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Background: Lung nodule incidence is increasing. Many nodules require biopsy to discriminate between benign and malignant causes. The gold standard for minimally invasive biopsy, CT scan-guided transthoracic needle biopsy (CT-TTNB), has not been compared directly with navigational bronchoscopy, a method that recently has seen rapid technological innovation and is associated with improving diagnostic yield and lower complication rates. Current estimates of the diagnostic usefulness of both methods are based largely on noncomparative data with significant risk for selection, referral, and publication biases. Research Question: Is contemporary navigational bronchoscopy noninferior to CT scan-guided transthoracic needle biopsy for the diagnosis of indeterminate pulmonary nodules? Study Design and Methods: Navigation Endoscopy to Reach Indeterminate Lung Nodules vs Transthoracic Needle Aspiration, a Randomized Controlled Study, is a multicenter, 1:1 randomized, parallel-group trial designed to ascertain whether electromagnetic navigational bronchoscopy with integrated digital tomosynthesis is noninferior to CT-TTNB for the diagnosis of peripheral lung nodules 10 to 30 mm in diameter with before testing probability of malignancy of at least 10%. The primary end point is diagnostic accuracy through 12 months of follow-up. Secondary end points include diagnostic yield, complication rate, procedure duration, need for additional invasive diagnostic procedures, and radiation exposure. Results: This article describes the protocol and rationale for the Navigation Endoscopy to Reach Indeterminate Lung Nodules vs Transthoracic Needle Aspiration, a Randomized Controlled Study, designed to answer the study question. Interpretation: The results of this rigorously designed trial will provide high-quality data regarding the management of lung nodules, a common clinical entity that often represents the earliest and most treatable stage of lung cancer. Several design challenges are described. Notably, all nodules are reviewed centrally by an independent interventional pulmonology and radiology adjudication panel relying on prespecified exclusions to ensure enrolled nodules are amenable to sampling by both methods while protecting against selection bias favoring either method. Conservative diagnostic yield and accuracy definitions with prespecified criteria for what nonmalignant findings may be considered diagnostic were chosen to avoid inflation of estimates of diagnostic usefulness. Trial Registry: ClinicalTrials.gov; No.: NCT04250194; URL: www.clinicaltrials.gov

Background:. Few evidence-based suggestions are available to help applicants and mentors improve reapplication outcomes. We sought to provide program directors' (PDs) perspectives on actionable steps to improve reapplicants' chances for a match. Methods:. The PDs were asked to rank positions unmatched applicants can pursue, steps these applicants can take for the next application cycle, and reasons why reapplicants do not match. Results:. Responses from 66 of 123 PDs were received (53.6% response rate). Obtaining new recommendation letters and rotating with orthopaedics were the highest 20 ranked steps unmatched applicants can take. No curriculum vitae (CV) improvement, poor interview, and poor letters of recommendation were the most important reasons hindering applicants from matching when reapplying. Conclusions:. Steps reapplicants could prioritize include obtaining new recommendation letters, rotating in orthopaedics, and producing new research items. CV strengthening and improving interview skills address the 2 main reasons why unmatched applicants failed in subsequent attempts. Level of Evidence:. Level IV

Purpose: An initiative to advocate for those underrepresented in radiation oncology. Methods and Materials: Inspired by the success of the #ILookLikeAnEngineer and #ILookLikeASurgeon campaigns, this initiative aimed to break down stereotypes in traditionally male-dominated fields. In honor of Marie Curie's birthday, on November 7, 2018, the Society for Women in Radiation Oncology launched a social media campaign called #WomenWhoCurie day. However, as the popularity of the social media campaign increased, it become evident that members of the wider radiation community, in particular women of color, nonbinary and transgender people did not feel supported by the #WomenWhoCurie movement. In November 2021, after consultation with diversity and inclusion leaders and members of other national radiation oncology organizations, Society for Women in Radiation Oncology launched #WeWhoCurie alongside the #WomenWhoCurie campaign for women and gender minorities in radiation oncology. Radiation oncologists, physicists, dosimetrist, therapists, nurses, and other professionals from around the world gathered and shared photos and social media posts throughout the day on multiple platforms including Facebook, Instagram, and Twitter. Results: In the year #WeWhoCurie, #WomenWhoCurie, #_______ WhoCurie campaign launched, we saw an increase in participation across the globe from 9 countries: the United States, Canada, Mexico, Brazil, Italy, Spain, China, New Zealand, and Australia. There were over 720 tweets contributing to the campaign with over 2000 messages, representing 3,365,444 “potential impacts”, or the number of times someone saw the hashtag. Conclusions: Through this campaign we aim to celebrate the incredible women, gender minorities, and allies who are “Curie-ing” patients with cancer and conducting cutting edge research to improve cancer care across the globe. As an organization we believe adding our voices to the masses will foster a culture of inclusion for everyone. Afterall, what good is the practice of radiation oncology if all are not equally welcome?

Purpose: To evaluate the accuracy of deep-learning-based auto-segmentation of the superior constrictor, middle constrictor, inferior constrictor, and larynx in comparison with a traditional multi-atlas-based method. Methods and Materials: One hundred and five computed tomography image datasets from 83 head and neck cancer patients were retrospectively collected and the superior constrictor, middle constrictor, inferior constrictor, and larynx were analyzed for deep-learning versus multi-atlas-based segmentation. Eighty-three computed tomography images (40 diagnostic computed tomography and 43 planning computed tomography) were used for training the convolutional neural network, and for atlas-based model training. The remaining 22 computed tomography datasets were used for validation of the atlas-based auto-segmentation versus deep-learning-based auto-segmentation contours, both of which were compared with the corresponding manual contours. Quantitative measures included Dice similarity coefficient, recall, precision, Hausdorff distance, 95th percentile of Hausdorff distance, and mean surface distance. Dosimetric differences between the auto-generated contours and manual contours were evaluated. Subjective evaluation was obtained from 3 clinical observers to blindly score the autosegmented structures based on the percentage of slices that require manual modification. Results: The deep-learning-based auto-segmentation versus atlas-based auto-segmentation results were compared for the superior constrictor, middle constrictor, inferior constrictor, and larynx. The mean Dice similarity coefficient values for the 4 structures were 0.67, 0.60, 0.65, and 0.84 for deep-learning-based auto-segmentation, whereas atlas-based auto-segmentation has Dice similarity coefficient results at 0.45, 0.36, 0.50, and 0.70, respectively. The mean 95th percentile of Hausdorff distance (cm) for the 4 structures were 0.41, 0.57, 0.59, and 0.54 for deep-learning-based auto-segmentation, but 0.78, 0.95, 0.96, and 1.23 for atlas-based auto-segmentation results, respectively. Similar mean dose differences were obtained from the 2 sets of autosegmented contours compared to manual contours. The dose–volume discrepancies and the average modification rates were higher with the atlas-based auto-segmentation contours. Conclusion: Swallowing-related structures are more accurately generated with DL-based versus atlas-based segmentation when compared with manual contours.

Introduction: Intra-articular distal humerus fractures present a challenge to orthopedic surgeons. Stable fixation is difficult to achieve in fractures with articular and metaphyseal comminution and osteoporotic bone. Hence, these fractures are more commonly being managed with total elbow arthroplasty. We describe a novel surgical technique that confers stable fixation, allowing for early range of motion resulting in a high rate of union, a functional range of motion, and excellent patient reported outcome scores without the activity restrictions of total elbow arthroplasty. Methods: Retrospective case series of 30 patients with AO/OTA type B and C intra-articular distal humerus fractures who underwent ORIF from 2014-2019 utilizing a novel surgical technique that focuses on reconstructing a comminuted articular surface through meticulous, transverse fixation of the tiny articular fragments with long, thin Kirchner wires, which are then bent over and trapped under locking compression plates to create a fixed angle support to the metadiaphysis. Results: Patient mean age of 59 (19-90) years and 61% were female. Median follow up was 1.2 years. Twenty-seven (87%) were type C fractures and 3 (13%) were type B. Five patients (16%) suffered a concurrent ipsilateral upper extremity injury and four (13%) had an open fracture. Two were polytrauma patients. All fractures healed with an average time to union of 11 weeks. Over 80% patients reported no or mild pain at final follow up. Mean arc of elbow motion was 102 degrees, mean QuickDASH score 25.2. Post-operative complications included ulnar nerve paresthesias (38%), wound infection (3.2%), heterotopic ossification (3.2%), and olecranon nonunion (3.2%). Eight patients underwent secondary procedures: 7 (23%) removal hardware, 3(9.6%) capsular release, 2 (6.4%) ulnar nerve transpositions, and 1 (3.2%) total elbow arthroplasty. Conclusion: We describe a novel surgical technique that we believe results in strong, stable fixation of complex intra-articular distal humerus fractures irrespective of bone quality. In our series, all fractures healed and post-operatively patients reported low levels of pain, achieved excellent elbow range of motion, high patient reported outcome scores. Patients should be counseled about high rates of post-operative ulnar nerve paresthesias that can be expected to improve over time and high reoperation rates for symptomatic hardware.

Children are known to disproportionately bear the health impacts of climate change, particularly children living in impoverished areas. Owing to their developing physiology and immature metabolism, distinct exposure behaviors, and reliance on adults for care and protection, children are uniquely susceptible to the adverse effects of our warming planet. Herein, we summarize the known impacts of climate change on pediatric skin health, including its effects on atopic dermatitis, vector-borne and other infectious diseases, nutritional deficiencies, and psychodermatoses.

Introduction: Given that an incidental pulmonary nodule (IPN) on chest computed tomography (CT) may represent nascent lung cancer, timely follow-up imaging is critical to assess nodule growth and the need for tissue sampling. We previously reported our institution’s systematic process to identify and track patients with an IPN associated with improved CT on follow-up. We hypothesized that this improvement may have led to a higher frequency of early-stage lung cancer. To evaluate this, we performed a study to determine whether cases of early-stage lung cancer were more likely to have had our tracking system applied to suspicious findings. Methods: An observational study was performed by identifying cases of lung cancer that were detected as IPNs on chest CT scans performed at our institution, from 2006 to 2016. A total of 314 cases were dichotomized into early-stage (stage 1) or late-stage (stages II to IV) disease. A multivariant regression analysis with modeling was used to determine factors associated with a diagnosis of early-stage disease. Factors included the use of the tracking system and nodule registry. Results: The following factors were independently associated with early-stage lung cancer: index nodule diameter, (OR = 0.971, confidence interval [CI]: 0.948–0.995], p = 0.016), adenocarcinoma histology (OR = 2.930 [CI: 1.695–5.064], p = 0.0001) and use of tracker phrases on CT reports (OR = 1.939 [CI: 1.126–3.339], p = 0.016). Conclusions: The application of a patient tracking system and computerized lung nodule registry lead to an increased frequency in the diagnosis of stage 1 NSCLC from IPNs. This is a meaningful outcome for patients and should be adapted for IPN management.

Background:. Letters of recommendation (LORs) are highly influential in the residency selection process. Differences in language and length of LORs by gender have been demonstrated for applicants applying to surgical residencies and fellowships. This had yet to be studied in orthopaedic surgery. Given the gender disparity in the field, we sought to investigate the impact of gender on orthopaedic residency applicant LORs. We hypothesized that differences in length and language would be present for women applicants as compared to men. Methods:. LORs for 2019 to 2020 applicants who applied to a single academic institution were selected for review. Female and male applicants were matched by medical school attended and United States Medical Licensing Examination Step 1 score. LORs were analyzed using both qualitative and quantitative analyses. Letters were evaluated for their word count, presence of language terms, and frequency of language terms. A similar subgroup language analysis was performed for standardized LORs (SLORs). Results:. Six hundred fifty-six applicants met the initial screening criteria—126 women and 530 men. After matching, 71 female applicants were paired with 111 male applicants. Word count was, on average, longer for female applicants. LORs for female applicants were more likely to contain language terms that characterized their ability, achievement, participation in athletics, awards received, fit, leadership, and personality traits. Of these terms, ability and participation in athletics were also found more frequently in LORs written for women. In addition, language characterizing technical skills was found more frequently in LORs of female applicants. Similar codes were found to be statistically significant in the SLOR subgroup analysis. Conclusion:. This study highlights that current orthopaedic surgery residency LORs do not appear to be biased by applicant gender. LORs were longer for female applicants and described them more positively. Future female orthopaedic residency applicants should be assured that current female candidates are applying with at least similar if not greater subjective qualifications to their male counterparts based on the findings of this study.

Background:. The Surgical Training and Educational Platform (STEP) was developed by the American Society for Surgery of the Hand (ASSH) as a cost-effective set of surgical simulation modules designed to assess critical skills in hand surgery. Previous study demonstrated that STEP can differentiate between novice trainees and board-certified, certificate of added qualification hand surgeons. The purpose of this study was to assess construct validity of STEP by testing its ability to differentiate psychomotor skill level among intermediate trainees. Methods:. We evaluated 30 residents from 2 orthopaedic residency programs on 8 modules: (1) lag screw fixation, (2) depth of plunge during bicortical drilling, (3) flexor tendon repair, (4) phalangeal fracture pinning, (5) central axis scaphoid fixation, (6) full-thickness skin graft harvest, (7) microsurgery, and (8) wrist arthroscopy. Spearman correlation was used to correlate total and task-specific scores to case log numbers, months in training, and number of hand surgery rotations. Results:. Senior residents had significantly higher mean number of total cases in their total case log (mean difference 96.2, 95% confidence interval [CI] 67.5-124.8, p < 0.01) and number of task-specific cases. Moderate correlation was observed between case log numbers and scaphoid fixation score (rs = 0.423, 95% CI 0.07-0.69) and total score (rs = 0.584, 95% CI 0.25-0.79). Moderate correlation was observed between months in training with: scaphoid fixation (rs = 0.377, 95% CI 0.01-0.66) and microsurgery (rs = 0.483, 95% CI 0.13-0.73); strong correlation was seen with total score (rs = 0.656, 95% CI 0.35-0.83). Moderate correlation with number of hand surgery rotations was observed with tendon repair (rs = 0.362, 95% CI −0.01 to 0.65), skin graft (rs = 0.385, 95% CI 0.01-0.66), wrist arthroscopy (rs = 0.391, 95% CI 0.02-0.67), microsurgery (rs = 0.461, 95% CI 0.10-0.71), and scaphoid fixation (rs = 0.578, 95% CI 0.25-0.79); and strong correlation was seen with total score (rs = 0.670, 95% CI 0.37-0.84). Discussion/Conclusion:. The STEP is a validated ASSH education tool that provides a cost-effective simulation for the assessment of fundamental psychomotor skills in hand surgery. Total STEP score correlated with total task-related case volumes as well as months in training and number of hand rotations. Scoring could be modified to improve the fidelity of assessing surgical performance. And, while both time and human resource consuming to perform, administer, and score, this study demonstrates construct validity of STEP in assessing the progression of surgical skill through residency.

The recent global events related to the coronavirus disease of 2019 pandemic have significantly changed the medical landscape and led to a shift in oncologic treatment perspectives. There is a renewed focus on preserving treatment outcomes while maintaining medical accessibility and decreasing medical resource utilization. Brachytherapy, which is a vital part of the treatment course of many cancers (particularly prostate and gynecologic cancers), has the ability to deliver hypofractionated radiation and thus shorten treatment time. Studies in the early 2000s demonstrated a decline in brachytherapy usage despite data showing equivalent or even superior treatment outcomes for brachytherapy in disease sites, such as the prostate and cervix. However, newer data suggest that this trend may be reversing. The renewed call for shorter radiation courses based on data showing equivalent outcomes will likely establish hypofractionated radiation as the standard of care across multiple disease sites. With shifting reimbursement, brachytherapy represents the pinnacle in hypofractionated, conformal radiation therapy, and with extensive long-term data in support of the treatment modality brachytherapy is primed for a renaissance.

Pulmonary seed embolization is a complication of prostatic brachytherapy with varying incidence rates. Key factors that reportedly influence the incidence of seed embolization include planning volume, quantity of seeds, seed placement, and type of seeds (stranded vs free). The clinical implications of seed migration are unclear because sequelae were not demonstrated in multiple short-term studies yet there have been several reports of long-term complications. We report a case of a 56-year-old patient who presented with dyspnea approximately 6 years after brachytherapy treatment for a very low-risk prostate cancer. Chest radiograph showed multiple linear densities overlying the right suprahilar lung. Computed tomography confirmed the location of the densities within the pulmonary arteries in the right upper lobe.

Background:. It has been postulated that injury to the medial collateral ligament (MCL) of the elbow is rare in cases of elbow fracture-dislocation, and if the MCL is torn, it does not require surgical repair. Elbow fracture-dislocations with MCL insufficiency are associated with recurrent instability, secondary surgery, and the development of posttraumatic arthritis. With the current study, our aim was to investigate whether evidence of an MCL attachment-site fracture on a radiograph or computed tomography (CT) scan is predictive of MCL insufficiency, the need for MCL repair, and postoperative instability. Methods:. This retrospective study included 219 patients (median age of 50 years; 53% female) with elbow fracture-dislocations treated at 2 Level-I trauma centers during the period of 2005 to 2016. Patients were followed for a median of 6.3 years to determine postoperative stability. Operative notes and radiology reports were reviewed to confirm MCL insufficiency and periarticular fractures. Radiographs and CT scans were analyzed by a musculoskeletal fellowship-trained emergency radiologist and a board-certified upper-extremity orthopaedic surgeon. Results:. Of the 33 patients with confirmed fractures at an MCL attachment site, 26 (79%) had MCL insufficiency, whereas of the 186 patients without fracture at an MCL attachment site, only 17 (9%) had MCL insufficiency. Of the 6 patients with an attachment-site fracture and MCL insufficiency who did not undergo initial MCL repair, 5 required reoperation. Of the 7 patients without an attachment-site fracture and with MCL insufficiency who did not undergo initial MCL repair, only 1 required reoperation. Conclusions:. Fractures involving an MCL attachment site, regardless of their size, help to predict MCL insufficiency. These fractures can be visualized using initial radiographs and CT scans that are routinely obtained. Additional research is required to assess these findings. Our findings further suggest that repairing an MCL-complex injury in cases of fracture-dislocation in which the fracture has occurred at an MCL attachment site may improve elbow stability and decrease the likelihood of requiring reoperation. Level of Evidence:. Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Glossopharyngeal neuralgia (GPN) is a neurological condition characterized by paroxysmal, stabbing-like pain along the distribution of the glossopharyngeal nerve that lasts from a couple of seconds to minutes. Pharmacological treatment with anticonvulsants is the first line of treatment; however, about 25% of patients remain symptomatic and require surgical intervention, which is usually done via microvascular decompression (MVD) with or without rhizotomy. More recently, the use of stereotactic radiosurgery (SRS) has been utilized as an alternative treatment method to relieve patient symptoms by causing nerve ablation. We conducted a systematic review to analyze whether MVD without rhizotomy is an equally effective treatment for GPN as MVD with the use of concurrent rhizotomy. Moreover, we sought to explore if SRS, a minimally invasive alternative surgical option, achieves comparable outcomes. We included retrospective studies and case reports in our search. We consulted PubMed and Medline, including articles from the year 2000 onwards. A total of 36 articles were included for review. Of all included patients with glossopharyngeal neuralgia, the most common offending artery compressing the glossopharyngeal nerve was the posterior inferior cerebellar artery (PICA). MVD alone was successful achieving pain relief immediately postoperatively in about 85% of patients, and also long term in 65-90% of patients. The most common complication found on MVD surgery was found to be transient hoarseness and transient dysphagia. Rhizotomy alone shows an instant pain relief in 85-100% of the patients, but rate of long-term pain relief was lower compared to MVD. The most common adverse effects observed after a rhizotomy were dysphagia and dysesthesia along the distribution of the glossopharyngeal nerve. SRS had promising results in pain reduction when using 75 Gy radiation or higher; however, long-term rates of pain relief were lower. MVD, rhizotomy, and SRS are effective methods to treat GPN as they help achieve instant pain relief and the decrease use of medication. Patients with MVD alone presented with less adverse effects than the group that underwent MVD plus rhizotomy. Although SRS may be a viable alternative treatment for GPN, further studies must be done to evaluate long-term treatment efficacy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Studies of the proteome would benefit greatly from methods to directly sequence and digitally quantify proteins and detect posttranslational modifications with single-molecule sensitivity. Here, we demonstrate single-molecule protein sequencing using a dynamic approach in which single peptides are probed in real time by a mixture of dye-labeled N-terminal amino acid recognizers and simultaneously cleaved by aminopeptidases. We annotate amino acids and identify the peptide sequence by measuring fluorescence intensity, lifetime, and binding kinetics on an integrated semiconductor chip. Our results demonstrate the kinetic principles that allow recognizers to identify multiple amino acids in an information-rich manner that enables discrimination of single amino acid substitutions and posttranslational modifications. With further development, we anticipate that this approach will offer a sensitive, scalable, and accessible platform for single-molecule proteomic studies and applications.

This is a first literature report of a case of uveitis along with severe systemic symptoms following verruca vulgaris treatment with intralesional Candida antigen. We believe the Candida injection was causative.

Self-neglect (SN) and frailty in older adults is associated with increased disability and mortality. Despite these commonalities, there have been no studies objectively assessing frailty in older adults who SN. This secondary analysis classified frailty in N = 37 older adults with Adult Protective Services validated SN using the Fried Frailty Phenotype (FFP) of weight loss, weakness, exhaustion, activity level, and walking speed. Overall, 3% were classified as robust, 62% as prefrail, and 35% as frail. Most (72%) were overweight/obese, with clinically significant decreases in activity level (60%) and walking speed (97%). Compared to the original FFP population, older adults who SN exhibit important differences in frailty phenotypes, and finding that the largest percentage of older adults who SN were prefrail may indicate a critical opportunity for intervening in this population to reduce future functional decline and mortality.

Background: Historically, identification of causal agents of disease has relied heavily on the ability to culture the organism in the laboratory and/or the use of pathogen-specific antibodies or sequence-based probes. However, these methods can be limiting: Even highly sensitive PCR-based assays must be continually updated due to signature degradation as new target strains and near neighbors are sequenced. Thus, there has been a need for assays that do not suffer as greatly from these limitations and/or biases. Recent advances in library preparation technologies for Next-Generation Sequencing (NGS) are focusing on the use of targeted amplification and targeted enrichment/capture to ensure that the most highly discriminating regions of the genomes of known targets (organism-unique regions and/or regions containing functionally important genes or phylogenetically-discriminating SNPs) will be sequenced, regardless of the complex sample background., Results: In the present study, we have assessed the feasibility of targeted sequence enhancement via amplification to facilitate detection of a bacterial pathogen present in low copy numbers in a background of human genomic material. Our results indicate that the targeted amplification of signature regions can effectively identify pathogen genomic material present in as little as 10 copies per ml in a complex sample. Importantly, the correct species and strain calls could be made in amplified samples, while this was not possible in unamplified samples., Conclusions: The results presented here demonstrate the efficacy of a targeted amplification approach to biothreat detection, using multiple highly-discriminative amplicons per biothreat organism that provide redundancy in case of variation in some primer regions. Importantly, strain level discrimination was possible at levels of 10 genome equivalents. Similar results could be obtained through use of panels focused on the identification of amplicons targeted for specific genes or SNPs instead of, or in addition to, those targeted for specific organisms (ongoing gene-targeting work to be reported later). Note that without some form of targeted enhancement, the enormous background present in complex clinical and environmental samples makes it highly unlikely that sufficient coverage of key pathogen(s) present in the sample will be achieved with current NGS technology to guarantee that the most highly discriminating regions will be sequenced.

Purpose: The aims of this study were to determine test-retest reliability and responsiveness of short-distance walking speed tests for persons with Parkinson disease (PD). Discriminant and convergent validity of walking speed tests were also examined., Methods: Eighty-eight participants with PD (mean age, 66 years) with mild to moderate severity (stages 1-4 on the Hoehn and Yahr Scale) were tested on medications. Measures of activity included the comfortable and fast 10-m walk tests (CWT, FWT), 6-min walk test (6MWT), mini balance evaluations systems test (mini-BEST Test), fear of falling (FoF), and the Activity-Specific Balance Confidence Scale (ABC). The mobility subsection of the PD quality of life-39 (PDQ39-M) served as a participation-based measure., Results: Test-retest reliability was high for both walking speed measures (CWT, ICC(2,1) = 0.98; FWT, ICC(2,1) = 0.99). Minimal detectable change (MDC(95)) for the CWT and FWT was 0.09 m/s and 0.13 m/s respectively. Participants at Hoehn & Yahr levels 3/4 demonstrated significantly slower walking speed with the CWT and FWT than participants at Hoehn & Yahr levels 1 and 2 (P < .01). The CWT and FWT were both significantly (P ≤ .002) correlated with all activity and participation-based measures., Conclusions: Short-distance walking speed tests are clinically useful measures for persons with PD. The CWT and FWT are highly reliable and responsive to change in persons with PD. Short distance walking speed can be used to discriminate differences in gait function between persons with mild and moderate PD severity. The CWT and FWT had moderate to strong associations with other activity and participation based measures demonstrating convergent validity., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The purpose of this study was to compare group boxing training to traditional group exercise on function and quality of life in persons with Parkinson disease (PD). A convenience sample of adults with PD (n = 31) were randomly assigned to boxing training or traditional exercise for 24-36 sessions, each lasting 90 minutes, over 12 weeks. Boxing training included: stretching, boxing (e.g. lateral foot work, punching bags), resistance exercises, and aerobic training. Traditional exercise included: stretching, resistance exercises, aerobic training, and balance activities. Participants were tested before and after completion of training on balance, balance confidence, mobility, gait velocity, gait endurance, and quality of life. The traditional exercise group demonstrated significantly greater gains in balance confidence than the boxing group (p < 0.025). Only the boxing group demonstrated significant improvements in gait velocity and endurance over time with a medium between-group effect size for the gait endurance (d = 0.65). Both groups demonstrated significant improvements with the balance, mobility, and quality of life with large within-group effect sizes (d ≥ 0.80). While groups significantly differed in balance confidence after training, both groups demonstrated improvements in most outcome measures. Supporting options for long-term community-based group exercise for persons with PD will be an important future consideration for rehabilitation professionals.

Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the "sensor" cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease.

Gastric cancer is the most common cancer in Asia and most developing countries. Despite the use of multimodality therapeutics, it remains the second leading cause of cancer death in the world. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens, generating 680 million informative short reads to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and miRNAs). A multilayer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations, and key differentially expressed miRNAs. Through this approach, we identified the central metabolic regulator AMP-activated protein kinase (AMPK)α as a potential functional target in Asian gastric cancer. Furthermore, we experimentally showed the translational relevance of this gene as a potential therapeutic target for early-stage gastric cancer in Asian patients. Together, our findings not only provide a valuable information resource for identifying and elucidating the molecular mechanisms of Asian gastric cancer, but also represent a general integrative framework to develop more effective therapeutic targets., (©2012 AACR.)

HIV Dependency Factors (HDFs) are a class of human proteins that are essential for HIV replication, but are not lethal to the host cell when silenced. Three previous genome-wide RNAi experiments identified HDF sets with little overlap. We combine data from these three studies with a human protein interaction network to predict new HDFs, using an intuitive algorithm called SinkSource and four other algorithms published in the literature. Our algorithm achieves high precision and recall upon cross validation, as do the other methods. A number of HDFs that we predict are known to interact with HIV proteins. They belong to multiple protein complexes and biological processes that are known to be manipulated by HIV. We also demonstrate that many predicted HDF genes show significantly different programs of expression in early response to SIV infection in two non-human primate species that differ in AIDS progression. Our results suggest that many HDFs are yet to be discovered and that they have potential value as prognostic markers to determine pathological outcome and the likelihood of AIDS development. More generally, if multiple genome-wide gene-level studies have been performed at independent labs to study the same biological system or phenomenon, our methodology is applicable to interpret these studies simultaneously in the context of molecular interaction networks and to ask if they reinforce or contradict each other.

This study compared head kinematic responses and step latency following an anteriorly directed postural perturbation between two groups (Young, mean age 27.39; Elderly, mean age 71.9). We further attempted to demonstrate, for the first time, a positive linear relationship between sagittal plane head angular velocities and stepping responses in both groups. It was hypothesized that the Elderly would demonstrate higher head angular velocities and greater step latencies than the Young. We also hypothesized that a positive linear relationship would show that, following a perturbation, trials where head angular velocity was low yielded quicker step responses. Each participant experienced three perturbations under five different visual conditions designed to alter visual input and head/trunk coordination. Repeated-measures ANOVA was used, with α set at 0.05. For each test condition, the Elderly consistently demonstrated longer step latencies while exhibiting higher head angular velocities. For each group, a positive linear relationship was shown between the two dependent variables (Young: r=0.86; Elderly, r=0.84). During a postural perturbation, as head angular velocity increased, stepping responses were delayed.

We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in >80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85α) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85β), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85α dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target.

Background: Infectious diseases result in millions of deaths each year. Physical interactions between pathogen and host proteins often form the basis of such infections. While a number of methods have been proposed for predicting protein-protein interactions (PPIs), they have primarily focused on intra-species protein-protein interactions., Methodology: We present an application of a supervised learning method for predicting physical interactions between host and pathogen proteins, using the human-HIV system. Using a Support Vector Machine with a linear kernel, we explore the use of a number of features including domain profiles, protein sequence k-mers, and properties of human proteins in a human PPI network. We achieve the best cross-validation performance when we use a combination of all three of these features. At a precision value of 70% we obtain recall values greater than 40%, depending on the ratio of positive examples to negative examples used during training. We use a classifier trained using these features to predict new PPIs between human and HIV proteins. We focus our discussion on those predicted interactions that involve human proteins known to be critical for HIV replication and propagation. Examples of predicted interactions with support in the literature include those necessary for viral attachment to the host membrane and subsequent invasion of the host cell., Significance: Unlike intra-species PPIs, host-pathogen PPIs have not yet been experimentally detected on a large scale, though they are likely to play important roles in pathogenesis and disease outcomes. Computational methods that can robustly and accurately predict host-pathogen PPIs hold the promise of guiding future experiments and gaining insights into potential mechanisms of pathogenesis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background and Purpose: A nontraditional form of exercise recently applied for patients with Parkinson disease (PD) is boxing training. The primary purpose of this case series is to describe the effects of disease severity and duration of boxing training (short term and long term) on changes in balance, mobility, and quality of life for patients with mild or moderate to severe PD. The feasibility and safety of the boxing training program also were assessed., Case Description: Six patients with idiopathic PD attended 24 to 36 boxing training sessions for 12 weeks, with the option of continuing the training for an additional 24 weeks (a seventh patient attended sessions for only 4 weeks). The 90-minute sessions included boxing drills and traditional stretching, strengthening, and endurance exercises. Outcomes were tested at the baseline and after 12, 24, and 36 weeks of boxing sessions (12-, 24-, and 36-week tests). The outcome measures were the Functional Reach Test, Berg Balance Scale, Activities-specific Balance Confidence Scale, Timed "Up & Go" Test, Six-Minute Walk Test, gait speed, cadence, stride length, step width, activities of daily living and motor examination subscales of the Unified Parkinson Disease Rating Scale, and Parkinson Disease Quality of Life Scale., Outcomes: Six patients completed all phases of the case series, showed improvements on at least 5 of the 12 outcome measures over the baseline at the 12-week test, and showed continued improvements at the 24- and 36-week tests. Patients with mild PD typically showed improvements earlier than those with moderate to severe PD., Discussion: Despite the progressive nature of PD, the patients in this case series showed short-term and long-term improvements in balance, gait, activities of daily living, and quality of life after the boxing training program. A longer duration of training was necessary for patients with moderate to severe PD to show maximal training outcomes. The boxing training program was feasible and safe for these patients with PD.

Background: Bacillus anthracis, Francisella tularensis, and Yersinia pestis are bacterial pathogens that can cause anthrax, lethal acute pneumonic disease, and bubonic plague, respectively, and are listed as NIAID Category A priority pathogens for possible use as biological weapons. However, the interactions between human proteins and proteins in these bacteria remain poorly characterized leading to an incomplete understanding of their pathogenesis and mechanisms of immune evasion., Methodology: In this study, we used a high-throughput yeast two-hybrid assay to identify physical interactions between human proteins and proteins from each of these three pathogens. From more than 250,000 screens performed, we identified 3,073 human-B. anthracis, 1,383 human-F. tularensis, and 4,059 human-Y. pestis protein-protein interactions including interactions involving 304 B. anthracis, 52 F. tularensis, and 330 Y. pestis proteins that are uncharacterized. Computational analysis revealed that pathogen proteins preferentially interact with human proteins that are hubs and bottlenecks in the human PPI network. In addition, we computed modules of human-pathogen PPIs that are conserved amongst the three networks. Functionally, such conserved modules reveal commonalities between how the different pathogens interact with crucial host pathways involved in inflammation and immunity., Significance: These data constitute the first extensive protein interaction networks constructed for bacterial pathogens and their human hosts. This study provides novel insights into host-pathogen interactions.

Purpose: To date, there has been little evidence to suggest the importance of foveal viewing versus peripheral retina viewing when trying to recover from a perturbation. The purposes of this investigation were to (1) determine whether a visual target can be stabilized on the fovea during a perturbation, (2) determine whether stepping responses following a perturbation are influenced by foveal fixation, and (3) compare gaze stability and stepping responses between young and aging adults., Materials/methods: Ten young adults and 10 aging adults were asked to wear an eye-tracking device linked to a kinematic tracking system during perturbations. Perturbations were delivered under 2 conditions: control (no instructions regarding gaze location were given) and earth-fixed (EF) (subjects were asked to fixate gaze on an EF target). Stepping responses were recorded via force plates. Gaze stability, reported as percent foveal fixation (% FF), was calculated from eye-tracking data. Step latencies (SLs) were computed from force plate data. A 2 x 2 analysis of variance was used to assess statistical significance between groups. For the young and aging adults, linear correlations were made to identify relationships between % FF and SL., Results: For each condition, aging adults took longer to initiate a step (control, P = .002; EF, P = .003). Young adults were better at maintaining gaze fixation than older adults (P = .0045). Linear correlations demonstrated significant negative relationships between SL and % FF for young (r = -0.76, P = .001) and older (r = -0.87, P = .0001) adults. As % FF increased, SL decreased., Conclusions: The ability to maintain gaze fixation of an EF target may be important in reducing SL following a perturbation. Older adult subjects demonstrated a decreased ability to fixate a target during balance tasks while also displaying longer SLs.

Several respiratory viruses, including influenza virus and severe acute respiratory syndrome coronavirus (SARS-CoV), produce more severe disease in the elderly, yet the molecular mechanisms governing age-related susceptibility remain poorly studied. Advanced age was significantly associated with increased SARS-related deaths, primarily due to the onset of early- and late-stage acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Infection of aged, but not young, mice with recombinant viruses bearing spike glycoproteins derived from early human or palm civet isolates resulted in death accompanied by pathological changes associated with ARDS. In aged mice, a greater number of differentially expressed genes were observed than in young mice, whose responses were significantly delayed. Differences between lethal and nonlethal virus phenotypes in aged mice could be attributed to differences in host response kinetics rather than virus kinetics. SARS-CoV infection induced a range of interferon, cytokine, and pulmonary wound-healing genes, as well as several genes associated with the onset of ARDS. Mice that died also showed unique transcriptional profiles of immune response, apoptosis, cell cycle control, and stress. Cytokines associated with ARDS were significantly upregulated in animals experiencing lung pathology and lethal disease, while the same animals experienced downregulation of the ACE2 receptor. These data suggest that the magnitude and kinetics of a disproportionately strong host innate immune response contributed to severe respiratory stress and lethality. Although the molecular mechanisms governing ARDS pathophysiology remain unknown in aged animals, these studies reveal a strategy for dissecting the genetic pathways by which SARS-CoV infection induces changes in the host response, leading to death.

Measles virus remains a substantial cause of morbidity and mortality, producing acute infection with a potential for development of viral persistence. To study the events underlying acute and persistent measles virus infection, we performed a global transcriptional analysis on murine neuroblastoma cells that were acutely or persistently infected with measles virus. In general, we found that acute infection induced significantly more gene expression changes than did persistent infection. A functional enrichment analysis to identify which host pathways were perturbed during each of these infections identified several pathways related to cholesterol biosynthesis, including cholesterol metabolic processes, hydroxymethylglutaryl-coenzyme A (CoA) reductase activity, and acetyl-CoA C-acetyltransferase activity. We also found that measles virus colocalized to lipid rafts in both acute and persistent infection models and that the majority of genes associated with cholesterol synthesis were downregulated in persistent infection relative to acute infection, suggesting a possible link with the defective viral budding in persistent infection. Further, we found that pharmacological inhibition of cholesterol synthesis resulted in the inhibition of viral budding during acute infection. In summary, persistent measles viral infection was associated with decreased cholesterol synthesis, a lower abundance of cholesterol and lipid rafts in the cell membrane, and inhibition of giant-cell formation and release of viral progeny.

To support their replication, viruses take advantage of numerous cellular factors and processes. Recent large-scale screens have identified hundreds of such factors, yet little is known about how viruses exploit any of these. Influenza virus infection post-translationally activates P58(IPK), a cellular inhibitor of the interferon-induced, dsRNA-activated eIF2alpha kinase, PKR. Here, we report that infection of P58(IPK) knockout mice with influenza virus resulted in increased lung pathology, immune cell apoptosis, PKR activation, and mortality. Analysis of lung transcriptional profiles, including those induced by the reconstructed 1918 pandemic virus, revealed increased expression of genes associated with the cell death, immune, and inflammatory responses. These experiments represent the first use of a mammalian infection model to demonstrate the role of P58(IPK) in the antiviral response. Our results suggest that P58(IPK) represents a new class of molecule, a cellular inhibitor of the host defense (CIHD), as P58(IPK) is activated during virus infection to inhibit virus-induced apoptosis and inflammation to prolong host survival, even while prolonging viral replication.

Protein-protein interactions (PPIs) play a vital role in initiating infection in a number of pathogens. Identifying which interactions allow a pathogen to infect its host can help us to understand methods of pathogenesis and provide potential targets for therapeutics. Public resources for studying host-pathogen systems, in particular PPIs, are scarce. To facilitate the study of host-pathogen PPIs, we have collected and integrated host-pathogen PPI (HP-PPI) data from a number of public resources to create the Pathogen Interaction Gateway (PIG). PIG provides a text based search and a BLAST interface for searching the HP-PPI data. Each entry in PIG includes information such as the functional annotations and the domains present in the interacting proteins. PIG provides links to external databases to allow for easy navigation among the various websites. Additionally, PIG includes a tool for visualizing a single HP-PPI network or two HP-PPI networks. PIG can be accessed at http://pig.vbi.vt.edu.

Infectious diseases result in millions of deaths each year. Mechanisms of infection have been studied in detail for many pathogens. However, many questions are relatively unexplored. What are the properties of human proteins that interact with pathogens? Do pathogens interact with certain functional classes of human proteins? Which infection mechanisms and pathways are commonly triggered by multiple pathogens? In this paper, to our knowledge, we provide the first study of the landscape of human proteins interacting with pathogens. We integrate human-pathogen protein-protein interactions (PPIs) for 190 pathogen strains from seven public databases. Nearly all of the 10,477 human-pathogen PPIs are for viral systems (98.3%), with the majority belonging to the human-HIV system (77.9%). We find that both viral and bacterial pathogens tend to interact with hubs (proteins with many interacting partners) and bottlenecks (proteins that are central to many paths in the network) in the human PPI network. We construct separate sets of human proteins interacting with bacterial pathogens, viral pathogens, and those interacting with multiple bacteria and with multiple viruses. Gene Ontology functions enriched in these sets reveal a number of processes, such as cell cycle regulation, nuclear transport, and immune response that participate in interactions with different pathogens. Our results provide the first global view of strategies used by pathogens to subvert human cellular processes and infect human cells. Supplementary data accompanying this paper is available at http://staff.vbi.vt.edu/dyermd/publications/dyer2008a.html.

Motivation: Infectious diseases such as malaria result in millions of deaths each year. An important aspect of any host-pathogen system is the mechanism by which a pathogen can infect its host. One method of infection is via protein-protein interactions (PPIs) where pathogen proteins target host proteins. Developing computational methods that identify which PPIs enable a pathogen to infect a host has great implications in identifying potential targets for therapeutics., Results: We present a method that integrates known intra-species PPIs with protein-domain profiles to predict PPIs between host and pathogen proteins. Given a set of intra-species PPIs, we identify the functional domains in each of the interacting proteins. For every pair of functional domains, we use Bayesian statistics to assess the probability that two proteins with that pair of domains will interact. We apply our method to the Homo sapiens-Plasmodium falciparum host-pathogen system. Our system predicts 516 PPIs between proteins from these two organisms. We show that pairs of human proteins we predict to interact with the same Plasmodium protein are close to each other in the human PPI network and that Plasmodium pairs predicted to interact with same human protein are co-expressed in DNA microarray datasets measured during various stages of the Plasmodium life cycle. Finally, we identify functionally enriched sub-networks spanned by the predicted interactions and discuss the plausibility of our predictions., Availability: Supplementary data are available at http://staff.vbi.vt.edu/dyermd/publications/dyer2007a.html., Supplementary Information: Supplementary data are available at Bioinformatics online.

Knowledge of toxins, virulence factors and antibiotic resistance genes is essential for bio-defense applications aimed at identifying 'functional' signatures for characterizing emerging or engineered pathogens. Whereas genetic signatures identify a pathogen, functional signatures identify what a pathogen is capable of. To facilitate rapid identification of sequences and characterization of genes for signature discovery, we have collected all publicly available (as of this writing), organized sequences representing known toxins, virulence factors, and antibiotic resistance genes in one convenient database, which we believe will be of use to the bio-defense research community. MvirDB integrates DNA and protein sequence information from Tox-Prot, SCORPION, the PRINTS virulence factors, VFDB, TVFac, Islander, ARGO and a subset of VIDA. Entries in MvirDB are hyperlinked back to their original sources. A blast tool allows the user to blast against all DNA or protein sequences in MvirDB, and a browser tool allows the user to search the database to retrieve virulence factor descriptions, sequences, and classifications, and to download sequences of interest. MvirDB has an automated weekly update mechanism. Each protein sequence in MvirDB is annotated using our fully automated protein annotation system and is linked to that system's browser tool. MvirDB can be accessed at http://mvirdb.llnl.gov/.

The Commission on Dental Accreditation (CODA) requires that General Practice Residency (GPR) programs report a summary of each resident's clinical experiences. The goal of this study was to determine the effectiveness of handheld computer technology in tracking residents' clinical procedures. In the academic years 2004-05 and 2005-06, University of Kentucky GPR residents were provided a Palm M130 with customized forms. These menu-driven forms allowed residents to record procedures. Residents synchronized the data to a centralized database. A separate reporting system interfaced with the database to allow administrators to produce detailed reports on each resident. At the end of the academic year, data were tabulated, clinical procedures were correlated with respective costs, and annual production was determined. Data from fourteen residents were analyzed. Types and frequencies of various clinical experiences were tabulated, financial production summaries assessed, and percentage distribution of procedures by discipline was examined. Palm technology has proven to be an effective tool in monitoring each resident's clinical experiences. This methodology was beneficial to residency directors by allowing the examination of the experience distribution of each discipline in dentistry to determine the range of experiences that residents achieved.

Background: MannDB was created to meet a need for rapid, comprehensive automated protein sequence analyses to support selection of proteins suitable as targets for driving the development of reagents for pathogen or protein toxin detection. Because a large number of open-source tools were needed, it was necessary to produce a software system to scale the computations for whole-proteome analysis. Thus, we built a fully automated system for executing software tools and for storage, integration, and display of automated protein sequence analysis and annotation data., Description: MannDB is a relational database that organizes data resulting from fully automated, high-throughput protein-sequence analyses using open-source tools. Types of analyses provided include predictions of cleavage, chemical properties, classification, features, functional assignment, post-translational modifications, motifs, antigenicity, and secondary structure. Proteomes (lists of hypothetical and known proteins) are downloaded and parsed from Genbank and then inserted into MannDB, and annotations from SwissProt are downloaded when identifiers are found in the Genbank entry or when identical sequences are identified. Currently 36 open-source tools are run against MannDB protein sequences either on local systems or by means of batch submission to external servers. In addition, BLAST against protein entries in MvirDB, our database of microbial virulence factors, is performed. A web client browser enables viewing of computational results and downloaded annotations, and a query tool enables structured and free-text search capabilities. When available, links to external databases, including MvirDB, are provided. MannDB contains whole-proteome analyses for at least one representative organism from each category of biological threat organism listed by APHIS, CDC, HHS, NIAID, USDA, USFDA, and WHO., Conclusion: MannDB comprises a large number of genomes and comprehensive protein sequence analyses representing organisms listed as high-priority agents on the websites of several governmental organizations concerned with bio-terrorism. MannDB provides the user with a BLAST interface for comparison of native and non-native sequences and a query tool for conveniently selecting proteins of interest. In addition, the user has access to a web-based browser that compiles comprehensive and extensive reports. Access to MannDB is freely available at http://manndb.llnl.gov/.