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Background and Purpose: Ultra-high dose-rate radiotherapy (FLASH) has been shown to mitigate normal tissue toxicities associated with conventional dose rate radiotherapy (CONV) without compromising tumor killing in preclinical models. A prominent challenge in preclinical radiation research, including FLASH, is validating both the physical dosimetry and the biological effects across multiple institutions., Materials and Methods: We previously demonstrated dosimetric reproducibility of two different electron FLASH devices at separate institutions using standardized phantoms and dosimeters. In this study, tumor-free adult female mice were given 10 Gy whole brain FLASH and CONV irradiation at both institutions and evaluated for the reproducibility and temporal evolution of multiple neurobiological endpoints., Results: FLASH sparing of behavioral performance on novel object recognition (4 months post-irradiation) and of electrophysiologic long-term potentiation (LTP, 5 months post-irradiation) was reproduced between institutions. Differences between FLASH and CONV on the endpoints of hippocampal neurogenesis (Sox2, doublecortin), neuroinflammation (microglial activation), and electrophysiology (LTP) were not observed at early times (48 h to 2 weeks), but recovery of immature neurons by 3 weeks was greater with FLASH., Conclusion: In summary, we demonstrated reproducible FLASH sparing effects on the brain between two different beams at two different institutions with validated dosimetry. FLASH sparing effects on the endpoints evaluated manifested at later but not the earliest time points., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Venous thromboembolism (VTE) is a potential complication of foot and ankle surgery. There is a lack of agreement on contributing risk factors and chemical prophylaxis requirements. The primary outcome of this study was to analyze the 90-day incidence of symptomatic VTE and VTE-related mortality in patients undergoing foot and ankle surgery and Achilles tendon (TA) rupture. Secondary aims were to assess the variation in the provision of chemical prophylaxis and risk factors for VTE., Methods: This was a multicentre, prospective national collaborative audit with data collection over nine months for all patients undergoing foot and ankle surgery in an operating theatre or TA rupture treatment, within participating UK hospitals. The association between VTE and thromboprophylaxis was assessed with a univariable logistic regression model. A multivariable logistic regression model was used to identify key predictors for the risk of VTE., Results: A total of 13,569 patients were included from 68 sites. Overall, 11,363 patients were available for analysis: 44.79% were elective (n = 5,090), 42.16% were trauma excluding TA ruptures (n = 4,791), 3.50% were acute diabetic procedures (n = 398), 2.44% were TA ruptures undergoing surgery (n = 277), and 7.10% were TA ruptures treated nonoperatively (n = 807). In total, 11 chemical anticoagulants were recorded, with the most common agent being low-molecular-weight heparin (n = 6,303; 56.79%). A total of 32.71% received no chemical prophylaxis. There were 99 cases of VTE (incidence 0.87% (95% CI 0.71 to 1.06)). VTE-related mortality was 0.03% (95% CI 0.005 to 0.080). Univariable analysis showed that increased age and American Society of Anesthesiologists (ASA) grade had higher odds of VTE, as did having previous cancer, stroke, or history of VTE. On multivariable analysis, the strongest predictors for VTE were the type of foot and ankle procedure and ASA grade., Conclusion: The 90-day incidence of symptomatic VTE and mortality related to VTE is low in foot and ankle surgery and TA management. There was notable variability in the chemical prophylaxis used. The significant risk factors associated with 90-day symptomatic VTE were TA rupture and high ASA grade., Competing Interests: J. Mangwani reports support from the Leicester Hospitals Charity, related to this study. J. Mangwani reports payment or honoraria for lectures, presentations, educational events from Orthosolutions, and royalties from Meshworks, unrelated to this study. K. Malhotra reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from NewClip Technics, unrelated to this study. L. W. Mason reports royalties or licenses, consulting fees, and patents planned, issued or pending from Orthosolutions, unrelated to this study., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Studies have reported lower incidence of prostate cancer in men living with HIV compared with men without HIV for reasons that remain unclear. Lower prostate cancer screening in men living with HIV could explain these findings. We describe receipt of prostate-specific antigen (PSA) test each calendar year by HIV status in Medicaid beneficiaries enrolled in 14 U.S. states, 2001-2015. A total of 15,299,991 Medicaid beneficiaries aged 18-64 with ≥7 months of continuous enrollment were included in analyses. HIV diagnosis and PSA tests were identified using non-drug claims. Incidence rate ratios comparing receipt of PSA test by HIV status adjusted for age, race/ethnicity, state of residence, calendar year, comorbid conditions, benign prostatic conditions, and receipt of testosterone-replacement therapy were estimated using Poisson regression. Models were also stratified by state, and estimates were pooled using random-effects meta-analysis to account for heterogeneity by state. Models were additionally stratified by age and race/ethnicity. There were 42,503 PSA tests over 314,273 person-years and 1,669,835 PSA tests over 22,023,530 person-years observed in beneficiaries with and without HIV, respectively. The incidence of PSA test was slightly lower in men living with HIV than men without HIV (incidence rate ratio [IRR] = 0.98; 95% confidence interval [CI]: 0.97, 0.99) when adjusting for state. In the pooled estimate, the rate was higher among men living with HIV (IRR = 1.11; 95% CI: 0.97, 1.27). Pooled estimates indicated approximately equal or higher rates of PSA test in men living with HIV compared with men without HIV across models stratified by age and race/ethnicity groups. Findings do not support the hypothesis that differences in prostate cancer screening explain differences in incidence by HIV status.

Disparities in HIV care by socioeconomic status, place of residence, and race/ethnicity prevent progress toward epidemic control. No study has comprehensively characterized the HIV care cascade among people with HIV enrolled in Medicaid - an insurance source for low-income individuals in the US. We analyzed data from 246,127 people with HIV enrolled in Medicaid 2001-2015, aged 18-64, living in 14 US states. We estimated the monthly prevalence of four steps of the care cascade: retained in care/adherent to ART; retained/not adherent; not retained/adherent; not retained/not adherent. Beneficiaries were retained in care if they had an outpatient care encounter every six months. Adherence was based on medication possession ratio. We estimated prevalence using a non-parametric multi-state approach, accounting for death as a competing event and for Medicaid disenrollment using inverse probability of censoring weights. Across 2001-2015, the proportion of beneficiaries with HIV who were retained/ART adherent increased, overall and in all subgroups. By 2015, approximately half of beneficiaries were retained in care, and 42% of beneficiaries were ART adherent. We saw meaningful differences by race/ethnicity and region. Our work highlights an important disparity in the HIV care cascade by insurance status during this time period.

Response inhibition is a crucial component of executive control. Although mainly studied in upper limb tasks, it is fully implicated in gait initiation. Here, we assessed the influence of proactive and reactive inhibitory control during gait initiation in healthy adult participants. For this purpose, we measured kinematics and electroencephalography (EEG) activity (event-related potential [ERP] and time-frequency data) during a modified Go/NoGo gait initiation task in 23 healthy adults. The task comprised Go-certain, Go-uncertain, and NoGo conditions. Each trial included preparatory and imperative stimuli. Our results showed that go-uncertainty resulted in delayed reaction time, without any difference for the other parameters of gait initiation. Proactive inhibition, that is, Go uncertain versus Go certain conditions, influenced EEG activity as soon as the preparatory stimulus. Moreover, both proactive and reactive inhibition influenced the amplitude of the ERPs (central P1, occipito-parietal N1, and N2/P3) and theta and alpha/low beta band activities in response to the imperative-Go-uncertain versus Go-certain and NoGo versus Go-uncertain-stimuli. These findings demonstrate that the uncertainty context; induced proactive inhibition, as reflected in delayed gait initiation. Proactive and reactive inhibition elicited extended and overlapping modulations of ERP and time-frequency activities. This study shows the protracted influence of inhibitory control in gait initiation., (© 2024 The Author(s). Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Prostate cancer (PCa) incidence is reportedly lower in men with HIV compared to men without HIV for unknown reasons. We describe PCa incidence by HIV status in Medicaid beneficiaries, allowing for comparison of men with and without HIV who are similar with respect to socioeconomic characteristics and access to healthcare. Men (N = 15,167,636) aged 18-64 with ≥7 months of continuous enrollment during 2001-2015 in 14 US states were retained for analysis. Diagnoses of HIV and PCa were identified using non-drug claims. We estimated cause-specific (csHR) comparing incidence of PCa by HIV status, adjusted for age, race-ethnicity, state of residence, year of enrollment, and comorbid conditions, and stratified by age and race-ethnicity. Hazard of PCa was lower in men with HIV than men without HIV (csHR = 0.89; 95% CI: 0.80, 0.99), but varied by race-ethnicity, with similar observations among non-Hispanic Black (csHR = 0.79; 95% CI: 0.69, 0.91) and Hispanic (csHR = 0.85; 95% CI: 0.67, 1.09), but not non-Hispanic white men (csHR = 1.17; 95% CI: 0.91, 1.50). Findings were similar in models restricted to men aged 50-64 and 40-49, but not in men aged 18-39. Reported deficits in PCa incidence by HIV status may be restricted to specific groups defined by age and race ethnicity.

Objective: To investigate the effects of directional subthalamic deep brain stimulation (STN-dDBS) on gait and balance disorders, including freezing of gait (FOG), in patients with advanced Parkinson's disease (PD)., Methods: We included 10 participants who underwent STN-DBS and presented severe preoperative FOG, in a randomized, double-blind, crossover study. We used segmented DBS electrodes to investigate whether directing the predicted volume of tissue activated (VTA) to overlap the central STN preferentially improved gait and balance disorders compared to directional DBS applied in the more posterior STN (sensorimotor). We also assessed non-directional (ring-mode) STN-DBS. Our primary outcome was gait and balance control measured using instrumented gait recordings. Each patient had a pre-operative structural and diffusion-weighted imaging to model individual VTAs and to examine cortico-subthalamic connectivity. We used linear mixed-effects models to contrast the effects of central STN-dDBS, posterior STN-dDBS, and ring-mode STN-DBS., Results: Central STN-dDBS produced significantly better improvement in gait and balance control compared to posterior STN-dDBS (p = 0.027), with fewer FOG episodes (p < 0.001). Conversely, ring-mode STN-DBS resulted in worsened postural control compared to central STN-dDBS (p = 0.009). The cortico-subthalamic connectivity with the STN VTAs involved mostly primary sensorimotor, premotor, and medial frontal cortices, with a higher overall cortico-STN connectivity with ring-mode STN-DBS., Interpretation: Central STN-dDBS represents the best option to improve gait and balance disorders in PD patients, including FOG. Our findings raise the possibility of reprogramming STN-DBS toward the central area in selected patients with disabling FOG and/or postural instability after surgery. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: To assess the feasibility and safety of conducting robot-mediated impairment training (RMIT) and robot-mediated task-specific training (RMTT). The device deployed is the Optimo Regen (OR ® ), capable of delivering both impairment-oriented training and task-specific training., Methods: This was a single-centre, randomized, single-blinded, two-arm, parallel group, controlled trial. Patients fulfilling criteria were randomized into either the RMIT or RMIT + RMTT group and provided with 20 h of robotic therapy on top of standard care., Results: A total of 4 patients were recruited, with 2 patients receiving treatment in each arm. The study was feasible, with a 66.7% enrolment rate, 75% completion rate, and 100% attendance for each intervention session. We achieved a 90% satisfaction rate with no serious adverse effects. All patients had improvement of motor power, Fugl-Meyer Assessment-Upper Extremity (FMA-UE), Functional Independence Measure (FIM), Hospital Anxiety and Depression Scale (HADS), and quality of life scores at 1 month. FIM continued to improve at 3 months post-commencement of intervention. There was relative ease of use of the device., Conclusion: This trial is feasible. A full-scale study is warranted, to compare RMIT against RMTT, which is a novel application., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tay, Zhang, Visperas, Koh, Lau and Neo.)

Per- and polyfluoroalkyl substances (PFAS) are anthropogenic chemicals commonly found in the environment. PFAS pose multifaceted challenges including identifying sources and exposure pathways, detecting and quantifying their presence, characterizing their fate and transport, and assessing their risks. PFAS and fluorotelomer polymers can be found in the pulp and paper (P&P) wastewater systems, but their behavior remains poorly understood. The constituents of P&P waste include lignin hydrolysis products, hence PFAS interactions with lignin likely affect PFAS removal efforts. This study employed quantitative ultra-performance liquid chromatography triple quadrupole mass spectrometry (UPLC-MS/MS) to investigate the sorption-desorption capacity and mechanisms of PFAS interaction with lignin. PFAS with sulfonate functional groups displayed higher affinity for lignin (solid phase) based on their partitioning coefficient (K d ), while PFAS with carboxylate head groups persisted in the P&P wastewater (aqueous phase). Sorption to lignin exhibited an increase with chain length (CF 2 ) n among compounds with the same functional group. Long-chain (C ≥ 6) PFAS demonstrated higher sorption compared to short-chain (C ≤ 5) homologs. The sorption-desorption capacities, partitioning coefficients, and kinetics of PFAS reported in this study can facilitate predictive models for PFAS and assist in the development of efficient P&P waste treatment and management., 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 B.V. All rights reserved.)

Objective. Neurofeedback (NF) is a cognitive training procedure based on real-time feedback (FB) of a participant's brain activity that they must learn to self-regulate. A classical visual FB delivered in a NF task is a filling gauge reflecting a measure of brain activity. This abstract visual FB is not transparently linked-from the subject's perspective-to the task performed (e.g., motor imagery (MI)). This may decrease the sense of agency, that is, the participants' reported control over FB. Here, we assessed the influence of FB transparency on NF performance and the role of agency in this relationship. Approach. Participants performed a NF task using MI to regulate brain activity measured using electroencephalography. In separate blocks, participants experienced three different conditions designed to vary transparency: FB was presented as either (1) a swinging pendulum, (2) a clenching virtual hand, (3) a clenching virtual hand combined with a motor illusion induced by tendon vibration. We measured self-reported agency and user experience after each NF block. Main results . We found that FB transparency influences NF performance. Transparent visual FB provided by the virtual hand resulted in significantly better NF performance than the abstract FB of the pendulum. Surprisingly, adding a motor illusion to the virtual hand significantly decreased performance relative to the virtual hand alone. When introduced in incremental linear mixed effect models, self-reported agency was significantly associated with NF performance and it captured the variance related to the effect of FB transparency on NF performance. Significance . Our results highlight the relevance of transparent FB in relation to the sense of agency. This is likely an important consideration in designing FB to improve NF performance and learning outcomes., (Creative Commons Attribution license.)

Background: Hallux rigidus is a common condition characterised by first metatarsophalangeal joint (MTPJ) degeneration, pain and limited range of motion (ROM). The gold standard surgical treatment is arthrodesis, providing good pain relief, but sacrifices ROM. The Cartiva synthetic cartilage implant (SCI) has been utilised as an interpositional arthroplasty, aiming to reduce pain whilst preserving range of motion. Current evidence for Cartiva SCI is limited. The aim was to evaluate the clinical outcomes of Cartiva SCI compared to arthrodesis undertaken in our centre., Methods: A retrospective cohort study was conducted, enrolling all adult patients who underwent primary first MTPJ SCI arthroplasty or arthrodesis for the treatment hallux rigidus. The primary outcome was a validated patient-reported outcome measure (PROM), the Manchester-Oxford Foot Questionnaire (MOXFQ). Secondary outcomes included EQ-5D, complication rates, VAS Pain and FAAM (ADL)., Results: Between 2017 and 2020 there were 33 cases divided into two groups (17 Cartiva SCI, 16 arthrodesis, mean age 59.0 ± 9.9 years) with a mean follow up of 2.3 years. There was no statistically significant difference in any of the MOXFQ, EQ-5D, VAS Pain or FAAM (ADL) outcome scores between the Arthrodesis and SCI groups (p > 0.05). The mean MOXFQ Index score was 7.2 ± 6.4 for the SCI group and 3.9 ± 5.8 for the Arthrodesis group at final follow up (p = 0.15). Although complications were high in both groups, the overall hallux reoperation rate was 29.4 % in the SCI cohort and 0.0 % for arthrodesis., Conclusion: This retrospective comparative study found no significant superiority of Cartiva SCI over arthrodesis in terms of PROMs. Due to the higher rate of further surgical intervention in the SCI cohort, we recommend arthrodesis as the preferred surgical option for hallux rigidus., Level of Evidence: III., Competing Interests: Declaration of Competing Interest There was no specific funding to support this study. This study was approved by the local clinical governance review. None of the authors have any conflicts of interest or financial disclosures to share., (Copyright © 2024 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Brain differences linked to autism spectrum disorder (ASD) can manifest before observable symptoms. Studying these early neural precursors in larger and more diverse cohorts is crucial for advancing our understanding of developmental pathways and potentially facilitating earlier identification. EEG is an ideal tool for investigating early neural differences in ASD, given its scalability and high tolerability in infant populations. In this context, we integrated EEG into an existing multi-site MRI study of infants with a higher familial likelihood of developing ASD. This paper describes the comprehensive protocol established to collect longitudinal, high-density EEG data from infants across five sites as part of the Infant Brain Imaging Study (IBIS) Network and reports interim feasibility and data quality results. We evaluated feasibility by measuring the percentage of infants from whom we successfully collected each EEG paradigm. The quality of task-free data was assessed based on the duration of EEG recordings remaining after artifact removal. Preliminary analyses revealed low data loss, with average in-session loss rates at 4.16 % and quality control loss rates at 11.66 %. Overall, the task-free data retention rate, accounting for both in-session issues and quality control, was 84.16 %, with high consistency across sites. The insights gained from this preliminary analysis highlight key sources of data attrition and provide practical considerations to guide similar research endeavors., 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 Ltd.. All rights reserved.)

Background: FLASH radiation therapy (RT) offers a promising avenue for the broadening of the therapeutic index. However, to leverage the full potential of FLASH in the clinical setting, an improved understanding of the biological principles involved is critical. This requires the availability of specialized equipment optimized for the delivery of conventional (CONV) and ultra-high dose rate (UHDR) irradiation for preclinical studies. One method to conduct such preclinical radiobiological research involves adapting a clinical linear accelerator configured to deliver both CONV and UHDR irradiation., Purpose: We characterized the dosimetric properties of a clinical linear accelerator configured to deliver ultra-high dose rate irradiation to two anatomic sites in mice and for cell-culture FLASH radiobiology experiments., Methods: Delivered doses of UHDR electron beams were controlled by a microcontroller and relay interfaced with the respiratory gating system. We also produced beam collimators with indexed stereotactic mouse positioning devices to provide anatomically specific preclinical treatments. Treatment delivery was monitored directly with an ionization chamber, and charge measurements were correlated with radiochromic film measurements at the entry surface of the mice. The setup for conventional dose rate irradiation utilized the same collimation system but at increased source-to-surface distance. Monte Carlo simulations and film dosimetry were used to characterize beam properties and dose distributions., Results: The mean electron beam energies before the flattening filter were 18.8 MeV (UHDR) and 17.7 MeV (CONV), with corresponding values at the mouse surface of 17.2 and 16.2 MeV. The charges measured with an external ion chamber were linearly correlated with the mouse entrance dose. The use of relay gating for pulse control initially led to a delivery failure rate of 20% (± 1 pulse); adjustments to account for the linac latency improved this rate to < 1/20. Beam field sizes for two anatomically specific mouse collimators (4 × 4 cm 2 for whole-abdomen and 1.5 × 1.5 cm 2 for unilateral lung irradiation) were accurate within < 5% and had low radiation leakage (< 4%). Normalizing the dose at the center of the mouse (∼0.75 cm depth) produced UHDR and CONV doses to the irradiated volumes with > 95% agreement., Conclusion: We successfully configured a clinical linear accelerator for increased output and developed a robust preclinical platform for anatomically specific irradiation, with highly accurate and precise temporal and spatial dose delivery, for both CONV and UHDR irradiation applications., (© 2024 American Association of Physicists in Medicine.)

Purpose: We conducted a multi-institutional dosimetric audit between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3-dimensional (3D) printed mouse phantom., Methods and Materials: A computed tomography (CT) scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene (∼1.02 g/cm 3 ) and polylactic acid (∼1.24 g/cm 3 ) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid (∼0.64 g/cm 3 ). Hounsfield units (HU), densities, and print-to-print stability of the phantoms were assessed. Three institutions were each provided a phantom and each institution performed 2 replicates of irradiations at selected anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film., Results: Compared with the reference CT scan, CT scans of the phantom demonstrated mass density differences of 0.10 g/cm 3 for bone, 0.12 g/cm 3 for lung, and 0.03 g/cm 3 for soft tissue regions. Differences in HU between phantoms were <10 HU for soft tissue and bone, with lung showing the most variation (54 HU), but with minimal effect on dose distribution (<0.5%). Mean differences between FLASH and CONV decreased from the first to the second replicate (4.3%-1.2%), and differences from the prescribed dose decreased for both CONV (3.6%-2.5%) and FLASH (6.4%-2.7%). Total dose accuracy suggests consistent pulse dose and pulse number, although these were not specifically assessed. Positioning variability was observed, likely due to the absence of robust positioning aids or image guidance., Conclusions: This study marks the first dosimetric audit for FLASH using a nonhomogeneous phantom, challenging conventional calibration practices reliant on homogeneous phantoms. The comparison protocol offers a framework for credentialing multi-institutional studies in FLASH preclinical research to enhance reproducibility of biologic findings., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Glenohumeral instability is a complex clinical problem with underlying pathology in the bony, labral, and capsular tissues. The rate of specific capsular injuries varies widely in the literature and the clinical importance of these specific injury patterns remains unclear., Methods: Following Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, a systematic review was performed of multiple databases for all primary research articles between 2008 and 2023 which included advanced imaging and included rates of capsular injury in patients with glenohumeral instability., Results: Twelve studies met inclusion criteria. The most prevalent capsular injury seen was in the inferior glenohumeral ligament (34.1%) across all studies, followed by anterior labroligamentous periosteal sleeve avulsions with 24.9% prevalence. Humeral avulsions of the glenohumeral ligaments lesions were the least common (6.2%) of subjects, followed closely by capsular tears (8.3%) of subjects., Conclusion: Capsular injury is commonly seen in magnetic resonance imaging of patients with anterior shoulder instability. Significant heterogeneity in language and imaging techniques was found in the existing literature. Further research is needed to explore these specific capsular lesions' clinical implications and rehabilitation strategies., (© 2024 The Authors.)

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target., Competing Interests: Declaration of interests M.G.F. is a consultant for Twentyeight-Seven Therapeutics and Blueprint Medicines. M.M. is an SAB member for Cygnal Therapeutics. K.L.L. is founder and equity holder of Travera Inc. and receives consulting fees from BMS, Integragen, and Rarecyte, and research support from Lilly, BMS, and Amgen. D.H. has acted as an advisor for Novartis in relation to ribociclib., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Models of measles transmission can be used to identify areas of high risk to tailor immunization strategies. Estimates of spatial connectivity can be derived from data such as mobile phone records, however it is not clear how this maps to the movement of children who are more likely to be infected. Using travel surveys across two districts in Zambia and national mobile phone data, we compared estimates of out-of-district travel for the population captured in the mobile phone data and child-specific travel from travel surveys. We then evaluated the impact of unadjusted and adjusted connectivity measures on simulated measles virus introduction events across Zambia. The number of trips made by children from the travel survey was three to five times lower than the general population estimates from mobile phone data. This decreased the percentage of districts with measles virus introduction events from 78% when using unadjusted data to 51% - 64% following adjustment. Failure to account for age-specific heterogeneities in travel estimated from mobile phone data resulted in overestimating subnational areas at high risk of introduction events, which could divert mitigation efforts to districts that are at lower risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Ankle osteoarthritis (OA) is less common than knee and hip OA, and 75% to 80% of all presentations are posttraumatic in nature, resulting from either ligamentous or bony injury to the ankle. While the ankle joint cartilage demonstrates capacity for self-restoration, the ankle joint is sensitive to aberrancies in biomechanics and the inflammatory milieu after an injury is thought to contribute to the onset of posttraumatic ankle OA. Conservative care for ankle OA is currently centered on pain reduction, and derivatives that may delay the progression of ankle OA are the subject of ongoing investigation. Surgical management for end-stage ankle OA currently focuses on ankle arthrodesis and total ankle arthroplasty. Specific indication for one procedure over the other is the topic of much debate. While total ankle arthroplasty has become more frequently used with the advent of newer generation systems, ankle arthrodesis may still be favored in younger patients with high-demand occupations., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

Multimorbidity, defined as having 2 or more chronic conditions, is a growing public health concern, but research in this area is complicated by the fact that multimorbidity is a highly heterogenous outcome. Individuals in a sample may have a differing number and varied combinations of conditions. Clustering methods, such as unsupervised machine learning algorithms, may allow us to tease out the unique multimorbidity phenotypes. However, many clustering methods exist, and choosing which to use is challenging because we do not know the true underlying clusters. Here, we demonstrate the use of 3 individual algorithms (partition around medoids, hierarchical clustering, and probabilistic clustering) and a clustering ensemble approach (which pools different clustering approaches) to identify multimorbidity clusters in the AIDS Linked to the Intravenous Experience cohort study. We show how the clusters can be compared based on cluster quality, interpretability, and predictive ability. In practice, it is critical to compare the clustering results from multiple algorithms and to choose the approach that performs best in the domain(s) that aligns with plans to use the clusters in future analyses., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Ultrahigh-dose-rate (FLASH) irradiation has been reported to reduce normal tissue damage compared with conventional dose rate (CONV) irradiation without compromising tumor control. This proof-of-concept study aims to develop a deep learning (DL) approach to quantify the FLASH isoeffective dose (dose of CONV that would be required to produce the same effect as the given physical FLASH dose) with postirradiation mouse intestinal histology images., Methods and Materials: Eighty-four healthy C57BL/6J female mice underwent 16 MeV electron CONV (0.12 Gy/s; n = 41) or FLASH (200 Gy/s; n = 43) single fraction whole abdominal irradiation. Physical dose ranged from 12 to 16 Gy for FLASH and 11 to 15 Gy for CONV in 1 Gy increments. Four days after irradiation, 9 jejunum cross-sections from each mouse were hematoxylin and eosin stained and digitized for histological analysis. CONV data set was randomly split into training (n = 33) and testing (n = 8) data sets. ResNet101-based DL models were retrained using the CONV training data set to estimate the dose based on histological features. The classical manual crypt counting (CC) approach was implemented for model comparison. Cross-section-wise mean squared error was computed to evaluate the dose estimation accuracy of both approaches. The validated DL model was applied to the FLASH data set to map the physical FLASH dose into the isoeffective dose., Results: The DL model achieved a cross-section-wise mean squared error of 0.20 Gy 2 on the CONV testing data set compared with 0.40 Gy 2 of the CC approach. Isoeffective doses estimated by the DL model for FLASH doses of 12, 13, 14, 15, and 16 Gy were 12.19 ± 0.46, 12.54 ± 0.37, 12.69 ± 0.26, 12.84 ± 0.26, and 13.03 ± 0.28 Gy, respectively., Conclusions: Our proposed DL model achieved accurate CONV dose estimation. The DL model results indicate that in the physical dose range of 13 to 16 Gy, the biologic dose response of small intestinal tissue to FLASH irradiation is represented by a lower isoeffective dose compared with the physical dose. Our DL approach can be a tool for studying isoeffective doses of other radiation dose modifying interventions., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Purpose: Concerns over chest wall toxicity has led to debates on treating tumors adjacent to the chest wall with single-fraction stereotactic ablative radiotherapy (SABR). We performed a secondary analysis of patients treated on the prospective iSABR trial to determine the incidence and grade of chest wall pain and modeled dose-response to guide radiation planning and estimate risk., Materials and Methods: This analysis included 99 tumors in 92 patients that were treated with 25 Gy in one fraction on the iSABR trial which individualized dose by tumor size and location. Toxicity events were prospectively collected and graded based on the CTCAE version 4. Dose-response modeling was performed using a logistic model with maximum likelihood method utilized for parameter fitting., Results: There were 22 grade 1 or higher chest wall pain events, including five grade 2 events and zero grade 3 or higher events. The volume receiving at least 11 Gy (V 11Gy ) and the minimum dose to the hottest 2 cc (D 2cc ) were most highly correlated with toxicity. When dichotomized by an estimated incidence of ≥ 20 % toxicity, the D 2cc  > 17 Gy (36.6 % vs. 3.7 %, p < 0.01) and V 11Gy  > 28 cc (40.0 % vs. 8.1 %, p < 0.01) constraints were predictive of chest wall pain, including among a subset of patients with tumors abutting or adjacent to the chest wall., Conclusion: For small, peripheral tumors, single-fraction SABR is associated with modest rates of low-grade chest wall pain. Proximity to the chest wall may not contraindicate single fractionation when using highly conformal, image-guided techniques with sharp dose gradients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B.L., Y.F.W., S.C., J.F., S.J., P.D., H.G., V.M., S.E., H.S., and A.L.C. report no disclosures. L.S. reports US patent: 16/809427. D.P. reports disclosures including a grant with RefleXion Medical Research. H.T. reports a contract with the Global Center for Biomedical Science and Engineering at Hokkaido University. M.F.G. reports disclosures including grants with Varian Medical Systems and stock holdings with Roche. M.Diehnreports disclosures including research support from AstraZeneca and Varian Medical Systems, royalties for patent licenses from Roche and Foresight Diagnostics, consulting fees from AstraZeneca, Boehringer Ingelheim, Genentech, Gritstone Bio, Illumina, and Regeneron, honoraria from Bristol Myers Squibb and Novartis, leadership as a board member of Foresight Diagnostics, and stock/options for CiberMed, Gritstone Bio, and Foresight Diagnostics. B.W.L. reports disclosures including grants with Varian Medical Systems, leadership as a board member of TibaRay, and stock holdings in TibaRay. L.K.V. reports disclosures including grants from RefleXion Medical., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Prostate cancer is projected to account for the greatest proportion of cancer-related burden among men with HIV. However, incidence is reportedly lower than in men without HIV, potentially due to differences in screening. Factors influencing receipt of screening in men with HIV are unknown. We described receipt of prostate-specific antigen (PSA) testing and assessed factors for association with receipt of PSA test., Methods: Demographics, measures of HIV and related care, and non-HIV care were assessed for association with receipt of first PSA test in men ≥40 years old each calendar year in 2000-2020 using univariable and multivariable Poisson regression. Models were additionally stratified by calendar period to identify changes in determinants of PSA test as prostate cancer screening guidelines changed., Results: Men (n = 2,063) 72% Non-Hispanic Black, median age of 47 (IQR: 41, 53), contributed median of 4.7 years (IQR: 2.3, 10.0) of follow-up. Receipt of antiretroviral therapy (aIRR = 1.33; 95% CI: 1.14, 1.55), engagement in HIV care (aIRR = 2.09; 95% CI: 1.66, 2.62), history of testosterone-replacement therapy (aIRR = 1.34; 95% CI: 1.19, 1.50), urologist evaluation (aIRR = 1.66; 95% CI: 1.35, 2.05), and receipt of PSA test in preceding two years (no elevated PSA aIRR = 2.37; 95% CI: 2.16, 2.61; elevated PSA aIRR = 4.35; 95% CI: 3.24, 5.84) were associated with PSA testing in men aged 50 or older. Associations varied across calendar time., Conclusion: Findings suggest men with greater interaction with healthcare are more likely to receive PSA test. Measures of control of HIV did not appear to influence the decision to screen., 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 Elsevier Inc. All rights reserved.)

Introduction: Ketamine has emerged as a promising treatment alternative for the management of chronic pain. Despite encouraging findings in civilian populations, and favourable results from trials examining its efficacy in military populations, there is still a dearth of information pointing to optimal specifications related to ketamine administration for pain, depression, and posttraumatic stress disorder (PTSD) in military populations. This meta-analysis and systematic review synthesised available evidence on the effectiveness, tolerability, and feasibility of ketamine in the management of chronic pain and mental health conditions in military populations., Methods: This review followed the Cochrane's Guide for systematic reviews of interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) as frameworks for data collection and synthesis., Results: A total of 11 studies and 22 independent samples were retained for data analyses. Across samples, improvements in pain, depression, and PTSD outcomes were evident, with the use of ketamine leading to significant reductions, g = 1.76, SE = 0.19, 95% CI (1.39, 2.13), Z = 9.26, p <.001. These effect sizes were robust with moderate-to-large effects. In addition, the reductions in symptoms were observed in both active-duty and Veteran groups, and for different routes of ketamine administration, frequencies of ketamine administration, duration of ketamine treatments, dosage, study design, and allowance for concurrent treatments., Discussion: This review provides a preliminary synthesis of available evidence which suggests that ketamine may be a potential option for the treatment of depression, PTSD, and chronic pain in military populations. The viability of ketamine as an alternative treatment may be particularly impactful for those who are treatment resistant, experience chronic symptoms, and/or have exhausted conventional treatments. More research is warranted in order verify the findings presented in this review., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Ein, Gervasio, Baker, Plouffe, Wanklyn, Burhan, Lau, Abreu, Wasiuta, Nazarov and Richardson.)

Purpose: COVID-19 continues to affect millions of individuals worldwide, both in the short and long term. The post-acute complications of SARS-CoV-2 infection, referred to as long COVID, result in diverse symptoms affecting multiple organ systems. Little is known regarding how the symptoms associated with long COVID progress and resolve over time. The Johns Hopkins COVID Long Study aims to prospectively examine the short-term and long-term consequences of COVID-19 in individuals both with and without a history of SARS-CoV-2 infection using self-reported data collected in an online survey., Participants: 16 764 adults with a history of SARS-CoV-2 infection and 799 adults without a history of SARS-CoV-2 infection who completed an online baseline survey., Findings to Date: This cohort profile describes the baseline characteristics of the Johns Hopkins COVID Long Study. Among 16 764 participants with a history of SARS-CoV-2 infection and defined long COVID status, 75% reported a very good or excellent health status prior to infection, 99% reported experiencing at least one COVID-19 symptom during the acute phase of infection, 9.9% reported hospitalisation and 63% were defined as having long COVID using the WHO definition., Future Plans: Analysis of longitudinal data will be used to investigate the progression and resolution of long COVID symptoms over time., Competing Interests: Competing interests: SHM receives material support from Abbott Laboratories (not related to this study)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diffuse midline gliomas (DMGs) are lethal primary brain tumors in children. The imipridones ONC201 and ONC206 induce mitochondrial dysfunction and have emerged as promising therapies for DMG patients. However, efficacy as monotherapy is limited, identifying a need for strategies that enhance response. Another hurdle is the lack of biomarkers that report on drug-target engagement at an early timepoint after treatment onset. Here, using 1 H-magnetic resonance spectroscopy, which is a non-invasive method of quantifying metabolite pool sizes, we show that accumulation of ψ-aminobutyric acid (GABA) is an early metabolic biomarker that can be detected within a week of ONC206 treatment, when anatomical alterations are absent, in mice bearing orthotopic xenografts. Mechanistically, imipridones activate the mitochondrial protease ClpP and upregulate the stress-responsive transcription factor ATF4. ATF4, in turn, upregulates glutamate decarboxylase, which synthesizes GABA, and downregulates ABAT , which degrades GABA, leading to GABA accumulation in DMG cells and tumors. Functionally, GABA secreted by imipridone-treated cells acts in an autocrine manner via the GABAB receptor to induce expression of superoxide dismutase (SOD1), which mitigates imipridone-induced oxidative stress and, thereby, curbs apoptosis. Importantly, blocking autocrine GABA signaling using the clinical stage GABAB receptor antagonist SGS-742 exacerbates oxidative stress and synergistically induces apoptosis in combination with imipridones in DMG cells and orthotopic tumor xenografts. Collectively, we identify GABA as a unique metabolic adaptation to imipridones that can be leveraged for non-invasive assessment of drug-target engagement and therapy. Clinical translation of our studies has the potential to enable precision metabolic therapy and imaging for DMG patients., One Sentence Summary: Imipridones induce GABA accumulation in diffuse midline gliomas, an effect that can be leveraged for therapy and non-invasive imaging.

Background: Prostate cancer is projected to be the most common cancer among people living with HIV; however, incidence of prostate cancer has been reported to be lower in men with HIV compared to men without HIV with little evidence to explain this difference. We describe prostate cancer incidence by HIV status in Medicaid beneficiaries, allowing for comparison of men with and without HIV who are similar with respect to socioeconomic characteristics and access to healthcare., Methods: Medicaid beneficiaries (N=15,167,636) aged 18-64 with ≥7 months of continuous enrollment during 2001-2015 in 14 US states were retained for analysis. Diagnoses of HIV and prostate cancer were identified using inpatient and other non-drug claims. We estimated cause-specific (csHR) and sub-distribution hazard ratios comparing incidence of prostate cancer by HIV status, adjusted for age, race-ethnicity, state of residence, year of enrollment, and comorbid conditions. Models were additionally stratified by age and race-ethnicity., Results: There were 366 cases of prostate cancer observed over 299,976 person-years among beneficiaries with HIV and 17,224 cases over 22,298,914 person-years in beneficiaries without HIV. The hazard of prostate cancer was lower in men with HIV than men without HIV (csHR=0.89; 95% CI: 0.80, 0.99), but varied by race-ethnicity, with similar observations among non-Hispanic Black (csHR=0.79; 95% CI: 0.69, 0.91) and Hispanic (csHR=0.85; 95% CI: 0.67, 1.09), but not non-Hispanic white men (csHR=1.17; 95% CI: 0.91, 1.50). Results were similar in models restricted to ages 50-64 and 40-49, except for a higher hazard of prostate cancer in Hispanic men with HIV in their 40s, while the hazard of prostate cancer was higher in men with HIV across all models for men aged 18-39., Conclusion: Reported deficits in prostate cancer incidence by HIV status may be restricted to specific groups defined by age and race-ethnicity.

Diffuse midline glioma (DMG) with H3K27M mutation is an aggressive and difficult to treat pediatric brain tumor. Recurrent gain of function mutations in H3.3 (H3.3A) and H3.1 (H3C2) at the 27th lysine to methionine (H3K27M) are seen in over 2/3 of DMGs, and are associated with a worse prognosis. Due to the anatomical location of DMG, traditional biopsy carries risk for neurologic injury as it requires penetration of vital midline structures. Further, radiographic (MRI) monitoring of DMG often shows nonspecific changes, which makes therapeutic monitoring difficult. This indicates a critical need for more minimally invasive methods, such as liquid biopsy, to understand, diagnose, and monitor H3K27M DMG. Here, we review the use of all modalities to date to detect biomarkers of H3K27M in cerebrospinal fluid (CSF), blood, and urine, and compare their effectiveness in detection, diagnosis, and monitoring treatment response. We provide specific detail of recent efforts to monitor CSF and plasma H3K27M cell-free DNA in patients undergoing therapy with the imipridone ONC201. Lastly, we discuss the future of therapeutic monitoring of H3K27M-DMG, including biomarkers such as mitochondrial DNA, mutant and modified histones, and novel sequencing-based approaches for improved detection methods., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Alcohol use was associated with elevated COVID-19 risk in the general population. People with HIV (PWH) have high prevalences of alcohol use. To evaluate the effect of alcohol use on COVID-19 risks among PWH, we estimated the risk of COVID-19 diagnosis and COVID-19-related hospitalization among PWH in routine care at 8 HIV primary care centers that contributed data to the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort according to their alcohol use just prior to the COVID-19 pandemic. The CNICS data repository includes demographic characteristics, clinical diagnoses, and laboratory test results from electronic medical records and other sources. Alcohol use, substance use, and mental health symptoms were self-reported on tablet-based standardized surveys. Alcohol use was categorized according to standard, sex-specific Alcohol Use Disorder Identification Test-Consumption instrument cut-offs. We followed 5,496 PWH (79% male, 48% Black race, median age = 53 years) from March 1, 2020 to December 31, 2020. Relative to PWH with no baseline alcohol use, the adjusted hazard ratio (aHR) of COVID-19 diagnosis was 1.09 (95% confidence interval [CI]: 0.78, 1.51) for lower-risk drinking and 1.19 (95%CI: 0.81, 1.73) for unhealthy drinking. The aHR of COVID-19-related hospitalization was 0.82 (95%CI: 0.33, 1.99) for lower-risk drinking and 1.25 (95%CI: 0.50, 3.09) for unhealthy drinking. Results were not modified by recent cocaine or non-prescribed opioid use, depressive symptoms, or diagnoses of alcohol use disorder. The study suggested a slightly increased, but not statistically significant risk of COVID-19 diagnosis and hospitalization associated with unhealthy alcohol use., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Substance use in people with HIV (PWH) negatively impacts antiretroviral therapy (ART) adherence. However, less is known about this in the current treatment era and the impact of specific substances or severity of substance use. We examined the associations of alcohol, marijuana, and illicit drug use (methamphetamine/crystal, cocaine/crack, illicit opioids/heroin) and their severity of use with adherence using multivariable linear regression in adult PWH in care between 2016 and 2020 at 8 sites across the US. PWH completed assessments of alcohol use severity (AUDIT-C), drug use severity (modified ASSIST), and ART adherence (visual analogue scale). Among 9400 PWH, 16% reported current hazardous alcohol use, 31% current marijuana use, and 15% current use of ≥1 illicit drugs. In multivariable analysis, current methamphetamine/crystal use, particularly common among men who had sex with men, was associated with 10.1% lower mean ART adherence ( p  < 0.001) and 2.6% lower adherence per 5-point higher severity of use (ASSIST score) ( p  < 0.001). Current and more severe use of alcohol, marijuana, and other illicit drugs were also associated with lower adherence in a dose-dependent manner. In the current HIV treatment era, individualized substance use treatment, especially for methamphetamine/crystal, and ART adherence should be prioritized.

Community-based serological studies are increasingly relied upon to measure disease burden, identify population immunity gaps, and guide control and elimination strategies; however, there is little understanding of the potential for and impact of sampling biases on outcomes of interest. As part of efforts to quantify measles immunity gaps in Zambia, a community-based serological survey using stratified multi-stage cluster sampling approach was conducted in Ndola and Choma districts in May-June 2022, enrolling 1245 individuals. We carried out a follow-up study among individuals missed from the sampling frame of the serosurvey in July-August 2022, enrolling 672 individuals. We assessed the potential for and impact of biases in the community-based serosurvey by i) estimating differences in characteristics of households and individuals included and excluded (77% vs 23% of households) from the sampling frame of the serosurvey and ii) evaluating the magnitude these differences make on healthcare-seeking behavior, vaccination coverage, and measles seroprevalence. We found that missed households were 20% smaller and 25% less likely to have children. Missed individuals resided in less wealthy households, had different distributions of sex and occupation, and were more likely to seek care at health facilities. Despite these differences, simulating a survey in which missed households were included in the sampling frame resulted in less than a 5% estimated bias in these outcomes. Although community-based studies are upheld as the gold standard study design in assessing immunity gaps and underlying community health characteristics, these findings underscore the fact that sampling biases can impact the results of even well-conducted community-based surveys. Results from these studies should be interpreted in the context of the study methodology and challenges faced during implementation, which include shortcomings in establishing accurate and up-to-date sampling frames. Failure to account for these shortcomings may result in biased estimates and detrimental effects on decision-making., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kostandova 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.)

Background: People with human immunodeficiency virus (HIV; PWH) in the United States have a lower incidence of colon cancer than the general population. The lower incidence may be explained by differences in receipt of screening. Thus, we sought to estimate colon cancer incidence under scenarios in which Medicaid beneficiaries, with or without HIV, followed the same screening protocols., Methods: We used data from 1.5 million Medicaid beneficiaries who were enrolled in 14 US states in 2001-2015 and aged 50-64 years; 72 747 beneficiaries had HIV. We estimated risks of colon cancer and death by age, censoring beneficiaries when they deviated from 3 screening protocols, which were based on Medicaid's coverage policy for endoscopies during the time period, with endoscopy once every 2, 4, or 10 years. We used inverse probability weights to control for baseline and time-varying confounding and informative loss to follow-up. Analyses were performed overall, by sex, and by race/ethnicity., Results: PWH had a lower incidence of colon cancer than beneficiaries without HIV. Compared with beneficiaries without HIV, the risk difference at age 65 years was -1.6% lower (95% confidence interval, -2.3% to -.7%) among PWH with the 2-year protocol and -0.8% lower (-1.3% to -.3%) with the 10-year protocol. Results were consistent across subgroup and sensitivity analyses., Conclusions: Our findings suggest that the lower risk of colon cancer that has been observed among PWH aged 50-64 years compared with those without HIV is not due to differences in receipt of lower endoscopy. Keywords: colon cancer, colorectal cancer screening, endoscopy, Medicaid, human immunodeficiency virus., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Intraperitoneal onlay mesh (IPOM) placement for small to medium-sized hernias has garnered negative attention due to perceived long-term risk of mesh-related complications. However, sparse data exists supporting such claims after minimally invasive (MIS) IPOM repairs and most is hindered by the lack of long-term follow-up. We sought to report long-term outcomes and mesh-related complications of MIS IPOM ventral hernia repairs., Methods and Procedures: Adult patients who underwent MIS IPOM ventral hernia repair at our institution were identified in the Abdominal Core Health Quality Collaborative database from October 2013 to October 2020. Outcomes included hernia recurrence and mesh-related complications or reoperations up to 6 years postoperatively., Results: A total of 325 patients were identified. The majority (97.2%) of cases were elective, non-recurrent (74.5%), and CDC class I (99.4%). Mean hernia width was 4.16 ± 3.86 cm. Median follow-up was 3.6 (IQR 2.8-5) years. Surgeon-entered or patient-reported follow-up was available for 253 (77.8%) patients at 3 years or greater postoperatively. One patient experienced an early small bowel obstruction and was reoperated on within 30 days. Two-hundred forty-five radiographic examinations were available up to 6 years postoperatively. Twenty-seven patients had hernia recurrence on radiographic examination up to 6 years postoperatively. During long-term follow-up, two mesh-related complications required reoperations: mesh removed for chronic pain and mesh removal at the time of colon surgery for perforated cancer. Sixteen additional patients required reoperation within 6 years for the following reasons: hernia recurrence (n = 5), unrelated intraabdominal pathology (n = 9), obstructed port site hernia (n = 1), and adhesive bowel obstruction unrelated to the prosthesis (n = 1). The rate of reoperation due to intraperitoneal mesh complications was 0.62% (2/325) with up to 6 year follow-up., Conclusion: Intraperitoneal mesh for repair of small to medium-sized hernias has an extremely low rate of long-term mesh-related complications. It remains a safe and durable option for hernia surgeons., (© 2024. The Author(s).)

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors' antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Introduction: 10-year outcomes in patients living with HIV who are diagnosed with prostate cancer are unknown., Methods: 52 patients living with HIV were diagnosed with prostate cancer. Disease-free survival stratified by clinical, pathologic, and HIV characteristics were examined., Results: No difference in disease-free survival was observed based on prostate cancer treatment modality, CD4 count, or HIV viral load., Conclusions: Prostate cancer outcomes in patients living with HIV are favorable irrespective of treatment modality., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose/objectives: Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection., Materials/methods: We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts., Results: Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation CONCLUSION: In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients., Competing Interests: Disclosure Billy W Loo: co-founder and board member of TibaRay and a consultant on a clinical trial steering committee of Beigene, and has received lecture honorarium from Mevion; Joel W Neal: ASCO; Millie Das: consulting with Genentech and Eurofins; participation on the advisory board for AstraZeneca, Beigene, Sanofi/Genzyme, and Janssen; and research with Merck, Genentech, CellSight, Novartis, AbbVie, United Therapeutics, Verily, Varian Medical Systems and Celgene; Heather Wakelee: grants with ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol-Myers Squibb, Clovis Oncology, Genentech/Roche, Merck, Novartis, SeaGen, Xcovery, and Helsinn; participation on the advisory board for AstraZeneca, Blueprint, Mirati, Merck, and Genentech/Roche; and leadership with International Association for the Study of Lung Cancer and ECOG-ACRIN; Maximilian Diehn: grants with Varian, Genentech, and AstraZeneca; royalties for patent license with Roche and Foresight Diagnostics; consulting fees with Roche Sequencing Solutions, Varian, BioNTech, RefleXion, Novartis, Illumina, Genentech, BioNTech, Boehringer Ingelheim, and Gritstone Oncology; patents with Roche, Foresight Diagnostics, and Celgene; participation on the advisory board for AstraZeneca, Genentech, Boehringer Ingel- heim, Illumina, and Gritstrone; leadership as a board member of Foresight Diagnostics; stock holdings with Foresight Diagnostics and CiberMed; and in-kin research from Illumina; Lucas Vitzthum: grants from RefleXion Medical; Mohona Roy: Speakers' Bureau: MJH Life Sciences; Research Funding: Varian Medical Systems (Inst) Nathaniel Myall: Honoraria: Patient Power The remaining authors declare no conflict of interest., (Published by Elsevier Inc.)

Background: Thrice-daily physiotherapy immediately following surgical repair of hip fracture has been shown to be safe and to reduce total hospital length of stay. However, implementing this is challenging with respect to health service funding and staffing. A novel approach may be to utilize an alternative workforce (allied health staff and student physiotherapists) to deliver two of the three daily treatments. However, how patients and staff may view such an approach is unknown. Thus, the aim of this qualitative study was to explore the views of inpatients with surgical repair of a hip fracture, their carers, health care professionals, and physiotherapy students about the implementation and acceptability of thrice-daily physiotherapy, with two sessions delivered by the alternative workforce (the BOOST study)., Methods: Semi-structured interviews and focus groups with patients, carers, health professionals and physiotherapy students. All interviews were digitally recorded and transcribed via verbatim. The transcripts were coded, and the data analysed via inductive thematic analysis., Results: A total of 37 interviews (32 one-to-one interviews and five focus group interviews) were analysed. Five main themes were identified: (1) individual perceptions of the intervention: inpatients/carer/staff/student, (2) implementation within the service and organisational context, (3) implementation strategies that were effective, (4) improvements to implementation strategies/barriers to implementation/unsuccessful strategies and (5) future directions of BOOST., Conclusions: The qualitative data revealed that higher frequency physiotherapy was well-received by inpatients and that staff/students involved in providing care perceived it as a safe, acceptable and valuable practice. Implementation of higher daily frequency of physiotherapy using an alternative workforce may feasibly be adopted for inpatients following hip fracture surgery., Trial Registration: This study was approved by the Human Research Ethics Committee (HREC) of the Western Sydney Local Health District (2020/ETH02718). Mutual recognition of approval was subsequently obtained from Northern Sydney Local Health District HREC., (© 2024. Crown.)

Background: Improved treatment strategies are needed for patients with locally advanced gastric cancer with poor response to neoadjuvant chemotherapy. We aimed to describe patterns of failure for patients with no or partial response (NR, PR) to preoperative chemotherapy., Patients and Methods: We analyzed patients with locally advanced gastric cancer treated from 2008 to 2022 with preoperative chemotherapy followed by surgery with D2 resection. We excluded patients who received radiation. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated. For patients with recurrent abdominal disease, hypothetical radiation clinical treatment volumes (CTV) were contoured on postoperative scans and compared with patterns of recurrence., Results: A total of 60 patients were identified. The most used preoperative chemotherapy was FLOT (38.6%), followed by FOLFOX (30%) and ECF/ECX/EOX (23.3%). Four (6.7%), 40 (66.7%), and 9 patients (15%) had a complete pathologic response (CR), PR, and NR to neoadjuvant therapy, respectively. Among patients without a CR, 3-year overall and progression-free survival rates were 62.3% (95% CI 48-76.6%) and 51.3% (95% CI 36.9-65.7%), respectively. Three-year cumulative incidence of LRF and DM were 8.4% (95% CI 0.4-16.4%) and 41.0% (95% CI 26.3-55.4%), respectively. Absolute rates of patients having the first site of recurrence encompassed by a postoperative radiation CTV was 2.0% for patients without a CR and 0% for patients with NR., Conclusions: Patients with locally advanced gastric cancer with less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival., (© 2023. Society of Surgical Oncology.)

Background: Life expectancy among people with HIV (PWH) is increasing, making chronic conditions-including cancer-increasingly relevant. Among PWH, cancer burden has shifted from AIDS-defining cancers (ADCs) toward non-AIDS-defining cancers (NADCs)., Setting: We described incidence of cancer in a claims-based cohort of Medicaid beneficiaries. We included 43,426,043 Medicaid beneficiaries (180,058 with HIV) from 14 US states, aged 18-64, with >6 months of enrollment (with no dual enrollment in another insurance) and no evidence of a prveious cancer., Methods: We estimated cumulative incidence of site-specific cancers, NADCs, and ADCs, by baseline HIV status, using age as the time scale and accounting for death as a competing risk. We compared cumulative incidence across HIV status to estimate risk differences. We examined cancer incidence overall and by sex, race/ethnicity, and calendar period., Results: PWH had a higher incidence of ADCs, infection-related NADCs, and death. For NADCs such as breast, prostate, and colon cancer, incidence was similar or higher among PWH below age 50, but higher among those without HIV by age 65. Incidence of lung and head and neck cancer was always higher for female beneficiaries with HIV, whereas the curves crossed for male beneficiaries. We saw only small differences in incidence trends by race/ethnicity., Conclusion: Our findings suggest an increased risk of certain NADCs at younger ages among PWH, even when compared against other Medicaid beneficiaries, and highlight the importance of monitoring PWH for ADCs and NADCs. Future work should explore possible mechanisms explaining the differences in incidence for specific cancer types., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Studies suggest a lower colorectal cancer (CRC) risk and lower or similar CRC screening among people with HIV (PWH) compared with the general population. We evaluated the incidence of lower endoscopy and average-onset (diagnosed at ≥50) and early-onset (diagnosed at <50) colon cancer by HIV status among Medicaid beneficiares with comparable sociodemographic factors and access to care., Methods: We obtained Medicaid Analytic eXtract (MAX) data from 2001 to 2015 for 14 states. We included 41 727 243 and 42 062 552 unique individuals with at least 7 months of continuous eligibility for the endoscopy and colon cancer analysis, respectively. HIV and colon cancer diagnoses and endoscopy procedures were identified from inpatient and other nondrug claims. We used Cox proportional hazards regression models to assess endoscopy and colon cancer incidence, controlling for age, sex, race/ethnicity, calendar year and state of enrollment, and comorbidities conditions., Results: Endoscopy and colon cancer incidence increased with age in both groups. Compared with beneficiaries without HIV, PWH had an increased hazard of endoscopy; this association was strongest among those 18-39 years [hazard ratio: 1.85, 95% confidence interval (95% CI) 1.77-1.92] and attenuated with age. PWH 18-39 years also had increased hazard of early-onset colon cancer (hazard ratio: 1.66, 95% CI:1.05-2.62); this association was attenuated after comorbidity adjustment. Hazard ratios were null among all beneficiaries less than 50 years of age. PWH had a lower hazard of average-onset colon cancer compared with those without HIV (hazard ratio: 0.79, 95% CI: 0.66-0.94)., Conclusion: PWH had a higher hazard of endoscopy, particularly at younger ages. PWH had a lower hazard of average-onset colon cancer. Early-onset colon cancer was higher among the youngest PWH but not associated with HIV overall., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: "Sick quitting," a phenomenon describing reductions in alcohol consumption following poor health, may explain observations that alcohol appears protective for frailty risk. We examined associations between frailty and reductions in drinking frequency among people with HIV (PWH). At six Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) sites between January 2012 and August 2021, we assessed whether frailty, measured through validated modified frailty phenotype, precedes reductions in drinking frequency. We associated time-updated frailty with quitting and reducing frequency of any drinking and heavy episodic drinking (HED), adjusted for demographic and clinical characteristics in Cox models. Among 5,654 PWH reporting drinking, 60% reported >monthly drinking and 18% reported ≥monthly HED. Over an average of 5.4 years, frail PWH had greater probabilities of quitting (HR: 1.56, 95% confidence interval [95% CI] [1.13-2.15]) and reducing (HR: 1.35, 95% CI [1.13-1.62]) drinking frequency, as well as reducing HED frequency (HR: 1.58, 95% CI [1.20-2.09]) versus robust PWH. Sick quitting likely confounds the association between alcohol use and frailty risk, requiring investigation for control., (Copyright © 2024 Association of Nurses in AIDS Care.)

Background: Ankle arthroscopy is commonly performed using a thigh tourniquet and is thought to improve visibility and reduce operative time. However, the current evidence is unclear as to whether the use of a tourniquet provides these benefits. The aim of this study was to investigate whether there is any clinical benefit of using a tourniquet in ankle arthroscopy., Methods: A systematic review following PRISMA guidelines was undertaken. All clinical studies published in Medline, Embase, PubMed and the Cochrane Library Database from inception until January 2023 reporting on the use of a tourniquet in ankle arthroscopy were included., Results: 180 studies were identified of which 3 (164 patients) met the inclusion criteria. All studies showed no statistically significant difference in mean surgical time and complication rate between the tourniquet and non-tourniquet groups. Overall, the quality of the evidence was moderate to poor without data in favour or against the routine use of tourniquets in ankle arthroscopy., Conclusion: The current literature suggests that there are no significant differences in mean surgical time and complication rate between the tourniquet and non-tourniquet groups., Competing Interests: Declaration of Competing Interest The authors whose names are listed above certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2023 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Background: Exergaming has been proposed to improve gait and balance disorders in Parkinson's disease (PD) patients. We aimed to assess the efficacy of a home-based, tailored, exergaming training system designed for PD patients with dopa-resistant gait and/or balance disorders in a controlled randomized trial., Methods: We recruited PD patients with dopa-resistant gait and/or balance disorders. Patients were randomly assigned (1:1 ratio) to receive 18 training sessions at home by playing a tailored exergame with full-body movements using a motion capture system (Active group), or by playing the same game with the computer's keyboard (Control group). The primary endpoint was the between-group difference in the Stand-Walk-Sit Test (SWST) duration change after training. Secondary outcomes included parkinsonian clinical scales, gait recordings, and safety., Results: Fifty PD patients were enrolled and randomized. After training, no significant difference in SWST change was found between groups (mean change SWST duration [SD] -3.71 [18.06] s after Active versus -0.71 [3.41] s after Control training, p = 0.61). Some 32% of patients in the Active and 8% in the Control group were considered responders to the training program (e.g., SWST duration change ≥2 s, p = 0.03). The clinical severity of gait and balance disorders also significantly decreased after Active training, with a between-group difference in favor of the Active training (p = 0.0082). Home-based training induced no serious adverse events., Conclusions: Home-based training using a tailored exergame can be performed safely by PD patients and could improve gait and balance disorders. Future research is needed to investigate the potential of exergaming., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The virtual reality (VR) environment is claimed to be highly immersive. Participants may thus be potentially unaware of their real, external world. The present study presented irrelevant auditory stimuli while participants were engaged in an easy or difficult visual working memory (WM) task within the VR environment. The difficult WM task should be immersive and require many cognitive resources, thus few will be available for the processing of task-irrelevant auditory stimuli. Sixteen young adults wore a 3D head-mounted VR device. In the easy WM task, the stimuli were nameable objects. In the difficult WM task, the stimuli were abstract objects that could not be easily named. A novel paradigm using event-related potentials (ERPs) was implemented to examine the feasibility of quantifying the extent of processing of task-irrelevant stimuli occurring outside of the VR environment. Auditory stimuli irrelevant to the WM task were presented concurrently at every 1.5 or 12 s in separate conditions. Performance on the WM task varied with task difficulty, with accuracy significantly lower during the difficult task. The auditory ERPs consisted of N1 and a later P2/P3a deflection which were larger when the auditory stimuli were presented slowly. ERPs were unaffected by task difficulty, but significant correlations were found. N1 and P2/P3a amplitudes were smallest when performance on the Easy WM task was highest. It is possible that even the easy WM task was so immersive and required many processing resources that few were available for the co-processing of the task-irrelevant auditory stimuli., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The rixosome defined in Schizosaccharomyces pombe and humans performs diverse roles in pre-ribosomal RNA processing and gene silencing. Here, we isolate and describe the conserved rixosome from Chaetomium thermophilum, which consists of two sub-modules, the sphere-like Rix1-Ipi3-Ipi1 and the butterfly-like Las1-Grc3 complex, connected by a flexible linker. The Rix1 complex of the rixosome utilizes Sda1 as landing platform on nucleoplasmic pre-60S particles to wedge between the 5S rRNA tip and L1-stalk, thereby facilitating the 180° rotation of the immature 5S RNP towards its mature conformation. Upon rixosome positioning, the other sub-module with Las1 endonuclease and Grc3 polynucleotide-kinase can reach a strategic position at the pre-60S foot to cleave and 5' phosphorylate the nearby ITS2 pre-rRNA. Finally, inward movement of the L1 stalk permits the flexible Nop53 N-terminus with its AIM motif to become positioned at the base of the L1-stalk to facilitate Mtr4 helicase-exosome participation for completing ITS2 removal. Thus, the rixosome structure elucidates the coordination of two central ribosome biogenesis events, but its role in gene silencing may adapt similar strategies., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Objectives: Policing is recognized as a highly stressful occupation, encompassing stressors not commonly encountered in other fields. In response, police-specific stress scales have been developed and used when studying police work. Despite changes in the composition of police personnel, most studies examining police working conditions focus on sworn police officers (SPO), excluding employees without police education (EWPE). To advance research and practice on stress in the police, align results, and increase the possibilities for comparisons across studies using police-specific measures (PSMs) we conducted a psychometric evaluation of the two scales in the Police Stress Questionnaire (PSQ). We examined whether adding "Not Applicable" to the response scales would reduce vulnerability and make the PSQ more robust., Method: Based on a survey with a randomised sample ( N = 560) of SPO and EWPE in the Norwegian Police, we tested the original factor structures of the PSQ through Confirmatory Factor Analysis including tests of factor structures from previous studies., Results: For all models, the indicators of fit indicated a poor fit with either our whole or stratified sample. The response choice 'Not Applicable' provided extended information for SPOs and EWPEs on the PSQ., Conclusions: To promote aligning results and enabling comparisons across studies using the PSQ, we suggest treating the PSQ scales as formative indexes, rather than reflective scales. Adding "Not Applicable" to the response scale offers an influential elaboration of the PSQ with beneficial and extended information. Generalised studies of stress in the police should include the entire population working there., 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.