Early Exposure to Orthopaedic Surgery.

INTRODUCTION: Disparities in early orthopaedic experiences among medical students prompt a critical examination of factors influencing the availability and nature of these exposures. While the current body of literature underscores the significance of early surgical exposure and mentorship in medical education, a notable gap exists in investigating early orthopaedic exposure and its specific impact on students from diverse backgrounds. METHODS: A 16-item questionnaire, approved by our institutional review board, was administered to fourth-year medical students (MS4) and first-year orthopaedic residents (PGY-1) across U.S. orthopaedic surgery programs during the 2022-2023 application cycle. The questionnaire assessed participants' initial orthopaedic exposures and factors influencing interest in the field. Two-proportion Z-test analyses were conducted to analyze the data, and thematic analysis was used to assess qualitative data involving free-response questions. RESULTS: Out of 72 total respondents, the study revealed that 83% of respondents encountered orthopaedics before medical school, with initial exposures stemming from various sources such as familial connections (28%), athletics (17%), and high school or college exposures (15%), including shadowing, athletics participation, and occupation-related exposure. Disparities were observed in the availability of orthopaedic mentors and early exposure opportunities between demographic groups. Statistical analyses highlighted significant differences in access to mentors who reflected students' identities between male and non-male participants (70% vs. 39%, p=0.02) and between white and non-white participants (69% vs. 36%, p=0.02). White participants were also more likely to first interact with a surgeon who treated them or their family members than non-white participants (35% vs 7%, p=0.04). Non-white participants were more likely than white participants to come by their first orthopaedic opportunity by searching for it independently (21% vs. 4%, p=0.03). Family and friend connections in orthopaedics were found to be influential in motivating students to pursue orthopaedics, with 40% of respondents indicating personal connections in medicine and 12% reporting family members who are orthopaedic surgeons. Research experiences were identified as important contributors to students' initial interest and motivation to ultimately pursue orthopaedics, especially those with diverse backgrounds. CONCLUSION: The findings underscore the importance of early orthopaedic exposures in shaping students' interest in the field, highlighting the need for more immersive pre-clinical year opportunities and enhanced mentorship programs. Addressing disparities in mentorship access and early exposure opportunities requires systemic changes and increased support for underrepresented minorities in orthopaedics. Initiatives like mentorship programs and research opportunities can help bridge gaps in access to early orthopaedic experiences. Medical schools should prioritise targeted early access to orthopaedic exposures for all students, regardless of background. This initiative aims to promote inclusivity and cultivate a more diverse orthopaedic workforce capable of meeting the evolving healthcare needs of society.

Evaluation of Patient Expectations and Outcomes after Distal Radius Fractures.

BACKGROUND: Patient expectations influence patient-reported outcomes after musculoskeletal injuries. The goal of this study is to determine how pretreatment expectations correlate with outcomes in patients with distal radius fractures. METHODS: Seventy-five patients with an isolated distal radius fracture were prospectively enrolled into nonoperative and operative cohorts. The Trauma Expectation Factor-Trauma Outcome Measure (TEF-TOM) score was the primary outcome measure. Trauma Expectation Factor scores were recorded at the time of enrollment, and TOM scores were recorded at 3, 6, and 12 months. Quick Disabilities of the Arm, Shoulder, and Hand (qDASH) and Patient-Rated Wrist Evaluation (PRWE) scores were also recorded. RESULTS: Trauma Outcome Measure scores at all time points were worse than expected (P < .01). Expectations were higher for patients younger than 65 years than for the 65+ group (P = .02). In patients aged 65+ years, mean TOM at 3 months was not significantly different than expected (P = .11) but decreased by 6 (P = .04) and 12 months (P < .01). Baseline TEF and TEF-TOM scores were not significantly different between operative and nonoperative groups (P = .37). Quick Disabilities of the Arm, Shoulder, and Hand and PRWE scores were not significantly different between age or treatment groups at the final follow-up. CONCLUSIONS: The overall treatment of distal radial injuries in our study did not meet patient expectations. Patients aged 65 years or older had lower expectations but were not able to predict their outcomes better than patients aged <65 years. There were no differences in TEF or TOM by treatment method. Patients demonstrated improved functional outcomes (qDASH/PRWE) at all time points regardless of age and treatment method.

Transcriptomic responses to antibiotic exposure in Mycobacterium tuberculosis.

Transcriptional responses in bacteria following antibiotic exposure offer insights into antibiotic mechanism of action, bacterial responses, and characterization of antimicrobial resistance. We aimed to define the transcriptional antibiotic response (TAR) in Mycobacterium tuberculosis (Mtb) isolates for clinically relevant drugs by pooling and analyzing Mtb microarray and RNA-seq data sets. We generated 99 antibiotic transcription profiles across 17 antibiotics, with 76% of profiles generated using 3-24 hours of antibiotic exposure and 49% within one doubling of the WHO antibiotic critical concentration. TAR genes were time-dependent, and largely specific to the antibiotic mechanism of action. TAR signatures performed well at predicting antibiotic exposure, with the area under the receiver operating curve (AUC) ranging from 0.84-1.00 (TAR <6 hours of antibiotic exposure) and 0.76-1.00 (>6 hours of antibiotic exposure) for upregulated genes and 0.57-0.90 and 0.87-1.00, respectfully, for downregulated genes. This work desmonstrates that transcriptomics allows for the assessment of antibiotic activity in Mtb within 6 hours of exposure.

Prostate Cancer Survivorship Essentials for men with prostate cancer on androgen deprivation therapy: protocol for a randomised controlled trial of a tele-based nurse-led survivorship care intervention (PCEssentials Hormone Therapy Study).

INTRODUCTION: Androgen deprivation therapy (ADT) is commonly used to treat men with locally advanced or metastatic prostate cancer. Men receiving ADT experience numerous side effects and frequently report unmet supportive care needs. An essential part of quality cancer care is survivorship care. To date, an optimal effective approach to survivorship care for men with prostate cancer on ADT has not been described. This protocol describes a randomised trial of tele-based nurse-led survivorship that addresses this knowledge gap: (1) determine the effectiveness of a nurse-led survivorship care intervention (PCEssentials), relative to usual care, for improving health-related quality of life (HR-QoL) in men with prostate cancer undergoing ADT and (2) evaluate PCEssentials implementation strategies and outcomes, including cost-effectiveness, compared with usual care. METHODS AND ANALYSIS: This is an effectiveness-implementation hybrid (type 1) trial with participants randomised to one of two arms: (1) minimally enhanced usual care and (2) nurse-led prostate cancer survivorship essentials (PCEssentials) delivered over four tele-based sessions, with a booster session 5 months after session 1. Eligible participants are Australian men with prostate cancer commencing ADT and expected to be on ADT for a minimum of 12 months. Participants are followed up at 3, 6 and 12 months postrecruitment. Primary outcomes are HR-QoL and self-efficacy. Secondary outcomes are psychological distress, insomnia, fatigue and physical activity. A concurrent process evaluation with participants and study stakeholders will be undertaken to determine effectiveness of delivery of PCEssentials. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Metro South Health HREC (HREC/2021/QMS/79429). All participants are required to provide written informed consent. Outcomes of this trial will be published in peer-reviewed journals. The findings will be presented at conferences and meetings, local hospital departments, participating organisations/clinical services, and university seminars, and communicated at community and consumer-led forums. TRIAL REGISTRATION NUMBER: ACTRN12622000025730.

Diagnosis and evaluation of prognosis of myelofibrosis: a British Society for Haematology guideline

This document represents an update of the British Society for Haematology (BSH) guideline on myelofibrosis (MF) first published in 2012 and updated in 2015.1 This guideline aims to provide healthcare professionals with clear guidance on the diagnosis and prognostic evaluation of primary my-elofibrosis (PMF), as well as post-polycythaemia vera myelo-fibrosis (post-PV MF) and post-essential thrombocythaemia myelofibrosis (post-ET MF). A section on prefibrotic MF is also included. A separate BSH Guideline covers the manage-ment of MF and is published alongside this guideline.

The management of myelofibrosis: a British Society for Haematology guideline

This document represents an update of the British Society for Haematology guideline on Myelofibrosis first published in 2012 and updated in 2015 These guidelines aim to pro-vide healthcare professionals with clear guidance on stratified management for primary myelofibrosis (PMF), as well as post-polycythaemia myelofibrosis (post-PV MF) and postessential thrombocythaemia myelofibrosis (post-ET MF). A separate BSH guideline covers the diagnosis and prognostic evaluation of myelofibrosis and is published alongside this guideline

Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms.

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.

Supportive interventions for carers of men with prostate cancer: systematic review and narrative synthesis.

PURPOSE: The objective of this study was to summarise the literature on current interventions available for carers of men with prostate cancer and analyse the outcomes of these interventions in supporting carers' needs. METHODS: A systematic review was conducted, searching databases MEDLINE, PsycINFO, CINAHL, Scopus and Cochrane, using terms related to prostate cancer, carers and interventions. Randomised controlled trials and non-randomised controlled trials of interventions for informal carers with or without patients were included. Data were analysed using descriptive and frequency statistics; interventions and their impact on carers' outcomes were reported on narratively. The SwiM guidelines were applied to guide data synthesis. RESULTS: Overall, 24 articles were included in the review. On average, participants were spouses (92%) and women (97%). Interventions largely rwere delivered face-to-face (42%) or used a combination of face to face and online modalities (38%). Two-thirds (63%) showed a significant improvement in carer's outcomes including psychological, sexual, physical and relationship/marital. The majority of studies (79%) tailored contents to carers' circumstances, most within a couples counselling format. Over one-third (42%) of studies focused on a range of supportive care needs, most commonly were psychological (58%), sexual (42%) and informational (25%). CONCLUSIONS: Interventions for carers of men with prostate cancer were largely face to face, patient-spouse focused and two-thirds had some measurable impact on carer's outcomes. Research continues to underserve other patient-carer roles, including non-spousal carers. Interventions delivered solely for carers are required to meet gaps in care, and determine the impact on carer outcomes. Further research and more targeted interventions are needed. PROSPERO REGISTRATION NUMBER: CRD42021249870.

Analysis of Genome-Wide Mutational Dependence in Naturally Evolving Mycobacterium tuberculosis Populations.

Pathogenic microorganisms are in a perpetual struggle for survival in changing host environments, where host pressures necessitate changes in pathogen virulence, antibiotic resistance, or transmissibility. The genetic basis of phenotypic adaptation by pathogens is difficult to study in vivo. In this work, we develop a phylogenetic method to detect genetic dependencies that promote pathogen adaptation using 31,428 in vivo sampled Mycobacterium tuberculosis genomes, a globally prevalent bacterial pathogen with increasing levels of antibiotic resistance. We find that dependencies between mutations are enriched in antigenic and antibiotic resistance functions and discover 23 mutations that potentiate the development of antibiotic resistance. Between 11% and 92% of resistant strains harbor a dependent mutation acquired after a resistance-conferring variant. We demonstrate the pervasiveness of genetic dependency in adaptation of naturally evolving populations and the utility of the proposed computational approach.

Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial.

PURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

Evaluation of two temperature storage conditions for full blood count samples from Lifeblood's donors.

BACKGROUND AND OBJECTIVES: Lifeblood completes full blood count samples for selected donors to assess their suitability for future donations. Removing the current practice for refrigerated (2-8°C) storage and aligning with room temperature (20-24°C) storage of other donor blood samples would produce significant efficiencies in blood donor centres. This study aimed to compare full blood count results under two temperature conditions. MATERIALS AND METHODS: Paired full blood count samples were collected from 250 whole blood or plasma donors. These were stored either refrigerated or room temperature for testing on arrival at the processing centre and the following day. The primary outcomes of interest included differences between mean cell volume, haematocrit, platelet count, white cell and differential counts, and the need to produce blood films, based on existing Lifeblood criteria. RESULTS: A statistically significant (p < 0.05) difference for most full blood count parameters results was found between the two temperature conditions. The number of blood films required was similar under each temperature condition. CONCLUSION: The clinical significance of the small numerical differences in results is considered minimal. Furthermore, the number of blood films required remained similar under either temperature condition. Given the significant reductions in time, processing and costs associated with room temperature over refrigerated processing, we recommend a further pilot study to monitor the broader impacts, with the intent to implement national storage of full blood count samples at room temperature within Lifeblood.

The Combination of Fractional Tendon Lengthening and the Wide Awake, Local Anesthesia, No Tourniquet Technique for Secondary Tendon Reconstruction.

Rupture is a major concern after primary flexor tendon repair. The predominant treatment for rupture of the primary repair is immediate surgical exploration and repeat repair. However, repeat repair is challenging, including achieving ideal tension in the flexor mechanism. Further, immediate repeat repair is associated with poor outcomes, particularly in the small finger. As such, there is a need to improve both the technique and outcomes of repeat repair of primary flexor tendon rupture. We present a case of primary flexor tendon repair rupture treated with a novel combination of fractional tendon lengthening and the wide awake, local anesthesia, no tourniquet technique. A combination of these techniques has multiple benefits. An intraoperative, dynamic assessment of the digits enables immediate optimization of the repair. Further, these techniques allow for better intraoperative patient education and communication, increasing the likelihood of adherence to postoperative therapy and better overall outcomes.

How Are Radial Height and Radial Shortening Defined in the Treatment of Distal Radius Fractures? A Critical Review.

BACKGROUND: Radial height is a radiographic parameter used to guide the treatment of distal radius fractures. However, it is often used synonymously with other terms, and there are substantial discrepancies in its measurement/definition. These discrepancies can alter the measurement of radial height and affect treatment decisions. The purpose of this review is to identify the different definitions of radial height in the literature relevant to distal radius fractures. METHODS: A literature review was conducted in the PubMed/MEDLINE database from inception to 2022. Full-length, English-language studies that pertained to distal radius fractures and reported radial height as a recorded measurement were included. The method of radial height measurement (definition) was extracted from included studies. Level of evidence was determined by the Oxford Centre for Evidence-based Medicine Levels of Evidence tool. RESULTS: A total of 385 studies were identified. Of these, 183 (47.5%) did not provide a definition for radial height. Of the studies that defined radial height, 50.9% (103/202) measured radial height from the radial styloid to the distal ulna, 10.9% (22/202) measured from the radial styloid to the distal radius, and 29.2% (59/202) were "other" definitions. CONCLUSIONS: There is substantial discrepancy in the way that radial height is measured and reported. We advocate for a standardized measurement of radial height (synonymous with radial length) from the radial styloid to the distal ulnar articular surface. Radial shortening is a different measurement and requires comparison with a reference value.

Differential inhibition of T-cell receptor and STAT5 signaling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia.

Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signaling. Dasatinib, initially developed as an immunosuppressive agent, is by contrast, also noted to result in enhanced tumor immunity in a subset of patients. We studied the impact of dasatinib in chronic myeloid leukemia patients and compared it with patients taking other tyrosine kinase inhibitors (TKI) and healthy controls. We found that patients on dasatinib showed inhibition of both T-cell receptor (TCR) and STAT5 signaling pathways, and reduced expression of Teffector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of regulatory T cells (Tregs) and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signaling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signaling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3-mediated T-cell exhaustion and preserve anti-tumor immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.

Essential thrombocythemia: challenges in clinical practice and future prospects.

Essential thrombocythemia (ET) was first described in 1934, and subsequently, progress has been made in better understanding the molecular pathogenesis and which patients may have greatest risk of progression or vascular events. However, it has been more than a decade since a new therapy has been approved for ET. We are beginning to understand more comprehensively both the heterogeneity of this disease, which is largely driven by driver mutation status, as well as the effect of disease-related symptoms, such as fatigue, on patients. In this review we provide a practical overview of diagnosis and management of ET with focus on challenging patient scenarios and some consideration of what comprehensive care might entail. Finally, we also discuss newer therapies and how these might be assessed.

Whole exome sequencing of FFPE samples-expanding the horizon of forensic molecular autopsies.

Forensic molecular autopsies have emerged as a tool for medical examiners to establish the cause of death. It is particularly useful in sudden unexplained deaths where the cause of death cannot be determined with a regular medical autopsy. We provide the first study of exome data from formalin-fixed paraffin-embedded samples (FFPE) paired with data from high-quality blood samples in forensic applications. The approach allows exploration of the potential to use FFPE samples for molecular autopsies and identify variants in extensive exome data. We leverage the high uniformity of the hybridization capture approach provided by Twist Bioscience to target the complete exome and sequence the libraries on a NextSeq 550. Our findings suggest that exome sequencing is feasible for 24 out of a total of 35 included FFPE samples. When successful, the coverage across the exome is comparatively high (> 90% covered to 20X) and uniform (fold80 below 1.5). Detailed variant comparisons for matched FFPE and blood samples show high concordance with few false variants (positive predictive value of 0.98 and a sensitivity of 0.97) with no distinct FFPE artefacts. Ultimately, we apply carefully constructed forensic gene panels in a stepwise manner to find genetic variants associated with the clinical phenotype and with relevance to the sudden unexplained death.

Patient Adherence With At-Home Hand and Wrist Exercises: A Randomized Controlled Trial of Video Versus Handout Format.

BACKGROUND: Patient adherence is important for maximizing patient outcomes. The purpose of this randomized controlled trial was to determine patient adherence and confidence in home therapy exercises of the hand and wrist at multiple time points when distributed by either paper handout or video. METHODS: Patients were prospectively enrolled and randomized in orthopedic clinics to either the handout or video exercise group. Exclusion criteria included patients less than 18 years old. Questionnaires were electronically distributed each week for 4 weeks following enrollment. Questionnaires assessed the frequency of exercise performance, percentage of exercises utilized, and confidence in performing the exercises correctly. The handout and video groups were compared via 2-sample t tests for continuous data and χ2 tests for categorical data. RESULTS: Of the 89 patients enrolled, 71 patients responded to the initial follow-up survey (80% of randomized patients), and 54 of these patients (76%) completed all surveys at each time point. The handout group (37 patients) and the video group (34 patients) had no differences in response rate or demographics. There were no differences in frequency, exercise utilization rate, or confidence in performing exercises between groups at week 1. However, the video group reported higher exercise utilization and confidence than the handout group at subsequent time points. CONCLUSIONS: Video-format distribution of home therapy exercises is superior to that of paper handout distribution for the distal upper extremity rehabilitation. Patients in the video group utilized more exercises and had higher confidence in completing them correctly following initiation of the exercise program.

Coronial postmortem reports and indirect COVID-19 pandemic-related mortality.

AIMS: Widespread disruption of healthcare services and excess mortality not directly attributed to COVID-19 occurred between March and May 2020. We undertook the first UK multicentre study of coroners' autopsies before and during this period using postmortem reports. METHODS: We reviewed reports of non-forensic coroners' autopsies performed during the first COVID-19 lockdown (23 March to 8 May 2020), and the same period in 2018. Deaths were categorised as natural non-COVID-19, COVID-19-related, non-natural (suicide, drug and alcohol-related, traumatic, other). We provided opinion regarding whether delayed access to medical care or changes in behaviour due to lockdown were a potential factor in deaths. RESULTS: Seven centres covering nine coronial jurisdictions submitted a total of 1100 coroners' autopsies (498 in 2018, 602 in 2020). In only 54 autopsies was death attributed to COVID-19 (9%). We identified a significant increase in cases where delays in accessing medical care potentially contributed to death (10 in 2018, 44 in 2020). Lockdown was a contributing factor in a proportion of suicides (24%) and drug and alcohol-related deaths (12%). CONCLUSIONS: Postmortem reports have considerable utility in evaluating excess mortality due to healthcare and wider societal disruption during a pandemic. They provide information at an individual case level that is not available from assessment of death certification data. Detailed evaluation of coroners' autopsy reports, supported by appropriate regulatory oversight, is recommended to mitigate disruption and indirect causes of mortality in future pandemics. Maintaining access to healthcare, including substance misuse and mental health services, is an important consideration.