Sebaceous carcinoma: evidence-based clinical practice guidelines.

Sebaceous carcinoma usually occurs in adults older than 60 years, on the eyelid, head and neck, and trunk. In this Review, we present clinical care recommendations for sebaceous carcinoma, which were developed as a result of an expert panel evaluation of the findings of a systematic review. Key conclusions were drawn and recommendations made for diagnosis, first-line treatment, radiotherapy, and post-treatment care. For diagnosis, we concluded that deep biopsy is often required; furthermore, differential diagnoses that mimic the condition can be excluded with special histological stains. For treatment, the recommended first-line therapy is surgical removal, followed by margin assessment of the peripheral and deep tissue edges; conjunctival mapping biopsies can facilitate surgical planning. Radiotherapy can be considered for cases with nerve or lymph node involvement, and as the primary treatment in patients who are ineligible for surgery. Post-treatment clinical examination should occur every 6 months for at least 3 years. No specific systemic therapies for advanced disease can be recommended, but targeted therapies and immunotherapies are being developed.

Editorial Commentary: There's More Meat on That Bone! Labral Hypertrophy Normalizes Femoral Head Coverage in Dysplastic Hips.

The size of the acetabular labrum has been shown to be larger in patients with acetabular hip dysplasia and smaller in patients with acetabular overcoverage. Compensatory morphologic changes to the acetabular labrum are potentially useful as an imaging biomarker of hip stability, and with additional future outcomes investigation, imaging measures may be used to guide the type and extent of hip preservation surgery.

Introduction of a virtual workstation into radiology medical student education.

OBJECTIVE. This article describes the creation of a virtual workstation for use by medical students and implementation of that workstation in the reading room. CONCLUSION. A radiology virtual workstation for medical students was created using OsiriX imaging software to authentically simulate the experience of interacting with cases selected to cover important musculoskeletal imaging diagnoses. A workstation that allows the manipulation and interpretation of complete anonymized DICOM images may enhance the educational experience of medical students.

Effectiveness of saltwater baths in the treatment of epidermolysis bullosa.

Current management of epidermolysis bullosa (EB) focuses on preventing secondary infections--a leading cause of mortality--by regularly cleaning and bandaging blisters and erosions and preventive bandaging of high-friction areas. Unfortunately the baths and showers used to remove bandages and clean the skin are often painful, causing lack of adherence and subsequent increases in infections, pain, and antimicrobial use. This study evaluates the hypothesis that bathing individuals with EB in saltwater is less painful than in normal bath water. The study also explores whether taking saltwater baths reduces infections as measured through skin pruritus, odor, discharge, and nonbathing pain. Participants recruited from the Children's Hospital Colorado Outpatient EB Clinic completed standardized questionnaires assessing the effects of the clinic's saltwater bathing recommendations; the data were analyzed using frequencies and Fisher tests. After starting saltwater baths, patients reported a significant reduction in pain (91%), pain medication use (66%), skin odor (31%), and skin discharge (44%). No significant differences were found with respect to the type of EB, age, length of time using baths, or amount of salt added. Saltwater baths are a noninvasive, low-cost, effective treatment that significantly reduces bathing pain, pain medication use, and some signs of skin infection. This treatment can be recommended to patients with all studied EB types without regard to age, the specific amount of salt used, bathing frequency, or pain level. Given the central role bathing and dressing changes play in the management of EB, the use of saltwater baths can lead to significant improvement in quality of life.

Validation of a new radiographic measurement of acetabular version: the transverse axis distance (TAD).

OBJECTIVES: This study has three aims: (1) validate a new radiographic measure of acetabular version, the transverse axis distance (TAD) by showing equivalent TAD accuracy in predicting CT equatorial acetabular version when compared to a previously validated, but more cumbersome, radiographic measure, the p/a ratio; (2) establish predictive equations of CT acetabular version from TAD; (3) calculate a sensitive and specific cut point for predicting excessive CT acetabular anteversion using TAD. MATERIALS AND METHODS: A 14-month retrospective review was performed of patients who had undergone a dedicated MSK CT pelvis study and who also had a technically adequate AP pelvis radiograph. Two trained observers measured the radiographic p/a ratio, TAD, and CT acetabular equatorial version for 110 hips on a PACS workstation. Mixed model analysis was used to find prediction equations, and ROC analysis was used to evaluate the diagnostic accuracy of p/a ratio and TAD. RESULTS: CT equatorial acetabular version can accurately be predicted from either p/a ratio (p < 0.001) or TAD (p < 0.001). The diagnostic accuracies of p/a ratio and TAD are comparable (p =0.46). Patients whose TAD is higher than 17 mm may have excessive acetabular anteversion. For that cutpoint, the sensitivity of TAD is 0.73, with specificity of 0.82. CONCLUSION: TAD is an accurate radiographic predictor of CT acetabular anteversion and provides an easy-to-use and intuitive point-of-care assessment of acetabular version in patients with hip pain.

The potential for double-loop learning to enable landscape conservation efforts.

As conservation increases its emphasis on implementing change at landscape-level scales, multi-agency, cross-boundary, and multi-stakeholder networks become more important. These elements complicate traditional notions of learning. To investigate this further, we examined structures of learning in the Landscape Conservation Cooperatives (LCCs), which include the entire US and its territories, as well as parts of Canada, Mexico, and Caribbean and Pacific island states. We used semi-structured interviews, transcribed and analyzed using NVivo, as well as a charrette-style workshop to understand the difference between the original stated goals of individual LCCs and the values and purposes expressed as the collaboration matured. We suggest double-loop learning as a theoretical framework appropriate to landscape-scale conservation, recognizing that concerns about accountability are among the valid points of view that must be considered in multi-stakeholder collaborations. Methods from the social sciences and public health sectors provide insights on how such learning might be actualized.

Rationalizing diverse binding mechanisms to the same protein fold: insights for ligand recognition and biosensor design.

The engineering of novel protein-ligand binding interactions, particularly for complex drug-like molecules, is an unsolved problem which could enable many practical applications of protein biosensors. In this work, we analyzed two engineer ed biosensors, derived from the plant hormone sensor PYR1, to recognize either the agrochemical mandipropamid or the synthetic cannabinoid WIN55,212-2. Using a combination of quantitative deep mutational scanning experiments and molecular dynamics simulations, we demonstrated that mutations at common positions can promote protein-ligand shape complementarity and revealed prominent differences in the electrostatic networks needed to complement diverse ligands. MD simulations indicate that both PYR1 protein-ligand complexes bind a single conformer of their target ligand that is close to the lowest free energy conformer. Computational design using a fixed conformer and rigid body orientation led to new WIN55,212-2 sensors with nanomolar limits of detection. This work reveals mechanisms by which the versatile PYR1 biosensor scaffold can bind diverse ligands. This work also provides computational methods to sample realistic ligand conformers and rigid body alignments that simplify the computational design of biosensors for novel ligands of interest.

An integrated technology for quantitative wide mutational scanning of human antibody Fab libraries.

Antibodies are engineerable quantities in medicine. Learning antibody molecular recognition would enable the in silico design of high affinity binders against nearly any proteinaceous surface. Yet, publicly available experiment antibody sequence-binding datasets may not contain the mutagenic, antigenic, or antibody sequence diversity necessary for deep learning approaches to capture molecular recognition. In part, this is because limited experimental platforms exist for assessing quantitative and simultaneous sequence-function relationships for multiple antibodies. Here we present MAGMA-seq, an integrated technology that combines multiple antigens and multiple antibodies and determines quantitative biophysical parameters using deep sequencing. We demonstrate MAGMA-seq on two pooled libraries comprising mutants of nine different human antibodies spanning light chain gene usage, CDR H3 length, and antigenic targets. We demonstrate the comprehensive mapping of potential antibody development pathways, sequence-binding relationships for multiple antibodies simultaneously, and identification of paratope sequence determinants for binding recognition for broadly neutralizing antibodies (bnAbs). MAGMA-seq enables rapid and scalable antibody engineering of multiple lead candidates because it can measure binding for mutants of many given parental antibodies in a single experiment.

An integrated technology for quantitative wide mutational scanning of human antibody Fab libraries.

Antibodies are engineerable quantities in medicine. Learning antibody molecular recognition would enable the in silico design of high affinity binders against nearly any proteinaceous surface. Yet, publicly available experiment antibody sequence-binding datasets may not contain the mutagenic, antigenic, or antibody sequence diversity necessary for deep learning approaches to capture molecular recognition. In part, this is because limited experimental platforms exist for assessing quantitative and simultaneous sequence-function relationships for multiple antibodies. Here we present MAGMA-seq, an integrated technology that combines multiple antigens and multiple antibodies and determines quantitative biophysical parameters using deep sequencing. We demonstrate MAGMA-seq on two pooled libraries comprising mutants of ten different human antibodies spanning light chain gene usage, CDR H3 length, and antigenic targets. We demonstrate the comprehensive mapping of potential antibody development pathways, sequence-binding relationships for multiple antibodies simultaneously, and identification of paratope sequence determinants for binding recognition for broadly neutralizing antibodies (bnAbs). MAGMA-seq enables rapid and scalable antibody engineering of multiple lead candidates because it can measure binding for mutants of many given parental antibodies in a single experiment.

Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?

OBJECTIVE: To evaluate the presence of pulmonary abnormalities in rheumatoid arthritis (RA)-related autoantibody-positive subjects without inflammatory arthritis. METHODS: Forty-two subjects who did not have inflammatory arthritis but were positive for anti-cyclic citrullinated peptide antibodies and/or ≥2 rheumatoid factor isotypes (a profile that is 96% specific for RA), 15 autoantibody-negative controls, and 12 patients with established seropositive early RA (<1-year duration) underwent spirometry and high-resolution computed tomography (HRCT) lung imaging. RESULTS: The median age of autoantibody-positive subjects was 54 years, 52% were female, and 38% were ever-smokers; these characteristics were not significantly different from those of autoantibody-negative control subjects. No autoantibody-positive subject had inflammatory arthritis based on joint examination. HRCT revealed that 76% of autoantibody-positive subjects had airways abnormalities including bronchial wall thickening, bronchiectasis, centrilobular opacities, and air trapping, compared with 33% of autoantibody-negative controls (P = 0.005). The prevalence and type of lung abnormalities among autoantibody-positive subjects were similar to those among patients with early RA. In 2 autoantibody-positive subjects with airways disease, inflammatory arthritis classifiable as articular RA developed ∼13 months after the lung evaluation. CONCLUSION: Airways abnormalities that are consistent with inflammation are common in autoantibody-positive subjects without inflammatory arthritis and are similar to airways abnormalities seen in patients with early RA. These findings suggest that the lung may be an early site of autoimmune-related injury and potentially a site of generation of RA-related autoimmunity. Further studies are needed to define the mechanistic role of lung inflammation in the development of RA.

Normal anatomy and imaging of the hip: emphasis on impingement assessment.

A comprehensive knowledge of normal hip anatomy and imaging techniques is essential in the evaluation and assessment of the patient with hip pain. This article reviews the osseous, soft tissue, and vascular components of the hip and the normal anatomical variants encountered in routine hip imaging. Basic and advanced hip imaging is discussed with particular emphasis on radiographic and computed tomography measurements and their utility in evaluating patients with developmental hip dysplasia and femoroacetabular impingement syndrome.

The anterior approach for a non-image-guided intra-articular hip injection.

PURPOSE: The purpose of this study was to investigate and validate the accuracy and safety of a technique using an anterior approach for non-image-guided intra-articular injection of the hip by use of anatomic landmarks. METHODS: We enrolled 55 patients. Injections were performed before supine hip arthroscopy after landmarking and before application of traction. After the needle insertion, success was confirmed with an air arthrogram and by direct visualization after arthroscope insertion. Accuracy and difficulty achieving correct needle placement were correlated with age, weight, height, body mass index, body type, gender, and surgical indication, as well as femoral and pelvic morphology. Forty-five patients who underwent injection in the office were followed up separately to document injection side effects. Needle placement accuracy was correlated to patients' demographics. All statistical tests with P values were 2 sided, with the level of significance set at P < .05. RESULTS: There were 51 correct needle placements and 4 misses, yielding a 93% success rate. The most common location for needle placement was the upper medial head-neck junction. Female gender was correlated with a more difficult needle placement and misses in relation to group size (P = .06). The reasons for misplacements of the needle were a high-riding trochanter, increased femoral version, thick adipose tissue over the landmarks, and variant of ilium morphology. Of 45 patients in the side effect study arm, 3 reported sensory changes of the lateral femoral cutaneous nerve that resolved within 24 hours. CONCLUSIONS: Hip injections by use of the direct anterior approach, from the intersection of the lines drawn from the anterior superior iliac spine and 1 cm distal to the tip of the greater trochanter, are safe and reproducible. Patient characteristics, such as increased subcutaneous adipose tissue or osseous anatomic variants, can lead to difficulty in placing the needle successfully. These characteristics can be predicted with the aid of physical examination and careful study of the pelvic radiographs. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Common framework mutations impact antibody interfacial dynamics and flexibility.

Introduction: With the flood of engineered antibodies, there is a heightened need to elucidate the structural features of antibodies that contribute to specificity, stability, and breadth. While antibody flexibility and interface angle have begun to be explored, design rules have yet to emerge, as their impact on the metrics above remains unclear. Furthermore, the purpose of framework mutations in mature antibodies is highly convoluted. Methods: To this end, a case study utilizing molecular dynamics simulations was undertaken to determine the impact framework mutations have on the VH-VL interface. We further sought to elucidate the governing mechanisms by which changes in the VH-VL interface angle impact structural elements of mature antibodies by looking at root mean squared deviations, root mean squared fluctuations, and solvent accessible surface area. Results and discussion: Overall, our results suggest framework mutations can significantly shift the distribution of VH-VL interface angles, which leads to local changes in antibody flexibility through local changes in the solvent accessible surface area. The data presented herein highlights the need to reject the dogma of static antibody crystal structures and exemplifies the dynamic nature of these proteins in solution. Findings from this work further demonstrate the importance of framework mutations on antibody structure and lay the foundation for establishing design principles to create antibodies with increased specificity, stability, and breadth.

Dynamics of SARS-CoV-2 Seroprevalence in a Large US population Over a Period of 12 Months.

Due to a combination of asymptomatic or undiagnosed infections, the proportion of the United States population infected with SARS-CoV-2 was unclear from the beginning of the pandemic. We previously established a platform to screen for SARS-CoV-2 positivity across a representative proportion of the US population, from which we reported that almost 17 million Americans were estimated to have had undocumented infections in the Spring of 2020. Since then, vaccine rollout and prevalence of different SARS-CoV-2 variants have further altered seropositivity trends within the United States population. To explore the longitudinal impacts of the pandemic and vaccine responses on seropositivity, we re-enrolled participants from our baseline study in a 6- and 12- month follow-up study to develop a longitudinal antibody profile capable of representing seropositivity within the United States during a critical period just prior to and during the initiation of vaccine rollout. Initial measurements showed that, since July 2020, seropositivity elevated within this population from 4.8% at baseline to 36.2% and 89.3% at 6 and 12 months, respectively. We also evaluated nucleocapsid seropositivity and compared to spike seropositivity to identify trends in infection versus vaccination relative to baseline. These data serve as a window into a critical timeframe within the COVID-19 pandemic response and serve as a resource that could be used in subsequent respiratory illness outbreaks.

The Adaptation for Conservation Targets (ACT) framework: a tool for incorporating climate change into natural resource management.

As natural resource management agencies and conservation organizations seek guidance on responding to climate change, myriad potential actions and strategies have been proposed for increasing the long-term viability of some attributes of natural systems. Managers need practical tools for selecting among these actions and strategies to develop a tailored management approach for specific targets at a given location. We developed and present one such tool, the participatory Adaptation for Conservation Targets (ACT) framework, which considers the effects of climate change in the development of management actions for particular species, ecosystems and ecological functions. Our framework is based on the premise that effective adaptation of management to climate change can rely on local knowledge of an ecosystem and does not necessarily require detailed projections of climate change or its effects. We illustrate the ACT framework by applying it to an ecological function in the Greater Yellowstone Ecosystem (Montana, Wyoming, and Idaho, USA)--water flows in the upper Yellowstone River. We suggest that the ACT framework is a practical tool for initiating adaptation planning, and for generating and communicating specific management interventions given an increasingly altered, yet uncertain, climate.

Higher rates of all-cause mortality and resource utilization during episodes-of-care for diabetic foot ulceration.

AIMS: Our primary objective was to determine whether all-cause rates of mortality and resource utilization were higher during periods of diabetic foot ulceration. In support of this objective, a secondary objective was to develop and validate an episode-of-care model for diabetic foot ulceration. METHODS: We evaluated data from the Medicare Limited Data Set between 2013 and 2019. We defined episodes-of-care by clustering diabetic foot ulcer related claims such that the longest time interval between consecutive claims in any cluster did not exceed a duration which was adjusted to match two aspects of foot ulcer episodes that are well-established in the literature: healing rate at 12 weeks, and reulceration rate following healing. We compared rates of outcomes during periods of ulceration to rates immediately following healing to estimate incidence ratios. RESULTS: The episode-of-care model had a minimum mean relative error of 4.2% in the two validation criteria using a clustering duration of seven weeks. Compared to periods after healing, all-cause inpatient admissions were 2.8 times more likely during foot ulcer episodes and death was 1.5 times more likely. CONCLUSIONS: A newly-validated episode-of-care model for diabetic foot ulcers suggests an underappreciated association between foot ulcer episodes and all-cause resource utilization and mortality.

Radiographic laxity of the trapeziometacarpal joint is correlated with generalized joint hypermobility.

PURPOSE: Increased joint laxity has been associated with the risk of ligament injury and development of osteoarthritis in large joints such as the knee, but this has not been investigated in depth in the hand. We hypothesized that generalized joint laxity would correlate with radiographic measures of trapeziometacarpal (TM) joint subluxation, as measured in carpometacarpal stress view radiographs. METHODS: We recruited volunteer subjects of all ages and examined them for generalized laxity using the Beighton-Horan index. A total of 163 subjects, 81 men and 82 women, with an average age of 48 years (range, 20-83 y), were examined. Each subject underwent a stress view radiograph of both TM joints using a previously described technique. Different examiners independently measured radial subluxation of the thumb metacarpal over the trapezium and the articular width of the thumb metacarpal and averaged them. The ratio of the radial subluxation to the articular width was calculated as a measure of radiographic TM laxity. RESULTS: The average Beighton score was 2 (range, 0-9). A total of 40 subjects had Beighton scores greater than 4. The mean stress view ratio was 0.31 (range, 0.06-0.58). When we calculated the Pearson correlation coefficient to assess the relationship between the stress view ratio and the Beighton score, a statistically significant correlation was demonstrated. CONCLUSIONS: In normal volunteers generalized joint laxity is positively correlated with increased mobility of the TM joint, as demonstrated on carpometacarpal stress view radiographs. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic I.

Investigating correlates of athletic identity and sport-related injury outcomes: a scoping review.

OBJECTIVES: To conduct a scoping review that (1) describes what is known about the relationship between athletic identity and sport-related injury outcomes and (2) describes the relationship that an injury (as an exposure) has on athletic identity (as an outcome) in athletes. DESIGN: Scoping review. PARTICIPANTS: A total of n=1852 athletes from various sport backgrounds and levels of competition. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary measure used within the studies identified was the Athletic Identity Measurement Scale. Secondary outcome measures assessed demographic, psychosocial, behavioural, physical function and pain-related constructs. RESULTS: Twenty-two studies were identified for inclusion. Samples were dominated by male, Caucasian athletes. The majority of studies captured musculoskeletal injuries, while only three studies included sport-related concussion. Athletic identity was significantly and positively associated with depressive symptom severity, sport performance traits (eg, ego-orientation and mastery-orientation), social network size, physical self-worth, motivation, rehabilitation overadherence, mental toughness and playing through pain, as well as injury severity and functional recovery outcomes. Findings pertaining to the association that an injury (as an exposure) had on athletic identity (as an outcome) were inconsistent and limited. CONCLUSIONS: Athletic identity was most frequently associated with psychosocial, behavioural and injury-specific outcomes. Future research should seek to include diverse athlete samples (eg, women, athletes of different races, para-athletes) and should continue to reference theoretical injury models to inform study methodologies and to specify variables of interest for further exploration.

Lower extremity reamputation in people with diabetes: a systematic review and meta-analysis.

In this study, we determined the reamputation-free survival to both limbs and to the contralateral limb only following an index amputation of any-level and assessed whether reamputation rates have changed over time. We completed a systematic search using PubMed and screened a total of 205 articles for data on reamputation rates. We reported qualitative characteristics of 56 studies that included data on reamputation rates and completed a meta-analysis on 22 of the studies which enrolled exclusively participants with diabetes. The random-effects meta-analysis fit a parametric survival distribution to the data for reamputations to both limbs and to the contralateral limb only. We assessed whether there was a temporal trend in the reamputation rate using the Mann-Kendall test. Incidence rates were high for reamputation to both limbs and to the contralateral limb only. At 1 year, the reamputation rate for all contralateral and ipsilateral reamputations was found to be 19% (IQR=5.1%-31.6%), and at 5 years, it was found to be 37.1% (IQR=27.0%-47.2%). The contralateral reamputation rate at 5 years was found to be 20.5% (IQR=13.3%-27.2%). We found no evidence of a trend in the reamputation rates over more than two decades of literature analyzed. The incidence of lower extremity reamputation is high among patients with diabetes who have undergone initial amputations secondary to diabetes, and rates of reamputation have not changed over at least two decades.

Regulatory Approved Monoclonal Antibodies Contain Framework Mutations Predicted From Human Antibody Repertoires.

Monoclonal antibodies (mAbs) are an important class of therapeutics used to treat cancer, inflammation, and infectious diseases. Identifying highly developable mAb sequences in silico could greatly reduce the time and cost required for therapeutic mAb development. Here, we present position-specific scoring matrices (PSSMs) for antibody framework mutations developed using baseline human antibody repertoire sequences. Our analysis shows that human antibody repertoire-based PSSMs are consistent across individuals and demonstrate high correlations between related germlines. We show that mutations in existing therapeutic antibodies can be accurately predicted solely from baseline human antibody sequence data. We find that mAbs developed using humanized mice had more human-like FR mutations than mAbs originally developed by hybridoma technology. A quantitative assessment of entire framework regions of therapeutic antibodies revealed that there may be potential for improving the properties of existing therapeutic antibodies by incorporating additional mutations of high frequency in baseline human antibody repertoires. In addition, high frequency mutations in baseline human antibody repertoires were predicted in silico to reduce immunogenicity in therapeutic mAbs due to the removal of T cell epitopes. Several therapeutic mAbs were identified to have common, universally high-scoring framework mutations, and molecular dynamics simulations revealed the mechanistic basis for the evolutionary selection of these mutations. Our results suggest that baseline human antibody repertoires may be useful as predictive tools to guide mAb development in the future.