Assessment of the Omius™ cooling headband effectiveness during a 70-min submaximal running effort followed by a 5-km time-trial in hot/humid conditions.

Exercise performed under hot/humid conditions can hinder endurance performance. The Omius™ headband (OH) is purported to reduce the perception of heat and improve performance. We examined the impact of OH on selected thermal and cardiovascular functions, subjective perceptions and running performance. Using a randomized crossover protocol, 10 trained male athletes (28 ± 4 years) completed two trials (OH and sham headband (SH), 35.0 ± 0.3 °C, 56 ± 3% relative humidity) comprising 70 min of running (60% V˙ O2max) followed by a 5-km running time-trial (TT). Heart rate, perceived exertion and whole-body thermal comfort did not significantly differ between conditions during the submaximal running effort and TT. Rectal temperature was higher with OH (0.11 ± 0.16 °C, p = 0.052) than SH prior to the submaximal running effort, however, no significant differences were observed between conditions regarding the changes in rectal temperature from baseline during the submaximal running effort and TT. Forehead temperature was significantly lower with OH than SH during the submaximal running effort, but no significant differences were observed at the end of the TT. Scores of perceived forehead thermal comfort was only significantly lower with OH than SH during the submaximal running effort. TT performance did not significantly differ between OH (19.8 ± 1.2 min) and SH (20.2 ± 1.0 min). In conclusion, OH improves forehead thermal comfort and reduces forehead temperature but not rectal temperature, heart rate and perceived exertion during, nor 5-km TT performance following, 70 min of submaximal running in the heat.

Neonatal Outcomes of Multiple Congenital Thoracic Lesions.

INTRODUCTION: Congenital pulmonary airway malformations (CPAM), intra- and extralobar bronchopulmonary sequestrations (iBPS/eBPS), CPAM-BPS hybrid lesions (HL), congenital lobar emphysema (CLE), bronchial atresia (BA), and foregut duplication cysts (FDC), collectively referred to as congenital thoracic lesions (CTL), are mostly solitary. Patients with multiple CTL are rare, and reports on such cases are scarce. To address this dearth, we analyzed a large multifocal CTL patient cohort. METHODS: Retrospective chart review of patients born between 1/1/2013 and 3/31/2023 who underwent surgery for a CTL at our tertiary center. Patients with radiological and surgical diagnosis of multifocal CTL, defined as ≥2 CTL present in more than one lobe were included to record pre-, peri-, and postnatal patient characteristics. RESULTS: Among 701 CTL patients, 74(10.5%) had multiple CTL. CTL multifocality was prenatally recognized correctly in 8(12.9%) patients. Most multiple CTL were right-sided, unilateral multilobar lesions (n=33, 44%). Bilateral CTL were found in 9(12.1%) patients. CPAM-CPAM lesions were the most prevalent CTL types (n=36, 49%). Genetic syndromes were confirmed in 3(4%) and additional congenital anomalies in 9(12.9%) patients, 5 of those had multiple congenital anomalies. Of 49(65%) patients with multilobar CTL, 25(51%) underwent bilobectomy and 24(49%) lung-sparing surgery. Length of stay was similar. Mortality was 5.4%. CONCLUSION: We report on the largest patient cohort with multiple CTL to date. Multiple CTL occurred in 1/10 patients with CTL, and only 12.9% were recognized prenatally. Lung-sparing surgery can be considered. Multiple additional congenital anomalies and genetic syndromes may be more common and genetic testing should be considered. Overall, outcomes in this patient population are favorable.

Systemic analysis of lipid metabolism from individuals to multi-organism systems.

Lipid metabolism is recognised as being central to growth, disease and health. Lipids, therefore, have an important place in current research on globally significant topics such as food security and biodiversity loss. However, answering questions in these important fields of research requires not only identification and measurement of lipids in a wider variety of sample types than ever before, but also hypothesis-driven analysis of the resulting 'big data'. We present a novel pipeline that can collect data from a wide range of biological sample types, taking 1 000 000 lipid measurements per 384 well plate, and analyse the data systemically. We provide evidence of the power of the tool through proof-of-principle studies using edible fish (mackerel, bream, seabass) and colonies of Bombus terrestris. Bee colonies were found to be more like mini-ecosystems and there was evidence for considerable changes in lipid metabolism in bees through key developmental stages. This is the first report of either high throughput LCMS lipidomics or systemic analysis in individuals, colonies and ecosystems. This novel approach provides new opportunities to analyse metabolic systems at different scales at a level of detail not previously feasible, to answer research questions about societally important topics.

Prognostic value of nucleotide excision repair and translesion DNA synthesis proteins in muscle-infiltrating bladder carcinoma.

BACKGROUND: Cisplatin (CDDP) remains a key agent in the treatment of muscle-infiltrating bladder carcinoma (MIBC). However, a proportion of MIBC patients do not respond to chemotherapy, which may be caused by the increased repair of CDDP-induced DNA damage. The purpose of this study was to explore the prognostic value of proteins involved in nucleotide excision repair (NER) and translesion DNA synthesis (TLS) in MIBC patients. METHODS: This is a retrospective analysis of 86 MIBC patients. The XPA, XPF, XPG, ERCC1, POLI, POLH and REV3L proteins were stained in primary bladder tumors and their levels were analyzed both in the total cohort and in a subgroup with metastatic urothelial carcinoma (mUC) that received gemcitabine and CDDP as a first-line therapy. Both cohorts were divided by percentage of cancer cells stained positive for each protein into subgroups with high and low expression. In the same manner, the combined expression of NER (XPA + ERCC1 + XPF + XPG) and TLS (POLI + POLH + REV3L), as the whole pathways, was analyzed. RESULTS: Mortality was 89.5% at the median follow-up of 120.2 months. In the total cohort, patients with tumors stained positive for XPA, XPG and POLI had significantly worse overall survival (OS) compared to those with negative staining [hazard ratio (HR) = 0.60, 0.62 and 0.53, respectively]. Both XPG and POLI were independent prognostic factors in multivariate analyses (MVA). In addition, an increase in NER and TLS pathway expression was significantly associated with worse OS in the total cohort (HR = 0.54 and 0.60, respectively). In the mUC subgroup, high POLI expression was associated with significant deterioration of OS (HR = 0.56) in univariate analyses, and its independent prognostic value was shown in MVA. CONCLUSIONS: Our study showed significant correlations between the tumor expression of XPG and POLI, as well as NER and TLS as the whole pathways, and inferior OS. Hence, they could constitute prognostic biomarkers and potentially promising therapeutic targets in MIBC. However, a prospective trial is required for further validation, thereby overcoming the limitations of this study.

Temporal Trends in Takotsubo Syndrome: Results From the International Takotsubo Registry.

BACKGROUND: The perception of takotsubo syndrome (TTS) has evolved significantly over the years, primarily driven by increased recognition of acute complications and mortality. OBJECTIVES: This study aimed to explore temporal trends in demographic patterns, risk factors, clinical presentations, and outcomes in patients with TTS. METHODS: Patients diagnosed with TTS between 2004 and 2021 were enrolled from the InterTAK (International Takotsubo) registry. To assess temporal trends, patients were divided into 6 groups, each corresponding to a 3-year interval within the study period. RESULTS: Overall, 3,957 patients were included in the study. There was a significant demographic transition, with the proportion of male patients rising from 10% to 15% (P = 0.003). Although apical TTS remained the most common form, the diagnosis of midventricular TTS increased from 18% to 28% (P = 0.018). The prevalence of physical triggers increased from 39% to 58% over the years (P < 0.001). There was a significant increase in 60-day mortality over the years (P < 0.001). However, a landmark analysis excluding patients who died within the first 60 days showed no differences in 1-year mortality (P = 0.150). CONCLUSIONS: This study of temporal trends in TTS highlights a transition in patients demographic with a growing prevalence among men, increasing recognition of midventricular TTS type, and increased short-term mortality and rates of cardiogenic shock in recent years. This transition aligns with the rising prevalence of physical triggers, as expression of increased recognition of TTS in association with acute comorbidities.

Haematopoietic stem cell transplantation for CTLA-4 insufficiency across Europe: an EBMT Inborn Errors Working Party study.

BACKGROUND: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterised by lymphoproliferation, dysgammaglobulinaemia, and multi-organ autoimmunity including cytopenias and colitis. OBJECTIVE: To examine the outcome of HSCT for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4-Ig therapy and pre-HSCT immune dysregulation on survival and immunological outcome. METHODS: Retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the Inborn Errors Working Party of EBMT. Primary endpoints were overall survival (OS) and disease- and chronic GvHD-free survival (DFS). Secondary endpoint was immunological outcome assessed by Immune Dysregulation Disease Activity (IDDA) score. RESULTS: Forty patients were included over a 25-year period. Pre-HSCT, 60% received CTLA-4-Ig and IDDA was 23.3 (3.9-84.0). Median age at HSCT was 14.2 (1.3-56.0) years. Patients received PBSC (58%) or marrow (43%) from MUD (75%), MMUD (12.5%) or MFD (12.5%). Median follow-up was 3 years (0.6-15 years) and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, 28/30 surviving patients are in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity pre-HSCT (IDDA<23, p=0.002 and p=0.006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant-related in 7/8 patients. CONCLUSION: This is the largest retrospective study of HSCT for CTLA-4 insufficiency to date. HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity.

Temporal Immune Profiling in the CSF and Blood of Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is a significant complication of aneurysmal subarachnoid hemorrhage (aSAH). This study profiled immune responses after aSAH and evaluated their association with DCI onset. METHODS: Twelve aSAH patients were enrolled. Leukocyte populations and cytokine levels were analyzed in cerebrospinal fluid (CSF) and peripheral blood (PB) on days 3, 5, 7, 10, and 14 post-aSAH. Peripheral blood mononuclear cells (PBMCs) were collected and their cytokine production quantified following stimulation. RESULTS: Mixed-effects models revealed distinct immune cell dynamics in CSF compared to blood. Natural killer T cell frequency increased over time in CSF only, while monocyte/macrophage numbers increased in both CSF and PBMCs. CD4+ HLA II+ T cells increased in circulation. Unstimulated PBMCs showed increased IL-1ß, IL-6, and TNFα production, peaking at 7 days post-aSAH, coinciding with typical DCI onset. Ex vivo stimulation of PBMCs showed that only IL-6 significantly changed over time. In CSF, cytokines peaked 5 days post-injury, preceding immune cell profile alterations. CONCLUSIONS: Our findings reveal a time-dependent immune response following aSAH, with distinct within-patient patterns in CSF and PB. The early CSF cytokine peak preceding immune cell changes suggests a potential mechanistic link and identifies the cytokine response as a promising therapeutic target. This cytokine surge may drive immune cell expansion and prime PBMCs for increased inflammatory activity, potentially contributing to DCI risk. Future studies should explore the importance and sources of specific cytokines in driving immune activation. These insights may inform the development of targeted immunomodulatory strategies for preventing or managing DCI in aSAH patients.

The Prevalence of Shoulder and Elbow Pathology in Major League Baseball Prospects From the Dominican Republic.

BACKGROUND: Rates of shoulder and elbow pathology are well documented among competitive baseball players in the United States; however, little is known about the prevalence of these pathologies in the Dominican Republic (DR). PURPOSE: To report the epidemiology of shoulder and elbow pathology among participants at a Major League Baseball scouting event in Santo Domingo, DR. STUDY DESIGN: Retrospective descriptive study. LEVEL OF EVIDENCE: 3. METHODS: All pitchers and position players who attended the 2021 scouting event were reviewed. Those with complete medical history, physical examination, imaging series, and radiology reports were included. All participants underwent shoulder and elbow radiography, while pitchers also underwent magnetic resonance imaging (MRI). All pathologic findings on imaging studies were recorded and compared among position players and pitchers. RESULTS: Seventy-five participants (average age, 17.9 years) were reviewed (42 position players, 33 pitchers); 72% and 32% had ≥1 abnormal finding on elbow and shoulder radiographs, respectively. Position players had significantly higher numbers of elbow radiographic findings compared with pitchers (81% vs 57.6%, P = 0.03) but similar numbers on shoulder radiograph (28.6% vs 33.3%, P = 0.66). Position players had high numbers of acromioclavicular separation (14.3%) and little leaguer's shoulder (14.3%) on shoulder radiograph, with olecranon osteophytes (23.8%) and medial epicondyle nonunions (11.9%) prevalent on elbow radiograph. Pitchers had high numbers of rotator cuff pathology (93.9%), labral tears (75.8%), and Bennett lesions (51.5%). On elbow imaging, pitchers had high numbers of ulnar collateral ligament (UCL) abnormalities (81.8%), olecranon osteophytes (69.7%), osteochondral lesions (18.2%), and medial epicondyle nonunions (12.1%). Two pitchers had complete UCL disruption (6.1%), while 8 had partial tears (24.2%). CONCLUSION: Dominican baseball prospects had high numbers of asymptomatic shoulder and elbow pathology on imaging studies. Knowledge of the prevalence of these pathologies can guide injury prevention programs in Dominican youth baseball.

Standardized intermittent shoreline boat electrofishing for slow-flowing rivers in Sweden.

Electrofishing is a common method for sampling fish in rivers. In Sweden, electrofishing has a long history, dating back to the 1950s, but the vast majority of surveys have been conducted by wading in shallow river stretches, leaving a data gap for non-wadable rivers. Boat electrofishing allows for surveys in deeper river sections, but limited numbers of operational electrofishing boats have led to standardisation of methods not being prioritized within Swedish water management. This method protocol describes the first Swedish standardised method for boat electrofishing, based on intermittent shoreline sampling in larger slow-flowing rivers. The paper describes:•General methodology for boat electrofishing operation•Data collection protocols•Discussion of current caveats for the methodIn the future, the methodology will be amended to cover a wider array of river types (e.g. faster flowing river sections). Hence, readers are advised to look for updates to the protocol.

A monoclonal antibody targeting the Nipah virus fusion glycoprotein apex imparts protection from disease.

Nipah virus (NiV) is a highly pathogenic paramyxovirus capable of causing severe respiratory and neurologic disease in humans. Currently, there are no licensed vaccines or therapeutics against NiV, underscoring the urgent need for the development of countermeasures. The NiV surface-displayed glycoproteins, NiV-G and NiV-F, mediate host cell attachment and fusion, respectively, and are heavily targeted by host antibodies. Here, we describe a vaccination-derived neutralizing monoclonal antibody, mAb92, that targets NiV-F. Structural characterization of the Fab region bound to NiV-F (NiV-F-Fab92) by cryo-electron microscopy analysis reveals an epitope in the DIII domain at the membrane distal apex of NiV-F, an established site of vulnerability on the NiV surface. Further, prophylactic treatment of hamsters with mAb92 offered complete protection from NiV disease, demonstrating beneficial activity of mAb92 in vivo. This work provides support for targeting NiV-F in the development of vaccines and therapeutics against NiV.IMPORTANCENipah virus (NiV) is a highly lethal henipavirus (HNV) that causes severe respiratory and neurologic disease in humans. Currently, there are no licensed vaccines or therapeutics against NiV, highlighting a need to develop countermeasures. The NiV surface displays the receptor binding protein (NiV-G, or RBP) and the fusion protein (NiV-F), which allow the virus to attach and enter cells. These proteins can be targeted by vaccines and antibodies to prevent disease. This work describes a neutralizing antibody (mAb92) that targets NiV-F. Structural characterization by cryo-electron microscopy analysis reveals where the antibody binds to NiV-F to neutralize the virus. This study also shows that prophylactic treatment of hamsters with mAb92 completely protected against developing NiV disease. This work shows how targeting NiV-F can be useful to preventing NiV disease, supporting future studies in the development of vaccines and therapeutics.

MRI Predicts Residual Disease and Outcomes in Watch-and-Wait Patients with Rectal Cancer.

Background MRI plays a crucial role in restaging locally advanced rectal cancer treated with total neoadjuvant therapy (TNT); however, prospective studies have not evaluated its ability to accurately select patients for nonoperative management. Purpose To evaluate the ability of restaging MRI to predict oncologic outcomes and identify imaging features associated with residual disease (RD) after TNT. Materials and Methods This was a secondary analysis of the Organ Preservation in Rectal Adenocarcinoma (OPRA) trial, which randomized participants from April 2014 to March 2020 with stages II or III rectal adenocarcinoma to undergo either induction or consolidation TNT. Participants enrolled in the OPRA trial who underwent restaging MRI were eligible for inclusion in the present study. Radiologists classified participants as having clinical complete response (cCR), near-complete clinical response (nCR), or incomplete clinical response (iCR) based on restaging MRI at a mean of 8 weeks ± 4 (SD) after treatment. Oncologic outcomes according to MRI response category were assessed using Kaplan-Meier curves. Logistic regression analysis was performed to identify imaging characteristics associated with RD. Results A total of 277 participants (median age, 58 years [IQR, 17 years]; 179 male) who were randomized in the OPRA trial had restaging MRI forms completed. The median follow-up duration was 4.1 years. Participants with cCR had higher rates of organ preservation compared with those with nCR (65.3% vs 41.6%, log-rank P < .001). Five-year disease-free survival for participants with cCR, nCR, and iCR was 81.8%, 67.6%, and 49.6%, respectively (log-rank P < .001). The MRI response category also predicted overall survival (log-rank P < .001), distant recurrence-free survival (log-rank P = .005), and local regrowth (log-rank P = .02). Among the 266 participants with at least 2 years of follow-up, 129 (48.5%) had RD. At multivariable analysis, the presence of restricted diffusion (odds ratio, 2.50; 95% CI: 1.22, 5.24) and abnormal nodal morphologic features (odds ratio, 5.04; 95% CI: 1.43, 23.9) remained independently associated with RD. Conclusion The MRI response category was predictive of organ preservation and survival. Restricted diffusion and abnormal nodal morphologic features on restaging MRI scans were associated with increased likelihood of residual tumor. ClinicalTrials.gov identifier: NCT02008656 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Milot in this issue.

Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology: Post Hoc Analysis of the STEP 1, 2, 3, and 5 Trials.

Importance: Obesity is associated with numerous psychosocial complications, making psychiatric safety a consideration for treating people with obesity. Few studies have investigated the psychiatric safety of newly available antiobesity medications. Objective: To evaluate the psychiatric safety of subcutaneous semaglutide, 2.4 mg, once weekly in people without known major psychopathology. Design, Setting, and Participants: This post hoc analysis of pooled data from the randomized, double-blind, placebo-controlled, multicenter phase 3a STEP 1, 2, and 3 trials (68 weeks; 2018-2020) and phase 3b STEP 5 trial (104 weeks; 2018-2021) included adults with overweight or obesity; STEP 2 participants also had type 2 diabetes. Trial designs have been published previously. Interventions: Semaglutide, 2.4 mg, vs placebo. Main Outcomes and Measures: Depressive symptoms and suicidal ideation/behavior were assessed using the Patient Health Questionnaire (PHQ-9) and Columbia-Suicide Severity Rating Scale, respectively. Psychiatric and nervous system disorder adverse events were investigated. Results: This analysis included 3377 participants in the STEP 1, 2, and 3 trials (2360 women [69.6%]; mean [SD] age, 49 [13] years) and 304 participants in STEP 5 (236 women [77.6%]; mean [SD] age, 47 [11] years). In the STEP 1, 2, and 3 trials, mean (SD) baseline PHQ-9 scores for the semaglutide, 2.4 mg, and placebo groups were 2.0 (2.3) and 1.8 (2.3), respectively, indicating no/minimal symptoms of depression. PHQ-9 scores at week 68 were 2.0 (2.9) and 2.4 (3.3), respectively; the estimated treatment difference (95% CI) between groups was -0.56 (-0.81 to -0.32) (P < .001). Participants treated with semaglutide vs placebo were less likely to shift (from baseline to week 68) to a more severe category of PHQ-9 depression (odds ratio, 0.63; 95% CI, 0.50-0.79; P < .001). Based on the Columbia-Suicide Severity Rating Scale, 1% or fewer of participants reported suicidal ideation/behavior during treatment, with no differences between semaglutide, 2.4 mg, and placebo. Psychiatric disorder adverse events were generally balanced between groups. Similar results were observed in STEP 5. Conclusions and Relevance: The results of this post hoc analysis suggest that treatment with semaglutide, 2.4 mg, did not increase the risk of developing symptoms of depression or suicidal ideation/behavior vs placebo and was associated with a small but statistically significant reduction in depressive symptoms (not considered clinically meaningful). People with obesity should be monitored for mental health concerns so they can receive appropriate support and care. Trial Registration: ClinicalTrials.gov Identifiers: STEP 1 (NCT03548935), 2 (NCT03552757), 3 (NCT03611582), and 5 (NCT03693430).

AFI manual planning versus HyperArc auto-planning: A head-to-head comparison of SRS plan quality.

INTRODUCTION: HyperArc (HA) auto-planning offers simplicity for the end user and consistently high-quality SRS plans. The "Ask For It" (AFI) optimization strategy offers a manual planning technique that, when coupled with R50%Analytic, can be guided to deliver a plan with an intermediate dose spill "as low as reasonably achievable" and high target dose conformity. A direct comparison of SRS plan quality obtained using the manual planning AFI strategy and HA has been performed. METHODS: Using a CT data set available from the Radiosurgery Society, 54 PTVs were created and used to generate 19 individual SRS/SRT cases. Case complexity ranged from single PTV plans to multiple PTV plans with a single isocenter. PTV locations ranged from relative isolation from critical structures to lesions within 1.5 mm of the optic apparatus and abutting the brainstem. All cases were planned using both the AFI and HA optimization strategies as implemented in the Varian Medical Systems Eclipse Treatment Planning System. A range of treatment plan quality metrics were obtained including Intermediate Dose Spill (R50%), Conformity Indices CIRTOG and CIPaddick, PTV Dose Coverage (Dn%), PTV Mean Dose, and Modulation Factor. The Wilcoxon Signed Rank Sum non-parametric statistical method was utilized to compare the obtained plan quality metrics. RESULTS: Statistically significant improvements were found for the AFI strategy for metrics R50%, CIRTOG, CIPaddick, and PTV Mean Dose (p < 0.001). HA achieved superior coverage for Dn% (p = 0.018), while the Modulation Factors were not significantly different for AFI compared to HA optimization (p = 0.13). CONCLUSION: This study provides evidence that the AFI manual planning strategy can produce high-quality planning metrics similar to the HA auto-planning method.

Follicular DNA Damage and Pesticide Exposure Among Latinx Children in Rural and Urban Communities.

The intersectional risks of children in United States immigrant communities include environmental exposures. Pesticide exposures and their biological outcomes are not well characterized in this population group. We assessed pesticide exposure and related these exposures to DNA double-strand breaks (DSBs) in Latinx children from rural, farmworker families (FW; N = 30) and from urban, non-farmworker families (NFW; N = 15) living in North Carolina. DSBs were quantified in hair follicular cells by immunostaining of 53BP1, and exposure to 72 pesticides and pesticide degradation products were determined using silicone wristbands. Cholinesterase activity was measured in blood samples. DSB frequencies were higher in FW compared to NFW children. Seasonal effects were detected in the FW group, with highest DNA damage levels in April-June and lowest levels in October-November. Acetylcholinesterase depression had the same seasonality and correlated with follicular DNA damage. Organophosphate pesticides were more frequently detected in FW than in NFW children. Participants with organophosphate detections had increased follicular DNA damage compared to participants without organophosphate detection. Follicular DNA damage did not correlate with organochlorine or pyrethroid detections and was not associated with the total number of pesticides detected in the wristbands. These results point to rural disparities in pesticide exposures and their outcomes in children from vulnerable immigrant communities. They suggest that among the different classes of pesticides, organophosphates have the strongest genotoxic effects. Assessing pesticide exposures and their consequences at the individual level is key to environmental surveillance programs. To this end, the minimally invasive combined approach used here is particularly well suited for children. Supplementary Information: The online version contains supplementary material available at 10.1007/s12403-023-00609-1.

Lead optimisation of OXS007417: in vivo PK profile and hERG liability modulation to optimise a small molecule differentiation agent for the potential treatment of acute myeloid leukaemia.

The development of a safe, efficacious, and widely effective differentiation therapy for AML would dramatically improve the outlook for many patients worldwide. To this aim, our laboratory has discovered a class of differentiation agents that demonstrate tumour regression in murine models in vivo. Herein, we report a lead optimisation process around compound OXS007417, which led to improved potency, solubility, metabolic stability, and off-target toxicity of this compound class. A hERG liability was investigated and successfully alleviated through addition of nitrogen atoms into key positions of the compound. OXS008255 and OXS008474 demonstrated an improved murine PK profile in respect to OXS007417 and a delay in tumour growth in a subcutaneous in vivo model using HL-60 cells.

Utilising accessible and reproducible neurological assessments in clinical studies: insights from use of the Neurological Impairment Scale in the multi-centre COVID-CNS study.

Reproducible and standardised neurological assessment scales are important in quantifying research outcomes. These scales are often performed by non-neurologists and/or non-clinicians and must be robust, quantifiable, reproducible, and comparable to a neurologist's assessment. COVID-CNS is a multi-centre study which utilised the Neurological Impairment Scale (NIS) as a core assessment tool in studying neurological outcomes following COVID-19 infection. We investigated the strengths and weaknesses of the NIS when used by non-neurology clinicians and non-clinicians, and compared performance to a structured neurological examination performed by a neurology clinician. Through our findings, we provide practical advice on how non-clinicians can be readily trained in conducting reproducible and standardised neurological assessments in a multi-centre study, as well as illustrating potential pitfalls of these tools.

Assessment of lesion insertion tool in pelvis PET/MR data with applications to attenuation correction method development.

BACKGROUND: In modern positron emission tomography (PET) with multi-modality imaging (e.g., PET/CT and PET/MR), the attenuation correction (AC) is the single largest correction factor for image reconstruction. One way to assess AC methods and other reconstruction parameters is to utilize software-based simulation tools, such as a lesion insertion tool. Extensive validation of these simulation tools is required to ensure results of the study are clinically meaningful. PURPOSE: To evaluate different PET AC methods using a synthetic lesion insertion tool that simulates lesions in a patient cohort that has both PET/MR and PET/CT images. To further demonstrate how lesion insertion tool may be used to extend knowledge of PET reconstruction parameters, including but not limited to AC. METHODS: Lesion quantitation is compared using conventional Dixon-based MR-based AC (MRAC) to that of using CT-based AC (CTAC, a "ground truth"). First, the pre-existing lesions were simulated in a similar environment; a total of 71 lesions were identified in 18 pelvic PET/MR patient images acquired with a time-of-flight simultaneous PET/MR scanner, and matched lesions were inserted contralaterally on the same axial slice. Second, synthetic lesions were inserted into four anatomic target locations in a cohort of four patients who didn't have any observed clinical lesions in the pelvis. RESULTS: The matched lesion insertions resulted in unity between the lesion error ratios (mean SUVs), demonstrating that the inserted lesions successfully simulated the original lesions. In the second study, the inserted lesions had distinct characteristics by target locations and demonstrated negative max-SUV%diff trends for bone-dominant sites across the patient cohort. CONCLUSIONS: The current work demonstrates that the applied lesion insertion tool can simulate uptake in pelvic lesions and their expected SUV values, and that the lesion insertion tool can be extended to evaluate further PET reconstruction corrections and algorithms and their impact on quantitation accuracy and precision.

Return to Driving Following Moderate-to-Severe Traumatic Brain Injury: A TBI Model System Longitudinal Investigation.

OBJECTIVE: To examine longitudinal patterns of return to driving (RTD), driving habits, and crash rates associated with moderate-to-severe traumatic brain injury (TBI). SETTING: Eight TBI Model System sites. PARTICIPANTS: Adults (N = 334) with TBI that required inpatient acute rehabilitation with follow-up of 197 and 218 at 1 and 2 years post-injury, respectively. Data collection at 2 years occurred almost exclusively during the pandemic, which may have affected results. DESIGN: Longitudinal and observational. MAIN MEASURES: Driving survey completed during rehabilitation and at phone follow-up 1 and 2 years after injury. RESULTS: The rate of RTD was 65% at 1-year follow-up and 70% at 2-year follow-up. RTD at both follow-up time points was positively associated with family income. The frequency of driving and distance driven were diminished compared to before injury. Limitation of challenging driving situations (heavy traffic, bad weather, and at night) was reported at higher rates post-injury than before injury. Crash rates were 14.9% in the year prior to injury (excluding crashes that resulted in TBI), 9.9% in the first year post-injury, and 6% during the second year. CONCLUSION: RTD is common after TBI, although driving may be limited in terms of frequency, distance driven, and avoiding challenging situations compared to before injury. Incidence of crashes is higher than population-based statistics; however, those who sustain TBI may be at higher risk even prior to injury. Future work is needed to better identify characteristics that influence the likelihood of crashes post-TBI.

"A Retrospective Evaluation of the Impact of Prenatal Diagnosis of Facial Clefts. Does Prenatal Diagnosis Matter?"

BACKGROUND: With the advent of improved prenatal detection, some patients with facial clefting are diagnosed prenatally while others are diagnosed postnatally. There is limited data regarding the utility of prenatal diagnosis and how this affects care of patients with facial clefts. METHODS AND MATERIALS: A retrospective chart review was performed. Children with incomplete demographic data and those with syndromic conditions were excluded. The data were analyzed via Fisher's exact tests and Kruskal-Wallis tests (p < 0.05). RESULTS: 106 patients met inclusion criteria. Facial clefting was diagnosed prenatally at different frequencies depending on type of facial cleft- patients with cleft palate alone were less likely to be identified prenatally (p < 0.0001). Patients diagnosed prenatally were seen by craniofacial specialists at an earlier age compared to those diagnosed after birth (0.27 months vs 0.7 months, p < 0.001). Similarly, those with prenatal diagnosis underwent surgery at a younger age compared to those who were diagnosed postnatally (median: 3.6 months vs 10.67 months, p < 0.001) and experienced shorter lag time (median: 3.4 months vs 8.4 months, p = 0.027) from consultation to surgery. Importantly, prenatal diagnosis resulted in pre-surgical therapy more often than in children diagnosed postnatally (86% vs 22.2%, p < 0.001). CONCLUSIONS: Our data suggests that patients with prenatal diagnosis of facial clefts were more likely to undergo pre-surgical therapy, presented to a craniofacial specialist at an earlier age, underwent surgery at an earlier age, and experienced less lag time between initial visit and surgery. More study is warranted to improve protocols for prenatal diagnoses to improve surgical outcomes.

Spectral-domain OCT characteristics of intraretinal hyper-reflective foci associated with age-related macular degeneration and diabetic retinopathy.

OBJECTIVE: The purpose of this study was to quantitatively analyze and compare OCT characteristics of intraretinal hyper-reflective foci (IHRF) in eyes with diabetic retinopathy (DR) versus age-related macular degeneration (AMD). DESIGN: a retrospective observational study. PARTICIPANTS: 54 treatment-naïve eyes (27 DR and 27 AMD). METHODS: The IHRF lesions in OCT B-scan were semi-automatically segmented. Mean reflectivity (MR), maximum diameter, circularity index (Cir), area, and the angle between the greatest linear dimension (GLD) and the horizontal were computed for each IHRF lesion. The presence and absence of a posterior shadow and the axial location were assessed. The MR was normalized using the vitreous and nerve fiber layer reflectance as dark and bright reference standards, respectively. RESULTS: A total of 1149 IHRF (1051 in DR and 98 in the AMD group) were identified, with a mean of 39 ± 36 lesions in DR eyes compared to only 4 ± 4 in AMD eyes (p < 0.001). The mean area of individual IHRF lesions was greater in DR eyes (1305 ± 1647 µm² vs 1031 ± 750 µm²; p = 0.016), but IHRF in AMD eyes had higher reflectivity (1.17 ± 0.14 vs 1.03 ± 0.17; p < 0.001). The angle of the GLD relative to the horizontal was greater in AMD eyes, indicating that IHRF in AMD eyes were more horizontally oriented. In AMD eyes, 88.8% of IHRF were located beneath the inner border of the outer nuclear layer (ONL), while in DR eyes, 56.9% were located there (p < 0.001). CONCLUSIONS: IHRF lesions in eyes with DR and AMD demonstrate significant differences, with IHRF in DR eyes tending to be larger and less hyper-reflective compared to AMD eyes.