The management of a professional footballer recovering from a surgical repair of the proximal adductor longus tendon through a return-to-performance pathway. A case report.

This case report details the management of a 23-year-old professional footballer who sustained a rupture of the proximal adductor longus (AL) tendon. Following surgical reattachment of the tendon, the player completed an eleven-phase return to performance (RTPerf) pathway designed to ensure a rapid and safe return to play (RTPlay). The pathway uses distinct phases that incorporate clinical, performance, and sport-specific criteria to guide decision-making throughout the process. This case report outlines the phases and criteria used in conjunction with shared decision-making by the interdisciplinary team (IDT) to ensure a successful RTPlay. The effectiveness of this pathway was demonstrated by the player's return to competitive play 12 weeks post-surgery.

Evaluating the impacts of digital ECG denoising on the interpretive capabilities of healthcare professionals.

Aims: Electrocardiogram (ECG) interpretation is an essential skill across multiple medical disciplines; yet, studies have consistently identified deficiencies in the interpretive performance of healthcare professionals linked to a variety of educational and technological factors. Despite the established correlation between noise interference and erroneous diagnoses, research evaluating the impacts of digital denoising software on clinical ECG interpretation proficiency is lacking. Methods and results: Forty-eight participants from a variety of medical professions and experience levels were prospectively recruited for this study. Participants' capabilities in classifying common cardiac rhythms were evaluated using a sequential blinded and semi-blinded interpretation protocol on a challenging set of single-lead ECG signals (42 × 10 s) pre- and post-denoising with robust, cloud-based ECG processing software. Participants' ECG rhythm interpretation performance was greatest when raw and denoised signals were viewed in a combined format that enabled comparative evaluation. The combined view resulted in a 4.9% increase in mean rhythm classification accuracy (raw: 75.7% ± 14.5% vs. combined: 80.6% ± 12.5%, P = 0.0087), a 6.2% improvement in mean five-point graded confidence score (raw: 4.05 ± 0.58 vs. combined: 4.30 ± 0.48, P < 0.001), and 9.7% reduction in the mean proportion of undiagnosable data (raw: 14.2% ± 8.2% vs. combined: 4.5% ± 2.4%, P < 0.001), relative to raw signals alone. Participants also had a predominantly positive perception of denoising as it related to revealing previously unseen pathologies, improving ECG readability, and reducing time to diagnosis. Conclusion: Our findings have demonstrated that digital denoising software improves the efficacy of rhythm interpretation on single-lead ECGs, particularly when raw and denoised signals are provided in a combined viewing format, warranting further investigation into the impact of such technology on clinical decision-making and patient outcomes.

Criteria for assessing evidence for biomarker-targeted therapies in rare cancers-an extrapolation framework.

Background: Advances in targeted therapy development and tumor sequencing technology are reclassifying cancers into smaller biomarker-defined diseases. Randomized controlled trials (RCTs) are often impractical in rare diseases, leading to calls for single-arm studies to be sufficient to inform clinical practice based on a strong biological rationale. However, without RCTs, favorable outcomes are often attributed to therapy but may be due to a more indolent disease course or other biases. When the clinical benefit of targeted therapy in a common cancer is established in RCTs, this benefit may extend to rarer cancers sharing the same biomarker. However, careful consideration of the appropriateness of extending the existing trial evidence beyond specific cancer types is required. A framework for extrapolating evidence for biomarker-targeted therapies to rare cancers is needed to support transparent decision-making. Objectives: To construct a framework outlining the breadth of criteria essential for extrapolating evidence for a biomarker-targeted therapy generated from RCTs in common cancers to different rare cancers sharing the same biomarker. Design: A series of questions articulating essential criteria for extrapolation. Methods: The framework was developed from the core topics for extrapolation identified from a previous scoping review of methodological guidance. Principles for extrapolation outlined in guidance documents from the European Medicines Agency, the US Food and Drug Administration, and Australia's Medical Services Advisory Committee were incorporated. Results: We propose a framework for assessing key assumptions of similarity of the disease and treatment outcomes between the common and rare cancer for five essential components: prognosis of the biomarker-defined cancer, biomarker test analytical validity, biomarker actionability, treatment efficacy, and safety. Knowledge gaps identified can be used to prioritize future studies. Conclusion: This framework will allow systematic assessment, standardize regulatory, reimbursement and clinical decision-making, and facilitate transparent discussions between key stakeholders in drug assessment for rare biomarker-defined cancers.

Many-Body Quantum Interference Route to the Two-Channel Kondo Effect: Inverse Design for Molecular Junctions and Quantum Dot Devices.

Molecular junctions-whether actual single molecules in nanowire break junctions or artificial molecules realized in coupled quantum dot devices-offer unique functionality due to their orbital complexity, strong electron interactions, gate control, and many-body effects from hybridization with the external electronic circuit. Inverse design involves finding candidate structures that perform a desired function optimally. Here we develop an inverse design strategy for generalized quantum impurity models describing molecular junctions, and as an example, use it to demonstrate that many-body quantum interference can be leveraged to realize the two-channel Kondo critical point in simple 4- or 5-site molecular moieties. We show that remarkably high Kondo temperatures can be achieved, meaning that entropy and transport signatures should be experimentally accessible.

LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax-resistant chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eµ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.

Identifying the Number of Steps Required for Familiarisation to Athletic Footwear in Healthy Older Adults.

INTRODUCTION: Research on athletic footwear familiarisation within an older population is sparse. This is problematic because unfamiliar footwear may act as a new perturbation and modify older adults' walking gait and stability. In addition, while athletic footwear has been suggested to enhance older adults' comfort and support during activities of daily living, the necessary period for familiarisation with athletic footwear is unknown. Therefore, this study aimed to identify the number of steps required for older adults to be familiarised with athletic footwear of different midsole thicknesses. METHODS: Twenty-six healthy and physically active community-dwelling older adults, 21 females (71.1 ± 4.5 years; 164.5 ± 5.3 cm; 68.4 ± 11.4 kg) and five males (70.6 ± 2.3 years; 175.2 ± 7.8 cm; 72.8 ± 9.7 kg), completed a walking-based protocol. Participants walked two trials of 200 steps at their habitual speed on a 10-m track of an optical measurement system in three footwear conditions: (1) New Balance® REVlite 890v6 (thick midsole); (2) New Balance® REVlite 1400v5 (moderate midsole); and (3) New Balance® Minimus 20v7 (thin midsole). Gait speed (m.s-1) and walking time (min) were analysed for each participant over the 400 steps. Number of required familiarisation steps were established over three analysis phases, consisting of steady-state gait assessment, averaging and analysis of blocks of 40 steps, and sequentially comparing these steps with a predetermined threshold. Footwear familiarisation was assumed when the mean gait speed fell within an acceptable level (±2 SD from 320 to 360 step values) and subsequently maintained. RESULTS: Most participants were familiarised with all three footwear conditions (thick n = 18; moderate and thin n = 20) after walking 80 steps. For all participants, the moderate midsole had the shortest familiarisation period (160 steps). The highest number of familiarisation steps was found in the thick (320 steps) and thin midsoles (240 steps) for some participants. CONCLUSION: A minimum of 320 familiarisation steps is recommended to account for both individual differences and midsole thicknesses. Implementing this walking-based footwear familiarisation protocol would improve validity of future studies, ensuring they analyse footwear effects rather than familiarisation with the footwear.

Recent Advances in Molecular and Genetic Research on Uveal Melanoma.

Uveal melanoma (UM), a distinct subtype of melanoma, presents unique challenges in its clinical management due to its complex molecular landscape and tendency for liver metastasis. This review highlights recent advancements in understanding the molecular pathogenesis, genetic alterations, and immune microenvironment of UM, with a focus on pivotal genes, such as GNAQ/11, BAP1, and CYSLTR2, and delves into the distinctive genetic and chromosomal classifications of UM, emphasizing the role of mutations and chromosomal rearrangements in disease progression and metastatic risk. Novel diagnostic biomarkers, including circulating tumor cells, DNA and extracellular vesicles, are discussed, offering potential non-invasive approaches for early detection and monitoring. It also explores emerging prognostic markers and their implications for patient stratification and personalized treatment strategies. Therapeutic approaches, including histone deacetylase inhibitors, MAPK pathway inhibitors, and emerging trends and concepts like CAR T-cell therapy, are evaluated for their efficacy in UM treatment. This review identifies challenges in UM research, such as the limited treatment options for metastatic UM and the need for improved prognostic tools, and suggests future directions, including the discovery of novel therapeutic targets, immunotherapeutic strategies, and advanced drug delivery systems. The review concludes by emphasizing the importance of continued research and innovation in addressing the unique challenges of UM to improve patient outcomes and develop more effective treatment strategies.

Late Holocene relative sea-level records from coral microatolls in Singapore.

Late Holocene relative sea-level (RSL) data are important to understand the drivers of RSL change, but there is a lack of precise RSL records from the Sunda Shelf. Here, we produced a Late Holocene RSL reconstruction from coral microatolls in Singapore, demonstrating for the first time the utility of Diploastrea heliopora microatolls as sea-level indicators. We produced 12 sea-level index points and three marine limiting data with a precision of < ± 0.2 m (2σ) and < ± 26 years uncertainties (95% highest density region). The data show a RSL fall of 0.31 ± 0.18 m between 2.8 and 0.6 thousand years before present (kyr BP), at rates between - 0.1 ± 0.3 and - 0.2 ± 0.7 mm/year. Surface profiles of the fossil coral microatolls suggest fluctuations in the rate of RSL fall: (1) stable between 2.8 and 2.5 kyr BP; (2) rising at ~ 1.8 kyr BP; and (3) stable from 0.8 to 0.6 kyr BP. The microatoll record shows general agreement with published, high-quality RSL data within the Sunda Shelf. Comparison to a suite of glacial isostatic adjustment (GIA) models indicate preference for lower viscosities in the mantle. However, more high quality and precise Late Holocene RSL data are needed to further evaluate the drivers of RSL change in the region and better constrain GIA model parameters.

Worldwide revision of synanthropic silverfish (Insecta: Zygentoma: Lepismatidae) combining morphological and molecular data.

Synanthropic silverfish are the best-known and most widely distributed insects of the order Zygentoma. However, there is a great gap in the knowledge and confusion about the geographic distribution and the diagnostic characteristics that allow their identification. In this work, we provide an exhaustive and deep analysis of the most common 9 synanthropic silverfish of the world, combining previously published and newly derived morphological and molecular data. Updated descriptions of Ctenolepisma calvum (Ritter, 1910) and Ctenolepisma (Sceletolepisma) villosum (Fabricius, 1775) are included, and morphological remarks, illustrations, and photographs of the remaining synanthropic species are provided to clarify their diagnosis and differentiation among them and from other free-living species. In addition, Ctenolepisma targionii (Grassi and Rovelli, 1889) is synonymized with C. villosum. A molecular phylogeny is presented based on the COI sequences of all the synanthropic species deposited in BOLD and GenBank, with 15 new sequences provided by this study. This has allowed us to detect and correct a series of identification errors based on the lack of morphological knowledge of several species. Moreover, 2 different lineages of Ctenolepisma longicaudatumEscherich, 1905 have also been detected. To help future studies, we also provide a taxonomic interpretation guide for the most important diagnostic characters of the order Zygentoma, as well as an identification key for all the Synanthropic studied species. Finally, an approximation of the global distribution of synanthropic silverfish is discussed. Several new records indicate that the expansion of these species, generally associated with the transport of goods and people, is still far from over.

The distinctive weathering crust habitat of a High Arctic glacier comprises discrete microbial micro-habitats.

Sunlight penetrates the ice surfaces of glaciers and ice sheets, forming a water-bearing porous ice matrix known as the weathering crust. This crust is home to a significant microbial community. Despite the potential implications of microbial processes in the weathering crust for glacial melting, biogeochemical cycles, and downstream ecosystems, there have been few explorations of its microbial communities. In our study, we used 16S rRNA gene sequencing and shotgun metagenomics of a Svalbard glacier surface catchment to characterise the microbial communities within the weathering crust, their origins and destinies, and the functional potential of the weathering crust metagenome. Our findings reveal that the bacterial community in the weathering crust is distinct from those in upstream and downstream habitats. However, it comprises two separate micro-habitats, each with different taxa and functional categories. The interstitial porewater is dominated by Polaromonas, influenced by the transfer of snowmelt, and exported via meltwater channels. In contrast, the ice matrix is dominated by Hymenobacter, and its metagenome exhibits a diverse range of functional adaptations. Given that the global weathering crust area and the subsequent release of microbes from it are strongly responsive to climate projections for the rest of the century, our results underscore the pressing need to integrate the microbiome of the weathering crust with other communities and processes in glacial ecosystems.

Pain-free bite force in a healthy population: Within-session test-retest reliability in different sitting positions.

BACKGROUND: Pain-free bite force (PFBF) is a promising measure to evaluate bite function in temporomandibular disorders (TMDs), yet the reliability of the measure is unknown. OBJECTIVES: Establish the (1) within-session test-retest reliability of PFBF in a healthy population for a single and mean of three trials in supported and unsupported sitting; (2) standard error of measurement (SEM) and minimal detectable change (MDC). METHODS: Thirty healthy participants (n = 15 female, mean [SD] age = 34.4 [11.0] years) completed two sessions (30-60 min apart) comprising three PFBF trials on each side, in both supported and unsupported sitting, to provide data for 60 (30 participants × two sides) test-retest assessments. Test-retest reliability for the first trial and mean of three trials in each position were determined using intraclass correlation coefficients (ICCs), before calculating the corresponding SEM and MDC for males (M) and females (F) respectively. RESULTS: Within-session reliability was considered excellent for a single trial in supported sitting (ICC = 0.85; SEM M/F = 99/84 N; MDC M/F = 275/232 N) and unsupported sitting (ICC = 0.91; SEM M/F = 72/59 N, MDC M/F = 200/163 N), and for a mean of three trials in supported sitting (ICC = 0.89; SEM M/F = 66/79 N, MDC M/F = 182/220 N) and unsupported sitting (ICC = 0.92; SEM M/F = 64/59 N, MDC M/F = 177/164 N). CONCLUSION: Single and a mean of three trials in supported and unsupported sitting appear reliable methods to measure PFBF in a healthy population. Testing PFBF using a mean of three trials in unsupported sitting appears superior over other methods though due to higher test-retest reliability, and lower SEM and MDC. Future studies should examine the reliability of PFBF in TMD populations.

Melanocytes in regenerative medicine applications and disease modeling.

Melanocytes are dendritic cells localized in skin, eyes, hair follicles, ears, heart and central nervous system. They are characterized by the presence of melanosomes enriched in melanin which are responsible for skin, eye and hair pigmentation. They also have different functions in photoprotection, immunity and sound perception. Melanocyte dysfunction can cause pigmentary disorders, hearing and vision impairments or increased cancer susceptibility. This review focuses on the role of melanocytes in homeostasis and disease, before discussing their potential in regenerative medicine applications, such as for disease modeling, drug testing or therapy development using stem cell technologies, tissue engineering and extracellular vesicles.

The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/ß-catenin signaling.

Acute myeloid leukemia (AML) is a highly aggressive hematologic cancer with poor survival across a broad range of molecular subtypes. Development of efficacious and well-tolerable therapies encompassing the range of mutations that can arise in AML remains an unmet need. The bromo- and extra-terminal domain (BET) family of proteins represents an attractive therapeutic target in AML due to their crucial roles in many cellular functions, regardless of any specific mutation. Many BET inhibitors (BETi) are currently in pre-clinical and early clinical development, but acquisition of resistance continues to remain an obstacle for the drug class. Novel methods to circumvent this development of resistance could be instrumental for the future use of BET inhibitors in AML, both as monotherapy and in combination. To date, many investigations into possible drug combinations of BETi with CDK inhibitors have focused on CDK9, which has a known physical and functional interaction with the BET protein BRD4. Therefore, we wished to investigate possible synergy and additive effects between inhibitors of these targets in AML. Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Dinaciclib and PLX51107 demonstrate additive effects in AML cell lines, primary AML samples, and in vivo. Further, we demonstrate novel activity of dinaciclib through inhibition of the canonical/ß-catenin dependent Wnt signaling pathway, a known resistance mechanism to BETi in AML. We show dinaciclib inhibits Wnt signaling at multiple levels, including downregulation of ß-catenin, the Wnt co-receptor LRP6, as well as many Wnt pathway components and targets. Moreover, dinaciclib sensitivity remains unaffected in a setting of BET resistance, demonstrating similar inhibitory effects on Wnt signaling when compared to BET-sensitive cells. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML.

Progress towards the UNAIDS 95-95-95 targets in the Fifth Botswana AIDS Impact Survey (BAIS V 2021): a nationally representative survey.

BACKGROUND: In 2014, UNAIDS set a goal to end the AIDS epidemic by achieving targets for the percentage of people living with HIV who were aware of their status, on antiretroviral therapy (ART), and virally suppressed. In 2020, these targets were revised to 95% for each measure (known as 95-95-95), to be reached among people living with HIV by 2025. We used data from the Fifth Botswana AIDS Impact Survey (BAIS V) to measure progress towards these testing and treatment targets in Botswana. METHODS: BAIS V used a two-stage cluster design to obtain a nationally representative sample of people aged 15-64 years in Botswana. During March-August, 2021, 14 763 consenting participants were interviewed and tested for HIV in their households by survey teams. HIV-positive specimens were tested for viral load, presence of antiretroviral drugs, and recency of infection using the HIV-1 limiting antigen avidity enzyme immunoassay. Estimates of HIV-positive status and use of ART were based on self-report and the analysis of blood specimens for antiretroviral drugs. Viral load suppression was defined as an HIV RNA concentration of less than 1000 copies per mL. HIV incidence was calculated using the recent infection testing algorithm. Data were weighted to account for the complex survey design. FINDINGS: The national HIV prevalence in Botswana among people aged 15-64 years was 20·8% and the annual incidence of HIV infection was 0·2%. 95·1% (men 93·0%, women 96·4%) of people living with HIV aged 15-64 years were aware of their status, 98·0% (men 97·2%, women 98·4%) of those aware were on ART, and 97·9% (men 96·6%, women 98·6%) of those on ART had viral load suppression. Among young people (aged 15-24 years) living with HIV, 84·5% were aware of their status, 98·5% of those aware were on ART, and 91·6% of those on ART had viral load suppression. The prevalance of viral load suppression among all people living with HIV was 91·8%, and varied by district-ranging from 85·3% in Gaborone to 100·0% in Selibe Phikwe. INTERPRETATION: BAIS V is the first population-based survey worldwide to report the achievement of the UNAIDS 95-95-95 goals, both overall and among women. Strategies to reach undiagnosed men and young people, including young women, are needed. FUNDING: US President's Emergency Plan for AIDS Relief.

Multifractal Analysis of Measures Arising from Random Substitutions.

We study regularity properties of frequency measures arising from random substitutions, which are a generalisation of (deterministic) substitutions where the substituted image of each letter is chosen independently from a fixed finite set. In particular, for a natural class of such measures, we derive a closed-form analytic formula for the Lq-spectrum and prove that the multifractal formalism holds. This provides an interesting new class of measures satisfying the multifractal formalism. More generally, we establish results concerning the Lq-spectrum of a broad class of frequency measures. We introduce a new notion called the inflation word Lq-spectrum of a random substitution and show that this coincides with the Lq-spectrum of the corresponding frequency measure for all q≥0. As an application, we obtain closed-form formulas under separation conditions and recover known results for topological and measure theoretic entropy.

AI-based soundscape analysis: Jointly identifying sound sources and predicting annoyancea).

Soundscape studies typically attempt to capture the perception and understanding of sonic environments by surveying users. However, for long-term monitoring or assessing interventions, sound-signal-based approaches are required. To this end, most previous research focused on psycho-acoustic quantities or automatic sound recognition. Few attempts were made to include appraisal (e.g., in circumplex frameworks). This paper proposes an artificial intelligence (AI)-based dual-branch convolutional neural network with cross-attention-based fusion (DCNN-CaF) to analyze automatic soundscape characterization, including sound recognition and appraisal. Using the DeLTA dataset containing human-annotated sound source labels and perceived annoyance, the DCNN-CaF is proposed to perform sound source classification (SSC) and human-perceived annoyance rating prediction (ARP). Experimental findings indicate that (1) the proposed DCNN-CaF using loudness and Mel features outperforms the DCNN-CaF using only one of them. (2) The proposed DCNN-CaF with cross-attention fusion outperforms other typical AI-based models and soundscape-related traditional machine learning methods on the SSC and ARP tasks. (3) Correlation analysis reveals that the relationship between sound sources and annoyance is similar for humans and the proposed AI-based DCNN-CaF model. (4) Generalization tests show that the proposed model's ARP in the presence of model-unknown sound sources is consistent with expert expectations and can explain previous findings from the literature on soundscape augmentation.

Metagenome-assembled genomes from High Arctic glaciers highlight the vulnerability of glacier-associated microbiota and their activities to habitat loss.

The rapid warming of the Arctic is threatening the demise of its glaciers and their associated ecosystems. Therefore, there is an urgent need to explore and understand the diversity of genomes resident within glacial ecosystems endangered by human-induced climate change. In this study we use genome-resolved metagenomics to explore the taxonomic and functional diversity of different habitats within glacier-occupied catchments. Comparing different habitats within such catchments offers a natural experiment for understanding the effects of changing habitat extent or even loss upon Arctic microbiota. Through binning and annotation of metagenome-assembled genomes (MAGs) we describe the spatial differences in taxon distribution and their implications for glacier-associated biogeochemical cycling. Multiple taxa associated with carbon cycling included organisms with the potential for carbon monoxide oxidation. Meanwhile, nitrogen fixation was mediated by a single taxon, although diverse taxa contribute to other nitrogen conversions. Genes for sulphur oxidation were prevalent within MAGs implying the potential capacity for sulphur cycling. Finally, we focused on cyanobacterial MAGs, and those within cryoconite, a biodiverse microbe-mineral granular aggregate responsible for darkening glacier surfaces. Although the metagenome-assembled genome of Phormidesmis priestleyi, the cyanobacterium responsible for forming Arctic cryoconite was represented with high coverage, evidence for the biosynthesis of multiple vitamins and co-factors was absent from its MAG. Our results indicate the potential for cross-feeding to sustain P. priestleyi within granular cryoconite. Taken together, genome-resolved metagenomics reveals the vulnerability of glacier-associated microbiota to the deletion of glacial habitats through the rapid warming of the Arctic.