alpha estimates, (b) distributions of scores, and (c) associations with criterion-related variables. Observed coefficient alpha estimates were lowest for a 2-point format compared with response formats with more options. However, supplemental analyses using ordinal alpha pointed to similar estimates across conditions. Using four or more response options better approximated a normal distribution for observed summary scores. We found no consistent evidence that criterion-related correlations increased with more response options. Collectively, these results suggest that the Rosenberg should be administered with at least four response options and we favor a 5-point Likert-type response format.

Animal models are fundamental to advance our knowledge of the underlying pathophysiology of bone loss and to study pharmaceutical countermeasures against it. The animal model of post-menopausal osteoporosis from ovariectomy is the most widely used preclinical approach to study skeletal deterioration. However, several other animal models exist, each with unique characteristics such as bone loss from disuse, lactation, glucocorticoid excess, or exposure to hypobaric hypoxia. The present review aimed to provide a comprehensive overview of these animal models to emphasize the importance and significance of investigating bone loss and pharmaceutical countermeasures from perspectives other than post-menopausal osteoporosis only. Hence, the pathophysiology and underlying cellular mechanisms involved in the various types of bone loss are different, and this might influence which prevention and treatment strategies are the most effective. In addition, the review sought to map the current landscape of pharmaceutical countermeasures against osteoporosis with an emphasis on how drug development has changed from being driven by clinical observations and enhancement or repurposing of existing drugs to today's use of targeted anti-bodies that are the result of advanced insights into the underlying molecular mechanisms of bone formation and resorption. Moreover, new treatment combinations or repurposing opportunities of already approved drugs with a focus on dabigatran, parathyroid hormone and abaloparatide, growth hormone, inhibitors of the activin signaling pathway, acetazolamide, zoledronate, and romosozumab are discussed. Despite the considerable progress in drug development, there is still a clear need to improve treatment strategies and develop new pharmaceuticals against various types of osteoporosis. The review also highlights that new treatment indications should be explored using multiple animal models of bone loss in order to ensure a broad representation of different types of skeletal deterioration instead of mainly focusing on primary osteoporosis from post-menopausal estrogen deficiency., Competing Interests: Declaration of Competing Interest The author declares that there are no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Static and dynamic bone histomorphometry and identification of bone cells in culture are labor-intensive and highly repetitive tasks. Several computer-assisted methods have been proposed to ease these tasks and to take advantage of the increased computational power available today. The present review aimed to provide an overview of contemporary methods utilizing specialized computer software to perform bone histomorphometry or identification of bone cells in culture. In addition, a brief historical perspective on bone histomorphometry is included. We identified ten publications using five different computer-assisted approaches (1) ImageJ and BoneJ; (2) Histomorph: OsteoidHisto, CalceinHisto, and TrapHisto; (3) Fiji/ImageJ2 and Trainable Weka Segmentation (TWS); (4) Visiopharm and artificial intelligence (AI); and (5) Osteoclast identification using deep learning with Single Shot Detection (SSD) architecture, Darknet and You Only Look Once (YOLO), or watershed algorithm (OC_Finder). The review also highlighted a substantial need for more validation studies that evaluate the accuracy of the new computational methods to the manual and conventional analyses of histological bone specimens and cells in culture using microscopy. However, a substantial evolution has occurred during the last decade to identify and separate bone cells and structures of interest. Most early studies have used simple image segmentation to separate structures of interest, whereas the most recent studies have utilized AI and deep learning. AI has been proposed to substantially decrease the amount of time needed for analyses and enable unbiased assessments. Despite the clear advantages of highly sophisticated computational methods, the limited nature of existing validation studies, particularly those that assess the accuracy of the third-generation methods compared to the second-generation methods, appears to be an important reason that these techniques have failed to gain wide acceptance., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Structural models of personality traits, particularly the five-factor model (FFM), continue to inform ongoing debates regarding what personality attributes and trait domains are central to psychopathy. A growing body of literature has linked the constructs of the triarchic model of psychopathy (boldness, meanness, disinhibition) to the FFM. Recently, researchers developed both item and regression-based measures of the triarchic model of psychopathy using the NEO Personality Inventory-Revised-a popular measure of the FFM. The current study examines the correlates of these two FFM-derived operationalizations of the triarchic model using data from the Collaborative Longitudinal Personality Disorders Study. The two approaches had strong convergent validity coefficients and similar patterns of criterion-related validity coefficients. Meanness related to greater personality pathology characterized by exploitation of others and poor attachment, whereas disinhibition related to indicators of greater negative affect and poor behavioral constraint. Boldness related to reduced negative affect and greater narcissistic personality traits. Although the item and regression-based approaches showed similar patterns of associations with criterion-variables, the item-based approach has some practical and psychometric advantages over the regression-based approach given strong correlations between the meanness and disinhibition scores from the regression approach.

Optic nerve infiltration is a rare but known complication of the central nervous system (CNS)-involving lymphoma and leukemic disorders. The diagnosis is often presumed and patients are empirically treated with systemic therapy and/or local radiation. Optic nerve biopsy is usually avoided due to the risk of permanent vision loss secondary to the procedure. We present a case of biopsy-proven leukemic optic neuropathy without optic nerve sheath or cerebrospinal fluid (CSF) involvement in a patient previously in remission from T-cell prolymphocytic leukemia (T-PLL). To our knowledge, this is the first documented case of T-PLL with biopsy-proven optic nerve invasion without CSF involvement and suggests possible perineural invasion or a sanctuary site from chemotherapy. We suggest that for patients with poor vision and suspected leukemic infiltration without other evidence of CNS involvement, both optic nerve and optic sheath biopsy should be performed for diagnosis and treatment.

Background: Bone fractures are common conditions of the musculoskeletal system. Several animal models of bone fractures have been established to help elucidate the complex process of bone healing. In the last decades, drill-hole bone defects have emerged as a method to study bone healing. Animal models of drill-hole defects are easy to standardize and do not require external fixation of the bone. However, current studies of drill-hole bone defects lack detailed descriptions of techniques and interstudy standardization., Objective: This systematic review aims to present a detailed description of the different methods used to induce drill-hole bone defects in long bones of laboratory animals and to provide a comprehensive overview of their methodology and potential for investigation of bone healing., Methods: A systematic search of PubMed and Embase will be performed of abstracts containing variations of the following four keywords: "long bone," "drill-hole," "regeneration," and "animal model." Abstract screening and full-text screening will be performed independently by 2 reviewers, and data will be extracted to a predesigned extraction protocol. The primary outcome of the included studies is the technique used to create the drill-hole bone defect, and secondary outcomes are any measurements or analyses of bone defect and regeneration. A narrative synthesis will be used to present the primary outcome, while information on secondary outcomes will be displayed graphically. The study protocol follows the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines., Results: Abstract and full-text screening is ongoing and is expected to be completed by October 2022. Data extraction will commence immediately after, and the manuscript is expected to be completed by December 2023. The systematic review will follow the PRISMA statement., Conclusions: The strength of this systematic review is that it provides a comprehensive methodological overview of the different drill-hole methods and their advantages and disadvantages. This will assist researchers in choosing which model to use when studying different aspects of bone healing., Trial Registration: International Prospective Register of Systematic Reviews CRD42020213076; https://tinyurl.com/bp56wdwe., International Registered Report Identifier (irrid): PRR1-10.2196/34887., (©Frederik Duch Bromer, Mikkel Bo Brent, Jesper Skovhus Thomsen, Annemarie Brüel. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 18.07.2022.)

Prolonged disuse and substantial mechanical unloading are particularly damaging to skeletal integrity. Preclinical studies in rodents and clinical studies have highlighted the need for potent bone anabolic drugs to counteract disuse-induced osteopenia. The aim of present study was to compare the efficacy of romosozumab (Scl-Ab) and abaloparatide (ABL), alone or in combination, to prevent botulinum toxin (BTX) induced bone loss in a rat model. Eighty female Wistar rats were divided into the following six groups: 1. Baseline (n = 12); 2. Control (Ctrl) (n = 12); 3. BTX (n = 12); 4. BTX + Scl-Ab (n = 16); 5. BTX + ABL (n = 12); and 6. BTX + Scl-Ab + ABL (n = 16). Disuse was achieved by injecting 4 IU BTX into the hind limb musculature at study start. Scl-Ab (25 mg/kg) was injected s.c. twice weekly, while ABL (80 μg/kg) was injected s.c. five days a week for four weeks. Hind limb disuse dramatically decreased muscle mass and skeletal integrity and deteriorated the cortical morphology and trabecular microstructure. Treatment with Scl-Ab alone prevented most of the adverse cortical and trabecular effects of disuse, while ABL monotherapy mainly attenuated the disuse-induced loss of femoral areal bone mineral density (aBMD). Moreover, the combination of Scl-Ab and ABL not only counteracted most of the negative skeletal effects of unloading, but also increased aBMD (+10% and +20%), epiphyseal trabecular bone volume fraction (BV/TV) (+25% and +73%), and metaphyseal bone strength (+18% and +30%) significantly above that of Scl-Ab or ABL monotherapy, respectively. The potent and additive osteoanabolic effect of Scl-Ab and ABL, when given in combination, is highly intriguing and underlines that an osteoanabolic bone gain can be maximized by utilizing two pharmaceuticals targeting different cellular signaling pathways. From a clinical perspective, a combination treatment may be warranted in patients where the osteoanabolic effect of either monotherapy is not sufficient, or if a dose-reduction is required due to adverse effects., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years., Methods: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed., Results: The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age., Conclusions: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Immunohistochemical quantification of inflammatory cells in skin biopsies is a valuable tool for diagnosing skin diseases and assessing treatment response. The quantification of individual cells in biopsies is time-consuming, tedious, and difficult. In this study, we presented and compared two methods for the quantification of CD8 + T cells in skin biopsies from patients with psoriasis using both commercial software (Adobe Photoshop) and open-source software (Qupath). In addition, we provided a detailed, step-by-step description of both methods. The methods are scalable by replacing the CD8 antibody with other antibodies to target different cells. Moreover, we investigated the correlation between quantifying CD8 + cells normalized to area or epidermal length and cell classifications, compared cell classifications in QuPath with threshold classifications in Photoshop, and analyzed the impact of data normalization to epidermal length or area on inflammatory cell densities in skin biopsies from patients with psoriasis. We found a satisfactory correlation between normalizing data to epidermal length and area for psoriasis skin. However, when non-lesional and lesional skin samples were compared, a significant underestimation of inflammatory cell density was found when data were normalized to area instead of epidermal length. Finally, Bland-Altman plots comparing Qupath and Photoshop to quantify inflammatory cell density demonstrated a good agreement between the two methods.

The origin and diversification of appendage types is a central question in vertebrate evolution. Understanding the genetic mechanisms that underlie fin and limb development can reveal relationships between different appendages. Here we demonstrate, using chemical genetics, a mutually agonistic interaction between Fgf and Shh genes in the developing dorsal fin of the channel catfish, Ictalurus punctatus . We also find that Fgf8 and Shh orthologs are expressed in the apical ectodermal ridge and zone of polarizing activity, respectively, in the median fins of representatives from other major vertebrate lineages. These findings demonstrate the importance of this feedback loop in median fins and offer developmental evidence for a median fin-first scenario for vertebrate paired appendage origins.

We present an exploratory post hoc analysis from the phase 3 CheckMate 214 trial of first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in a subgroup of 108 patients with advanced renal cell carcinoma (aRCC) without prior nephrectomy and with an evaluable primary tumor, a population under-represented in clinical trials. Patients with clear cell aRCC were randomized to NIVO+IPI every 3 wk for four doses followed by NIVO monotherapy, or sunitinib every day for 4 wk (6-wk cycle). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and primary tumor shrinkage were assessed. PFS and ORR were assessed per independent radiology review committee using RECIST version 1.1. With minimum study follow-up of 4 yr for intent-to-treat patients, OS favored NIVO+IPI (n = 53) over sunitinib (n = 55; hazard ratio 0.63, 95% confidence interval 0.40-1.0) among patients without prior nephrectomy. ORR was higher (34% vs 15%; p = 0.0041) and median duration of response was longer with NIVO+IPI versus sunitinib (20.5 vs 14.1 mo); the best overall response was partial response in either arm. A ≥30% reduction in the diameter of intact target renal tumors was achieved in 35% of patients with NIVO+IPI versus 20% with sunitinib. Safety was consistent with the global study population. In conclusion, in patients with aRCC without prior nephrectomy and with an evaluable primary tumor, NIVO+IPI showed survival benefits and renal tumor reduction versus sunitinib. This trial is registered at ClinicalTrials.gov as NCT02231749. PATIENT SUMMARY: In an exploratory analysis of a large global trial (CheckMate 214), we observed positive outcomes (both survival and tumor response to treatment) with nivolumab plus ipilimumab over sunitinib in a subgroup of patients with advanced kidney cancer who did not undergo removal of their primary kidney tumor. This subset of patients represents a population that has not been studied in clinical trials and for whom outcomes with new immunotherapy combination regimens are not yet known. We conclude that treatment with nivolumab plus ipilimumab offers these patients a survival benefit versus sunitinib, consistent with that observed in the overall study, as well as a notable kidney tumor reduction., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The phase 3 CheckMate 214 trial demonstrated higher response rates and improved overall survival with nivolumab plus ipilimumab versus sunitinib in first-line therapy for advanced clear-cell renal cell carcinoma (RCC). An unmet need exists to identify patients with RCC who are most likely to benefit from treatment with nivolumab plus ipilimumab., Methods: In exploratory analyses, pretreatment levels of programmed death ligand 1 were assessed by immunohistochemistry. Genomic and transcriptomic biomarkers (including tumor mutational burden and gene expression signatures) were also investigated., Results: Biomarkers previously associated with benefit from immune checkpoint inhibitor-containing regimens in RCC were not predictive for survival in patients with RCC treated with nivolumab plus ipilimumab. Analysis of gene expression identified an association between an inflammatory response and progression-free survival with nivolumab plus ipilimumab., Conclusions: The exploratory analyses reveal relationships between molecular biomarkers and provide supportive data on how the inflammation status of the tumor microenvironment may be important for identifying predictive biomarkers of response and survival with combination immunotherapy in patients with RCC. Further validation may help to provide biomarker-driven precision treatment for patients with RCC., Competing Interests: Competing interests: RJM reports consulting fees from Aveo, Calithera, Eisai, Eli Lilly, EMD Serono, Genentech, Merck, Novartis AG, Pfizer, and Roche, and contracted research to employer MSKCC for Bristol Myers Squibb, Eisai, Exelixis, Genentech, Merck, Pfizer, and Roche. TC reports personal and institutional research undertaken for Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb/ER Squibb & Sons LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine, Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, and Tracon; consulting/honoraria or advisory roles from Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb/ER Squibb & Sons LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine Inc, Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, NiKang, Novartis, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, and Up-to-Date; travel, accommodations, expenses, and medical writing in relation to consulting, advisory roles, or honoraria; participation in CME-related events by OncLive, PVI, MJH Life Sciences, and in the NCI GU steering committee; owning Pionyr and Tempest stock; and patents filed, royalties, and other intellectual properties related to biomarkers of immune checkpoint inhibitors and ctDNA. TC is also supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. DM reports honoraria from Alkermes, Bristol Myers Squibb, Calithera Biosciences, Eisai, Eli Lilly, EMD Serono, Iovance, Merck, Pfizer, and Werewolf Therapeutics; and research support from Alkermes Inc, Bristol Myers Squibb, Exelixis, Genentech, Merck, Pfizer, and X4 Pharma. TP reports honoraria for advisory/research boards from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; institutional grants and funding from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and fees for travel and accommodation expenses from AstraZeneca, Ipsen, MSD, Roche, and Pfizer. YV reports no conflicts of interest. SG is employed by, and owns stock in, Bristol Myers Squibb. JY is employed by, and owns stock in, Bristol Myers Squibb. CH is employed by Bristol Myers Squibb. RA is employed by, and owns stock in, Bristol Myers Squibb. SP-C is employed by, and a shareholder of, Bristol Myers Squibb. SSS is employed by, and owns stock in, Bristol Myers Squibb. MBM is currently employed by BeiGene and owns stock in Bristol Myers Squibb. MW-R is currently employed by Agios Pharmaceuticals and owns stock in Agios Pharmaceuticals and Bristol Myers Squibb. MBM, MW-R, and PR-M were employees of Bristol Myers Squibb at the time this work was conducted., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Exposure to hypobaric hypoxia at high altitude puts mountaineers at risk of acute mountain sickness. The carbonic anhydrase inhibitor acetazolamide is used to accelerate acclimatization, when it is not feasible to make a controlled and slow ascend. Studies in rodents have suggested that exposure to hypobaric hypoxia deteriorates bone integrity and reduces bone strength. The study investigated the effect of treatment with acetazolamide and the bisphosphonate, zoledronate, on the skeletal effects of exposure to hypobaric hypoxia. Eighty 16-week-old female RjOrl : SWISS mice were divided into five groups: 1. Baseline; 2. Normobaric; 3. Hypobaric hypoxia; 4. Hypobaric hypoxia + acetazolamide, and 5. Hypobaric hypoxia + zoledronate. Acetazolamide was administered in the drinking water (62 mg/kg/day) for four weeks, and zoledronate (100 μg/kg) was administered as a single subcutaneous injection at study start. Exposure to hypobaric hypoxia significantly increased lung wet weight and decreased femoral cortical thickness. Trabecular bone was spared from the detrimental effects of hypobaric hypoxia, although a trend towards reduced bone volume fraction was found at the L4 vertebral body. Treatment with acetazolamide did not have any negative skeletal effects, but could not mitigate the altitude-induced bone loss. Zoledronate was able to prevent the altitude-induced reduction in cortical thickness. In conclusion, simulated high altitude affected primarily cortical bone, whereas trabecular bone was spared. Only treatment with zoledronate prevented the altitude-induced cortical bone loss. The study provides preclinical support for future studies of zoledronate as a potential pharmacological countermeasure for altitude-related bone loss., 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 © 2022 Brent, Simonsen, Thomsen and Brüel.)

Mountaineering and exposure to high altitude result in physiological adaptations to the reduced inspiratory oxygen availability. Acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) are well-described harmful effects of exposure to high altitude. Common to AMS, HAPE, and HACE are distinct clinical signs and symptoms of impaired function. However, several studies have suggested that high altitude might result in a substantial bone loss, which usually does not produce any apparent symptoms. This review aims to provide a comprehensive overview of, and map current knowledge of the skeletal effects of hypobaric hypoxia and high altitude. PubMed and Embase were searched from inception to September 6, 2021, to identify studies investigating the skeletal effects of exposure to hypobaric hypoxia and high altitude. Three hundred sixty titles and abstracts were screened, and 20 full-text articles were included (16 in vivo studies and four real-world human studies). In rodents, simulated high altitude up to 2900 m did not result in any adverse skeletal effects. In contrast, studies exposing animals to very high altitude (3500-5500 m) reported substantial reductions in BMD, cortical morphology, and bone strength, as well as deteriorated trabecular microstructure. Detrimental microstructural effects were also reported in rats exposed to simulated extreme altitude (6000 m). Finally, real-world human studies in mountaineers suggested high altitude exposure reduced bone mineral density (BMD) and that the harmful skeletal effects of hypobaric hypoxia were not entirely recovered after 12 months. In conclusion, in vivo and real-world studies demonstrated high altitude exposure results in adverse skeletal effects. The underlying mechanism for hypobaric hypoxia-induced bone loss is not elucidated., (Copyright © 2021 The Author. Published by Elsevier Inc. All rights reserved.)

Mountaineers at high altitude are at increased risk of acute mountain sickness as well as high altitude pulmonary and cerebral edema. A densitometric study in mountaineers has suggested that expeditions at high altitude decrease bone mineral density. Surprisingly, the in vivo skeletal effects of hypobaric hypoxia are largely unknown, and have not been studied using advanced contemporary methods to assess bone microstructure. Eighty-four 22-week-old female mice were divided into seven groups with 12 mice in each group: 1. Baseline; 2. Normobaric, 4 weeks; 3. Hypobaric hypoxia, 4 weeks; 4. Normobaric, 8 weeks; 5. Hypobaric hypoxia, 8 weeks; 6. Normobaric, 12 weeks; and 7. Hypobaric hypoxia, 12 weeks. Hypobaric hypoxia mice were housed in hypobaric chambers at an ambient pressure of 500 mbar (5500 m altitude), while normobaric mice were housed at sea level atmospheric pressure for 4, 8, or 12 weeks, respectively. Hypobaric hypoxia had a profound impact on femoral cortical bone and L4 trabecular bone, while the effect on femoral trabecular bone was less pronounced. Hypobaric hypoxia reduced the bone strength of the femoral mid-diaphysis and L4 at all time-points. At femoral cortical bone, hypobaric hypoxia reduced bone formation through fewer mineralizing surfaces and lower bone formation rate after 2 weeks. In addition, bone strength decreased, and C-terminal telopeptide of type I collagen (CTX-I) increased independently of the duration of exposure to simulated high altitude. At L4, hypobaric hypoxia resulted in a substantial reduction in bone volume fraction, trabecular thickness, and trabecular number after 4 weeks of exposure. Hypobaric hypoxia reduced bone strength and femoral bone mass, while femoral trabecular bone was much less affected, indicating the skeletal response to hypobaric hypoxia differ between cortical and trabecular bone. These findings provide initial preclinical support for future clinical studies in mountaineers to assess bone status and bone strength after exposure to prolonged high altitude exposure., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Due to the rarity and often discrete nature of hamate body fractures, timely diagnosis requires a high level of suspicion on the part of the clinician. Here, the authors have compiled the findings from 6 cohort studies and 33 case reports describing hamate body fractures in order to summarize the natural history, management, and outcomes of these infrequent injuries., Recent Findings: Fractures of the hamate body typically occur in the coronal plane through axial loading of the metacarpals or loading in the transverse plane by a compressive force. Standard radiographs of the wrist frequently miss hamate fractures. Oblique and carpal tunnel views can be obtained when a fracture of the hamate is suspected. Advanced imaging with high-resolution computed tomography should also be considered if radiographs are negative and high suspicion for fracture remains or for the purpose of pre-operative planning. Co-existing injuries often include subluxation or dislocation of the 4th and 5th metacarpals with or without fracture. Non-displaced injuries that are stable may be treated non-operatively with immobilization. Displaced or unstable fracture patterns typically require closed reduction and percutaneous pinning versus open reduction internal fixation in order to restore anatomical alignment and maximize outcomes. Hamate body fractures are uncommon fractures of the carpus. When appropriately treated, patients with hamate body fractures usually recover full pain-free range of motion and preserved grip strength. Complications are usually secondary to late presentation or noncompliance., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Osteoporosis is a debilitating disease characterized by reduced bone mineral density and an increased risk of fractures. This review aims to provide a comprehensive overview of, and map current knowledge, obtained from preclinical and clinical studies of the osteoanabolic agent abaloparatide. PubMed and Embase were meticulously searched from inception to May 4, 2021.178 titles and abstracts were screened, and 57 full-text articles were assessed for inclusion. A total of 55 articles were included; 5 (9%) in vitro studies, 21 (38%) in vivo studies, and 29 (53%) clinical studies. Preclinical in vitro studies have demonstrated receptor conformation preferability, structural insights into the receptor-agonist complex, and proliferative effects of abaloparatide on osteoblasts. Preclinical studies have shown abaloparatide to be similarly effective to teriparatide using comparable doses in both ambulating mice and rats challenged by disuse. Other animal studies have reported that abaloparatide effectively mitigates or prevents bone loss from ovariectomy, orchiectomy, and glucocorticoids and improves fracture healing. The pivotal clinical study ACTIVE demonstrated 18 months of treatment with abaloparatide substantially increase bone mineral density and reduce fracture risk in post-menopausal women compared with placebo. The extension study ACTIVExtend highlighted that subsequent treatment with alendronate sustained the bone gained by abaloparatide treatment and the reduced fracture risk for up to two years. Post-hoc sub-group analyses have also supported the efficacy and safety of abaloparatide treatment independent of various baseline risk factors. In conclusion, mounting evidence from preclinical and clinical studies has uniformly reported that abaloparatide increases bone mineral density and reduces fracture risk., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The naturally occurring chicken mutant talpid 2 (ta 2 ), best known for its limb and craniofacial defects, has long served as a valuable tool for developmental biologists studying growth and patterning of craniofacial structures and the limb. The mutant provides a unique tool to examine the molecular and cellular processes regulating limb development., Results: This mutant also provides unique insights into the evolution of developmental genetic programs. Previous work defined the appearance of atavistic dentition in ta 2 embryos. Herein we describe the appearance of ancestral characters of the hindlimb in embryonic ta 2 chicken embryos., Conclusion: As the ta 2 phenotype arises as a result of mutation in C2CD3 and disrupted cilia function, this mutant provides genetic and developmental insight into the causes of asymmetry in the limb and also a model for the evolution of the avian hindlimb., (© 2021 American Association of Anatomists.)

The bowfin (Amia calva) is a ray-finned fish that possesses a unique suite of ancestral and derived phenotypes, which are key to understanding vertebrate evolution. The phylogenetic position of bowfin as a representative of neopterygian fishes, its archetypical body plan and its unduplicated and slowly evolving genome make bowfin a central species for the genomic exploration of ray-finned fishes. Here we present a chromosome-level genome assembly for bowfin that enables gene-order analyses, settling long-debated neopterygian phylogenetic relationships. We examine chromatin accessibility and gene expression through bowfin development to investigate the evolution of immune, scale, respiratory and fin skeletal systems and identify hundreds of gene-regulatory loci conserved across vertebrates. These resources connect developmental evolution among bony fishes, further highlighting the bowfin's importance for illuminating vertebrate biology and diversity in the genomic era., (© 2021. The Author(s).)

Objectives: This first-in-human feasibility study was undertaken to translate the novel low-voltage MultiPulse Therapy (MPT) (Cardialen, Inc., Minneapolis, Minnesota), which was previously been shown to be effective in preclinical studies in terminating atrial fibrillation (AF), into clinical use., Background: Current treatment options for AF, the most common arrhythmia in clinical practice, have limited success. Previous attempts at treating AF by using implantable devices have been limited by the painful nature of high-voltage shocks., Methods: Forty-two patients undergoing AF ablation were recruited at 6 investigational centers worldwide. Before ablation, electrode catheters were placed in the coronary sinus, right and/or left atrium, for recording and stimulation. After the induction of AF, MPT, which consists of up to a 3-stage sequence of far- and near-field stimulation pulses of varied amplitude, duration, and interpulse timing, was delivered via temporary intracardiac leads. MPT parameters and delivery methods were iteratively optimized., Results: In the 14 patients from the efficacy phase, MPT terminated 37 of 52 (71%) of AF episodes, with the lowest median energy of 0.36 J (interquartile range [IQR]: 0.14 to 1.21 J) and voltage of 42.5 V (IQR: 25 to 75 V). Overall, 38% of AF terminations occurred within 2 seconds of MPT delivery (p < 0.0001). Shorter time between AF induction and MPT predicted success of MPT in terminating AF (p < 0.001)., Conclusions: MPT effectively terminated AF at voltages and energies known to be well tolerated or painless in some patients. Our results support further studies of the concept of implanted devices for early AF conversion to reduce AF burden, symptoms, and progression., Competing Interests: Funding Support and Author Disclosures This study was supported by Cardialen Inc., Minneapolis, Minnesota; Medtronic Plc., Dublin, Ireland; and the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number 1 R43 HL107055-01. Dr. Ng was supported by the National Institute of Health Research (NIHR) (Clinical Lectureship 1716) and British Heart Foundation (RG/16/3/32175). Drs. Ng, Qureshi, and Peters were supported the Imperial College Centre for Cardiac Engineering and the NIHR Imperial Biomedical Research Centre. Drs. Ng, Mead, Peters and Efimov have or had consulting agreements with Cardialen. Mr. Shelton and Drs. Bourn and Sharma are current or former employees of Cardialen. Drs. Efimov and Peters are shareholders of Cardialen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Glucocorticoids (GCs), such as prednisolone, are widely used to treat inflammatory diseases. Continuously long-term or high dose treatment with GCs is one of the most common causes of secondary osteoporosis and is associated with sarcopenia and increased risk of debilitating osteoporotic fragility fractures. Abaloparatide (ABL) is a potent parathyroid hormone-related peptide analog, which can increase bone mineral density (aBMD), improve trabecular microarchitecture, and increase bone strength. The present study aimed to investigate whether GC excess blunts the osteoanabolic effect of ABL. Sixty 12-13-week-old female RjOrl:SWISS mice were allocated to the following groups: Baseline, Control, ABL, GC, and GC + ABL. ABL was administered as subcutaneous injections (100 μg/kg), while GC was delivered by subcutaneous implantation of a 60-days slow-release prednisolone-pellet (10 mg). The study lasted four weeks. GC induced a substantial reduction in muscle mass, trabecular mineral apposition rate (MAR) and bone formation rate (BFR/BS), and endocortical MAR compared with Control, but did not alter the trabecular microarchitecture or bone strength. In mice not receiving GC, ABL increased aBMD, bone mineral content (BMC), cortical and trabecular microarchitecture, mineralizing surface (MS/BS), MAR, BFR/BS, and bone strength compared with Control. However, when administered concomitantly with GC, the osteoanabolic effect of ABL on BMC, cortical morphology, and cortical bone strength was blunted. In conclusion, at cortical bone sites, the osteoanabolic effect of ABL is generally blunted by short-term GC excess.

Bromer, Frederik Duch, Mikkel Bo Brent, Michael Pedersen, Jesper Skovhus Thomsen, Annemarie Brüel, and Casper Bindzus Foldager. The effect of normobaric intermittent hypoxia therapy on bone in normal and disuse osteopenic mice. High Alt Med Biol . 22: 225-234, 2021. Background: Systemic intermittent hypoxia therapy (IHT) has been shown to elicit beneficial effects on multiple physiological systems. However, only few studies have investigated the effect of long-term normobaric IHT on bone mass and mechanical and microstructural properties. The aim of the present study was to examine the effect of IHT on bone in both healthy and osteopenic mice. Materials and Methods: Thirty mice were stratified into four groups: Ctrl, Ctrl+IHT, Botox, and Botox+IHT. Osteopenia was induced by injecting Botox into the right hindlimb of the mice causing paralysis and disuse. IHT animals were placed in a normobaric hypoxia-chamber (10% oxygen) for 1 hour twice daily 5 days/week. Animals were sacrificed after 21 days, and DEXA, micro-computed tomography, and mechanical testing were performed on the femora. Results: As expected, Botox resulted in a significant reduction of bone mineral content (-23.4%), area bone mineral density (-19.1%), femoral neck strength (F max : -54.7%), bone volume fraction (bone volume/tissue volume: -41.8%), and trabecular thickness (-32.4%). IHT had no measurable effect on the bone properties in either healthy or osteopenic mice. Conclusion: The study confirmed that Botox led to loss of bone mass, deterioration of trabecular microstructure, and loss of bone strength. These changes were not influenced by IHT. Notably, IHT had no detrimental effect on bone in either healthy or osteopenic mice. This indicates that IHT of ailments outside of the skeletal system may be administered without causing harm to the bone.

Objective: Several different animal models are used to study disuse-induced bone loss. This systematic review aims to give a comprehensive overview of the animal models of disuse-induced bone loss and provide a detailed narrative synthesis of each unique animal model., Methods: PubMed and Embase were systematically searched for animal models of disuse from inception to November 30, 2019. In addition, Google Scholar and personal file archives were searched for relevant publications not indexed in PubMed or Embase. Two reviewers independently reviewed titles and abstracts for full-text inclusion. Data were extracted using a predefined extraction scheme to ensure standardization., Results: 1964 titles and abstracts were screened of which 653 full-text articles were included. The most common animal species used to model disuse were rats (59%) and mice (30%). Males (53%) where used in the majority of the studies and genetically modified animals accounted for 7%. Twelve different methods to induce disuse were identified. The most frequently used methods were hindlimb unloading (44%), neurectomy (15%), bandages and orthoses (15%), and botulinum toxin (9%). The median time of disuse was 21 days (quartiles: 14 days, 36 days) and the median number of animals per group subjected to disuse was 10 (quartiles: 7, 14). Random group allocation was reported in 43% of the studies. Fewer than 5% of the studies justified the number of animals per group by a sample size calculation to ensure adequate statistical power., Conclusion: Multiple animal models of disuse-induced bone loss exist, and several species of animals have successfully been studied. The complexity of disuse-induced bone loss warrants rigid research study designs. This systematic review emphasized the need for standardization of animal disuse research and reporting.

Three bone anabolic pharmaceuticals are currently approved for treatment of osteoporosis, teriparatide (PTH (1-34)), the parathyroid hormone-related protein analog abaloparatide (ABL), and romosozumab. The present study compared the effect of intermittent PTH (1-34) and ABL on bone tissue directly mole-to-mole in female mice. Forty-seven C57BL/6 mice were randomly allocated to the following groups: Baseline ( n = 11), Control (Ctrl) ( n = 12), PTH ( n = 12), and ABL ( n = 12). The mice were injected s.c. with PTH (100 µg/kg), ABL (96 µg/kg), or saline (Ctrl) five days a week for three weeks. To assess the effect of PTH and ABL, the hindlimb bones were analyzed with DXA, µCT, mechanical testing, dynamic bone histomorphometry, and histological quantification of bone cells. In addition, serum calcium concentration was determined. PTH and ABL significantly increased femoral areal bone mineral density (aBMD) (borderline significant p = 0.06 for PTH), femoral mid-diaphyseal bone strength, femoral metaphyseal and epiphyseal and vertebral bone volume fraction (BV/TV), connectivity density, volumetric bone mineral density (vBMD), and bone formation rate (BFR/BS) compared to Ctrl. In addition, ABL also significantly increased mid-diaphyseal cortical thickness and bone area compared to Ctrl. Neither PTH nor ABL significantly increased bone strength at the femoral neck. In conclusion, abaloparatide and PTH have similar bone anabolic properties when compared directly mole-to-mole in mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2021 Brent, Stoltenborg, Brüel and Thomsen.)

Case: A 31-year-old man with recurrent instability after treatment of a terrible triad elbow fracture-dislocation that was reconstructed with revision coronoid fixation and a novel use of a medially applied internal joint stabilizer (IJS)., Conclusion: A medially applied IJS is an option to supplement coronoid fixation in cases with tenuous repair because of comminution or relative coronoid insufficiency. This location may be more protective for this instability pattern and, in revision settings, can avoid a second lateral incision., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B428)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

In virtually all areas of psychology, the question of whether a particular construct has a prospective effect on another is of fundamental importance. For decades, the cross-lagged panel model (CLPM) has been the model of choice for addressing this question. However, CLPMs have recently been critiqued, and numerous alternative models have been proposed. Using the association between low self-esteem and depression as a case study, we examined the behavior of seven competing longitudinal models in 10 samples, each with at least four waves of data and sample sizes ranging from 326 to 8,259. The models were compared in terms of convergence, fit statistics, and consistency of parameter estimates. The traditional CLPM and the random intercepts cross-lagged panel model (RI-CLPM) converged in every sample, whereas the other models frequently failed to converge or did not converge properly. The RI-CLPM exhibited better model fit than the CLPM, whereas the CLPM produced more consistent cross-lagged effects (both across and within samples) than the RI-CLPM. We discuss the models from a conceptual perspective, emphasizing that the models test conceptually distinct psychological and developmental processes, and we address the implications of the empirical findings with regard to model selection. Moreover, we provide practical recommendations for researchers interested in testing prospective associations between constructs and suggest using the CLPM when focused on between-person effects and the RI-CLPM when focused on within-person effects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objectives: There is an 18.9% discard rate among kidney allografts. Here, we aimed to determine predictors of kidney discard and construct an index to identify high-probability discard kidney allografts prior to procurement., Materials and Methods: A total of 102 246 potential kidney allograft donors from the Organ Procurement and Transplantation Network database were used in this analysis. The cohort was randomized into 2 groups. The training set included 67% of the cohort and was used to derive a predictive index for discard that comprised 21 factors identified by univariate and multivariate logistic regression analysis. The validation set included 33% and was used to internally validate the kidney discard risk index., Results: In 77.3% of donors, at least 1 kidney was used for transplant, whereas in 22.7% of donors, both kidneys were discarded. The kidney discard risk index was highly predictive of discard with a C statistic of 0.89 (0.88-0.89). The bottom 10th percentile had a discard rate of 0.73%, whereas the top 10th percentile had a discard rate of 83.65%. The 3 most predictive factors for discard were age, creatinine level, and hepatitis C antibody status., Conclusions: We identified 21 factors predictive of discard prior to donor procurement and used these to develop a kidney discard risk index with a C statistic of 0.89.

The day reconstruction method (DRM) is an approach to measuring well-being that is designed to approximate the rich data that can be obtained from intensive repeated measures designs like those used in the experience sampling method (ESM). Although some preliminary tests of the validity of the DRM have been conducted, these typically focus on agreement between the 2 methods at very broad levels, rather than focusing on whether the 2 methods provide similar information about the exact same moments. This article reports 2 studies that use ESM and DRM to assess the same moments. Agreement between the 2 measures varied considerably depending on the focus of the analysis. For aggregate assessments of total time spent in situations and average affect in situations, agreement was high; for between-person differences in time use and experienced affect, agreement varied across situations; and for within-person differences in both situations and affect, agreement was quite low. In addition, we found preliminary evidence that the DRM may be more influenced by expectations regarding the pleasantness of situations as compared with ESM. These results suggest that for many common purposes, the DRM does not provide the same information as ESM. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Quantification of osteoclasts to assess bone resorption is a time-consuming and tedious process. Since the inception of bone histomorphometry and manual counting of osteoclasts using bright-field microscopy, several approaches have been proposed to accelerate the counting process using both free and commercially available software. However, most of the present alternatives depend on manual or semi-automatic color segmentation and do not take advantage of artificial intelligence (AI). The present study directly compare estimates of osteoclast-covered surfaces (Oc.S/BS) obtained by the conventional manual method using a bright-field microscope to that obtained by a new AI-assisted method. We present a detailed step-by-step guide for the AI-based method. Tibiae from Wistar rats were either enzymatically stained for TRAP or immunostained for cathepsin K to identify osteoclasts. We found that estimation of Oc.S/BS by the new AI-assisted method was considerably less time-consuming, while still providing similar results to the conventional manual method. In addition, the retrainable AI-module used in the present study allows for fully automated overnight batch processing of multiple annotated sections.•Bone histomorphometry•AI-assisted osteoclast identification•TRAP and cathepsin K., (© 2021 The Author(s). Published by Elsevier B.V.)

Changes in appendage structure underlie key transitions in vertebrate evolution. Addition of skeletal elements along the proximal-distal axis facilitated critical transformations, including the fin-to-limb transition that permitted generation of diverse modes of locomotion. Here, we identify zebrafish mutants that form supernumerary long bones in their pectoral fins. These new bones integrate into musculature, form joints, and articulate with neighboring elements. This phenotype is caused by activating mutations in previously unrecognized regulators of appendage patterning, vav2 and waslb, that function in a common pathway. This pathway is required for appendage development across vertebrates, and loss of Wasl in mice causes defects similar to those seen in murine Hox mutants. Concordantly, formation of supernumerary bones requires Hox11 function, and mutations in the vav2/wasl pathway drive enhanced expression of hoxa11b, indicating developmental homology with the forearm. Our findings reveal a latent, limb-like pattern ability in fins that is activated by simple genetic perturbation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The current investigation tested predictions from the interactionist model (IM) of socioeconomic influences on the development of negative personality traits with respect to feelings of alienation and low well-being. The model tested proposed that lower family socioeconomic status would lead to fewer parenting and material investments in the next generation adolescent, which in turn would be associated with higher levels of adolescent negative personality traits. The IM also predicted a transactional process in which adolescent negative personality attributes would then deter future socioeconomic success during adulthood which, in turn, would hinder adult development in terms of greater feelings of alienation and diminished well-being. Analyses with a cohort of 347 adolescents followed for over 20 years produced findings consistent with these predictions. Moreover, additional analyses with 282 of the third generation children of these cohort members demonstrated that this same process was being replicated in the third generation. The findings suggest reciprocal or transactional influences that promote the development of negative personality attributes and accumulating personal, economic and social advantages over time and generations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Genetic and environmental factors account for variability in a range of developmental outcomes, including socioeconomic status (SES). The challenge is to find ways to incorporate genetic information based on studies using biologically related family members (i.e., studies not involving twins). To address this issue, we computed polygenic scores associated with educational attainment (Lee et al., 2018) for the Family Transitions Project (e.g., R. D. Conger & Conger, 2002) and incorporated them into the model tested by R. D. Conger, Martin, and Masarik, (2021). Polygenic scores correlated with observed educational attainment for all relevant members of the Family Transitions Project. Moreover, polygenic scores were correlated with many of the other constructs in the R. D. Conger et al. (2021) model, pointing to the relevance of genetic factors for process models of SES attainment. At the same time, the primary pathways described by R. D. Conger et al. (2021) remained viable when polygenic scores were included in the analyses, suggesting that the environmental pathways predicted by the interactionist model (e.g., R. D. Conger, Conger, & Martin, 2010) are still tenable. The current study thereby illustrates how genetic information can be included in tests of developmental models to clarify SES attainment across generations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

We critique Roy et al.'s (2020; this issue) approach to characterizing the item-level factor structure of the three scales of the Triarchic Psychopathy Measure (TriPM), in light of the manner in which the TriPM scales were developed, the purposes they were designed to serve, and the growing body of evidence supporting their construct validity. We focus on three major points: (1) The TriPM scales are item-based factor scales - i.e., item sets designed to index broad factors of larger multi-scale (parent) inventories; (2) item-level structural analysis can be useful for representing broad dimensions tapped by such scales, but it cannot be expected to provide an accurate picture of narrower subdimensions (facets) assessed by their parent inventories; and (3) it is critical to consider the nomological networks of the TriPM scales (and other triarchic scale measures) in appraising their effectiveness as operationalizations of the triarchic model constructs. We illustrate the first and second of these points by applying Roy et al.'s analytic approach to the trait scales of the NEO-FFI, which were developed to index broad personality dimensions of the multi-scale NEO-PI-R. We address the third point with reference to the growing body of literature supporting the construct validity of the TriPM scales and demonstrating their utility for advancing an integrative understanding of psychopathy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Personality is not the most popular subfield of psychology. But, in one way or another, personality psychologists have played an outsized role in the ongoing "credibility revolution" in psychology. Not only have individual personality psychologists taken on visible roles in the movement, but our field's practices and norms have now become models for other fields to emulate (or, for those who share Baumeister's (2016, https://doi.org/10.1016/j.jesp.2016.02.003) skeptical view of the consequences of increasing rigor, a model for what to avoid). In this article we discuss some unique features of our field that may have placed us in an ideal position to be leaders in this movement. We do so from a subjective perspective, describing our impressions and opinions about possible explanations for personality psychology's disproportionate role in the credibility revolution. We also discuss some ways in which personality psychology remains less-than-optimal, and how we can address these flaws., Competing Interests: Competing Interests: Brent Donellan, David Funder, Brent Roberts, Julia Rohrer, Luke Smillie, and Simine Vazire are members of the editorial board of the journal.

Damage of the lower motor neuron cell bodies or their axons results in reduced or abolished voluntary movement accompanied by a substantial loss of bone and muscle mass. Intermittent parathyroid hormone 1-34 (PTH) (teriparatide) is one of the most potent bone-anabolic treatment regimens. ActRIIA-mFc is an activin type IIA decoy receptor that increases bone mass mediated by inhibition of the activin receptor signaling pathway. We investigated whether PTH or ActRIIA-mFc alone or in combination could prevent loss of bone and muscle mass induced by injecting botulinum toxin A (BTX) into the right hind limb in mice. Seventy-two 16-week-old female C57BL/6 mice were allocated to the following groups: Baseline, Control, BTX, BTX + ActRIIA-mFc (10 mg/kg), BTX + PTH (100 μg/kg), and BTX + ActRIIA-mFc + PTH. The mice were sacrificed after three weeks of disuse and treatment. In contrast to monotherapy with PTH, ActRIIA-mFc alone or in combination with PTH was able partly or completely to prevent disuse-induced loss of whole femoral bone mass, trabecular thickness, and bone strength. Moreover, an additive effect of ActRIIA-mFc and PTH on areal bone mineral density and trabecular bone volume was found. In summary, ActRIIA-mFc and PTH in combination were more effective in preventing disuse-induced bone loss and deterioration of trabecular micro-architecture than either treatment alone., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC., Patients and Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics., Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3-22.9); n = 65; HR, 0.45 (95% CI, 0.3-0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33-0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged., Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population. See related commentary by Hwang et al., p. 5 ., (©2020 American Association for Cancer Research.)