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Objectives: This study explored the hypothesis that social determinants of health, including racial and economic differences, may impact orthopaedic trauma outcomes in patients undergoing open reduction and internal fixation of humeral shaft fractures., Design: Retrospective., Setting: Single, academic, tertiary level I trauma center., Patient Selection Criteria: Adults with midshaft humerus fractures (Orthopaedic Trauma Association/Association of Osteosynthesis 12) were treated operatively with plate fixation from May 2011 to May 2021 with a minimum follow-up of 9 months., Outcome Measures and Comparisons: Radiographic fracture healing, complication rates, and patient-reported outcomes were investigated. Social determinants of health were assessed using the Area Deprivation Index (ADI). Demographics, complication rates, and patient-reported clinical outcomes were compared between the first and fourth ADI quartiles., Results: One hundred ninety-six patients fit the study criteria. The average age of the cohort was 47 years with 100 women (51%). Comparisons of the least deprived quartile (n = 49) with the most deprived quartile (n = 49) yielded similar sex distribution (59% vs. 43% females, P = 0.15), fewer non-White patients (8% vs. 51%, P < 0.01), older average age (51 vs. 43 years, P = 0.05), similar body mass index (30.5 vs. 31.8, P = 0.45), and higher Charlson Comorbidity Index (2.2 vs. 1.1, P = 0.03). While nonunion rates were similar ( P = 0.20) between groups, the most deprived quartile had 2.3 times greater odds of postoperative complications ( P = 0.04). Patients in the most deprived group exhibited higher Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference scores ( P < 0.01) and PROMIS Depression (D) scores ( P = 0.01), with lower PROMIS Physical Function scores ( P < 0.01) at 6-month follow-up than the least deprived cohort. The most deprived cohort had 3 times higher odds of missing scheduled appointments within the first postoperative year ( P < 0.01), resulting in a significantly higher no-show rate ( P < 0.01) than the least deprived cohort. Regression analysis including several demographic and injury factors identified that ADI was significantly associated with the occurrence of any missed appointments ( P < 0.01), no-show rates ( P = 0.04), and experiencing one of the following postoperative complications during recovery: nonunion, radial nerve injury, or dysfunction ( P = 0.03)., Conclusions: Patients experiencing greater resource deprivation faced increased odds of complications, missed appointments, and poorer PROMIS outcomes following humeral shaft fracture fixation. These findings suggest that baseline socioeconomic disparities predict unfavorable postoperative outcomes even given favorable baseline health status according to the Charlson Comorbidity Index score., Level of Evidence: Prognostic, Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We sought to determine the risk factors for the development of de Quervain tenosynovitis after distal radius fractures. Our hypothesis is that longer periods of immobilization and higher-energy fracture patterns will correlate with the development of de Quervain tenosynovitis., Methods: This is a 10-year retrospective study of 1451 consecutive patients with distal radius fractures presenting to a large academic institution. The incidence and relative risk of de Quervain tenosynovitis within 1 year of sustaining a distal radius fracture were analyzed., Results: In total, 41 patients developed posttraumatic de Quervain tenosynovitis at an average time of 6.5 months. In the operative cohort, the incidence was 2.2%, and that of the nonoperative group was 3.8%. Among all affected patients, 78% admitted to strenuous, overuse activities or careers. Compared with the unaffected cohort, the de Quervain tenosynovitis group was more likely to be female and black with similar age and body mass index. The traumatic cohort was less likely to respond to corticosteroid injections. A separate extensor pollicis brevis (EPB) sheath was noted in all patients requiring surgical release., Conclusions: Patients with a nonoperative distal radius fracture were 4.2 times more likely to develop de Quervain's than the general population, and those treated operatively were 2.4 times more likely. These patients were more likely to be female, black, and engage in strenuous overuse activities or careers. They demonstrated higher-energy fracture patterns and worse response to corticosteroid injections, more frequently requiring surgical decompression. Among those requiring surgery, patients were 2.5 times more likely to have a separate EPB sheath than those with atraumatic Quervain's., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Otolaryngologists play an increasing role in managing cough, but little data exists examining the demographics of this patient population and the referral patterns that influence their access to care. This study sought to elucidate these factors using a longitudinal, nationwide database to minimize sampling bias and identify trends representative of the national population., Study Design: Nationally representative survey., Setting: National Ambulatory Medical Care Survey (NAMCS)., Methods: Visits with a diagnosis and chief complaint of cough between 2005 and 2019 in NAMCS were examined. Univariable and multivariable analyses were performed to compare patient demographics between visits to surgical specialists, medical specialists, and primary care physicians., Results: Otolaryngologists made up more than 84% of surgical specialist visits. There was a 0.52% [0.20%-0.84%] increase per year in the proportion of visits attributed to surgical specialists. Based on a sensitivity analysis of the multivariable model, Hispanic patients (adjusted odds ratio, aOR: 0.88 [0.78-0.99] vs White) and patients living outside of metropolitan areas (aOR: 0.77 [0.61-0.99] vs living within) were less likely to see surgical specialists than primary care doctors for their cough. Patients who were referred (aOR: 1.47 [1.28-1.72] vs not referred) and with chronic cough (aOR: 1.47 [1.23-1.75] vs acute/subacute) were more likely to see a surgical specialist., Conclusion: Otolaryngologists are increasingly called upon to evaluate and consider treatment for cough. Identifying patient groups with limited access underscores the need for enhanced education about otolaryngologists' roles and integrated care approaches to improve access to specialized cough treatment., Level of Evidence: Level 4., (© 2024 The Author(s). Otolaryngology–Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology– Head and Neck Surgery Foundation.)

Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Le Pen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Multiple studies have demonstrated that cancer cells with microsatellite instability (MSI) are intolerant to loss of the Werner syndrome helicase (WRN), whereas microsatellite-stable (MSS) cancer cells are not. Therefore, WRN represents a promising new synthetic lethal target for developing drugs to treat cancers with MSI. Given the uncertainty of how effective inhibitors of WRN activity will prove in clinical trials, and the likelihood of tumours developing resistance to WRN inhibitors, alternative strategies for impeding WRN function are needed. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that target specific proteins for degradation. Here, we engineered the WRN locus so that the gene product is fused to a bromodomain (Bd)-tag, enabling conditional WRN degradation with the AGB-1 PROTAC specific for the Bd-tag. Our data revealed that WRN degradation is highly toxic in MSI but not MSS cell lines. In MSI cells, WRN degradation caused G 2 /M arrest, chromosome breakage and ATM kinase activation. We also describe a multi-colour cell-based platform for facile testing of selective toxicity in MSI versus MSS cell lines. Together, our data show that a degrader approach is a potentially powerful way of targeting WRN in MSI cancers and paves the way for the development of WRN-specific PROTAC compounds., (© 2024. The Author(s).)

The diversity of germ cell developmental strategies has been well documented across many vertebrate clades. However, much of our understanding of avian primordial germ cell (PGC) specification and differentiation has derived from only one species, the chicken (Gallus gallus). Of the three major classes of birds, chickens belong to Galloanserae, representing less than 4% of species, while nearly 95% of extant bird species belong to Neoaves. This represents a significant gap in our knowledge of germ cell development across avian species, hampering efforts to adapt genome editing and reproductive technologies developed in chicken to other birds. We therefore applied single-cell RNA sequencing to investigate inter-species differences in germ cell development between chicken and zebra finch (Taeniopygia castanotis), a Neoaves songbird species and a common model of vocal learning. Analysis of early embryonic male and female gonads revealed the presence of two distinct early germ cell types in zebra finch and only one in chicken. Both germ cell types expressed zebra finch Germline Restricted Chromosome (GRC) genes, present only in songbirds among birds. One of the zebra finch germ cell types expressed the canonical PGC markers, as did chicken, but with expression differences in several signaling pathways and biological processes. The second zebra finch germ cell cluster was marked by proliferation and fate determination markers, indicating beginning of differentiation. Notably, these two zebra finch germ cell populations were present in both male and female zebra finch gonads as early as HH25. Using additional chicken developmental stages, similar germ cell heterogeneity was identified in the more developed gonads of females, but not males. Overall, our study demonstrates a substantial heterochrony in zebra finch germ cell development compared to chicken, indicating a richer diversity of avian germ cell developmental strategies than previously known., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Determine the effect of temporary vocal fold augmentation on refractory chronic cough (RCC) in patients with glottic insufficiency (GI) due to vocal fold atrophy., Methods: Retrospective electronic chart review was conducted for patients with a diagnosis of bilateral vocal fold atrophy and RCC undergoing vocal fold augmentation with carboxymethylcellulose (CMC). Patients with vocal fold immobility were excluded, and cough must have been present for at minimum 8weeks. VHI-10, CSI, and RSI scores along with subjective overall patient report of chronic cough improvement were collected., Results: A total of 28 patients underwent 30 vocal fold augmentation procedures with CMC. All had undergone extensive cough work-up and treatment trials prior to their augmentation procedure. From chart review, 13 overall subjectively reported satisfactory improvement in their cough, 5 reported partial improvement, and 7 reported no improvement in their cough. An uncertain effect on cough was documented in 5 (either patient was uncertain or no mention of cough symptom in the interval chart history note). For those subjects with both pre- and post-augmentation data, mean preaugmentation CSI: 22.08± 6.8 (n = 13); VHI-10: 13.6± 8.9 (n = 18); RSI: 22.4± 7.5 (n = 17). Mean postaugmentation CSI was 20.7± 9.2 (n = 13); VHI-10: 15.2± 8.2 (n = 18); RSI: 21.1± 5.8 (n = 17). Mean pre-post change in CSI was -1.4± 5.1 (P = 0.175, n = 13, range -10 to +6)., Conclusions: Vocal fold augmentation seems to provide subjective cough improvement in some patients with concurrent GI due to vocal fold atrophy and RCC. It can be offered as a diagnostic trial, on which further augmentation may be offered, for patients with persistent cough despite prior work-up and treatment trials. Further controlled prospective studies are needed to identify factors that are predictive of successful cough improvement following vocal fold augmentation, as well as the effect of durable augmentation in those patients who had improvement with a diagnostic trial., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thomas L. Carroll reports a relationship with Pentax Medical, GSK, Ambu that includes: consulting or advisory. Thomas L. Carroll reports a relationship with Sofregen Medical Inc. that includes: board membership. Thomas L. Carroll reports a relationship with N-Zyme Biomedical that includes: consulting or advisory and equity or stocks. Thomas L. Carroll reports a relationship with Plural Publishing that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

The ATR kinase protects cells against DNA damage and replication stress and represents a promising anti-cancer drug target. The ATR inhibitors (ATRi) berzosertib and gartisertib are both in clinical trials for the treatment of advanced solid tumors as monotherapy or in combination with genotoxic agents. We carried out quantitative phospho-proteomic screening for ATR biomarkers that are highly sensitive to berzosertib and gartisertib, using an optimized mass spectrometry pipeline. Screening identified a range of novel ATR-dependent phosphorylation events, which were grouped into three broad classes: (i) targets whose phosphorylation is highly sensitive to ATRi and which could be the next generation of ATR biomarkers; (ii) proteins with known genome maintenance roles not previously known to be regulated by ATR; (iii) novel targets whose cellular roles are unclear. Class iii targets represent candidate DNA damage response proteins and, with this in mind, proteins in this class were subjected to secondary screening for recruitment to DNA damage sites. We show that one of the proteins recruited, SCAF1, interacts with RNAPII in a phospho-dependent manner and recruitment requires PARP activity and interaction with RNAPII. We also show that SCAF1 deficiency partly rescues RAD51 loading in cells lacking the BRCA1 tumor suppressor. Taken together these data reveal potential new ATR biomarkers and new genome maintenance factors., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Shoulder arthroscopy and arthroplasty are increasingly common procedures used to address shoulder pathologies. This study sought to evaluate the incidence of hand-related pathologies, including carpal tunnel syndrome (CTS), cubital tunnel syndrome (CuTS), trigger finger (TF), de Quervain tenosynovitis, and Dupuytren disease following shoulder arthroscopy and arthroplasty procedures. We hypothesized that patients undergoing shoulder surgery would have a higher incidence of hand-related pathologies within 1 year of surgery compared to controls., Methods: This was a retrospective analysis of 12,179 patients who underwent shoulder arthroscopy or arthroplasty surgery that were subsequently diagnosed with CTS, CuTS, TF, de Quervain tenosynovitis, or Dupuytren disease within 1 year after surgery. Relative risk of having associated hand pathologies following shoulder surgery was compared to controls., Results: In total, 10,285 patients underwent shoulder arthroscopy procedures during this period, of whom 815 (7.9%) had an associated hand pathology within 1 year from their shoulder procedure. Arthroscopic surgery was associated with an increased likelihood of having a hand pathology (RR 1.65, 95% CI 1.54-1.76), CTS (RR 1.57, 95% CI 1.42-1.73), CuTS (RR 2.25, 95% CI 1.94-2.61), TF (RR 1.76, 95% CI 1.53-2.03), and Dupuytren disease (RR 2.02, 95% CI 1.54-2.65), but was not associated with a higher likelihood of having de Quervain tenosynovitis. In total, 1,894 patients underwent shoulder arthroplasty procedures during this period, of whom 188 (9.9%) had an associated hand pathology within 1 year. Shoulder arthroplasty was associated with an increased likelihood of having a hand pathology (RR 2.04, 95% CI 1.78-2.34), CTS (RR 2.10, 95% CI 1.72-2.57), CuTS (RR 3.29, 95% CI 2.48-4.39), and TF (RR 1.99, 95% CI 1.47-2.70), but was not associated with an increased likelihood of having de Quervain tenosynovitis or Dupuytren disease., Conclusions: Shoulder arthroscopy and arthroplasty procedures were associated with an increased likelihood of having a CTS, CuTS, or a TF diagnosis made within 1 year of surgery. Only shoulder arthroscopy procedures were associated with a higher likelihood of having Dupuytren disease. Neither shoulder arthroscopy nor arthroplasty procedures were associated with an increased likelihood of a diagnosis of de Quervain tenosynovitis. These associations, however, do not necessarily imply causation, and further investigation is warranted to delineate this relationship., Type of Study/level of Evidence: Differential Diagnosis/Symptom Prevalence Study Level 3., Competing Interests: No benefits in any form have been received or will be received related directly to this article., (© 2024 The Authors.)

Biallelic pathogenic variants in the essential DNA repair gene BRCA2 causes Fanconi anemia, complementation group FA-D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under SHH activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown. To identify such lesions, we assessed both GCP neurodevelopment and tumor formation using a mouse model with deletion of exons three and four of Brca2 in the central nervous system, coupled with global Trp53 loss. Brca2 Δex3-4 ;Trp53 -/- animals developed SHH subgroup medulloblastomas with complete penetrance. Whole-genome sequencing of the tumors identified structural variants with breakpoints enriched in areas overlapping G-quadruplexes (G4s). Brca2 -deficient GCPs exhibited decreased replication speed in the presence of the G4-stabilizer pyridostatin. Pif1 helicase, which resolves G4s during replication, was highly upregulated in tumors, and Pif1 knockout in primary MB tumor cells resulted in increased genome instability upon pyridostatin treatment. These data suggest that G4s may represent sites prone to replication stalling in highly proliferative GCPs and without BRCA2, G4s become a source of genome instability. Tumor cells upregulate G4-resolving helicases to facilitate rapid proliferation through G4s highlighting PIF1 helicase as a potential therapeutic target for treatment of BRCA2 -deficient medulloblastomas., Competing Interests: Competing Interest Statement A.S. is an advisor to Rocket Pharmaceuticals. Other authors have declared that no conflict of interest exists.

Branched ubiquitin (Ub) chains constitute a sizable fraction of Ub polymers in human cells. Despite their abundance, our understanding of branched Ub function in cell signaling has been stunted by the absence of accessible methods and tools. Here we identify cellular branched-chain-specific binding proteins and devise approaches to probe K48-K63-branched Ub function. We establish a method to monitor cleavage of linkages within complex Ub chains and unveil ATXN3 and MINDY as debranching enzymes. We engineer a K48-K63 branch-specific nanobody and reveal the molecular basis of its specificity in crystal structures of nanobody-branched Ub chain complexes. Using this nanobody, we detect increased K48-K63-Ub branching following valosin-containing protein (VCP)/p97 inhibition and after DNA damage. Together with our discovery that multiple VCP/p97-associated proteins bind to or debranch K48-K63-linked Ub, these results suggest a function for K48-K63-branched chains in VCP/p97-related processes., (© 2024. The Author(s).)

Background: Serious illness conversations may help patients avoid unwanted treatments. We previously piloted the telehealth Serious Illness Care Program (SICP) for older adults with acute myeloid leukemia and myelodysplastic syndrome., Objective: In this study, we aimed to understand the experience of the telehealth SICP from the clinician's perspective., Methods: We studied 10 clinicians who delivered the telehealth SICP to 20 older adults with acute myeloid leukemia or myelodysplastic syndrome. Quantitative outcomes included confidence and acceptability. Confidence was measured using a 22-item survey (range 1-7; a higher score is better). Acceptability was measured using an 11-item survey (5-point Likert scale). Hypothesis testing was performed at α=.10 (2-tailed) due to the pilot nature and small sample size. Clinicians participated in audio-recorded qualitative interviews at the end of the study to discuss their experience., Results: A total of 8 clinicians completed the confidence measure and 7 clinicians completed the acceptability measure. We found a statistically significant increase in overall confidence (mean increase of 0.5, SD 0.6; P=.03). The largest increase in confidence was in helping families with reconciliation and goodbye (mean 1.4, SD 1.5; P=.04). The majority of clinicians agreed that the format was simple (6/7, 86%) and easy to use (6/7, 86%). Clinicians felt that the telehealth SICP was effective in understanding their patients' values about end-of-life care (7/7, 100%). A total of three qualitative themes emerged: (1) the telehealth SICP deepened relationships and renewed trust; (2) each telehealth SICP visit felt unique and personal in a positive way; and (3) uninterrupted, unrushed time optimized the visit experience., Conclusions: The telehealth SICP increased confidence in having serious illness conversations while deepening patient-clinician relationships., Trial Registration: ClinicalTrials.gov NCT04745676; https://www.clinicaltrials.gov/study/NCT04745676., (©Marissa LoCastro, Ying Wang, Tristan Yu, Soroush Mortaz-Hedjri, Jason Mendler, Sally Norton, Rachelle Bernacki, Thomas Carroll, Heidi Klepin, Lucy Wedow, Sean Goonan, Hannah Erdos, Brenda Bagnato, Jane Liesveld, Eric Huselton, Benzi Kluger, Kah Poh Loh. Originally published in JMIR Formative Research (https://formative.jmir.org), 27.06.2024.)

Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupt broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss leads to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrate impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype., (© 2024. The Author(s).)

The formation of functional epithelial tubules is a central feature of many organ systems. Although the process of tubule formation by epithelial cells is well-studied, the way in which tubules connect with each other (i.e. anastomose) to form functional networks both in vivo and in vitro is not well understood. A key, unanswered question in the kidney is how the renal vesicles of the embryonic kidney connect with the nascent collecting ducts to form a continuous urinary system. We performed a ligand-receptor pair analysis on single cell RNA-seq data from embryonic mouse kidney tubules undergoing anastomosis to select candidates that might mediate this process in vivo . This analysis identified hepatocyte growth factor (HGF), which has known roles in cell proliferation, migration, and tubulogenesis, as one of several possible candidates. To test this possibility, we designed a novel assay to quantitatively examine epithelial tubule anastomosis in vitro using epithelial spheroids with fluorescently-tagged apical surfaces to enable direct visualization of anastomosis. This revealed that HGF is a potent inducer of tubule anastomosis. Tubule anastomosis occurs through a proliferation-independent mechanism that acts through the MAPK signaling cascade and matrix metalloproteinases (MMPs), the latter suggestive of a role in extracellular matrix turnover. Accordingly, treatment of explanted embryonic mouse kidneys with HGF and collagenase was sufficient to induce kidney tubule anastomosis. These results lay the groundwork for investigating how to promote functional interconnections between tubular epithelia, which have important clinical implications for utilizing in vitro grown kidney tissue in transplant medicine., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Objectives: To test the hypothesis that primary osteosynthesis of humeral shaft fractures may lead to more favorable clinical, functional, and patient-reported outcomes than fixation following a trial of nonoperative management., Design: Retrospective cohort review., Setting: Academic level I trauma center., Patient Selection Criteria: Adult patients who presented with humeral shaft fractures and ultimately underwent open reduction and internal fixation (ORIF) from May 2011 to May 2021. Patients who underwent ORIF within 2 weeks of injury were grouped into the primary osteosynthesis cohort, and patients who underwent ORIF >4 weeks from the date of injury were grouped into the trial of nonoperative cohort., Outcome Measures and Comparisons: Postoperative complications, elbow arc of motion, time to radiographic union, and patient-reported outcomes were investigated and compared between the primary osteosynthesis and trial of nonoperative management cohorts., Results: One hundred twenty-seven patients fit the study criteria, 84 underwent primary osteosynthesis and 43 trialed initial nonoperative treatment. No differences were found in patient demographics between the primary osteosynthesis and trial of nonoperative management cohorts, including age (53 ± 19 vs. 57 ± 18; P = 0.25), sex (39% vs. 44% male, 61% vs. 56% female; P = 0.70), and Body Mass Index (BMI) (30 ± 6 vs. 32 ± 9; P = 0.38). The average time to operative intervention in the primary osteosynthesis group was 4 days (0-14 days) and 105 days (28-332 days) in the trial of nonoperative treatment group ( P < 0.01). No differences were found with regard to intraoperative blood loss, total operative time, time to radiographic union (determined using the Radiographic Union Scores for Humeral scoring system), or overall complication rates, including primary and secondary radial nerve injuries ( P = 0.23 and 0.86, respectively). Patients reported similar patient-reported outcomes measurement information system pain interference ( P = 0.73), depression (D) ( P = 0.99), and physical function ( P = 0.66) scores at their 6-month postsurgical follow-up visits., Conclusions: Patients who attempted a trial of nonoperative management for humeral shaft fractures before ORIF had similar clinical, functional, and patient-reported outcomes as those who underwent primary osteosynthesis., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Alterations in the tumor suppressor ATRX are recurrently observed in mesenchymal neoplasms. ATRX has multiple epigenetic functions including heterochromatin formation and maintenance and regulation of transcription through modulation of chromatin accessibility. Here, we show in murine mesenchymal progenitor cells (MPCs) that Atrx deficiency aberrantly activated mesenchymal differentiation programs. This includes adipogenic pathways where ATRX loss induced expression of adipogenic transcription factors and enhanced adipogenic differentiation in response to differentiation stimuli. These changes are linked to loss of heterochromatin near mesenchymal lineage genes together with increased chromatin accessibility and gains of active chromatin marks. We additionally observed depletion of H3K9me3 at transposable elements, which are derepressed including near mesenchymal genes where they could serve as regulatory elements. Finally, we demonstrated that loss of ATRX in a mesenchymal malignancy, undifferentiated pleomorphic sarcoma, results in similar epigenetic disruption and de-repression of transposable elements. Together, our results reveal a role for ATRX in maintaining epigenetic states and transcriptional repression in mesenchymal progenitors and tumor cells and in preventing aberrant differentiation in the progenitor context., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: Chatbot Generative Pre-trained Transformer (ChatGPT) is an artificial intelligence-powered language model chatbot able to help otolaryngologists in practice and research. The ability of ChatGPT in generating patient-centered information related to laryngopharyngeal reflux disease (LPRD) was evaluated., Methods: Twenty-five questions dedicated to definition, clinical presentation, diagnosis, and treatment of LPRD were developed from the Dubai definition and management of LPRD consensus and recent reviews. Questions about the four aforementioned categories were entered into ChatGPT-4. Four board-certified laryngologists evaluated the accuracy of ChatGPT-4 with a 5-point Likert scale. Interrater reliability was evaluated., Results: The mean scores (SD) of ChatGPT-4 answers for definition, clinical presentation, additional examination, and treatments were 4.13 (0.52), 4.50 (0.72), 3.75 (0.61), and 4.18 (0.47), respectively. Experts reported high interrater reliability for sub-scores (ICC = 0.973). The lowest performances of ChatGPT-4 were on answers about the most prevalent LPR signs, the most reliable objective tool for the diagnosis (hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring (HEMII-pH)), and the criteria for the diagnosis of LPR using HEMII-pH., Conclusion: ChatGPT-4 may provide adequate information on the definition of LPR, differences compared to GERD (gastroesophageal reflux disease), and clinical presentation. Information provided upon extra-laryngeal manifestations and HEMII-pH may need further optimization. Regarding the recent trends identifying increasing patient use of internet sources for self-education, the findings of the present study may help draw attention to ChatGPT-4's accuracy on the topic of LPR., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The objective of this work was to gather an international consensus group to propose a global definition and diagnostic approach of laryngopharyngeal reflux (LPR) to guide primary care and specialist physicians in the management of LPR., Methods: Forty-eight international experts (otolaryngologists, gastroenterologists, surgeons, and physiologists) were included in a modified Delphi process to revise 48 statements about definition, clinical presentation, and diagnostic approaches to LPR. Three voting rounds determined a consensus statement to be acceptable when 80% of experts agreed with a rating of at least 8/10. Votes were anonymous and the analyses of voting rounds were performed by an independent statistician., Results: After the third round, 79.2% of statements (N = 38/48) were approved. LPR was defined as a disease of the upper aerodigestive tract resulting from the direct and/or indirect effects of gastroduodenal content reflux, inducing morphological and/or neurological changes in the upper aerodigestive tract. LPR is associated with recognized non-specific laryngeal and extra-laryngeal symptoms and signs that can be evaluated with validated patient-reported outcome questionnaires and clinical instruments. The hypopharyngeal-esophageal multichannel intraluminal impedance-pH testing can suggest the diagnosis of LPR when there is >1 acid, weakly acid or nonacid hypopharyngeal reflux event in 24 h., Conclusion: A global consensus definition for LPR is presented to improve detection and diagnosis of the disease for otolaryngologists, pulmonologists, gastroenterologists, surgeons, and primary care practitioners. The approved statements are offered to improve collaborative research by adopting common and validated diagnostic approaches to LPR., Level of Evidence: 5 Laryngoscope, 134:1614-1624, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Post-translational modifications (PTMs) on histones are a key source of regulation on chromatin through impacting cellular processes, including gene expression 1 . These PTMs often arise from metabolites and are thus impacted by metabolism and environmental cues 2-7 . One class of metabolically regulated PTMs are histone acylations, which include histone acetylation, butyrylation, crotonylation and propionylation 3,8 . As these PTMs can be derived from short-chain fatty acids, which are generated by the commensal microbiota in the intestinal lumen 9-11 , we aimed to define how microbes impact the host intestinal chromatin landscape, mainly in female mice. Here we show that in addition to acetylation, intestinal epithelial cells from the caecum and distal mouse intestine also harbour high levels of butyrylation and propionylation on lysines 9 and 27 of histone H3. We demonstrate that these acylations are regulated by the microbiota and that histone butyrylation is additionally regulated by the metabolite tributyrin. Tributyrin-regulated gene programmes are correlated with histone butyrylation, which is associated with active gene-regulatory elements and levels of gene expression. Together, our study uncovers a regulatory layer of how the microbiota and metabolites influence the intestinal epithelium through chromatin, demonstrating a physiological setting in which histone acylations are dynamically regulated and associated with gene regulation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: The purpose of this study is to evaluate the outcomes of operatively treated Mason Type III radial head fractures. Additionally, this project seeks to assess efficacy of PROMIS in evaluating post-operative outcomes for this patient population., Methods: A total of 143 patients who underwent operative treated Mason Type III radial head fractures were analyzed retrospectively. PROMIS physical function (PF), PROMIS upper extremity (UE), PROMIS pain interference (PI), demographic variables, and range of motion were collected and analyzed over 12-month follow-up., Results: Radial head arthroplasty (RHA) was performed on 89 patients, open reduction and internal fixation (ORIF) was performed on 47 patients, and radial head excision was performed on 7 patients. Among the RHA patients, PROMIS PF, PI and UE demonstrated a change of -1.33 (p < 0.05), -1.48 (p < 0.05), and 2.23 (p < 0.05) respectively from injury to 12-months. Among the ORIF patients, PROMIS PF, PI and UE demonstrated a change of 3.22 (p < 0.05), -1.56 (p < 0.05), and 2.09 (p < 0.05) respectively from injury to 12-months. At the pre-operative and 12-month visits, the RHA group demonstrated lower PROMIS PF scores 34.75 vs 38.02 (p < 0.05) and 33.42 vs 41.24 (p < 0.05) respectively. Ther was no difference in PROMIS PI, UE, or elbow range of motion between the two groups at 6- or 12-month follow-up (p > 0.05)., Conclusion: Comparing the RHA and ORIF groups, there was no difference in PROMIS PI or UE scores nor was there a clinically significant improvement at the 6- or 12-month mark. The ORIF group demonstrated improved PROMIS PF at all follow-up periods and did show a clinically significant improvement. Patient Acceptable Symptom State (PASS) correlated only with PROMIS UE at 6- and 12- months for both groups., (© 2024 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Purpose: Carpal tunnel syndrome is the most common peripheral nerve compressive neuropathy in clinical practice. Patients who fail nonsurgical management are indicated for carpal tunnel release (CTR), which can be performed open or endoscopically. Efforts have been made to utilize local anesthesia instead of monitored anesthesia care (MAC) for endoscopic release. This study seeks to compare perioperative surgical times and postoperative outcomes in patients undergoing endoscopic CTR with local anesthesia versus MAC., Methods: This is a 6-year retrospective study of 1,036 patients undergoing isolated endoscopic CTR with MAC (n = 607) versus local (n = 429) anesthesia within an outpatient surgical center. A combination of chi-square and t tests was used to compare the patient characteristics, operative details, and outcomes., Results: The local cohort demonstrated significantly shorter postoperative time to discharge (15.9 ± 9.8 vs 53.8 ± 11.0 minutes; P < .05), total time spent in surgical center (83.2 ± 18.7 vs 129.3 ± 20.7 minutes; P < .05), shorter total operating room time (26.7 ± 4.3 vs 29.0 ± 4.1 minutes; P < .05) and tourniquet time (12.4 ± 2.5 vs 13.1 ± 2.1 minutes; P < .05). Preoperative and postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) scores were similar between the cohorts ( P > .05); however, PROMIS pain interference improved to a higher degree between pre- and post-op in the local group (-1.5 vs -0.8; P  = .02). Early and late surgical complications were similar between the groups ( P > .05)., Conclusions: Patients within the MAC cohort demonstrated longer postoperative time to discharge and total time in the surgical center. The MAC cohort had longer operating room and tourniquet time, albeit not clinically significant. Surgical complications and PROMIS scores were similar between the two groups. Our findings suggest that local anesthesia is a safe and effective option for endoscopic CTR and may offer advantages in cost and convenience for patients., Type of Study/level of Evidence: Retrospective cohort study/therapeutic III., Competing Interests: No benefits in any form have been received or will be received related directly to this article., (© 2024 The Authors.)

Objectives: Silk-hyaluronic acid (silk-HA) is a novel vocal fold augmentation material used in humans since July 2020. We aim to describe indications, voice outcomes, and longevity data for silk-HA injectable when used for vocal fold injection (VFI) augmentation in a large cohort of patients with longer-term follow-up than preliminary clinical studies., Methods: Retrospective chart review of Silk-HA injections for glottic insufficiency (GI) and follow-up between July 2020 and November 2023. Subject demographics, diagnoses, volume of material injected, VHI-10 data, time from injection, need for reinjection, and complications were collected. Blinded perceptual voice analysis of randomly selected pre- and post-intervention voice samples for unilateral vocal fold paralysis patients was performed by three voice-specialized speech-language pathologists, and changes in VHI-10 determined at various time intervals up to 1year and beyond., Results: A total of 160 silk-HA injection procedures were performed: 59% female, with a mean age of 66± 13 (range 21-90) years. Ninety-four subjects had unilateral paralysis (58.4%); the remainder had scar, atrophy, paresis, or a combination thereof. Mean volume of silk-HA injected was 0.24± 0.14 cc. Major complications were rare, most notable for laryngoscopic evidence of hemilaryngeal edema (n = 6, 3.8%), with a readmission rate to hospital of 1.3% (n = 2). There was a statistically significant decrease in paired ΔVHI-10 and CAPE-V ratings for each of the postoperative follow-up intervals. A total of 24 (27.2%) repeat medialization procedures were recommended following silk-HA injection for unilateral paralysis., Conclusions: This study demonstrates that silk-HA is a safe product for VFI augmentation, and effective injectable for the treatment of GI due to unilateral vocal fold paralysis. Based on the current data, it is reasonable to counsel patients that they should expect benefit for several months following the injection. If patients reach 1year from their injection with a stable and satisfactory outcome, the majority experience ongoing benefit without need for additional procedures, however, the final duration of clinical effect appears to be years, but it is yet to be determined., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

The properties of the cell types that are selectively vulnerable in Huntington's disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here, we employed serial fluorescence-activated nuclear sorting (sFANS), deep molecular profiling, and single-nucleus RNA sequencing (snRNA-seq) of motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors and selected samples from cingulate, visual, insular, and prefrontal cortices to demonstrate loss of layer 5a pyramidal neurons in HD. Extensive mHTT CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layers 6a and 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Distal radius fractures with severely osteoporotic bone or articular comminution can provide challenges to fixation with traditional volar locked plating alone. The purpose of this study was to evaluate the clinical, radiographic, and patient reported outcomes of patients undergoing distal radius fixation with volar locked plating and adjunctive dorsal bridge plating., Methods: We retrospectively identified 16 patients with distal radius fractures who underwent our preferred surgical technique for fixation. Patients underwent volar locked plate fixation as well as dorsal bridge fixation at time of surgery. Seven patients were indicated for severe articular comminution with volar rim fragmentation (44%), three patients were revised for nonunion after previous volar locked late fixation (19%), and six patients had severely osteoporotic bone with articular comminution (38%). Two patients (13%) sustained AO/OTA 23-A3 distal radius fracture, two patients (13%) had a 23-B3 fracture, two patients (13%) had a 23-C2 fracture and ten patients (63%) had a 23-C3 fracture., Results: The average patient age was 51.8 years ± 20.6. Patients were followed for an average of 12.2±6.3 months. The dorsal bridge plate was removed at an average of 11.1±2.4 weeks. The average post-operative radial inclination was 18.9±2.4°, radial height 12.4 mm ± 2.6 mm, and volar tilt 7.1±1.9°. There were no cases of deep or superficial infection. After dorsal bridge plate removal, patients demonstrated an average wrist extension of 55.3±9.5°, flexion 54.4±12.8°, radial deviation 15.7±3.2°, 25.2±3.9 degrees of ulnar deviation., Conclusion: Distal radius fractures in the setting of severely osteoporotic bone, salvage procedures, articular comminution, volar rim fractures, and revision surgery present uniquely difficult surgical challenges. Volar locked plating with adjunctive dorsal bridge plating can be used with good short- and long-term results., (© 2024 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

DNA replication through a challenging genomic landscape is coordinated by the replisome, which must adjust to local conditions to provide appropriate replication speed and respond to lesions that hinder its progression. We have previously shown that proteasome shuttle proteins, DNA Damage Inducible 1 and 2 (DDI1/2), regulate Replication Termination Factor 2 (RTF2) levels at stalled replisomes, allowing fork stabilization and restart. Here, we show that during unperturbed replication, RTF2 regulates replisome localization of RNase H2, a heterotrimeric enzyme that removes RNA from RNA-DNA heteroduplexes. RTF2, like RNase H2, is essential for mammalian development and maintains normal replication speed. However, persistent RTF2 and RNase H2 at stalled replication forks prevent efficient replication restart, which is dependent on PRIM1, the primase component of DNA polymerase α-primase. Our data show a fundamental need for RTF2-dependent regulation of replication-coupled ribonucleotide removal and reveal the existence of PRIM1-mediated direct replication restart in mammalian cells., (© 2024. The Author(s).)

Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington's disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity., (© 2024. The Author(s).)

Objectives: To analyze pre to posttreatment voice changes regarding the type of reflux in patients with acid, weakly acid or alkaline laryngopharyngeal reflux (LPR)., Methods: Patients with LPR, diagnosed using hypopharyngeal-esophageal multichannel intraluminal impedance pH-monitoring (HEMII-pH), were prospectively recruited from three University Hospitals. Patients were treated with a combination of diet, proton pump inhibitors, magaldrate and alginate for 3 months. The following clinical and voice quality outcomes were studied pre to posttreatment according to the type of reflux (acid, weakly acid, nonacid): HEMII-pH, gastrointestinal endoscopy features, reflux symptom score (RSS), reflux sign assessment (RSA), voice handicap index (VHI), perceptual voice assessment (grade of dysphonia and roughness), aerodynamic and acoustic measurements., Results: From December 2018 to March 2021, 160 patients completed the evaluations, accounting for 60 acid, 52 weakly acid, and 48 alkaline cases of LPR. There were no baseline differences in clinical and voice quality outcomes between groups. RSS and RSA significantly improved from pre to posttreatment in the entire cohort and in all patient groups. VHI, dysphonia and roughness, maximum phonation time, Jitter, Shimmer and noise to harmonic ratio significantly improved from pre to posttreatment. Individuals with alkaline reflux reported better voice quality improvements as compared to acid and weakly acid reflux patients., Conclusion: Patients with acid and alkaline reflux reported better posttreatment voice quality outcomes as compared to weakly acid reflux patients. Future basic science and clinical studies are needed to better understand the histological changes of the vocal folds due to reflux of varying pH types and gastroduodenal enzyme content., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research.

Objective: The aim of this study was to compare the efficacy of voice therapy combined with standard anti-reflux therapy in reducing symptoms and signs of laryngopharyngeal reflux (LPR)., Methods: A randomised clinical trial was conducted. Fifty-two patients with LPR diagnosed by 24 h multichannel intraluminal impedance-pH monitoring were randomly allocated in two groups: medical treatment (MT) and medical plus voice therapy (VT). Clinical symptoms and laryngeal signs were assessed at baseline and after 3 months of treatment with the Reflux Symptom Index (RSI), Reflux Finding Score (RFS), Voice Handicap Index (VHI) and GRBAS scales., Results: Groups had similar scores at baseline. At 3-month follow-up, a significant decrease in RSI and RFS total scores were found in both groups although it appeared to be more robust in the VT group. G and R scores of the GRBAS scale significantly improved after treatment in both groups, with better results in the VT group. The VHI total score at 3 months improved more in the VT group (VHI delta 9.54) than in the MT group (VHI delta 5.38) (p < 0.001)., Conclusions: The addition of voice therapy to medications and diet appears to be more effective in improving treatment outcomes in subjects with LPR. Voice therapy warrants consideration in addition to medication and diet when treating patients with LPR., (Copyright © 2024 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

Clinicians need palliative care (PC) skills to provide good patient care. Primary PC (PPC) is the PC knowledge and skills provided by non-PC specialists and are distinct from specialist PC (SPC), the complex interventions provided by specialty trained clinicians. There is no consensus as to the specific PPC knowledge and skills that should be taught or the methods that should be used. We describe an educational system that incorporates a suite of tools that PC educators can easily adapt to the PC educational requests of training programs to evaluate the PPC educational needs of training programs and then to create customized educational programs that regularly adjusts to the input of trainees and faculty. We hope others can use this program to decrease the burden on the PC educators and provide a tailored PPC education program for training programs within their institutions., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Coronal Plane Alignment of the Knee (CPAK), is an informative way to classify native knee alignment types, but does not consider posterior tibial slope, an important variable in knee kinematics. We hypothesized that tibial slope would have a significant effect on knee kinematics and warrant consideration in addition to the CPAK system., Methods: We examined 335 adult patients with osteoarthritis receiving total knee arthroplasty. We measured the lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), and posterior tibial slope angle (PTS). Knees were categorized into CPAK classes and subdivided into types 'A' (PTS 8°) or 'B' (PTS >8°). We recorded pre-and-post operative knee flexion, and extension/flexion gaps in all subjects., Results: CPAK classes VII-IX were not seen. Classes I and II comprised a plurality of all knees. One-third of all knees were type B. CPAK classes III, IV, and VI had greater type B proportions, but this was not statistically significant. Type B knees had greater flexion both pre-op ( p < .001 ) and post-op ( p = .043 ); type A knees had greater flexion improvement pre-to-post operatively ( p = .045 ). Type A knees had greater medial and lateral flexion-extension gap change pre-operatively ( p = .021 ) and ( p = .027 ), respectively. Type B knees had greater medial-lateral gap imbalance preoperatively in both flexion and extension., Discussion/conclusion: Our results suggest that there are important pre and post-operative differences in medial and lateral femorotibial gap balance between type A and B knees that require consideration for intra-operative balancing. Differences in knee flexion further solidify that PTS is an important variable that affects kinematics before and after TKA. We propose the addition of PTS types A and B to the existing CPAK classes. This is an easy and logical way to create a comprehensive classification system in both coronal and sagittal planes that captures further differences in knee kinematics., Competing Interests: ZM, JC, MB, and TC have no interests to declare. CD has taken consulting fees from Klick Health, honoraria from Depuy Synthes, and fees for expert testimony from Smith Sovik Kendrick & Sugnet PC within the last 36 months; they have no disclosures from the time period that this study was conducted., (© 2024 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Biophysical factors, including changes in mechanical stiffness, have been shown to influence the morphogenesis of developing organs. There is a lack of experimental techniques, however, that can probe the mechanical properties of embryonic tissues-especially those which are not mechanically or optically accessible, such as the visceral organs of the developing mouse embryo. Here, using the embryonic kidney as a model system, we describe a method to use microindentation to quantify tissue-level regional differences in the mechanical properties of an embryonic organ. This technique is generalizable and can be used to quantify patterns of tissue stiffness within other developing organ systems. Going forward, these data will enable new experimental studies of the role of biophysical cues during organogenesis., (© 2024. The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Distal radius fractures (DRFs) indicated for operative intervention are most commonly treated with volar-locked plating (VLP); however, dorsal bridge plating (DBP) has been used as an alternative fixation method. The purpose of this study was to use a propensity score to match and compare the radiographic and clinical outcomes of patients undergoing isolated VLP or DBP for DRFs., Methods: We performed a retrospective, propensity score-matched analysis of patients undergoing isolated VLP or DBP treatment for isolated DRFs from 2015 to 2022 at a single level-1 trauma center. Patients were propensity score-matched by a total of eight demographic and comorbidity factors, AO Foundation/Orthopedic Trauma Association classification, and preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) scores. Our primary outcomes included postoperative complications, wrist and forearm range of motion (ROM), grip strength, and radiographic measurements, including radial height, radial inclination, volar tilt, and articular step-off., Results: Overall, 415 DBP and 2075 VLP were successfully propensity score-matched and included in this study. Grip strength and ROM measurements at the 6-month follow-up, including wrist flexion, wrist extension, forearm pronation, forearm supination, radial deviation, and ulnar deviation, were increased in the VLP compared with DBP ( P < .05). Complication rates among both the groups were relatively low; however, the rates of malunion and nonunion were significantly higher among the DBP group ( P < .05). Radial height, radial inclination, and articular step-off were improved in the VLP group compared with the DBP group ( P < .05); however, volar tilt was similar between groups. PROMIS upper extremity and physical function were significantly higher among the VLP group ( P < .05). No significant difference was noted in PROMIS pain interference between the groups., Conclusions: When compared with DBP, patients undergoing VLP are more likely to have improved clinical and radiographic outcomes. Although improvement in wrist and forearm ROM and radiographic parameters is statistically significant, it may not be clinically relevant., Type of Study/level of Evidence: Therapeutic III., (© 2023 The Authors.)

Abstract: Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) feel shocked and bewildered when diagnosed. Serious illness conversations (SICs) may increase disease understanding and preparations for the future. However, SICs often happen late, in part because of clinician-perceived patient discomfort. Telehealth may promote patient comfort by allowing SICs to take place at home. This study assesses the feasibility and usability of a telehealth-delivered Serious Illness Care Program (SICP) for older adults with AML and MDS. We conducted a single-arm pilot study including 20 older adults with AML and MDS. Feasibility was measured using retention rate, with >80% considered feasible. Usability was measured using telehealth usability questionnaire (TUQ; range, 1-7): >5 considered usable. We collected other outcomes including acceptability and disease understanding and conducted post-visit qualitative interviews to elicit feedback. Hypothesis testing was performed at α = 0.10 owing to the pilot nature and small sample size. Retention rate was 95% (19/20); mean TUQ scores were 5.9 (standard deviation [SD], 0.9) and 5.9 (SD, 1.1) for patients and caregivers, respectively. We found the SICP to be acceptable. The majority of patients found the SICP to be very or extremely worthwhile (88.2%; 15/17), and reported it increased closeness with their clinician (75.0%; 12/16). After their visit, patient estimates of curability, and overall life expectancy aligned more closely with those of their clinicians. In qualitative interviews, most patients said that they would recommend this program to others (89.5%, 17/19). This study demonstrated that delivery of the telehealth SICP to older patients with AML and MDS is feasible, usable, and acceptable. This trial is registered at www.clinicaltrials.gov as #NCT04745676., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Insects and mammals have independently evolved odorant receptor genes that are arranged in large genomic tandem arrays. In mammals, each olfactory sensory neuron chooses to express a single receptor in a stochastic process that includes substantial chromatin rearrangements. Here, we show that ants, which have the largest odorant receptor repertoires among insects, employ a different mechanism to regulate gene expression from tandem arrays. Using single-nucleus RNA sequencing, we found that ant olfactory sensory neurons choose different transcription start sites along an array but then produce mRNA from many downstream genes. This can result in transcripts from dozens of receptors being present in a single nucleus. Such rampant receptor co-expression at first seems difficult to reconcile with the narrow tuning of the ant olfactory system. However, RNA fluorescence in situ hybridization showed that only mRNA from the most upstream transcribed odorant receptor seems to reach the cytoplasm where it can be translated into protein, whereas mRNA from downstream receptors gets sequestered in the nucleus. This implies that, despite the extensive co-expression of odorant receptor genes, each olfactory sensory neuron ultimately only produces one or very few functional receptors. Evolution has thus found different molecular solutions in insects and mammals to the convergent challenge of selecting small subsets of receptors from large odorant receptor repertoires., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Given the relatively high false negative rate of electrodiagnostic studies (EDX) in patients with clinically diagnosed ulnar neuropathy at the elbow (UNE), we sought to determine whether an alternative objective test could more effectively detect UNE. Additionally, we proposed to determine the relationship between the cross-sectional area (CSA) of the ulnar nerve on ultrasound (US), EDX, and clinical symptoms., Methods: This was a retrospective study of patients presenting with symptomatic UNE. The performance characteristics of EDX versus ultrasound were calculated using the clinical diagnosis of UNE as the reference standard. Standard EDX studies and US of the ulnar nerve were analyzed. Maximal CSA of the ulnar nerve and EDX severity were analyzed for patients with each combination of US-positive/negative and EDX-positive/negative findings., Results: Analysis was performed on 89 patients and 115 nerves with signs and symptoms of cubital tunnel syndrome. In total, 56 (49%) nerves were diagnosed as mild UNE, 32 (28%) nerves were diagnosed as moderate UNE, 17 (15%) nerves were diagnosed as severe UNE, and 10 (8%) nerves were negative for UNE by EDX. Maximal-maximal CSA was highly correlated with disease severity as determined by nerve conduction studies/electromyography. Compared with EDX+/US+, patients with EDX-/US+ showed higher rates of ulnar sensory loss and elbow tenderness with similar rates of positive Tinel and intrinsic muscle atrophy. In this sample of patients with clinically diagnosed UNE, 91.3% of the patients demonstrated positive EDX studies, whereas 94.8% had a positive US., Conclusions: Ultrasound is an alternative to EDX that could be incorporated clinically in the diagnosis and management of UNE. Ultrasound was able to consistently detect clinically positive cubital tunnel syndrome demonstrating its utility as a confirmatory or supplemental test to the clinical assessment if one is required. Ultrasound additionally may be able to better identify patients with early stages of UNE with negative EDX findings., Type of Study/level of Evidence: Diagnostic IV., (Copyright © 2023 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess: (1) the Eating Assessment Tool (EAT-10) with item response theory (IRT) to determine which individual items provide the most information, (2) the extent to which dysphagia is measured with subsets of items while maintaining precise score estimates, and (3) if 5-item scales have the differing discriminatory ability, as compared to the parent 10-item instrument., Methods: Prospectively collected data from 2,339 patients who completed the EAT-10 questionnaire during evaluation at a tertiary care otolaryngology clinic were utilized. IRT analyses provided discrimination and location parameters associated with individual questions. Residual item correlations were also assessed for redundant information. Based on these results, three 5-item subsets were further evaluated using item information function curves. Areas under receiver-operator characteristic curves (ROC-AUC) were also calculated to evaluate the discriminatory ability for dysphagia-related clinical diagnoses., Results: Item discrimination parameter estimates ranged from 1.71 to 5.46, with higher values indicating more information. Residual item correlations were determined within item pairs, and location parameters were calculated. Based on these data, in combination with clinical utility, three 5-item subsets were proposed and assessed. ROC-AUC analyses demonstrated no significant difference between the EAT-5-Alpha subset and the original 10-item instrument for discriminating dysphagia as a primary diagnosis (0.88, 0.88). The EAT-5-Clinical subset outperformed the original 10 instruments in ROC-AUC for aspiration. The EAT-5-Range subset was significantly associated with problems with thin liquids., Conclusions: IRT analyses distinguished three proposed 5-item subsets of the EAT-10 instrument, supporting shorter survey options, while still reflecting the impact of dysphagia without significant loss of discrimination., Level of Evidence: 3 (Diagnostic testing with consistently applied reference standards, partial blinding). Laryngoscope, 133:3327-3333, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

The kidney vasculature has a complex architecture that is essential for renal function. The molecular mechanisms that direct development of kidney blood vessels are poorly characterized. We identified a regionally restricted, stroma-derived signaling molecule, netrin 1 (Ntn1), as a regulator of renal vascular patterning in mice. Stromal progenitor (SP)-specific ablation of Ntn1 (Ntn1SPKO) resulted in smaller kidneys with fewer glomeruli, as well as profound defects of the renal artery and transient blood flow disruption. Notably, Ntn1 ablation resulted in loss of arterial vascular smooth muscle cell (vSMC) coverage and in ectopic SMC deposition at the kidney surface. This was accompanied by dramatic reduction of arterial tree branching that perdured postnatally. Transcriptomic analysis of Ntn1SPKO kidneys revealed dysregulation of vSMC differentiation, including downregulation of Klf4, which we find expressed in a subset of SPs. Stromal Klf4 deletion similarly resulted in decreased smooth muscle coverage and arterial branching without, however, the disruption of renal artery patterning and perfusion seen in Ntn1SPKO. These data suggest a stromal Ntn1-Klf4 axis that regulates stromal differentiation and reinforces stromal-derived smooth muscle as a key regulator of renal blood vessel formation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Introduction: COVID-19 had numerous objective and subjective effects on resident physician education. We intended to examine objective changes in orthopedic education that occurred during the COVID pandemic and other trends from 2018 to 2022 by analyzing surgical case logs from Accreditation Counsel for Graduate Medical Education (ACGME) approved American orthopedics programs. We hypothesized that surgical case load during the COVID pandemic would remain similar to pre-pandemic levels and case logs would show a general upward trend., Methods: We analyzed 3146 resident case-logs from the ACGME national case-log report from academic years (AY) 2018-2022. Surgical cases were classified by their Current Procedural Terminology (CPT) codes and grouped by anatomical location (shoulder, hand, etc.)., Results: From AY 18-19 to "peak pandemic" AY 19-20, resident caseloads either had no change or increased in every orthopedic discipline with few exceptions. Residents performed fewer shoulder ( p < 0.0001 ), wrist ( p = 0.0023 ), knee ( p < 0.0001 ) and leg/ankle ( p = .0019 ) arthroscopies in AY 19-20 than AY 18-19. Hip arthroscopy was notably unchanged. Oncology, Spine, and Foot/Toes did not see any change from AY 18-19 to 21-22 while Microsurgeries decreased ( p = .0061 ). There were substantial differences between high volume (90th percentile) residents, and low volume (10th percentile) residents. All other anatomic areas saw significant increases in caseload over those four academic years., Discussion/conclusion: COVID had numerous effects on the orthopedic residency experience, however, any decreases in operative load were small, and largely isolated to the 19-20 AY. Microscopic and arthroscopic surgeries decreased during peak pandemic AY 19-20 when elective surgeries experienced cancellations. This illustrates that these areas of orthopedic education may be supplemented outside of the operating room if similar circumstances arise in the future. Otherwise, resident surgical caseloads continue to rise and show no signs of slowing., Competing Interests: All authors involved in any capacity of the creation of this manuscript have no financial or other interests to declare., (© 2023 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Background: First tarsometatarsal joint arthrodesis is a common procedure performed by podiatrists and orthopedic surgeons. There remains debate on how useful CT scans are in assessing fusion status in the post-operative patient. The purpose of our study was to determine the reliability among both orthopedic surgeons and radiologists in reviewing both postoperative radiographs and CT in order to determine if fusion had occurred in patients undergoing 1st tarsometatarsal arthrodesis. A secondary purpose of this study was to determine if CT offered improved inter- and intra-rater reliability when compared to plain radiographs., Methods: Patients who underwent 1st tarsometatarsal arthrodesis were retrospectively reviewed and those who underwent CT post-operatively for persistent pain were identified. Orthopedic surgeons and radiologists then analyzed the radiographs and CT of these patients for union with a threshold for union being set at 50% of the joint being fused. Imaging was then re-evaluated by the same provider 6 months later., Results: 24 patients were identified meeting inclusion criteria. Inter-rater reliability and intra-rater reliability for assessment of 1st tarsometatarsal arthrodesis were better with CT compared to radiographs; however, this association was not deemed reliable. Both imaging modalities were not able to assess union status confidently and reliably across reviewers, although CT scan had better intra-rater reliability., Conclusions: While CT is frequently used to assess fusion in patients who have underwent 1st tarsometatarsal arthrodesis, it was not found to be better than radiographs. Practitioners should reconsider the use CT as the gold standard when assessing fusion in this population., Competing Interests: Conflict of interestThe authors declare that they have no competing interests., (© Indian Orthopaedics Association 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: Perilunate fracture dislocation (PLFD) injuries are associated with the development of acute carpal tunnel syndrome (CTS). The purpose of our study was to identify the factors that increase the likelihood of developing CTS in patients with PLFD. Additionally, we attempted to classify patients who did not initially undergo carpal tunnel release (CTR) at the time of injury but eventually underwent CTR within the follow-up period., Methods: Patients presenting to a level-1 trauma center with isolated PLFDs (Mayfield III-IV) were retrospectively identified by using CPT and ICD-10 codes. Polytraumatized patients, those with a history of previous wrist trauma, or those with previous carpal tunnel symptoms or surgery were excluded. Outcomes of interest included the development of acute CTS, pre- and post-reduction changes in CTS symptoms, and associated hand and wrist fractures. Chi-square tests, Kruskal-Wallis tests, and multivariate logistic regression were used to examine the predictors of developing CTS after a PLFD., Results: In total, 43 patients were included in the final cohort, with a mean age of 44 years, of which 77% were men. The most common fracture of the carpus included scaphoid fractures (9/43, 21%). The average time from presentation to reduction was 636 minutes. Acute CTS symptoms before reduction were present in 26% of the patients and increased post-reduction to 28%. No difference exists between the time to sedation and the presence of acute carpal tunnel symptoms ( P >.05). During initial surgical intervention, 79% underwent CTR (27/34). Of the seven patients who did not initially undergo a CTR, 57% (4/7) required a CTR within the follow-up period., Conclusion: Reduction of PLFDs did not significantly improve the number of patients with acute CTS. More than 50% of the patients who did not undergo a CTR at the initial surgery required a CTR within the follow-up period., Type of Study/level of Evidence: Prognostic III., (© 2023 The Authors.)

Background: Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) is characterized by breathing difficulties in association with excessive supraglottic or glottic laryngeal narrowing. The condition is common and can occur independently; however, it may also be comorbid with other disorders or mimic them. Presentations span multiple specialties and misdiagnosis or delayed diagnosis is commonplace. Group-consensus methods can efficiently generate internationally accepted diagnostic criteria and descriptions to increase clinical recognition, enhance clinical service availability, and catalyze research., Objectives: We sought to establish consensus-based diagnostic criteria and methods for VCD/ILO., Methods: We performed a modified 2-round Delphi study between December 7, 2021, and March 14, 2022. The study was registered at ANZCTR (Australian New Zealand Clinical Trials Registry; ACTRN12621001520820p). In round 1, experts provided open-ended statements that were categorized, deduplicated, and amended for clarity. These were presented to experts for agreement ranking in round 2, with consensus defined as ≥70% agreement., Results: Both rounds were completed by 47 international experts. In round 1, 1102 qualitative responses were received. Of the 200 statements presented to experts across 2 rounds, 130 (65%) reached consensus. Results were discussed at 2 international subject-specific conferences in June 2022. Experts agreed on a diagnostic definition for VCD/ILO and endorsed the concept of VCD/ILO phenotypes and clinical descriptions. The panel agreed that laryngoscopy with provocation is the gold standard for diagnosis and that ≥50% laryngeal closure on inspiration or Maat grade ≥2 define abnormal laryngeal closure indicative of VCD/ILO., Conclusions: This Delphi study reached consensus on multiple aspects of VCD/ILO diagnosis and can inform clinical practice and facilitate research., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

5-Methylcytosine (5mC) and DNA methyltransferases (DNMTs) are broadly conserved in eukaryotes but are also frequently lost during evolution. The mammalian SNF2 family ATPase HELLS and its plant ortholog DDM1 are critical for maintaining 5mC. Mutations in HELLS, its activator CDCA7, and the de novo DNA methyltransferase DNMT3B, cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, a genetic disorder associated with the loss of DNA methylation. We here examine the coevolution of CDCA7, HELLS and DNMTs. While DNMT3, the maintenance DNA methyltransferase DNMT1, HELLS, and CDCA7 are all highly conserved in vertebrates and green plants, they are frequently co-lost in other evolutionary clades. The presence-absence patterns of these genes are not random; almost all CDCA7 harboring eukaryote species also have HELLS and DNMT1 (or another maintenance methyltransferase, DNMT5). Coevolution of presence-absence patterns (CoPAP) analysis in Ecdysozoa further indicates coevolutionary linkages among CDCA7, HELLS, DNMT1 and its activator UHRF1. We hypothesize that CDCA7 becomes dispensable in species that lost HELLS or DNA methylation, and/or the loss of CDCA7 triggers the replacement of DNA methylation by other chromatin regulation mechanisms. Our study suggests that a unique specialized role of CDCA7 in HELLS-dependent DNA methylation maintenance is broadly inherited from the last eukaryotic common ancestor., Competing Interests: HF, IW, QJ, JL, TC No competing interests declared, (© 2023, Funabiki et al.)