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Abstract Chronic disease management and follow-up are vital for realizing sustained patient well-being and optimal health outcomes. Recent advancements in wearable technologies, particularly wrist-worn devices, offer promising solutions for longitudinal patient monitoring, replacing subjective, intermittent self-reporting with objective, continuous monitoring. However, collecting and analyzing data from wearables presents several challenges, such as data entry errors, non-wear periods, missing data, and wearable artifacts. In this work, we explore these data analysis challenges using two real-world datasets (mBrain21 and ETRI lifelog2020). We introduce practical countermeasures, including participant compliance visualizations, interaction-triggered questionnaires to assess personal bias, and an optimized pipeline for detecting non-wear periods. Additionally, we propose a visualization-oriented approach to validate processing pipelines using scalable tools such as tsflex and Plotly-Resampler. Lastly, we present a bootstrapping methodology to evaluate the variability of wearable-derived features in the presence of partially missing data segments. Prioritizing transparency and reproducibility, we provide open access to our detailed code examples, facilitating adaptation in future wearable research. In conclusion, our contributions provide actionable approaches for improving wearable data collection and analysis.

Abstract Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

Objective Tuberous sclerosis complex (TSC) is a genetic disorder primarily characterized by the development of multisystem benign tumors. Epilepsy is the most common neurologic manifestation, affecting 80%‐90% of TSC patients. The diffuse structural brain abnormalities and the multifocal nature of epilepsy in TSC pose diagnostic challenges when evaluating patients for epilepsy surgery. Methods We retrospectively reviewed the safety experience and efficacy outcomes of five adult TSC patients who were treated with direct brain‐responsive neurostimulation (RNS System, NeuroPace, Inc). Results The average follow‐up duration was 20 months. All five patients were responders (≥50% disabling seizure reduction) at last follow‐up. The median reduction in disabling seizures was 58% at 1 year and 88% at last follow‐up. Three of the five patients experienced some period of seizure freedom ranging from 3 months to over 1 year. Significance In this small case series, we report the first safety experience and efficacy outcomes in patients with TSC‐associated drug‐resistant focal epilepsy treated with direct brain‐responsive neurostimulation.

Abstract Community‐based conservation has been identified as a solution to biodiversity loss, climate change and the reduction of rural poverty. The heterogeneity in social and economic inequalities often acts as a barrier to community engagement in resource management and further inhibits the distributional equity of social and ecological outcomes. This study presents a participatory impact assessment (PIA) framework that evaluated the outcomes of a cross‐sector community‐led conservation initiative. Community members involved in the programme identified activities and outcomes for the conservation cooperative (CC), ranking the influence of the former on the latter as well as their daily life through multiple focus group discussions (FGDs). Participants were asked to rank the impact of activities on outcomes and the scale of the outcome which was totalled to identify the most impactful programme activities and outcomes during the project period. Community members reported improved income, health, education and the creation of a locally led natural resource management system. Members also reported improved crab harvest rates and reduced mangrove deforestation. Environmental outcomes identified by community members through the PIA were verified through a secondary spatial analysis and mud crab independent fisheries monitoring. The results support the hypothesis that environmental non‐governmental organizations (NGOs) need to consider a multi‐dimensional view of human well‐being, and that cross‐sector integrated interventions may be effective at improving multiple outcomes. Future steps should focus on spatial replication of the CC programme which will provide further insights by testing for differences in outcomes between villages, how those are impacted by pre‐existing social and ecological systems and comparing outcomes between control sites that did not receive interventions. A free Plain Language Summary can be found within the Supporting Information of this article.

Summary: Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Abstract Background The development of next generation sequencing (NGS) methods led to a rapid rise in the generation of large genomic datasets, but the development of user-friendly tools to analyze and visualize these datasets has not developed at the same pace. This presents a two-fold challenge to biologists; the expertise to select an appropriate data analysis pipeline, and the need for bioinformatics or programming skills to apply this pipeline. The development of graphical user interface (GUI) applications hosted on web-based servers such as Shiny can make complex workflows accessible across operating systems and internet browsers to those without programming knowledge. Results We have developed GENAVi (Gene Expression Normalization Analysis and Visualization) to provide a user-friendly interface for normalization and differential expression analysis (DEA) of human or mouse feature count level RNA-Seq data. GENAVi is a GUI based tool that combines Bioconductor packages in a format for scientists without bioinformatics expertise. We provide a panel of 20 cell lines commonly used for the study of breast and ovarian cancer within GENAVi as a foundation for users to bring their own data to the application. Users can visualize expression across samples, cluster samples based on gene expression or correlation, calculate and plot the results of principal components analysis, perform DEA and gene set enrichment and produce plots for each of these analyses. To allow scalability for large datasets we have provided local install via three methods. We improve on available tools by offering a range of normalization methods and a simple to use interface that provides clear and complete session reporting and for reproducible analysis. Conclusion The development of tools using a GUI makes them practical and accessible to scientists without bioinformatics expertise, or access to a data analyst with relevant skills. While several GUI based tools are currently available for RNA-Seq analysis we improve on these existing tools. This user-friendly application provides a convenient platform for the normalization, analysis and visualization of gene expression data for scientists without bioinformatics expertise.

BackgroundSocial support plays an important role for health outcomes. Support for those living with chronic conditions may be particularly important for their health, and even for their survival. The role of support for the survival of cancer patients after receiving an allogeneic hematopoietic cell transplant (alloHCT) is understudied. To better understand the link between survival and support, as well as different sources and functions of support, we conducted two studies in alloHCT patients. First, we examined whether social support is related to survival (Study 1). Second, we examined who provides which support and which specific support-related functions and tasks are fulfilled by lay caregivers and healthcare professionals (Study 2).MethodsIn Study 1, we conducted a retrospective chart review of alloHCT patients (N = 173, 42.8% female, age: M = 49.88) and registered availability of a dedicated lay caregiver and survival. In Study 2, we prospectively followed patients after alloHCT (N = 28, 46.4% female, age: M = 53.97, 46.4% ethnic minority) from the same hospital, partly overlapping from Study 1, who shared their experiences of support from lay caregivers and healthcare providers in semi-structured in-depth interviews 3 to 6 months after their first hospital discharge.ResultsPatients with a dedicated caregiver had a higher probability of surviving to 100 days (86.7%) than patients without a caregiver (69.6%), OR = 2.84, p = 0.042. Study 2 demonstrated the importance of post-transplant support due to patients’ emotional needs and complex self-care regimen. The role of lay caregivers extended to many areas of patients’ daily lives, including support for attending doctor’s appointments, managing medications and financial tasks, physical distancing, and maintaining strict dietary requirements. Healthcare providers mainly fulfilled medical needs and provided informational support, while lay caregivers were the main source of emotional and practical support.ConclusionThe findings highlight the importance of studying support from lay caregivers as well as healthcare providers, to better understand how they work together to support patients’ adherence to recommended self-care and survival.

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: Loss of correction in hallux valgus (HV) deformity following distal chevron metatarsal osteotomy (DCO) has been demonstrated in short-term follow-up with HV recurrence rates of up to 75% reported in the long-term. The purpose of this study was to evaluate the radiographic effect of the DCO on the anatomic and mechanical axes of the first metatarsal. Our hypothesis was that patients undergoing DCO would have improvement in the mechanical metatarsal axis but worsening of the anatomic axis. Methods: This was a retrospective single surgeon case series of all patients who underwent DCO for HV between 2017 and 2019. Patients were included if they had both preoperative and postoperative weightbearing foot radiographs. The primary outcomes were the change in anatomic first-second intermetatarsal angle (a1-2IMA, defined by the metatarsal diaphyseal axis) and the change in mechanical first-second intermetatarsal angle (m1-2IMA, defined by the axis from the center of the metatarsal head to the metatarsal base). Secondary outcomes included the change in hallux valgus angle (HVA) and medial sesamoid position (medial sesamoid in relation to the mechanical axis of the metatarsal). Change in second-third intermetatarsal angle (2-3IMA, defined by the metatarsal diaphyseal axis) was measured to control for any inconsistencies in radiographic technique. Given the relatively small patient cohort, the non-parametric Wilcoxon signed rank test and Mann Whitney U test were used for statistical analysis. Results: 41 feet were included for analysis with a mean follow-up of 20.4 weeks. The a1-2IMA increased significantly (mean, 4.0 degrees, p

Category: Midfoot/Forefoot Introduction/Purpose: The aim of this study was to determine the outcomes and early complications following the implantation of a novel hydrogel synthetic cartilage implant (SCI) for the treatment of hallux rigidus by a single surgeon. This implant was FDA approved for implantation for the treatment of hallux rigidus in the United States in July 2016. Methods: A retrospective chart review of consecutive patients who underwent treatment for hallux rigidus with an SCI between August 2016 and June 2018 by a single surgeon was performed. Demographic information, radiographic assessment, and concomitant surgical procedures performed were evaluated for all patients. Post operatively, PROMIS physical function and pain scores, patient satisfaction, reoperation, conversion to arthrodesis, and need for further clinical treatment were collected. Seventy SCI were implanted in 65 patients. Follow up averaged 16.3 months (Range 6-27 months). Results: 16% (11/67) of patients were very satisfied, 31% (21/67) were satisfied, 22% (15/67) were neutral, 6% (4/67) were dissatisfied, and 24% (16/67) were very dissatisfied with their outcome. PROMIS physical function scores averaged 43, indicating mild dysfunction compared to population norms. PROMIS pain interference scores averaged 59, indicating mild pain compared to population norms. 50% (35/70) required a corticosteroid injection post-operatively. 24% (17/70) required advanced imaging with MRI post-operatively. There was a 13% reoperation rate for all-cause reoperation, and a 2.9% rate of conversion to arthrodesis. Subgroup analysis showed that patients undergoing Moberg osteotomy at time of SCI performed better than patients undergoing SCI alone. Conclusion: Synthetic cartilage implantation yielded modest patient satisfaction, mild dysfunction in physical measures, and a large proportion requiring further treatment and workup post operatively. We believe patient selection and counseling on the potential for continued pain and dysfunction in the early postoperative period following this procedure are important before proceeding with synthetic cartilage implantation for hallux rigidus.

Ischemic stroke is a rare condition to afflict the pediatric population. Congenital cardiomyopathy represents one of several possible etiologies in children. We report a 9-year-old boy who developed right middle cerebral artery stroke secondary to primary restrictive cardiomyopathy. In the absence of pediatric guidelines, the child met adult criteria for mechanical thrombectomy given the small core infarct and large penumbra. The literature suggests children may benefit from mechanical thrombectomy in carefully selected cases. Our patient exemplifies specific circumstances in which acute stroke therapy with thrombolysis and thrombectomy may be safe.

Category: Ankle Arthritis Introduction/Purpose: Total ankle arthroplasty (TAA) is commonly pursued for patients with painful arthritis. As the number of TAA increases, so too will the associated economic burden. In the current healthcare environment, savings are in the national spotlight. Studies of total joint arthroplasty (THA and TKA) have demonstrated that outpatient surgery decreases surgical costs.1,2 Additionally, outpatient THA and TKA have not been associated with increased complication or readmission rates.3–6 Outpatient TAA are becoming more common which may lead to decreased costs of care. Despite the potential savings, TAA remains an “inpatient-only procedure” for Medicare patients. Currently, there are no clinical studies examining the safety of outpatient TAA. In this study, we retrospectively reviewed 65 consecutive outpatient TAA to identify complication rates and patient risk factors. Methods: The medical records of 65 consecutive outpatient TAA from October 2012 to May 2016 with a minimum of 6-month follow-up were reviewed. All patients received popliteal and saphenous blocks with bupivacaine and epinephrine prior to surgery and were managed with oral NSAID and narcotic pain medication post-operatively. All patients received a STAR total ankle prosthesis. Demographics, comorbidities, ASA and perioperative complications including wound breakdown, infection, revision and non-revision surgeries were compared to historic controls. Mean follow up was 16.6 +/- 9.1 months (range, 6-42 months). Results: The overall complication rate in this series was 21.8%. One ankle (1.5%) had a wound breakdown requiring debridement and flap coverage. This patient had a history of Polycythemia Vera with re-thrombosis of their popliteal artery one month after TAA surgery. Two ankles (3%) had deep infections. Nine ankles (13.8%) required non-revision surgery. Three ankles (4.6%) required posterior capsular release, one ankle (1.5%) required medial malleolar screws for symptomatic stress reaction, and three ankles (4.6%) required arthroscopic or open gutter release. Two ankles (3%) required revision surgery. One for talar component subsidence in a patient with Charcot-Marie-Tooth managed with an arthrodesis at eleven months. The other revision was performed for aseptic tibial component loosening and managed with conversion to an INBONE prosthesis at seven months. Conclusion: This study demonstrates the safety of outpatient TAA. The combination of regional anesthesia and oral narcotics provided a satisfactory outpatient experience and zero patients required readmission for pain control. The one wound complication (1.5%) was attributed to arterial occlusion and not outpatient management. This compares to the 6.6-28% wound breakdown rate found in the literature.7–10 Our revision surgery rate (3%) was comparable to the 3.1-16.5% rate found in the literature, and was also not attributed to outpatient management.7–10 We feel this demonstrates that outpatient TAA can be performed safely.

A major weakness in many high-throughput genomic studies is the lack of consideration of a clinical environment where one patient at a time must be evaluated. We examined generalizable and platform-specific sources of variation from NanoString gene expression data on both ovarian cancer and Hodgkin lymphoma patients. A reference-based strategy, applicable to single-patient molecular testing is proposed for batch effect correction. The proposed protocol improved performance in an established Hodgkin lymphoma classifier, reducing batch-to-batch misclassification while retaining accuracy and precision. We suggest this strategy may facilitate development of NanoString and similar molecular assays by accelerating prospective validation and clinical uptake of relevant diagnostics.

Objective: This study aimed to build formative knowledge on socio-structural barriers, protective factors, and HIV sexual risk amongst Central-Asian female migrants in Moscow. Methods: Data collection included ethnographic interviews in Moscow with a purposive sample of 30 unmarried female migrants, 15 from Kyrgyzstan and 15 from Tajikistan. Results: Study participants reported difficulties with acquiring documents for legal status, financial insecurity, discrimination, sexual harassment, and lack of support. Based on analysis of the cases, one pathway linked lack of legal documentation and instrumental support with elevated sexual risk. Another pathways linked traditional cultural attitudes with both no and moderate sexual risk. Conclusion: Future HIV prevention efforts with Central Asian female migrants in Moscow should be multilevel and include: increasing HIV and prevention knowledge and skills, promoting condom use with regular partners, identifying and supporting cultural attitudes that protect against HIV sexual risk behaviors, facilitating legal status, building community support, and increasing economic options.

Following activation, T cells are released from lymph nodes to traffic via the blood to effector sites. The re-entry of these activated T cells into tissues represents a critical step for them to carry out local effector functions. Here we have assessed defects in effector T cells that are acutely depleted in Myosin-IIA (MyoIIA) and show a T cell intrinsic requirement for this motor to facilitate the diapedesis step of extravasation. We show that MyoIIA accumulates at the rear of T cells undergoing trans-endothelial migration. T cells can extend protrusions and project a substantial portion of their cytoplasm through the endothelial wall in the absence of MyoIIA. However, this motor protein plays a crucial role in allowing T cells to complete the movement of their relatively rigid nucleus through the endothelial junctions. In vivo, this defect manifests as poor entry into lymph nodes, tumors and into the spinal cord, during tissue-specific autoimmunity, but not the spleen. This suggests that therapeutic targeting of this molecule may allow for differential attenuation of tissue-specific inflammatory responses.

Hormonal therapy resistance remains a considerable barrier in the treatment of breast cancer. Activation of the Akt-PI3K-mTOR pathway plays an important role in hormonal therapy resistance. Our recent preclinical and clinical studies showed that the addition of a histone deacetylase inhibitor re-sensitized hormonal therapy resistant breast cancer to tamoxifen. As histone deacetylases are key regulators of Akt, we evaluated the effect of combined treatment with the histone deacetylase inhibitor PCI-24781 and tamoxifen on Akt in breast cancer cells. We demonstrate that while both histone deacetylase and estrogen receptor inhibition down regulate AKT mRNA and protein, their concerted effort results in down regulation of AKT activity with induction of cell death. Histone deacetylase inhibition exerts its effect on AKT mRNA through an estrogen receptor-dependent mechanism, primarily down regulating the most abundant isoform AKT1. Although siRNA depletion of AKT modestly induces cell death, when combined with an anti-estrogen, cytotoxicity is significantly enhanced. Thus, histone deacetylase regulation of AKT mRNA is a key mediator of this therapeutic combination and may represent a novel biomarker for predicting response to this regimen.

Past work has demonstrated infants' robust statistical learning across visual and auditory modalities. However, the specificity of representations produced via visual statistical learning has not been fully explored. The current study addressed this by investigating infants' abilities to identify previously learned object sequences when some object features (e.g., shape, face) aligned with prior learning and other features did not. Experiment 1 replicated past work demonstrating that infants can learn statistical regularities across sequentially presented objects and extended this finding to 16-month-olds. In Experiment 2, infants viewed test sequences in which one object feature (e.g., face) had been removed but the other feature (e.g., shape) was maintained, resulting in failure to identify familiar sequences. We further probed learning specificity by assessing infants' recognition of sequences when one feature was altered rather than removed (Experiment 3) and when one feature was uncorrelated with the original sequence structure (Experiment 4). In both cases, infants failed to identify sequences in which object features were not identical between learning and test. These findings suggest that infants are limited in their ability to generalize the statistical structure of an object sequence when the objects' features do not align between learning and test.

Native language statistical regularities about allowable phoneme combinations (i.e., phonotactic patterns) may provide learners with cues to support word learning. The current research investigated the association between infants' native language phonotactic knowledge and their word learning progress, as measured by vocabulary size. In the experiment, 19-month-old infants listened to a corpus of nonce words that contained novel phonotactic patterns. All words began with "illegal" consonant clusters that cannot occur in native (English) words. The rationale for the task was that infants with fragile phonotactic knowledge should exhibit stronger learning of the novel illegal phonotactic patterns than infants with robust phonotactic knowledge. We found that infants with smaller vocabularies showed stronger phonotactic learning than infants with larger vocabularies even after accounting for general cognition. We propose that learning about native language structure may promote vocabulary development by providing a foundation for word learning; infants with smaller vocabularies may have weaker support from phonotactics than infants with larger vocabularies. Furthermore, stored vocabulary knowledge may promote the detection of phonotactic patterns even during infancy.

The present experiments investigated the flexibility of statistical word segmentation. There is ample evidence that infants can use statistical cues (e.g., syllable transitional probabilities) to segment fluent speech. However, it is unclear how effectively infants track these patterns in unfamiliar phonological systems. We examined whether English-learning 14-month-olds could segment continuous speech in an artificial language consisting of Mandarin Chinese syllables. Syllable transitional probabilities provided the only reliable word boundary cues. In Experiment 1, we found that males segmented the language; they reliably discriminated words from the language versus across-word sequences. Females did not display reliable discrimination. In Experiment 2, when the test items were designed to have less overlap in their statistical structure, males and females displayed successful learning. Variation in direction of preference was revealing about infants' processing in the tasks. Taken together, the findings indicate that infants' statistical word segmentation abilities are sufficiently robust for processing speech streams containing foreign sounds.

Abstract Background Diabetes mellitus (DM) is a worldwide pandemic affecting 500 million people. It is known to be associated with increased susceptibility to soft tissue infections (STI). Despite being a major public health burden, the literature relating the effects of DM and the presentation, severity and healing of STIs in general surgical patients remain limited. Method We conducted a retrospective review of all patients admitted with STI in a tertiary teaching hospital over a 12-month period. Patient demographics and surgical outcomes were collected and analysed. Results During the study period, 1059 patients were admitted for STIs (88% required surgery). DM was an independent risk factor for LOS. Diabetic patients presented with higher body-mass index (28 vs. 26), larger abscess size (24 vs. 14 cm2) and had a longer length of stay (4.4 days vs. 2.9 days). They also underwent a higher proportion of wide debridement and application of negative pressure wound therapy (42% vs. 35%). More diabetic patients underwent subsequent re-operation within the same sitting (8 vs. 4). Diabetic patients were two times more likely to present with carbuncles (p = 0.02). Conclusion The incidence of STIs among DM patients represent a significant disease burden, surgeons should consider intensive patient counselling and partnering with primary care providers in order to help reduce the incidence of future STI admissions based upon lifestyle modification and glucose control.