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More than twenty years ago, the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties began the conversion of graduate medical education from a structure- and process-based model to a competency-based framework. The educational outcomes assessment tool, known as the Milestones, was introduced in 2013 for seven specialties and by 2015 for the remaining specialties, including pediatric surgery. Designed to be an iterative process with improvements over time based on feedback and evidence-based literature, the Milestones started the evolution from 1.0 to 2.0 in 2016. The formation of Pediatric Surgery Milestones 2.0 began in 2019 and was finalized in 2021 for implementation in the 2022-2023 academic year. Milestones 2.0 are fewer in number and are stated in more straightforward language. It incorporated the harmonized milestones, subcompetencies for non-patient care and non-medical knowledge that are consistent across all medical and surgical specialties. There is a new Supplemental Guide that lists examples, references and links to other assessment tools and resources for each subcompetency. Milestones 2.0 represents a continuous process of feedback, literature review and revision with goals of improving patient care and maintaining public trust in graduate medical education's ability to self-regulate. LEVEL OF EVIDENCE: V.

Breast cancer is the most commonly diagnosed cancer and second-leading cause of cancer deaths in women. Breast cancer stem cells (BCSCs) promote metastasis and therapeutic resistance contributing to tumor relapse. Through activating genes important for BCSCs, transcription factors contribute to breast cancer metastasis and therapeutic resistance, including the signal transducer and activator of transcription (STAT) family of transcription factors. The STAT family consists of six major isoforms, STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6. Canonical STAT signaling is activated by the binding of an extracellular ligand to a cell-surface receptor followed by STAT phosphorylation, leading to STAT nuclear translocation and transactivation of target genes. It is important to note that STAT transcription factors exhibit diverse effects in breast cancer; some are either pro- or anti-tumorigenic while others maintain dual, context-dependent roles. Among the STAT transcription factors, STAT3 is the most widely studied STAT protein in breast cancer for its critical roles in promoting BCSCs, breast cancer cell proliferation, invasion, angiogenesis, metastasis, and immune evasion. Consequently, there have been substantial efforts in developing cancer therapeutics to target breast cancer with dysregulated STAT3 signaling. In this comprehensive review, we will summarize the diverse roles that each STAT family member plays in breast cancer pathobiology, as well as, the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators in the context of breast cancer treatment.

Purpose Fractional flow reserve (FFR) has been demonstrated in some studies to predict long-term coronary artery bypass graft (CABG) patency. Quantitative flow ratio (QFR) is an emerging technology which may predict FFR. In this study, we hypothesised that QFR would predict long-term CABG patency and that QFR would offer superior diagnostic performance to quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS). Methods A prospective study was performed on patients with left main coronary artery disease who were undergoing CABG. QFR, QCA and IVUS assessment was performed. Follow-up computed tomography coronary angiography and invasive coronary angiography was undertaken to assess graft patency. Results A total of 22 patients, comprising of 65 vessels were included in the analysis. At a median follow-up of 3.6 years post CABG (interquartile range, 2.3 to 4.8 years), 12 grafts (18.4%) were occluded. QFR was not statistically significantly higher in occluded grafts (0.81 ± 0.19 vs. 0.69 ± 0.21; P = 0.08). QFR demonstrated a discriminatory power to predict graft occlusion (area under the receiver operating characteristic curve, 0.70; 95% confidence interval [CI], 0.52 to 0.88; P = 0.03). At long-term follow-up, the risk of graft occlusion was higher in vessels with a QFR > 0.80 (58.6% vs. 17.0%; hazard ratio, 3.89; 95% CI, 1.05 to 14.42; P = 0.03 by log-rank test). QCA (minimum lumen diameter, lesion length, diameter stenosis) and IVUS (minimum lumen area, minimum lumen diameter, diameter stenosis) parameters were not predictive of long-term graft patency. Conclusions QFR may predict long-term graft patency in patients undergoing CABG.

What is this summary about? This is a summary of an article about the Cincinnati study, which was published in the Journal of Comparative Effectiveness Research in January 2020. The Cincinnati study reviewed data from 435 males with Duchenne muscular dystrophy, also known as DMD, who were treated at the Cincinnati Children's Hospital Medical Center. DMD is a rare disease that worsens over time. People with DMD experience inflammation in their muscles and muscle loss over time. They also experience bone problems such as an abnormally bent spine, also known as scoliosis, as well as heart and lung problems. What happened in the Cincinnati study? Prednisone and deflazacort are steroids that help to reduce muscle inflammation and are used as treatments for DMD. The study researchers wanted to further understand the differences between using prednisone and deflazacort in males with DMD by reviewing data from past medical records of patients seen in clinics rather than in clinical studies. This is known as gathering real-world evidence. In the Cincinnati study, the researchers compared males with DMD who started taking prednisone as their first steroid treatment with males who started taking deflazacort as their first steroid treatment. What were the results? Overall, the researchers found that the participants who took deflazacort were able to walk until a later age before they needed to use a wheelchair, compared with those who took prednisone. They also had a lower risk of scoliosis and developed it at a later age. What do the results of the study mean? These results helped the researchers to learn more about the differences between how well prednisone and deflazacort work in males with DMD based on their medical records.

Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events.

Background. Social support is important for stroke rehabilitation. Conventionally, social support is evaluated from the level of support received. However, the bidirectional support hypothesis postulated that self-perceived social support is optimized if individuals provide and receive social support in a balanced manner. The Brief 2-Way Social Support Scale (Brief 2-Way SSS) is a social support instrument measuring the reciprocity of receiving and giving emotional and instrumental social support. Objective. (1) To translate and culturally adapt the English version of the Brief 2-Way SSS into Chinese (Cantonese) (Brief 2-Way SSS-C), (2) to report the results of validation of the Brief 2-Way SSS-C, and (3) to investigate the level of social support in people with stroke in Hong Kong. Methods. The Brief 2-Way SSS-C was produced following the standard forward-backward translation model. People with stroke ( n = 109 ) and age-matched controls ( n = 53 ) were recruited through a university-affiliated neurorehabilitation laboratory. Results. The Brief 2-Way SSS-C demonstrated excellent content validity, acceptable to good internal consistency (Cronbach’s alpha of 0.74–0.88), and good test-retest reliability (intraclass correlation coefficient of 0.76–0.81). There were no ceiling or floor effects, and the MDC95 across all subscales was 4. The Brief 2-Way SSS-C subscales had significant correlations with various health-related outcome measures. People with stroke had a lower level of social support than the age-matched healthy controls. Conclusions. The Brief 2-Way SSS-C is a culturally relevant, reliable, and valid outcome measure for the level of social support in community-dwelling people with stroke.

Background Anal melanoma is rare. Surgery is standard of care for non-metastatic disease. There are limited data supporting adjuvant therapy. We sought to examine the impact of adjuvant radiation, chemotherapy and immunotherapy on survival. Methods The National Cancer Database was queried. Factors associated with overall survival were examined by Kaplan-Meier and Cox proportional hazards analyses. Patients were grouped by treatment regimen. Results 450 patients had complete treatment data: surgery alone (63.8%), surgery + radiation (14.9%), surgery + chemotherapy (7.6%), surgery + immunotherapy (9.6%) and non-surgical treatment (4.2%). Median survival was 27.2 months. Node-positive patients had worse survival than node-negative (22.4 vs. 36.8 months; p = 0.0002). Non-surgical treatment yielded worse survival than any surgery-inclusive regimen (10.4 vs. 27.8 months; p = 0.0002). No adjuvant modality conferred a survival advantage. By multivariate analysis, increasing age (HR/1 year = 1.02, p = 0.012) and node positivity (HR = 2.10, p = 0.0002) negatively impacted survival. Conclusion Adjuvant therapy for non-metastatic anal melanoma does not appear to influence survival.

An academic career in aging research is filled with the incredible highs of important discoveries that improve the lives of older adults and repeated lows when papers and grants are rejected or studies are negative. To normalize the experience of setbacks and failures in aging research, we invited three senior investigators to share their journeys of persistence and resilience as they have navigated their research careers. This career development symposium was presented at the 2021 Annual Scientific Meeting of the American Geriatrics Society, which was held virtually. We aimed to connect researchers in aging, especially trainees and junior investigators, through personal stories of persistence and shared strategies to build resilience and respond to setbacks with a growth mindset.

This open-label, multicenter, single-arm, phase 2 study assessed the safety and efficacy of blinatumomab consolidation therapy in adult patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL; International Prognostic Index 3-5 and/or double-/triple-hit or double MYC/BCL-2 expressors) who achieved complete response (CR), partial response (PR), or stable disease (SD) following run-in with 6 cycles of R-chemotherapy (NCT03023878). Of the 47 patients enrolled, 28 received blinatumomab. Five patients (17.9%) experienced grade 4 treatment-emergent adverse events of interest (neutropenia, n = 4; infection, n = 1). Two deaths reported at the end of the study were unrelated to treatment with blinatumomab (disease progression, n = 1; infection, n = 1). 3/4 patients with PR and 4/4 patients with SD after R-chemotherapy achieved CR following blinatumomab. Consolidation with blinatumomab in patients with newly diagnosed, high-risk DLBCL who did not progress under R-chemotherapy was better tolerated than in previous studies where blinatumomab was used for treatment of patients with lymphoma.

Biologic treatment options for Crohn's disease (CD) are increasing and providers will need enhanced support in integrating these therapies into routine practice. Using phase 3 clinical trial programs in CD, we have previously built and validated clinical decision support tools for achieving clinical remission (CREM) with vedolizumab and ustekinumab in CD.1-4 We now aim to develop a clinical decision support tool for infliximab in CD.

Chromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double-strand breaks in a one-off catastrophic event. Rearrangements associated with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double-strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n = 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses and in vivo validation in patient-derived xenograft mouse models confirmed the efficacy of the combinatorial treatment.

Whether tumor suppressor candidate 2 (TUSC2) plays an important role in glioblastoma (GBM) progression is largely unknown. Whether TUSC2 undergoes polyubiquitination is unknown. Herein, we report that TUSC2 protein expression is reduced/lost in GBM compared to normal brain due to protein destabilization; TUSC2 mRNA is equally expressed in both tissues. NEDD4 E3 ubiquitin ligase polyubiquitinates TUSC2 at residue K71, and the TUSC2-K71R mutant is resistant to NEDD4-mediated proteasomal degradation. Analysis of GBM specimens showed NEDD4 protein is highly expressed in GBM and the level is inversely correlated with TUSC2 protein levels. Furthermore, TUSC2 restoration induces apoptosis and inhibits patient-derived glioma stem cells (PD-GSCs) in vitro and in vivo. Conversely, TUSC2-knockout promotes PD-GSCs in vitro and in vivo. RNA-Seq analysis and subsequent validations showed GBM cells with TUSC2- knockout expressed increased Bcl-xL and were more resistant to apoptosis induced by a Bcl-xL-specific BH3 mimetic. A TUSC2- knockout gene signature created from the RNA-seq data predicts poor patient survival. Together, these findings establish that NEDD4-mediated polyubiquitination is a novel mechanism for TUSC2 degradation in GBM and that TUSC2 loss promotes GBM progression in part through Bcl-xL upregulation.

Purpose To conduct a systematic review to evaluate the clinical parameters for periodontal diseases in individuals with cleft lip and/or palate (CL/P). Methods The authors searched six indexed databases without language restriction through July 2021. The eligibility criteria were observational studies that compared the periodontal clinical measures of individuals with CL/P to those without CL/P. Meta-analysis was conducted using random-effects models with inverse variance weighting. Results The literature search generated 1277 records, and 40 full-text articles were reviewed. Twenty-three studies comprising 3,235 individuals from 4 continents fulfilled our selection criteria. The meta-analysis revealed significant difference in mean plaque index scores (MD = 0.31, 95%CI = 0.22, 0.41), gingival index scores (MD = 0.50, 95%CI = 0.24, 0.77) and periodontal pocket depth (MD = 0.64, 95%CI = 0.12, 1.16) between individuals with and without CL/P. A slight increase in clinical attachment loss was detected among individuals with CL/P; however, such an increase may have little clinical significance. Conclusions As age is positively related to periodontal disease progression, and individuals with CL/P are more likely to present with more plaque accumulation and gingival inflammation, clinicians should reinforce preventive dental care from an early age.

Background and Aims Current endoscopic scoring indices such as the Simple Endoscopic Score for Crohn’s Disease [SES-CD] quantify the degree of mucosal inflammation in Crohn’s disease [CD] but lack prognostic potential. The Modified Multiplier of the SES-CD [MM-SES-CD] quantifies the endoscopic burden of CD and can be accessed online [https://www.mcmasteribd.com/mm-ses-cd]. This analysis aims to establish MM-SES-CD thresholds that classify CD endoscopic burden into inactive/very mild, mild, moderate, and severe disease based on the probability of achieving endoscopic remission [ER] on active therapy at 1 year. Methods This post-hoc analysis included pooled data from three CD clinical trials [n = 350 patients, baseline SES-CD ≥3 with ulceration]. Disease category severity was determined using the maximum Youden Index. Achievement of ER between severity categories was compared using chi square tests. Time to clinical remission [CR] was compared using Kaplan-Meier survival curves. Results MM-SES-CD severity categories were established as very mild/remission [score Conclusions We have established numerical MM-SES-CD cut-offs that categorise endoscopic disease severity and have demonstrated that they are prognostic for 1-year ER and CR.

The ability to imitate observed actions serves as an efficient method for learning novel movements and is specifically impaired (without concomitant gross motor impairments) in the neurological disorder of limb apraxia, a disorder common after left hemisphere stroke. Research with apraxic patients has advanced our understanding of how people imitate. However, the role of proprioception in imitation has been rarely assessed directly. Prior work has proposed that proprioceptively sensed body position is transformed into a visual format, supporting the attainment of a desired imitation goal represented visually (i.e., how the movement should look when performed). In contrast, we hypothesized a more direct role for proprioception: we suggest that movement goals are also represented proprioceptively (i.e., how a desired movement should feel when performed), and the ability to represent or access such proprioceptive goals is deficient in apraxia. Using a novel imitation task in which a robot cued meaningless trajectories proprioceptively or visually, we probed the role of each sensory modality. We found that patients with left hemisphere stroke were disproportionately worse than controls at imitating when cued proprioceptively versus visually. This proprioceptive versus visual disparity was associated with apraxia severity as assessed by a traditional imitation task, but could not be explained by general proprioceptive impairment or speed-accuracy trade-offs. These data suggest that successful imitation depends in part on the ability to represent movement goals in terms of how those movements should feel, and that deficits in this ability contribute to imitation impairments in patients with apraxia.

This study investigated the associations among bilingual phonological awareness, morphological awareness, and vocabulary by focusing on their genetic and environmental etiologies. It also explored the influence of family socio-economic status (SES) and language exposure amount on the genetic and environmental effects. A twin study was conducted with 349 pairs of Chinese-English bilingual twins (mean age = 7.37 years). Cross-language transfer was found in phonological and morphological awareness but not in vocabulary knowledge. A common genetic overlap was found among these bilingual abilities. We also found a common shared environmental effect that may account for the cross-language transfer in phonological awareness and the associations among English abilities. SES and language exposure were significant environmental influences on bilingual phonological awareness and English vocabulary. More teaching in Chinese was related to a stronger genetic effect on Chinese morphological awareness, whereas more teaching in English was related to a stronger environmental impact on English abilities.

Purpose: Mutations in STK11 (LKB1) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TIME) and resistance to immunotherapy. The mechanisms underpinning the establishment and maintenance of a cold TIME in LKB1-mutant LUAD remain poorly understood. In this study, we investigated the role of the LKB1 substrate AMPK in immune evasion in human non—small cell lung cancer (NSCLC) and mouse models and explored the mechanisms involved. Experimental Design: We addressed the role of AMPK in immune evasion in NSCLC by correlating AMPK phosphorylation and immune-suppressive signatures and by deleting AMPKα1 (Prkaa1) and AMPKα2 (Prkaa2) in a KrasG12D-driven LUAD. Furthermore, we dissected the molecular mechanisms involved in immune evasion by comparing gene-expression signatures, AMPK activity, and immune infiltration in mouse and human LUAD and gain or loss-of-function experiments with LKB1- or AMPK-deficient cell lines. Results: Inactivation of both AMPKα1 and AMPKα2 together with Kras activation accelerated tumorigenesis and led to tumors with reduced infiltration of CD8+/CD4+ T cells and gene signatures associated with a suppressive TIME. These signatures recapitulate those in Lkb1-deleted murine LUAD and in LKB1-deficient human NSCLC. Interestingly, a similar signature is noted in human NSCLC with low AMPK activity. In mechanistic studies, we find that compromised LKB1 and AMPK activity leads to attenuated antigen presentation in both LUAD mouse models and human NSCLC. Conclusions: The results provide evidence that the immune evasion noted in LKB1-inactivated lung cancer is due to subsequent inactivation of AMPK and attenuation of antigen presentation.

Background: Gut microbial alterations have been linked to chronic liver disease and hepatocellular carcinoma (HCC). The role of the oral microbiome in liver cancer development has not been widely investigated. Methods: Bacterial 16S rRNA sequences were evaluated in oral samples from 90 HCC cases and 90 controls who were a part of a larger U.S. case–control study of HCC among patients diagnosed from 2011 to 2016. Results: The oral microbiome of HCC cases showed significantly reduced alpha diversity compared with controls (Shannon P = 0.002; Simpson P = 0.049), and beta diversity significantly differed (weighted Unifrac P = 0.004). The relative abundance of 30 taxa significantly varied including Cyanobacteria, which was enriched in cases compared with controls (P = 0.018). Cyanobacteria was positively associated with HCC [OR, 8.71; 95% confidence interval (CI), 1.22–62.00; P = 0.031] after adjustment for age, race, birthplace, education, smoking, alcohol, obesity, type 2 diabetes, Hepatitis C virus (HCV), Hepatitis B virus (HBV), fatty liver disease, aspirin use, other NSAID use, laboratory batch, and other significant taxa. When stratified by HCC risk factors, significant associations of Cyanobacteria with HCC were exclusively observed among individuals with negative histories of established risk factors as well as females and college graduates. Cyanobacterial genes positively associated with HCC were specific to taxa producing microcystin, the hepatotoxic tumor promotor, and other genes known to be upregulated with microcystin exposure. Conclusions: Our study provides novel evidence that oral Cyanobacteria may be an independent risk factor for HCC. Impact: These findings support future studies to further examine the causal relationship between oral Cyanobacteria and HCC risk.

Background: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). Objective: To model the relationships between handgrip strength, mobility, and MRI volumetry. Methods: We selected 38 participants with Alzheimer’s disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. Results: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. Conclusion: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.

Background: effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. Objectives: use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. Methods: retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). Results: cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54-6.32), 7.04 (4.16-11.93), and 6.52 (3.79-11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. Conclusion: cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators., Financial support for this study was provided entirely by a contract with EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA (CrossRef Funder ID: 10.13039/100004755). The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report. The following authors are employed by the sponsor: NT and SLW.

Background Spinal stenosis is a narrowing of the spinal canal that may compress neurological tissues resulting in pain and disability. Although previous qualitative studies have solicited data regarding the life experience of patients with spinal stenosis or their opinions on relevant non-surgical treatments, their data was collected from participants in a controlled setting. Therefore, it remains unclear whether patients’ or caregivers’ concerns/opinions about spinal stenosis would be different in a non-experimental environment. Since Twitter is a popular online platform for people to share information and interact, it may reveal people’s thoughts and attitudes about spinal stenosis. This study aimed to identify tweets that are related to spinal stenosis on Twitter, and to categorize them into common themes. Methods A social media monitoring and analysis software program (TalkWalker) was used to search relevant tweets using the keywords 'spinal stenosis' and 'stenosis' between 29 May 2019 and 24 June 2020. Two independent reviewers screened and conducted content analysis of the tweets and classified the tweets into different themes. Results Of 510 identified tweets, 362 tweets met the selection criteria. Five themes were identified: (1) compromised physical, psychological, and social wellbeing (n = 173); (2) diverse treatment options (n = 69); (3) coping strategies (n = 30); (4) dissemination of scientific information (n = 86); and (5) health policy (n = 4). Most of the tweets revealed negative impacts of spinal stenosis on patients' physical and psychosocial wellbeing. People with spinal stenosis shared their experiences and sought helps from others, while some people used Twitter to disseminate relevant information and research findings. Conclusions This is the first study exploring Twitter using an online analytical tool to identify themes related to spinal stenosis. The approach not only helps understand people’s concerns about spinal stenosis in an uncontrolled environment, but also can be adopted to monitor influences of diseases or public health education on Twitter users.

OBJECTIVE Medical students often feel inadequately prepared for the responsibilities of surgical internship because of insufficient exposure to resident responsibilities prior to starting residency. This lack of preparation may contribute to burnout and attrition early in residency. Sub-internships should provide these experiences. Significant variation, however, exists in the structure of these rotations. We conducted a targeted needs assessment to inform the development of a didactic curriculum to address gaps in the surgical sub-internship experience and better prepare students for general surgery residency. DESIGN A 25-item needs assessment survey was developed and distributed to senior medical students in their surgical sub-internship, current junior residents, and prior students (alumni) from the past 4 years who matched into general surgery residencies at other institutions. SETTING Geisel School of Medicine at Dartmouth/Dartmouth-Hitchcock Medical Center, a tertiary-care academic medical center. PARTICIPANTS Nine senior medical students; 12 current residents and 14 alumni, including 9 PGY-1, 13 PGY-2, and 4 PGY-3 residents. RESULTS The topics rated most important by medical students were floor management topics, specifically lines, tubes, and drains, hypotension, post-operative fever, chest pain, oliguria, and post-operative pain. In contrast, there was a wider variety of topics rated highly by residents. Residents emphasized non-technical communication and documentation skills. Residents at every training level rated presenting patients on rounds as the most important skill for incoming interns to acquire, whereas only one-third of medical students considered this to be an essential topic. CONCLUSIONS Medical students rank management of common clinical problems as the most critical aspect in their preparation for residency. Residents recognized these topics as important, but also placed high emphasis on non-technical communication and documentation skills. The findings from this need's assessment can be used to guide content structure for a sub-intern curriculum.

Introduction Agitation and impaired cognitive functioning are common symptoms of dementia, which require costly medication regimens that are associated with adverse effects. This study investigates the effects of dance interventions on agitation and cognitive function in people living with dementia in institutional care facilities. Methods Five electronic databases were searched for eligible studies on dance interventions for people living with dementia published between 2002 and 2021. Standard deviation and post mean values were extracted. Within-group Hedges’ g was computed for individual studies. Results Six randomised controlled trials and three non-randomised studies of satisfactory quality, with a total of 610 participants, were included. Statistical analysis found significant improvements in agitation and cognitive functioning with dance interventions. Discussion This review provided favourable evidence on the effects of dance interventions on agitation and cognitive functions in people with dementia. However, given the limited evidence, more studies are needed to confirm the effects.

The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has completely transformed the functioning of health care facilities. These changes have also significantly affected the work of dental health professionals. Due to the high infectivity of the virus and the fact that transmission occurs primarily through respiratory droplets, both dental patients and professionals are particularly exposed to coronavirus infection. In order to reduce the risk of COVID-19 transmission, a number of medical societies have issued recommendations for the provision of health care services during the pandemic. The article is based mainly on the recommendations of the Polish Ministry of Health, since WHO recommendations underline that following updated local guidelines is of highest importance. It is impossible to outline uniform guidelines for all dental specialists in the world, as the pandemic develops at differing rates in different countries and each country requires guidelines adapted to the current local epidemiological situation. The publication features an additional review of foreign literature and guidelines proposed by individual dental societies. The article presents an overview of guidelines related to the functioning of dental offices, dental treatment procedures and recommended personal protective equipment, as well as underlines the overriding principle that both physicians and dental practitioners should first and foremost take care of their own health in order to be able to protect others. Med Pr. 2021;72(5):561-8.Szerząca się pandemia COVID-19, choroby wywołanej przez SARS-CoV-2, spowodowała diametralne zmiany w funkcjonowaniu placówek ochrony zdrowia, co wpłynęło także w znacznym stopniu na pracę lekarzy dentystów. Ze względu na wysoką zakaźność i przede wszystkim kropelkową drogę przenoszenia się SARS-CoV-2 pacjenci, tak jak personel gabinetów stomatologicznych, są szczególnie narażeni na zakażenie koronawirusem. W celu ograniczenia ryzyka rozprzestrzeniania się COVID-19 wiele towarzystw medycznych wydało rekomendacje na temat postępowania przy udzielaniu świadczeń zdrowotnych w pandemii. Niniejszy artykuł w głównej mierze został opracowany na podstawie zaleceń polskiego Ministerstwa Zdrowia, ponieważ według rekomendacji Światowej Organizacji Zdrowia przestrzeganie lokalnych zaktualizowanych wytycznych jest najistotniejsze. Nie ma możliwości przygotowania jednolitych wskazówek dla wszystkich lekarzy dentystów na świecie, ponieważ pandemia rozwija się w różnych krajach w innym tempie i każde państwo wymaga wytycznych dostosowanych do aktualnej sytuacji epidemiologicznej. Publikację dodatkowo uzupełniono przeglądem piśmiennictwa zagranicznego oraz wytycznymi proponowanymi przez poszczególne towarzystwa stomatologiczne. W artykule przedstawiono rekomendacje dotyczące funkcjonowania gabinetów stomatologicznych, wykonywania procedur stomatologicznych oraz zalecanych środków ochrony osobistej. Podkreślono nadrzędną zasadę, aby w pierwszej kolejności zarówno lekarze, jak i lekarze dentyści dbali o swoje zdrowie po to, żeby pomagać innym. Med. Pr. 2021;72(5):561–568.

Virtual forms of communication have been integrated into academic surgery now more than ever. The COVID-19 pandemic accelerated its implementation in an effort to support social-distancing. Academic surgery is now learning valuable lessons from early experiences to optimally integrate this communication mode. The Society of Asian Academic Surgeons convened an expert panel during the society's fifth annual meeting that explores these lessons. Realms of virtual communication including meetings, networking, surgery department administration, social media, application processes, and advice for early or mid-career academic surgeons are explored. Virtual conferences pose a new challenge by removing the in-person component that is evident to be integral to networking, collaboration, and all aspects of academic socialization. Strategies such as creating virtual chat rooms, mentor-mentee virtual introductions, and deliberate interactions can enhance the experience. Virtual administrative meetings require special attention to preparation and strategies to insure engagement. Social media can be a valuable tool to integrate into academic careers but special attention needs to be made to utilize it deliberately and not to shy away from our individuality. The interview process can be enhanced when made virtual to give opportunities to those typically disadvantaged in the usual, in-person process.

Background and Aims This study evaluated the minimal clinically important short-term improvement in the Modified Multiplier Simple Endoscopic Score for crohn’s Disease [MM-SES-CD], a novel modified scoring system of the SES-CD, which reliably predicted 1-year endoscopic remission [ER]. Methods This post-hoc analysis of two CD clinical trial programmes pooled data of 198 participants with baseline ulcers and SES-CD ≥3, who had baseline, post-induction [8–12 weeks], and 1-year endoscopic assessments. Different cut-off values for endoscopic response were evaluated using receiver operating characteristic [ROC] curves, positive likelihood ratios [PLR], and negative likelihood ratios [NLR]. ER [SES-CD Results MM-SES-CD ≥40% reduction from baseline was selected as the cut-off maximising PLR and minimising NLR. Among 7.6% [15/198] participants achieving this cut-off post-induction, 1-year ER was 46.7%. One-year ER was 16.9% among those not achieving this cut-off. This threshold predicted 1-year ER with 95.0% (95% confidence interval [CI] 90.4%–97.8%) specificity and a PLR of 3.7 [95% CI 1.4–9.5], which was higher than traditional endoscopic response criteria of SES-CD ≥50% reduction [specificity 62.5%, 95% CI 54.5%–70.0%; PLR 1.9, 95% CI 1.4–2.5]. Lower thresholds of MM-SES-CD reduction also were highly specific for 1-year ER [e.g., MM-SES-CD ≥20% reduction was achieved in 19.7% of patients with 83.1% specificity]. Conclusions In CD patients, post-induction endoscopic response defined by MM-SES-CD ≥40% reduction from baseline identified patients most likely to achieve 1-year ER.

Purpose To describe a novel technique in unfolding an endothelium-in Descemet membrane (DM) graft. Methods New surgical technique description Results We describe a novel technique that allows immediate and controlled unfolding of the endothelium-in Descemet membrane graft that was successful in 5 of our DMEK patients. It is essential to acquire this “side press-and-release” technique when the graft does not unfold spontaneously as expected. Conclusions This controlled and simple manoeuvre is an efficient and safe method of unfolding an endothelium-in DM graft.

INTRODUCTION/AIMS Glucocorticoid-induced osteoporosis with vertebral fractures is frequent in patients with Duchenne muscular dystrophy (DMD). In this study, we evaluated the effects of oral bisphosphonate (BP) therapy on the prevalence and severity of vertebral fractures by vertebral morphometry assessment. METHODS We reviewed the records and radiographs of patients with DMD who had been treated with oral BP (weekly alendronate) and had undergone routine spine radiographic monitoring for glucocorticoid-induced osteoporosis at Cincinnati Children's Hospital Medical Center between 2010 and 2017. Study outcomes were thoracic and lumbar vertebral fracture prevalence and severity, assessed by Genant semiquantitative grading of vertebral morphometry, for up to 5 years of treatment. RESULTS Fifty-two patients (median age, 11.8 years; 88% prepubertal; 31% nonambulatory) had been treated with long-term glucocorticoids (median duration, 4.7 years at BP start). Most patients (75%) had mild vertebral height loss or fractures (Genant grade = 0 or 1) at baseline. The prevalence of vertebral fractures at each year of treatment was not statistically different from that at baseline (P = .08-1.00). Serial radiographs showed no longitudinal change in severity by Genant grade in most vertebrae (64%-80%). Improvement in vertebral fracture grade was observed in some patients. DISCUSSION We observed stable prevalence of vertebral fractures and no change in severity by Genant grade in most vertebrae for up to 5 years of treatment. Oral BP may mitigate development or progression of vertebral fractures and be beneficial for secondary prevention of glucocorticoid-induced osteoporosis in this population.

Paediatric trigger finger is a rare condition distinct from paediatric trigger thumb and adult trigger digits. We performed a systematic review of paediatric trigger finger presentation and aetiology in order to guide workup and management. Fifty-one studies with 193 patients and 398 trigger fingers were included. Most patients had a single, unilateral trigger finger (54%). Fifty-five patients (29%) had an underlying condition, such as mucopolysaccharidosis; these cases appeared to be associated with multiple or bilateral trigger fingers or with carpal tunnel syndrome. All patients with mucopolysaccharidosis were treated surgically. Conservative management was reported in 33% of all patients, and two-thirds of these did not need further intervention. Patients undergoing surgical release infrequently had recurrence of triggering (6%). We propose an algorithmic approach for patients presenting with paediatric trigger finger. Presence of bilateral or multiple trigger digits or concomitant carpal tunnel syndrome should raise suspicion for an atypical underlying pathology.

Rett syndrome (RTT) is a severe neurological disorder and a leading cause of intellectual disability in young females. RTT is mainly caused by mutations found in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Despite extensive studies, the molecular mechanism underlying RTT pathogenesis is still poorly understood. Here, we report MeCP2 as a key subunit of a higher-order multiunit protein complex Rbfox/LASR. Defective MeCP2 in RTT mouse models disrupts the assembly of the MeCP2/Rbfox/LASR complex, leading to reduced binding of Rbfox proteins to target pre-mRNAs and aberrant splicing of Nrxns and Nlgn1 critical for synaptic plasticity. We further show that MeCP2 disease mutants display defective condensate properties and fail to promote phase-separated condensates with Rbfox proteins in vitro and in cultured cells. These data link an impaired function of MeCP2 with disease mutation in splicing control to its defective properties in mediating the higher-order assembly of the MeCP2/Rbfox/LASR complex., MeCP2 mutations can cause Rett syndrome, a severe childhood neurological disorder. Here the authors show that MeCP2 mediates the higher-order assembly of a large splicing complex Rbfox/LASR, which is disrupted in the mouse models of Rett syndrome.

Background Hospital reviews posted online by patients are unsolicited and less structured than Hospital Consumer Assessment of Healthcare Providers and Systems surveys. The differences between online review platforms and their degrees of correlation with validated satisfaction and safety measures are unknown. Methods We identified 515 large acute care teaching hospitals in the United States. We collected patient satisfaction results and postsurgical patient safety indicators from Hospital Compare. We also collected hospital star ratings (1–5) from Facebook, Google, and Yelp. Mean ratings were compared with paired t tests. Concordance between ratings websites, Hospital Consumer Assessment of Healthcare Providers and Systems scores, and surgical safety indicators were assessed with Pearson’s correlation coefficient. Results Mean Facebook ratings (3.81, interquartile range 3.5–4.3) were more favorable than Google (3.26, interquartile range 2.8–3.6) or Yelp (2.59, interquartile range 2.3–2.9). Facebook ratings were least strongly correlated with the Hospital Consumer Assessment of Healthcare Providers and Systems recommended hospital score (ρ = 0.356). Google was modestly correlated (ρ = 0.479), and Yelp was most strongly correlated (ρ = 0.500). The negative correlation between crowdsourced rating and composite safety indicator was too small to be meaningful on any platform. Conclusion There is variation between platforms in consumer ratings of hospitals. Ratings on Facebook are more favorable than Google or Yelp. These are independently correlated with Hospital Consumer Assessment of Healthcare Providers and Systems scores. These findings suggest that unstructured consumer reviews generally reflect similar directionality as Hospital Consumer Assessment of Healthcare Providers and Systems satisfaction scores. Users should be aware of the significant difference between platforms. Consumer ratings platforms are not consistently correlated with postsurgical patient safety indicators, so online ratings may not reflect the safety of surgical care received.

The effects of DNASE1L3 or DNASE1 deficiency on cell-free DNA (cfDNA) methylation were explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wild-type cfDNA, cfDNA in DNASE1L3-deficient mice was significantly hypomethylated, while cfDNA in DNASE1-deficient mice was hypermethylated. The cfDNA hypomethylation in DNASE1L3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in DNASE1-deficient mice, demonstrating the preference of DNASE1 to cleave in hypomethylated OCRs and CGIs. We also observed a substantial decrease of fragment ends at methylated CpGs in the absence of DNASE1L3, thereby demonstrating that DNASE1L3 prefers to cleave at methylated CpGs. Furthermore, we found that methylation levels of cfDNA varied by fragment size in a periodic pattern, with cfDNA of specific sizes being more hypomethylated and enriched for OCRs and CGIs. These findings were confirmed in DNASE1L3-deficient human cfDNA. Thus, we have found that nuclease-mediated cfDNA fragmentation markedly affects cfDNA methylation level on a genome-wide scale. This work provides a foundational understanding of the relationship between methylation, nuclease biology, and cfDNA fragmentation.

Transgenic breast cancer mouse models are critical tools for preclinical studies of human breast cancer. Genetic editing of the murine mammary gland allows for modeling of abnormal genetic events frequently found in human breast cancers. Genetically engineered mouse models (GEMMs) of breast cancer employ tissue-specific genetic manipulation for tumorigenic induction within the mammary tissue. Under the transcriptional control of mammary-specific promoters, transgenic mouse models can simulate spontaneous mammary tumorigenesis by expressing one or more putative oncogenes, such as MYC, HRAS, and PIK3CA. Alternatively, the Cre-Lox system allows for tissue-specific deletion of tumor suppressors, such as p53, Rb1, and Brca1, or specific knock-in of putative oncogenes. Thus, GEMMs can be designed to implement one or more genetic events to induce mammary tumorigenesis. Features of GEMMs, such as age of transgene expression, breeding quality, tumor latency, histopathological characteristics, and propensity for local and distant metastasis, are variable and strain-dependent. This review aims to summarize currently available transgenic breast cancer mouse models that undergo spontaneous mammary tumorigenesis upon genetic manipulation, their varying characteristics, and their individual genetic manipulations that model aberrant signaling events observed in human breast cancers.

The relative proportion of trauma patients who are older adults continues to rise as the population ages. Older adults who experience trauma have unique needs compared with their younger counterparts. There are specific considerations that must take into account. Treating older adults with traumatic injuries requires specific skills, knowledge, and specialized protocols to optimize outcomes. This article reviews the most important aspects of geriatric trauma care. We focus on presentation and initial resuscitation, triage guidelines and the issue of undertriage, the importance of multidisciplinary and specialized geriatric care, and common injuries and their management.

Using paired serum samples obtained from patients with illness associated with increases in anti-human coronavirus OC43 (HCoV-OC43) or anti-HCoV-229E antibodies, we examined the possibility of false-positive results detected in a recombinant severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) nucleocapsid protein immunoglobulin G enzyme-linked immunosorbent assay (ELISA). Three of the 21 and 1 of the 7 convalescent-phase serum samples from persons with increases in antibodies against HCoV-OC43 and HCoV-229E, respectively, tested positive by the recombinant SARS-CoV nucleocapsid protein-based ELISA. None of these samples were found to contain a specific antibody in the recombinant SARS-CoV spike polypeptide-based Western blot assay.

Dynamic intron retention (IR) in vertebrate cells is of widespread biological importance. Aberrant IR is associated with numerous human diseases including several cancers. Despite consistent reports demonstrating that intrinsic sequence features can help introns evade splicing, conflicting findings about cell type- or condition-specific IR regulation by trans-regulatory and epigenetic mechanisms demand an unbiased and systematic analysis of IR in a controlled experimental setting. We integrated matched mRNA sequencing (mRNA-Seq), whole-genome bisulfite sequencing (WGBS), nucleosome occupancy methylome sequencing (NOMe-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) data from primary human myeloid and lymphoid cells. Using these multi-omics data and machine learning, we trained two complementary models to determine the role of epigenetic factors in the regulation of IR in cells of the innate immune system. We show that increased chromatin accessibility, as revealed by nucleosome-free regions, contributes substantially to the retention of introns in a cell-specific manner. We also confirm that intrinsic characteristics of introns are key for them to evade splicing. This study suggests an important role for chromatin architecture in IR regulation. With an increasing appreciation that pathogenic alterations are linked to RNA processing, our findings may provide useful insights for the development of novel therapeutic approaches that target aberrant splicing.

Introduction Functional dyspepsia (FD) is diagnosed based on self-reported symptoms and negative upper gastrointestinal endoscopic findings. The Rome criteria were not adopted as a diagnostic instrument in clinical guidelines due to their complexity. Different guidelines used relatively simple symptom assessment schemes with contents that vary significantly. A previously evaluated short Reference Standard may serve as a more standardised tool for guidelines. We evaluated its diagnostic accuracy against the Rome IV criteria in a cross-sectional study in Hong Kong. Methods A total of 220 dyspeptic patients sampled consecutively from a tertiary hospital and the community completed the Rome IV diagnostic questionnaire, which was translated into Cantonese-Chinese, and the Reference Standard. Sensitivity, specificity, positive and negative likelihood ratios (LRs), and area under the receiver operating characteristics curve (AUC), with 95% confidence intervals (CIs), were calculated. Results Among the participants, 160 (72.7%) fulfilled the Reference Standard with negative upper gastrointestinal endoscopic results. The Reference Standard identified patients with Rome IV-defined FD with 91.1% (95% CI 82.6%–96.4%) sensitivity and 37.6% (95% CI 29.6%–46.1%) specificity. The positive and negative LRs were 1.46 (95% CI 1.26–1.69) and 0.24 (95% CI 0.11–0.49), respectively. The AUC value was 0.64 (95% CI 0.59–0.69). Conclusions The Reference Standard can rule out patients without Rome IV-defined FD. It may be used as an initial screening tool for FD in settings where the use of the Rome IV criteria is impractical. It may also provide a uniform definition and diagnostic rule for future updates of clinical guidelines.

In April 2022, the Intergovernmental Panel on Climate Change stated clearly that without immediate and deep reductions in greenhouse gas emissions, it would be impossible to limit global temperature rise to 1.5 °C above pre-industrial levels. A growing body of research shows an increasing reaction to witnessing or experiencing current climate impacts and concern regarding apparent inaction in response, manifests as negative cognitive, emotional, and behavioural responses, including eco-anxiety. This commentary contends that nature-based activities (NBAs) have a potentially important, but currently neglected, role to play in supporting those experiencing eco-anxiety. However, existing research limitations hinder their adoption in the United Kingdom's social prescribing agenda and they remain a largely untapped therapeutic resource that need to be mainstreamed into clinical and social care provision. The paper calls for investment in research that advances our understanding of the individual and community benefits of NBAs, the longevity of their impact, and their associated, comparative and opportunity costs.

Knowledge on the distribution and abundance of organisms is fundamental to understanding their roles within ecosystems and their ecological importance for other taxa. Such knowledge is currently lacking for insects, which have long been regarded as the “little things that run the world”. Even for ubiquitous insects, such as ants, which are of tremendous ecological significance, there is currently neither a reliable estimate of their total number on Earth nor of their abundance in particular biomes or habitats. We compile data on ground-dwelling and arboreal ants to obtain an empirical estimate of global ant abundance. Our analysis is based on 489 studies, spanning all continents, major biomes, and habitats. We conservatively estimate total abundance of ground-dwelling ants at over 3 × 10 15 and estimate the number of all ants on Earth to be almost 20 × 10 15 individuals. The latter corresponds to a biomass of ∼12 megatons of dry carbon. This exceeds the combined biomass of wild birds and mammals and is equivalent to ∼20% of human biomass. Abundances of ground-dwelling ants are strongly concentrated in tropical and subtropical regions but vary substantially across habitats. The density of leaf-litter ants is highest in forests, while the numbers of actively ground-foraging ants are highest in arid regions. This study highlights the central role ants play in terrestrial ecosystems but also major ecological and geographic gaps in our current knowledge. Our results provide a crucial baseline for exploring environmental drivers of ant-abundance patterns and for tracking the responses of insects to environmental change.

Behavioral health problems are ubiquitous in today's society. Social, environmental, and physical stressors impact our daily activities and wellness, contributing to mental health conditions, both diagnosed and undiagnosed, as well as substance use. We know that populations and identities are not equally impacted. Populations who experience greater stressors suffer more. Structures and systems cause and reinforce inequities in health, inclusive of behavioral health. Still, there is insufficient understanding of the existing disparities in behavioral health. Right now, what do we know? And perhaps more importantly, what do we know that we do not know? Behavioral health itself is an inequity in health care. Predominantly isolated from physical health, we still have not achieved parity in preventive measures, access, management, or reimbursement for care. We cannot let what we do not know prevent us from advocating for adequate resource allocation and prioritizing community driven solutions for populations with the greatest needs. These efforts must shift from programmatic interventions to full-scale paradigm shifts in public policy and adoption of disaggregated racial data to effectively narrow the gaps in equality and help us address behavioral health with the respect deserved to balance inequities. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

In eukaryotes, alternative pre-mRNA splicing allows a single gene to encode different protein isoforms that function in many biological processes, and they are used as biomarkers or therapeutic targets for diseases. Although protein isoforms in the human genome are well annotated, we speculate that some low-abundance protein isoforms may still be under-annotated because most genes have a primary coding product and alternative protein isoforms tend to be under-expressed. A peptide coencoded by a novel exon and an annotated exon separated by an intron is known as a novel junction peptide. In the absence of known transcripts and homologous proteins, traditional whole-genome six-frame translation-based proteogenomics cannot identify novel junction peptides, and it cannot capture novel alternative splice sites. In this article, we first propose a strategy and tool for identifying novel junction peptides, called CJunction, which we then integrate into a proteogenomics process specifically designed for novel protein isoform discovery and apply to the analysis of a deep-coverage HeLa mass spectrometry data set with identifier PXD004452 in ProteomeXchange. We succeeded in identifying and validating three novel protein isoforms of two functionally important genes, NHSL1 (causative gene of Nance-Horan syndrome) and EEF1B2 (translation elongation factor), which validate our hypothesis. These novel protein isoforms have significant sequence differences from the annotated gene-coding products introduced by the novel N-terminal, suggesting that they may play importantly different functions.

BACKGROUND Practice guidelines recommend neoadjuvant chemoradiation (NCR) for locally advanced rectal cancer (LARC). We examined guideline adherence in a healthcare system serving a region with socioeconomic disparities and poor cancer outcomes. METHODS Retrospective analysis of factors associated with guideline adherence. RESULTS 63.1% of stage II/III LARC patients received NCR. Factors associated with adherence included white race (OR = 2.15, p = 0.024), private insurance (OR = 2.70, p = 0.005), employed status (OR = 2.30, p = 0.031), age at diagnosis (OR = 0.74, p = 0.032), appropriate local staging (OR = 9.17, p < 0.0001), and diagnosis later in the study period (OR per 1 year = 1.20, p = 0.006). By multivariate analysis, private insurance (OR = 2.51, p = 0.023), younger age (OR per 10 years = 0.72, p = 0.048) and appropriate local staging (OR = 6.67, p

Introduction This article describes the development of a unique mapping of the Kurtzke Functional Systems Scores (KFSS) from International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes among multiple sclerosis (MS) patients within a US Integrated Delivery Network (IDN). Valid identification of increasing disability may allow deeper insight into MS progression and possible treatments. Methods This cohort study identified MS patients in the IDN, Intermountain Healthcare. Experienced clinicians and informaticists mapped electronic health record ICD-9-CM codes to KFSS components generating a modified Kurtzke Expanded Disability Status Scale (EDSS). Modified EDSS scores were used to assess disability progression by calculating means, medians, ranges, and changes in KFSS and modified EDSS scores. Results Overall, 608/2960 (20.5%) patients were identified as having MS progression and presented a wide range of scores on the EDSS 10-point scale. The median (range) first and second EDSS scores were 0 (0–6) and 5 (1–8), respectively. The median (range) change from first to second score was 5 (1–7.5). The median first KFSS score for all systems was 0, and the mean differed among components. The highest mean first KFSS score (1.06) was measured for sensory function and lowest (0.12) for cerebellar functions. Of the 544 patients with their first EDSS scores in the ≤ 2.5 group, 75.2% and 15.1% had their second EDSS scores in group 3–5.5 and ≥ 6, respectively. Of the 62 patients with their first EDSS score in the 3–5.5 group, 58.1% had their second EDSS scores in group ≥ 6. Conclusion This innovative mapping technique is a promising method for future comparative effectiveness and safety research of Disease-Modifying Therapy in Real-World Data repositories. Future research to validate and expand on this method in another healthcare database is encouraged. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01858-9.

Background Disparities in gender representation at medical meetings have been documented despite women representing half of medical school graduating classes. Lack of role models is touted as one of a myriad of factors that perpetuate gender imbalance, particularly in the field of surgery. We evaluated the trend in gender distribution of participants at the Royal Australasian College of Surgeons (RACS) Annual Scientific Congress (ASC) and whether there was a correlation between the gender distribution of the organising committee and speakers and chairpersons invited to attend. Methods RACS ASC programmes from 2013 to 2018 were retrospectively analysed, examining the gender distribution of speakers, chairpersons and conveners. Trend analysis of distribution was performed, and a generalized linear mixed model was used to investigate the effect of the gender of the conveners on gender of session chairpersons and speakers. Results Between 2013 and 2018, there were non-significant increases in female speakers invited to speak from 14.9 to 21.7% (p = 0.064) and female conveners appointed from 11 to 19% (p = 0.115), but there was a significant increase in female chairs from 9.6 to 21.6% p p p Conclusion Visible role models are important in the pursuit of gender equity in surgery in order to break down stereotypes and the hidden curriculum. Intentional effort is required to achieve parity, and such efforts could include appointing more women to organising committees of scientific meetings.

The COVID-19 pandemic has become a worldwide health crisis. So far, most studies have focused on the epidemiology and pathogenesis of this infectious disease. Little attention has been given to the disease sequelae in patients recovering from COVID-19, and nothing is known about the mechanisms underlying these sequelae. Herein, we profiled the serum proteome of a cohort of COVID-19 patients in the disease onset and recovery stages. Based on the close integration of our proteomic analysis with clinical data, we propose that COVID-19 is associated with prolonged disorders in cholesterol metabolism and myocardium, even in the recovery stage. We identify potential biomarkers for these disorders. Moreover, severely affected patients presented more serious disturbances in these pathways. Our findings potentially support clinical decision-making to improve the prognosis and treatment of patients.

Hemostatic agents are routinely used in vascular surgery to complement proper suture techniques and decrease the risk of perioperative bleeding. A relative lack of comparative research studies have left surgeons with the option of choosing hemostatic agents based on their personal experience. The present review has highlighted the efficacy and safety of hemostatic agents and categorized them according to their primary mechanism of action and cost.A systematic search strategy encompassing hemostatic agent products was deployed in the PubMed database. Single-center and multicenter, randomized, controlled trials with10 patients were included in the present study.We reviewed 12 studies on the efficacy and safety of hemostatic agents compared with manual compression or other hemostatic agents. Using the time to hemostasis as the primary end point, all studies had found hemostatic agents to be significantly more efficient than manual compression. Likewise, adhesives (high pressure sealants) and dual agents (containing biologically active and absorbable components) were found to be more efficient, but costlier, than agents with either biologically active or absorbable components only. Agents with porcine or bovine constituents were found to trigger anaphylactic reactions in rare cases. Additionally, the absence of fibrin stabilizing factor XIII in a brand of fibrin sealant was speculated to reduce the affinity of the fibrin sealant for the expanded polytetrafluoroethylene graft. The cost of agents varied greatly depending on their active ingredient.Hemostatic agents appear to be highly effective at decreasing the risk of bleeding during surgical procedures. Although some hemostatic agents were demonstrated to achieve hemostasis faster than others, most are able to control bleeding within 10 minutes. Based on the limited data, the least expensive agents might suffice for limited suture lines used in routine procedures.

PURPOSE: To determine patient and disease characteristics associated with functional disability among adults with advanced non–small-cell lung cancer (NSCLC). METHODS: In a prospective cohort of participants newly diagnosed with advanced NSCLC and beginning systemic treatment, functional disability in usual activities, mobility, and self-care was measured using the EuroQol-5D-5L at baseline. Demographics, comorbidities, brain metastases, Eastern Cooperative Oncology Group performance status (ECOG PS), and psychologic variables (depression [Patient Health Questionnaire-9] and anxiety [Generalized Anxiety Disorder 7-item scale]) were captured. Patients were classified into two disability groups (none-slight or moderate-severe) on the basis of total functional status scores. Differences between disability groups were determined (chi-square and t tests). Associations between patient characteristics and baseline disability were assessed using logistic regression. RESULTS: Among 173 participants, mean age was 63.3 years, 56% were male, 83% had ECOG PS 0-1, and 41% had brain metastases. Baseline disability was present in 39% of participants, with patients having moderate to severe disability in usual activities (37.6%), mobility (26.6%), and self-care (5.2%). Depressive and/or anxiety symptoms ranged from none to severe (Patient Health Questionnaire 9-item scale M = 6.5, SD = 5.3). Depressive symptoms were the only characteristic associated with a higher odds of baseline disability (adjusted odds ratio [aOR]: 1.26; 95% CI, 1.15 to 1.38; P < .001). Participants with poorer ECOG PS (aOR: 4.64; 95% CI, 1.84 to 11.68; P = .001) and depressive symptoms (aOR: 1.15; 95% CI, 1.07 to 1.24; P < .001) had higher odds of moderate-severe mobility disability compared with the none-slight disability group. CONCLUSION: More than one third of all adults with advanced NSCLC have moderate-severe functional disability at baseline. Psychologic symptoms were significantly associated with moderate-severe baseline disability.

Background and aim Crohn's disease (CD) patients who previously failed anti-tumor necrosis factor (TNF) therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared with standard doses in CD patients who failed anti-TNF. Methods In this retrospective observational study, CD patients who failed anti-TNF and received adalimumab were categorized according to their post-induction maintenance regimen; 40 mg subcutaneous (sc) weekly or 80 mg sc every other week were defined as a high-dose (HD) maintenance regimen, and 40 mg sc every other week was defined as a standard-dose (SD) maintenance regimen. The primary outcome was time to treatment failure. Cox proportional hazards regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline covariates. Results Forty patients started on HD regimens following induction, and 77 patients received the SD regimen. The median time to failure in the HD group was 6.6 years (interquartile range [IQR] 4.0-9.6) and 3.0 years (IQR 0.9-9.4) in the SD group (log-rank test P = 0.006). Patients on HD adalimumab had a lower hazard rate of treatment failure (hazard ratio: 0.27; 95% confidence interval [0.12, 0.62]; P = 0.002) compared with SD patients. No difference in adverse events was identified between groups (30% vs 31.2%, P = 1.0). Results were similar in the propensity score-matched cohort. Conclusions High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.