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It is common for community-based healthcare providers (CHPs)-many of whom have not received specialised training in wound care-to deliver initial and ongoing management for various wound types and diverse populations. Wounds in any setting can rapidly transition to a stalled, hard-to-heal wound (HTHW) that is not following a normal healing trajectory. Failure to recognise or address issues that cause delayed healing can lead to increased costs, healthcare utilisation and suffering. To encourage early intervention by CHPs, a panel of wound care experts developed actionable evidence-based recommendations for CHPs delineating characteristics and appropriate care in identifying and treating HTHWs. A HTHW is a wound that fails to progress towards healing with standard therapy in an orderly and timely manner and should be referred to a qualified wound care provider (QWCP) for advanced assessment and diagnosis if not healed or reduced in size by 40%-50% within 4 weeks. HTHWs occur in patients with multiple comorbidities, and display increases in exudate, infection, devitalised tissue, maceration or pain, or no change in wound size. CHPs can play an important initial role by seeing the individual's HTHW risk, addressing local infection and providing an optimal wound environment. An easy-to-follow one-page table was developed for the CHP to systematically identify, evaluate and treat HTHWs, incorporating a basic toolkit with items easily obtainable in common office/clinic practice settings. A flow chart using visual HTHW clinical cues is also presented to address CHPs with different learning styles. These tools encourage delivery of appropriate early interventions that can improve overall healthcare efficiency and cost.

This study examined the use of voice recognition technology in perioperative services (Periop) to enable Periop staff to record workflow milestones using mobile technology. The use of mobile technology to improve patient flow and quality of care could be facilitated if such voice recognition technology could be made robust. The goal of this experiment was to allow the Periop staff to provide care without being interrupted with data entry and querying tasks. However, the results are generalizable to other situations where an engineering manager attempts to improve communication performance using mobile technology. This study enhanced Google's voice recognition capability by using post-processing classifiers (i.e., bag-of-sentences, support vector machine, and maximum entropy). The experiments investigated three factors (original phrasing, reduced phrasing, and personalized phrasing) at three levels (zero training repetition, 5 training repetitions, and 10 training repetitions). Results indicated that personal phrasing yielded the highest correctness and that training the device to recognize an individual's voice improved correctness as well. Although simplistic, the bag-of-sentences classifier significantly improved voice recognition correctness. The classification efficiency of the maximum entropy and support vector machine algorithms was found to be nearly identical. These results suggest that engineering managers could significantly enhance Google's voice recognition technology by using post-processing techniques, which would facilitate its use in health care and other applications.

Solid-state lithium metal batteries (SSLBs) using inorganic solid-state electrolytes (SSEs) have attracted extensive scientific and commercial interest owing to their potential to provide higher energy density and safety than conventional Li-ion batteries. These batteries are subject to external pressure during both their manufacturing processes (fabrication pressure) and their operation (stack pressure). This pressure not only affects the intrinsic properties of both the electrolytes (such as ionic conductivity and electrochemical voltage window) and the electrodes (such as ion transport and structural variation) but also determines the cyclability and safety of the whole battery. Hence, understanding the effect of pressure is essential when designing high-performance SSLBs. This Review aims to elucidate the coupling between external pressure and electrochemistry in these batteries. We summarize the effects of external pressure on SSEs and electrodes, and on the interfaces between the components. We analyse the overall electrochemical performance and safety of the batteries under external pressure. Finally, we clarify the dominant challenges in achieving pressure-proof and low-pressure SSLBs, laying out a perspective for future breakthroughs.

Solid-state lithium metal batteries (SSLBs) using inorganic solid-state electrolytes (SSEs) have attracted extensive scientific and commercial interest owing to their potential to provide higher energy density and safety than conventional Li-ion batteries. These batteries are subject to external pressure during both their manufacturing processes (fabrication pressure) and their operation (stack pressure). This pressure not only affects the intrinsic properties of both the electrolytes (such as ionic conductivity and electrochemical voltage window) and the electrodes (such as ion transport and structural variation) but also determines the cyclability and safety of the whole battery. Hence, understanding the effect of pressure is essential when designing high-performance SSLBs. This Review aims to elucidate the coupling between external pressure and electrochemistry in these batteries. We summarize the effects of external pressure on SSEs and electrodes, and on the interfaces between the components. We analyse the overall electrochemical performance and safety of the batteries under external pressure. Finally, we clarify the dominant challenges in achieving pressure-proof and low-pressure SSLBs, laying out a perspective for future breakthroughs.

PURPOSE: Despite therapeutic advances, outcomes for patients with platinum-resistant/refractory ovarian cancer remain poor. Selective glucocorticoid receptor modulation with relacorilant may restore chemosensitivity and enhance chemotherapy efficacy. METHODS: This three-arm, randomized, controlled, open-label phase II study (ClinicalTrials.gov identifier: NCT03776812) enrolled women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer, or ovarian carcinosarcoma treated with ≤4 prior chemotherapeutic regimens. Patients were randomly assigned 1:1:1 to (1) nab-paclitaxel (80 mg/m2) + intermittent relacorilant (150 mg the day before, of, and after nab-paclitaxel); (2) nab-paclitaxel (80 mg/m2) + continuous relacorilant (100 mg once daily); or (3) nab-paclitaxel monotherapy (100 mg/m2). Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) by investigator assessment; objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety were secondary end points. RESULTS: A total of 178 women were randomly assigned. Intermittent relacorilant + nab-paclitaxel improved PFS (hazard ratio [HR], 0.66; log-rank test P = .038; median follow-up, 11.1 months) and DOR (HR, 0.36; P = .006) versus nab-paclitaxel monotherapy, while ORR was similar across arms. At the preplanned OS analysis (median follow-up, 22.5 months), the OS HR was 0.67 (P = .066) for the intermittent arm versus nab-paclitaxel monotherapy. Continuous relacorilant + nab-paclitaxel showed numerically improved median PFS but did not result in significant improvement over nab-paclitaxel monotherapy. Adverse events were comparable across study arms, with neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia being the most common grade ≥3 adverse events. CONCLUSION: Intermittent relacorilant + nab-paclitaxel improved

Heterochromatin spreading, the expansion of repressive chromatin structure from sequence-specific nucleation sites, is critical for stable gene silencing. Spreading re-establishes gene-poor constitutive heterochromatin across cell cycles but can also invade gene-rich euchromatin de novo to steer cell fate decisions. How chromatin context (i.e. euchromatic, heterochromatic) or different nucleation pathways influence heterochromatin spreading remains poorly understood. Previously, we developed a single-cell sensor in fission yeast that can separately record heterochromatic gene silencing at nucleation sequences and distal sites. Here we couple our quantitative assay to a genetic screen to identify genes encoding nuclear factors linked to the regulation of heterochromatin nucleation and the distal spreading of gene silencing. We find that mechanisms underlying gene silencing distal to a nucleation site differ by chromatin context. For example, Clr6 histone deacetylase complexes containing the Fkh2 transcription factor are specifically required for heterochromatin spreading at constitutive sites. Fkh2 recruits Clr6 to nucleation-distal chromatin sites in such contexts. In addition, we find that a number of chromatin remodeling complexes antagonize nucleation-distal gene silencing. Our results separate the regulation of heterochromatic gene silencing at nucleation versus distal sites and show that it is controlled by context-dependent mechanisms. The results of our genetic analysis constitute a broad community resource that will support further analysis of the mechanisms underlying the spread of epigenetic silencing along chromatin.

Heterochromatin spreading, the expansion of repressive chromatin structure from sequence-specific nucleation sites, is critical for stable gene silencing. Spreading re-establishes gene-poor constitutive heterochromatin across cell cycles but can also invade gene-rich euchromatin de novo to steer cell fate decisions. How chromatin context (i.e. euchromatic, heterochromatic) or different nucleation pathways influence heterochromatin spreading remains poorly understood. Previously, we developed a single-cell sensor in fission yeast that can separately record heterochromatic gene silencing at nucleation sequences and distal sites. Here we couple our quantitative assay to a genetic screen to identify genes encoding nuclear factors linked to the regulation of heterochromatin nucleation and the distal spreading of gene silencing. We find that mechanisms underlying gene silencing distal to a nucleation site differ by chromatin context. For example, Clr6 histone deacetylase complexes containing the Fkh2 transcription factor are specifically required for heterochromatin spreading at constitutive sites. Fkh2 recruits Clr6 to nucleation-distal chromatin sites in such contexts. In addition, we find that a number of chromatin remodeling complexes antagonize nucleation-distal gene silencing. Our results separate the regulation of heterochromatic gene silencing at nucleation versus distal sites and show that it is controlled by context-dependent mechanisms. The results of our genetic analysis constitute a broad community resource that will support further analysis of the mechanisms underlying the spread of epigenetic silencing along chromatin.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or DTRs). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

The retrotrapezoid nucleus (RTN) is a key brainstem locus for central respiratory control. Chemosensitive neurons in the RTN have been shown to be intrinsically sensitive to changes in CO2/H+ and to regulate breathing in a CO2/H+-dependent manner. However, astroglial cells also contribute to RTN chemoreception by providing a CO2/H+-dependent purinergic drive that enhances neural activity, likely via a mechanism involving the inhibition of Kir4.1 channels. We recently found that an inducible astroglial cell-specific Kir4.1 potassium channel knockout mouse had reduced breathing responses to hypercapnic conditions, demonstrating that Kir4.1 channels are important mediators of central chemoreception and respiratory control. Kir4.1 expression or activity in animal models has also been shown to be reduced in various pathological conditions including epilepsy, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and Huntington's disease. Furthermore, respiratory dysfunction has been implicated in the progression of such neurodegenerative disorders. We assessed respiratory brainstem Kir4.1 expression levels using immunohistochemistry and qPCR in both young adult (2–3 months) and aged (9 months) rodent AD transgenic model tissue. Our preliminary findings show Kir4.1 expression levels in astrocytes (Aldh1L1+ astroglial cells) were significantly higher in the RTN compared to hippocampal regions, as well as being significantly increased in aged tissue. Interestingly, Kir4.1 levels were consistently greater in female tissue compared to male tissue. Furthermore, astrocyte Kir4.1 expression levels were lower in aged TgF344-AD RTN tissue than in TgF344-WT controls. These findings did not appear to be restricted to cell bodies as preliminary data suggests Kir4.1 expression is also reduced at perivascular astrocyte end feet in the TgF344-AD RTN. This data demonstrates that altered Kir4.1 expression in neurodegenerative disease is not restricted to upper brain regions but may also

The United States is more politically divided than any other wealthy democracy in modern history. This thesis examines the role of discourse in the polarization process and suggests a way to change course. Using a social constructionist approach and an analytical framework focusing on definitions, metaphors, and identity, it analyzes the discourse of the Civil War and 9/11 to understand how these elements influence the understanding and outcomes of sociocultural events. It then examines the current political landscape, including the events at the Capitol on January 6, 2021, through the same discursive lens. This thesis finds that today’s political discourse is strikingly similar to that of the Civil War and 9/11, pitting the “true heirs” of the nation against an evil “other” using the same rhetorical devices. This similarity suggests that the language of division is consistent, and that the framework is broadly applicable. Given the catastrophic outcomes of the Civil War and 9/11 and the subsequent Global War on Terror (GWOT), the nation must take steps to change its discourse. This thesis concludes by providing recommendations that take advantage of the transformative potential of the framework’s components, which include pragmatic definitions, generative metaphors, and complex identities., Civilian, City of Tamarac Fire Rescue, Approved for public release. Distribution is unlimited.

We demonstrate the construction of robust counterfactual explanations for support vector machines (SVM), where the privacy mechanism that publicly releases the classifier guarantees differential privacy. Privacy preservation is essential when dealing with sensitive data, such as in applications within the health domain. In addition, providing explanations for machine learning predictions is an important requirement within so-called high risk applications, as referred to in the EU AI Act. Thus, the innovative aspects of this work correspond to studying the interaction between three desired aspects: accuracy, privacy, and explainability. The SVM classification accuracy is affected by the privacy mechanism through the introduced perturbations in the classifier weights. Consequently, we need to consider a trade-off between accuracy and privacy. In addition, counterfactual explanations, which quantify the smallest changes to selected data instances in order to change their classification, may become not credible when we have data privacy guarantees. Hence, robustness for counterfactual explanations is needed in order to create confidence about the credibility of the explanations. Our demonstrator provides an interactive environment to show the interplay between the considered aspects of accuracy, privacy, and explainability.

RATIONALE: Acute respiratory failure is a life-threatening clinical outcome in critically ill pediatric patients. In severe cases, patients can require mechanical ventilation (MV) for survival. Early recognition of these patients can potentially help clinicians alter the clinical course and lead to improved outcomes. OBJECTIVES: To build a data-driven model for early prediction of the need for mechanical ventilation in pediatric intensive care unit (PICU) patients. METHODS: The study consists of a single-center retrospective observational study on a cohort of 13,651 PICU patients admitted between 1/01/2010 and 5/15/2018 with a prevalence of 8.06% for MV due to respiratory failure. XGBoost (extreme gradient boosting) and a convolutional neural network (CNN) using medication history were used to develop a prediction model that could yield a time-varying risk-score-a continuous probability of whether a patient will receive MV-and an ideal global threshold was calculated from the receiver operating characteristics (ROC) curve. The early prediction point (EPP) was the first time the risk-score surpassed the optimal threshold, and the interval between the EPP and the start of the MV was the early warning period (EWT). Spectral clustering identified patient groups based on risk-score trajectories after EPP. RESULTS: A clinical and medication history-based model achieved a 0.89 area under the ROC curve (AUROC), 0.6 sensitivity, 0.95 specificity, 0.55 positive predictive value (PPV), and 0.95 negative predictive value (NPV). Early warning time (EWT) median [inter-quartile range] of this model was 9.9[4.2-69.2] hours. Clustering risk-score trajectories within a six-hour window after the early prediction point (EPP) established three patient groups, with the highest risk groups PPV being 0.92. CONCLUSIONS: This study uses a unique method to extract and apply medication history information, such as time-varying variables, to identify patients who may need mechanical ventilation

Although dementia research has been dominated by Alzheimer's disease (AD), most dementia in older people is now recognised to be due to mixed pathologies, usually combining vascular and AD brain pathology. Vascular cognitive impairment (VCI), which encompasses vascular dementia (VaD) is the second most common type of dementia. Models of VCI have been delayed by limited understanding of the underlying aetiology and pathogenesis. This review by a multidisciplinary, diverse (in terms of sex, geography and career stage), cross-institute team provides a perspective on limitations to current VCI models and recommendations for improving translation and reproducibility. We discuss reproducibility, clinical features of VCI and corresponding assessments in models, human pathology, bioinformatics approaches, and data sharing. We offer recommendations for future research, particularly focusing on small vessel disease as a main underpinning disorder.

Existing literature widely reports on the value of collaborations between mathematicians and mathematics educators, and also how complex those collaborations can be. In this paper, we report on four collaborations that sought to address what mathematics is and who gets to do it. Drawing on the literature and from the careful and intentional work of the collaborators, we offer a framework to capture the richness of those collaborations – one that acknowledges the importance of acknowledging and welcoming the extensive personal and professional experience of each person involved in the collaboration – and a look at how collaborations built with that intentionality and acknowledgment can be impactful for students and institutions and be personally and professionally rewarding for the collaborators.

Deep learning (DL) models can harness electronic health records (EHRs) to predict diseases and extract radiologic findings for diagnosis. With ambulatory chest radiographs (CXRs) frequently ordered, we investigated detecting type 2 diabetes (T2D) by combining radiographic and EHR data using a DL model. Our model, developed from 271,065 CXRs and 160,244 patients, was tested on a prospective dataset of 9,943 CXRs. Here we show the model effectively detected T2D with a ROC AUC of 0.84 and a 16% prevalence. The algorithm flagged 1,381 cases (14%) as suspicious for T2D. External validation at a distinct institution yielded a ROC AUC of 0.77, with 5% of patients subsequently diagnosed with T2D. Explainable AI techniques revealed correlations between specific adiposity measures and high predictivity, suggesting CXRs' potential for enhanced T2D screening.

Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor-infiltrating T and B cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS-associated neuroblastomas. We found greater B and T cell infiltration in OMAS-associated tumors compared to controls and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (MHC) class II allele HLA-DOB∗01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.

Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor-infiltrating T and B cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS-associated neuroblastomas. We found greater B and T cell infiltration in OMAS-associated tumors compared to controls and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (MHC) class II allele HLA-DOB∗01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.

Heterochromatin spreading, the expansion of gene-silencing structures from DNA-encoded nucleation sites, occurs in distinct settings. Spreading re-establishes gene-poor constitutive heterochromatin every cell cycle, but also invades gene-rich euchromatin de novo to steer cell fate decisions. How chromatin context, i.e. euchromatic, heterochromatic, or different nucleator types, influences the determinants of this process remains poorly understood. By screening a nuclear function gene deletion library in fission yeast using a previously established heterochromatin spreading sensor system, we identified regulators that positively or negatively alter the propensity of a nucleation site to spread heterochromatin. We find that different chromatin contexts are dependent on unique sets of genes for the regulation of heterochromatin spreading. Further, we find that spreading in constitutive heterochromatin requires Clr6 histone deacetylase complexes containing the Fkh2 transcription factor, while the Clr3 deacetylase is globally required for silencing. Fkh2 acts by recruiting Clr6 to nucleation-distal chromatin sites. Our results segregate the pathways that control lateral heterochromatin spreading from those that instruct DNA-directed assembly in nucleation.

Protection of euchromatin from invasion by gene-repressive heterochromatin is critical for cellular health and viability. In addition to constitutive loci such as pericentromeres and subtelomeres, heterochromatin can be found interspersed in gene-rich euchromatin, where it regulates gene expression pertinent to cell fate. While heterochromatin and euchromatin are globally poised for mutual antagonism, the mechanisms underlying precise spatial encoding of heterochromatin containment within euchromatic sites remain opaque. We investigated ectopic heterochromatin invasion by manipulating the fission yeast mating type locus boundary using a single-cell spreading reporter system. We found that heterochromatin repulsion is locally encoded by Set1/COMPASS on certain actively transcribed genes and that this protective role is most prominent at heterochromatin islands, small domains interspersed in euchromatin that regulate cell fate specifiers. Sensitivity to invasion by heterochromatin, surprisingly, is not dependent on Set1 altering overall gene expression levels. Rather, the gene-protective effect is strictly dependent on Set1's catalytic activity. H3K4 methylation, the Set1 product, antagonizes spreading in two ways: directly inhibiting catalysis by Suv39/Clr4 and locally disrupting nucleosome stability. Taken together, these results describe a mechanism for spatial encoding of euchromatic signals that repel heterochromatin invasion.

Cell type specification in multicellular systems is due, at least in part, to differential access to and usage of the genomic DNA which is common to all cells, leading to cell type specific gene expression. This genomic pattern in enacted through the formation of gene-repressive heterochromatin, a nuclear ultrastructure, which silences transcription of genes embedded in the underlying DNA that are orthogonal to the intended cell fate and expands progressively, in a process known as spreading, while cells proceed through lineage commitment. Importantly, once the cell type specific pattern of gene expression has been established, it must be recapitulated over repeated cell division to ensure faithful maintenance of cell identity and avoid disease. Both the mechanisms which direct this process of differential expansion and the features of heterochromatin domains which are critical to its robust inheritance have not been fully elucidated. Utilizing a genetically tractable fission yeast model that recapitulates features of the metazoan chromatin environment, we interrogated the requirements for spatial and temporal regulation of heterochromatin domain formation. We find that at cell identity loci, robust gene silencing and the capacity to remember heterochromatin states over repeated division requires the collaboration of multiple sequence elements with distinct spreading properties and capacities to resist chromatin perturbations. Additionally, we find chromatin context dependent requirements for genetic regulation of the spreading process. Lastly, we described a mechanism for regulating the spatial expansion of heterochromatin domains that relies on the mutually antagonistic signals and properties that differ between hetero- and eu- chromatin domains.

Cell type specification in multicellular systems is due, at least in part, to differential access to and usage of the genomic DNA which is common to all cells, leading to cell type specific gene expression. This genomic pattern in enacted through the formation of gene-repressive heterochromatin, a nuclear ultrastructure, which silences transcription of genes embedded in the underlying DNA that are orthogonal to the intended cell fate and expands progressively, in a process known as spreading, while cells proceed through lineage commitment. Importantly, once the cell type specific pattern of gene expression has been established, it must be recapitulated over repeated cell division to ensure faithful maintenance of cell identity and avoid disease. Both the mechanisms which direct this process of differential expansion and the features of heterochromatin domains which are critical to its robust inheritance have not been fully elucidated. Utilizing a genetically tractable fission yeast model that recapitulates features of the metazoan chromatin environment, we interrogated the requirements for spatial and temporal regulation of heterochromatin domain formation. We find that at cell identity loci, robust gene silencing and the capacity to remember heterochromatin states over repeated division requires the collaboration of multiple sequence elements with distinct spreading properties and capacities to resist chromatin perturbations. Additionally, we find chromatin context dependent requirements for genetic regulation of the spreading process. Lastly, we described a mechanism for regulating the spatial expansion of heterochromatin domains that relies on the mutually antagonistic signals and properties that differ between hetero- and eu- chromatin domains.

Protection of euchromatin from invasion by gene-repressive heterochromatin is critical for cellular health and viability. In addition to constitutive loci such as pericentromeres and subtelomeres, heterochromatin can be found interspersed in gene-rich euchromatin, where it regulates gene expression pertinent to cell fate. While heterochromatin and euchromatin are globally poised for mutual antagonism, the mechanisms underlying precise spatial encoding of heterochromatin containment within euchromatic sites remain opaque. We investigated ectopic heterochromatin invasion by manipulating the fission yeast mating type locus boundary using a single-cell spreading reporter system. We found that heterochromatin repulsion is locally encoded by Set1/COMPASS on certain actively transcribed genes and that this protective role is most prominent at heterochromatin islands, small domains interspersed in euchromatin that regulate cell fate specifiers. Sensitivity to invasion by heterochromatin, surprisingly, is not dependent on Set1 altering overall gene expression levels. Rather, the gene-protective effect is strictly dependent on Set1's catalytic activity. H3K4 methylation, the Set1 product, antagonizes spreading in two ways: directly inhibiting catalysis by Suv39/Clr4 and locally disrupting nucleosome stability. Taken together, these results describe a mechanism for spatial encoding of euchromatic signals that repel heterochromatin invasion.

Heterochromatin spreading, the expansion of gene-silencing structures from DNA-encoded nucleation sites, occurs in distinct settings. Spreading re-establishes gene-poor constitutive heterochromatin every cell cycle, but also invades gene-rich euchromatin de novo to steer cell fate decisions. How chromatin context, i.e. euchromatic, heterochromatic, or different nucleator types, influences the determinants of this process remains poorly understood. By screening a nuclear function gene deletion library in fission yeast using a previously established heterochromatin spreading sensor system, we identified regulators that positively or negatively alter the propensity of a nucleation site to spread heterochromatin. We find that different chromatin contexts are dependent on unique sets of genes for the regulation of heterochromatin spreading. Further, we find that spreading in constitutive heterochromatin requires Clr6 histone deacetylase complexes containing the Fkh2 transcription factor, while the Clr3 deacetylase is globally required for silencing. Fkh2 acts by recruiting Clr6 to nucleation-distal chromatin sites. Our results segregate the pathways that control lateral heterochromatin spreading from those that instruct DNA-directed assembly in nucleation.

Protection of euchromatin from invasion by gene-repressive heterochromatin is critical for cellular health and viability. In addition to constitutive loci such as pericentromeres and subtelomeres, heterochromatin can be found interspersed in gene-rich euchromatin, where it regulates gene expression pertinent to cell fate. While heterochromatin and euchromatin are globally poised for mutual antagonism, the mechanisms underlying precise spatial encoding of heterochromatin containment within euchromatic sites remain opaque. We investigated ectopic heterochromatin invasion by manipulating the fission yeast mating type locus boundary using a single-cell spreading reporter system. We found that heterochromatin repulsion is locally encoded by Set1/COMPASS on certain actively transcribed genes and that this protective role is most prominent at heterochromatin islands, small domains interspersed in euchromatin that regulate cell fate specifiers. Sensitivity to invasion by heterochromatin, surprisingly, is not dependent on Set1 altering overall gene expression levels. Rather, the gene-protective effect is strictly dependent on Set1s catalytic activity. H3K4 methylation, the Set1 product, antagonizes spreading in two ways: directly inhibiting catalysis by Suv39/Clr4 and locally disrupting nucleosome stability. Taken together, these results describe a mechanism for spatial encoding of euchromatic signals that repel heterochromatin invasion.

Learning Objectives: To survey graduating EM residents on their perceptions of the EM job market and its effect on their desire to pursue fellowship training.Background: The COVID-19 pandemic has resulted in changes to the emergency medicine (EM) workforce which pose challenges to residents graduating from EM training programs. New graduates face increasing uncertainty in the search for their first job. EM graduates in 2020 and 2021 saw a notable decrease in opportunities compared to years prior. ACEP’s Workforce Study (April 2021) predicts a surplus of emergency physicians by 2030. Objectives: To survey graduating EM residents on their perceptions of the EM job market and its effect on their desire to pursue fellowship training.Methods: We surveyed senior residents (PGY2 and above) at three- and four-year EM residency programs in the greater NYC area. Paper surveys were mailed out to each of the programs with a return envelope; a virtual link to complete the survey was also made available. Surveys were distributed from August 2021 to November 2021 to 22 EM residency programs (695 residents). Participation was voluntary and anonymous. The only demographic information gathered was program name and PGY level.Results: A total of 412 senior residents from the 22 EM residency programs completed the survey. Of the 412 seniors, 183 were PGY2s, 174 were PGY3s, and 55 were PGY4s and 5s (we included responses from residents in combined EM/IM programs). Survey questions and results are summarized in Table 1. Compared to colleagues in previous years, graduating EM residents anticipated broadening their job search. 58% of those considering fellowship after residency stated that their interest in fellowship has increased due to anticipated challenges in the job market (difficulty securing a full-time attending position).Conclusions: The majority of senior residents expressed concern about the current and future EM job market. How and where EM graduates apply for jobs may be

Case presentation. A 16-year-old female presented to the emergency department with a four-day history of right lower quadrant abdominal pain for several hours. The patient was afebrile and physical examination was notable for isolated tenderness in the right lower quadrant. Ultrasound and computed tomography demonstrated an adnexal cystic structure. Pelvic magnetic resonance imaging was ordered to better characterize the pathology. Discussion. Isolated fallopian tube torsion is an uncommon entity requiring prompt surgical intervention. Recognition and appropriate management are essential.

Case Presentation: A 16-year-old female presented to the emergency department with acute onset of right lower quadrant abdominal pain for several hours. The patient was afebrile and physical examination was notable for isolated tenderness in the right lower quadrant. Ultrasound and computed tomography demonstrated an adnexal cystic structure. Pelvic magnetic resonance imaging was ordered to better characterize the pathology.Discussion: Isolated fallopian tube torsion is an uncommon entity requiring prompt surgical intervention. Recognition and appropriate management are essential.

ISBN 978-91-7737-167-0 Författarna och Iustus Förlag AB, Uppsala 2022

We demonstrate the construction of robust counterfactual explanations for support vector machines (SVM), where the privacy mechanism that publicly releases the classifier guarantees differential privacy. Privacy preservation is essential when dealing with sensitive data, such as in applications within the health domain. In addition, providing explanations for machine learning predictions is an important requirement within so-called high risk applications, as referred to in the EU AI Act. Thus, the innovative aspects of this work correspond to studying the interaction between three desired aspects: accuracy, privacy, and explainability. The SVM classification accuracy is affected by the privacy mechanism through the introduced perturbations in the classifier weights. Consequently, we need to consider a trade-off between accuracy and privacy. In addition, counterfactual explanations, which quantify the smallest changes to selected data instances in order to change their classification, may become not credible when we have data privacy guarantees. Hence, robustness for counterfactual explanations is needed in order to create confidence about the credibility of the explanations. Our demonstrator provides an interactive environment to show the interplay between the considered aspects of accuracy, privacy, and explainability.

ISBN 978-91-7737-167-0 Författarna och Iustus Förlag AB, Uppsala 2022

ISBN 978-91-7737-167-0 Författarna och Iustus Förlag AB, Uppsala 2022

ISBN 978-91-7737-167-0 Författarna och Iustus Förlag AB, Uppsala 2022

Case Presentation: A 16-year-old female presented to the emergency department with acute onset of right lower quadrant abdominal pain for several hours. The patient was afebrile and physical examination was notable for isolated tenderness in the right lower quadrant. Ultrasound and computed tomography demonstrated an adnexal cystic structure. Pelvic magnetic resonance imaging was ordered to better characterize the pathology.Discussion: Isolated fallopian tube torsion is an uncommon entity requiring prompt surgical intervention. Recognition and appropriate management are essential.

Learning Objectives: To survey graduating EM residents on their perceptions of the EM job market and its effect on their desire to pursue fellowship training.Background: The COVID-19 pandemic has resulted in changes to the emergency medicine (EM) workforce which pose challenges to residents graduating from EM training programs. New graduates face increasing uncertainty in the search for their first job. EM graduates in 2020 and 2021 saw a notable decrease in opportunities compared to years prior. ACEP’s Workforce Study (April 2021) predicts a surplus of emergency physicians by 2030. Objectives: To survey graduating EM residents on their perceptions of the EM job market and its effect on their desire to pursue fellowship training.Methods: We surveyed senior residents (PGY2 and above) at three- and four-year EM residency programs in the greater NYC area. Paper surveys were mailed out to each of the programs with a return envelope; a virtual link to complete the survey was also made available. Surveys were distributed from August 2021 to November 2021 to 22 EM residency programs (695 residents). Participation was voluntary and anonymous. The only demographic information gathered was program name and PGY level.Results: A total of 412 senior residents from the 22 EM residency programs completed the survey. Of the 412 seniors, 183 were PGY2s, 174 were PGY3s, and 55 were PGY4s and 5s (we included responses from residents in combined EM/IM programs). Survey questions and results are summarized in Table 1. Compared to colleagues in previous years, graduating EM residents anticipated broadening their job search. 58% of those considering fellowship after residency stated that their interest in fellowship has increased due to anticipated challenges in the job market (difficulty securing a full-time attending position).Conclusions: The majority of senior residents expressed concern about the current and future EM job market. How and where EM graduates apply for jobs may be

Case presentation. A 16-year-old female presented to the emergency department with a four-day history of right lower quadrant abdominal pain for several hours. The patient was afebrile and physical examination was notable for isolated tenderness in the right lower quadrant. Ultrasound and computed tomography demonstrated an adnexal cystic structure. Pelvic magnetic resonance imaging was ordered to better characterize the pathology. Discussion. Isolated fallopian tube torsion is an uncommon entity requiring prompt surgical intervention. Recognition and appropriate management are essential.

ISBN 978-91-7737-167-0 Författarna och Iustus Förlag AB, Uppsala 2022

The constituents of dark matter are still unknown, and the viable possibilities span a vast range of masses. The physics community has established searching for sub-GeV dark matter as a high priority and identified accelerator-based experiments as an essential facet of this search strategy. A key goal of the accelerator-based dark matter program is testing the broad idea of thermally produced sub-GeV dark matter through experiments designed to directly produce dark matter particles. The most sensitive way to search for the production of light dark matter is to use a primary electron beam to produce it in fixed-target collisions. The Light Dark Matter eXperiment (LDMX) is an electron-beam fixed-target missing-momentum experiment that realizes this approach and provides unique sensitivity to light dark matter in the sub-GeV range. This contribution provides an overview of the theoretical motivation, the main experimental challenges, how LDMX addresses these challenges, and projected sensitivities. We further describe the capabilities of LDMX to explore other interesting new and standard physics, such as visibly-decaying axion and vector mediators or rare meson decays, and to provide timely electronuclear scattering measurements that will inform the modeling of neutrino-nucleus scattering for DUNE., Comment: 26 pages, 17 figures. Contribution to Snowmass 2021

The study of law and information technology comes with an inherent contradiction in that while technology develops rapidly and embraces notions such as internationalization and globalization, traditional law, for the most part, can be slow to react to technological developments and is also predominantly confined to national borders. However, the notion of the rule of law defies the phenomenon of law being bound to national borders and enjoys global recognition. However, a serious threat to the rule of law is looming in the form of an assault by technological developments within artificial intelligence (AI). As large strides are made in the academic discipline of AI, this technology is starting to make its way into digital decision-making systems and is in effect replacing human decision-makers. A prime example of this development is the use of AI to assist judges in making judicial decisions. However, in many circumstances this technology is a ‘black box’ due mainly to its complexity but also because it is protected by law. This lack of transparency and the diminished ability to understand the operation of these systems increasingly being used by the structures of governance is challenging traditional notions underpinning the rule of law. This is especially so in relation to concepts especially associated with the rule of law, such as transparency, fairness and explainability. This article examines the technology of AI in relation to the rule of law, highlighting the rule of law as a mechanism for human flourishing. It investigates the extent to which the rule of law is being diminished as AI is becoming entrenched within society and questions the extent to which it can survive in the technocratic society.

PURPOSE: To report the long-term observations of the electrode-tissue interface and perceptual stability in humans after chronic stimulation with a 44-channel suprachoroidal retinal implant. METHODS: Four subjects (S1-4) with end-stage retinitis pigmentosa received the implant unilaterally (NCT03406416). Electrode impedances, electrode-retina distance (measured using optical coherence tomography imaging), and perceptual thresholds were monitored up to 181 weeks after implantation as the subjects used the prosthesis in the laboratory and in daily life. Stimulation charge density was limited to 32 µC/cm2 per phase. RESULTS: Electrode impedances were stable longitudinally. The electrode-retina distances increased after surgery and then stabilized, and were well-described by an asymptotic exponential model. The stabilization of electrode-retina distances was variable between subjects, stabilizing after 45 weeks for S1, 63 weeks for S2, and 24 weeks for S3 (linear regression; Pgradient > 0.05). For S4, a statistically significant increase in electrode-retina distance persisted (P < 0.05), but by the study end point the rate of increase was clinically insignificant (exponential model: 0.33 µm/wk). Perceptual electrical thresholds were stable in one subject, decreased over time in two subjects (linear model; P < 0.05), and increased slightly in one subject but remained within the predefined charge limits (P = 0.02). CONCLUSIONS: Chronic stimulation with the suprachoroidal retinal prosthesis over 3 years resulted in stable impedances, small individual changes in perceptual electrical thresholds, and no clinically significant increase in electrode-retina distances after a period of settling after surgery. TRANSLATIONAL RELEVANCE: Chronic stimulation with the 44-channel suprachoroidal retinal implant with a charge density of up to 32 µC/cm2 per phase is suitable for long-term use in humans.

The constituents of dark matter are still unknown, and the viable possibilities span a vast range of masses. The physics community has established searching for sub-GeV dark matter as a high priority and identified accelerator-based experiments as an essential facet of this search strategy. A key goal of the accelerator-based dark matter program is testing the broad idea of thermally produced sub-GeV dark matter through experiments designed to directly produce dark matter particles. The most sensitive way to search for the production of light dark matter is to use a primary electron beam to produce it in fixed-target collisions. The Light Dark Matter eXperiment (LDMX) is an electron-beam fixed-target missing-momentum experiment that realizes this approach and provides unique sensitivity to light dark matter in the sub-GeV range. This contribution provides an overview of the theoretical motivation, the main experimental challenges, how LDMX addresses these challenges, and projected sensitivities. We further describe the capabilities of LDMX to explore other interesting new and standard physics, such as visibly-decaying axion and vector mediators or rare meson decays, and to provide timely electronuclear scattering measurements that will inform the modeling of neutrino-nucleus scattering for DUNE., Comment: 26 pages, 17 figures. Contribution to Snowmass 2021