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Metabolic acidosis (MAc)—an extracellular pH (pHo) decrease caused by a [HCO3−]o decrease at constant [CO2]o—usually causes intracellular pH (pHi) to fall. Here we determine the extent to which the pHi decrease depends on the pHo decrease vs the concomitant [HCO3−]o decrease. We use rapid-mixing to generate out-of-equilibrium CO2/HCO3− solutions in which we stabilize [CO2]o and [HCO3−]o while decreasing pHo (pure acidosis, pAc), or stabilize [CO2]o and pHo while decreasing [HCO3−]o (pure metabolic/down, pMet↓). Using the fluorescent dye 2′,7′-bis-2-carboxyethyl)-5(and-6)carboxyfluorescein (BCECF) to monitor pHi in rat hippocampal neurons in primary culture, we find that—in naïve neurons—the pHi decrease caused by MAc is virtually the sum of those caused by pAc (∼70%) + pMet↓ (∼30%). However, if we impose a first challenge (MAc1, pAc1, or pMet↓1), allow the neurons to recover, and then impose a second challenge (MAc2, pAc2, or pMet↓2), we find that pAc/pMet↓ additivity breaks down. In a twin-challenge protocol in which challenge #2 is MAc, the pHo and [HCO3−]o decreases during challenge #1 must be coincident in order to mimic the effects of MAc1 on MAc2. Conversely, if challenge #1 is MAc, then the pHo and [HCO3−]o decreases during challenge #2 must be coincident in order for MAc1 to produce its physiological effects during the challenge #2 period. We conclude that the history of challenge #1 (MAc1, pAc1, or pMet↓1)—presumably as detected by one or more acid-base sensors—has a major impact on the pHi response during challenge #2 (MAc2, pAc2, or pMet↓2).

Black men in the United States face disproportionately high rates of firearm violence, leading to death and disability more often than males of other racial/ethnic groups. Managing life after such injuries involves significant challenges in daily activities, employment, and pain management. Despite the critical impacts of firearm-related disabilities on Black men, their experiences remain largely unexplored by disability scholars, public health researchers, and practitioners. This oversight is alarming, as Black men with firearm-acquired disabilities encounter considerable structural barriers to achieving health and social objectives. Our team focuses on: (a) the experiences of Black men with firearm-acquired disabilities, (b) the lack of literature on their lived realities, and (c) new pathways for disability and public health research. Recognizing and addressing the invisibility of violently injured Black men in research is crucial for advancing equity, social justice, and representation across society. We argue that disability justice is a vital starting point for acknowledging the social experiences of gunshot wound survivors. More research is needed to understand the experiences of these young Black men who have been largely ignored in public health and disability narratives. It is essential for clinicians and policymakers to grasp how this neglect affects conventional views on health, accessibility, and well-being, underscoring the need for a more inclusive and equitable approach.

Introduction: Older adults racialized as Black experience higher rates of dementia than those racialized as White. Structural racism produces socioeconomic challenges, described by artist Marvin Gaye as ?hang ups, let downs, bad breaks, setbacks? that likely contribute to dementia disparities. Robust dementia literature suggests socioeconomic factors may also be key resiliencies. Methods: We linked state-level data reflecting the racialized landscape of economic opportunity across the 20th Century from the U.S. Census (1930?2010) with individual-level data on cognitive outcomes from the U.S. Health and Retirement Study participants racialized as Black. A purposive sample of participants born after the Brown v. Board ruling (born 1954?59) were selected who completed the modified Telephone Interview for Cognitive Status between 2010 and 2020 (N=1381). We tested associations of exposure to structural racism and resilience before birth, and during childhood, young-adulthood, and midlife with cognitive trajectories in mid-late life using mixed-effects regression models. Results: Older adults born in places with higher state-level structural socioeconomic racism experienced a more rapid cognitive decline in later life compared to those with lower levels of exposure. In addition, participants born in places with higher levels of state-level structural socioeconomic resilience experienced slower cognitive change over time than their counterparts. Discussion: These findings reveal the impact of racist U.S. policies enacted in the past that influence cognitive health over time and dementia risk later in life.

This report describes the process of conducting a participatory evaluation of a local public health department and community partners' joint efforts to address structural racism and advance health equity in Chicago, Illinois. The participatory evaluation is guided by a multi-partner advisory group composed of academic researchers and research assistants at a local public university; leadership and frontline staff at the local public health department; and individuals employed through local community-based organizations. This report details three key action points in the participatory evaluation process, highlighting the challenges and opportunities that arise while evaluating health equity interventions aimed at institutional and structural change. Insights gleaned from this process can inform ongoing and future participatory evaluation efforts and contribute to the establishment of best practices for partnering across institutions to reshape systems and power relationships to advance health equity.

Abstract Catalysts are often employed to enable nonisothermal reaction kinetic studies when tracking cure progression of polyurethane reactions. However, when quickly reacting, catalyzed materials are prepared through mixing followed by the addition of fillers or additives, subsequent processing of the partially reacted material becomes difficult. Here, chemorheology is used to track changes in viscoelastic properties of uncatalyzed polybutadiene‐diisocyanate reactions for multiple days, which quantifies the degree of cure during polymerization. Viscosity profiles are accurately captured by the two‐stage Arrhenius model (r2>0.95), and conversion progress is adequately represented by the Kamal–Sourour model (r2>0.76). Transition state analysis via Wynne–Jones–Eyring–Evans theory (WJEE) reveals the presence of an associative mechanism according to entropic and enthalpic activation energies ΔS# = −96.9 J K−1 and ΔH# = 36.4 kJ, respectively. These rheokinetic modeling results align with Fourier transform infrared spectroscopy findings. To the knowledge, no rheokinetic studies have tracked cure progress of this uncatalyzed system for the extended timeframe presented here. The cure profile also presents unique viscosity growth, representative of molecular weight buildup, compared to catalyzed systems. This finding emphasizes the novelty of applying previously developed chemorheological models to multiday thermosetting reactions within a flow field in a manner that is generalizable to many long‐term curing systems.

Purpose: The implementation of regional government is based on the principle of regional autonomy. The implementation of local government is also marked by the change in the system from centralization to decentralization which is directed at accelerating the realization of the welfare of the Indonesian people. Therefore, each region is required to be more independent in managing and managing its government affairs, including in managing regional finances. One of the vital cycles in regional financial management is reporting carried out at the end of each accounting period, in the form of local government financial reports (LKPD). LKPD can be used as a means of conducting performance analysis so that it can increase the role of financial reports themselves. Therefore, the author will conduct more in-depth research to determine the performance of the Kupang City Regional Government over the last 5 years. Design/methodology/approach: This research uses a quantitative descriptive approach. The data collection method will be carried out with documentation. The data is a Budget Realization Report contained in the BPK Audit Results Report for 2018-2022. Findings: The data is then analyzed using financial ratio analysis in the form of regional financial independence ratios, regional financial dependence ratios, degree of decentralization ratios, ratios of effectiveness of regional original income, ratios of regional financial efficiency, harmony ratios and growth ratios. The results of the study stated that the role of the central government was more dominant in financing the administration of the Kupang City regional government, the financial dependence of the local government on the center in the form of transfer income during the last 5 years was very high, the percentage of local original income was less when compared to the total income, the effectiveness of regional original income during The last 5 years have been quite effective. local governments need quite large funds and even increase yearly as long as they finance government operations, but capital expenditures are decreasing yearly. On the other hand, revenue growth from 2018 to 2022 tends to decrease, while the growth in operating expenditures and capital expenditures has fluctuated over the past 5 years. Therefore, the Regional Government of Kupang City is expected to maximize the revenue potential in the region. This is to reduce the dominance of the central government in financing the implementation of the Kupang City Regional Government. Paper type: Research Paper

This personal narrative is a critical reflection and affirmation letter to Black women. Throughout this commentary, at the end of each section, I have included what I call “gems”. I hope they serve as a manifesto for our collective healing from working in institutions that center on the ideologies and practices of dominance. This piece particularly focuses on the dominant ideology and practice of “whiteness” within institutions as a surveillance tool through policy that directly impacts Black women’s wellbeing through gender anti-black racism. Through storytelling and drawing on Black feminist scholarship, this narrative exposes the challenges I faced with institutional policies and practices as I pursued my career in both academia and social service work. Throughout this narrative, I highlight how the undercurrent of whiteness is embedded in the foundation of institutional policy and practices. This narrative serves as a demand for institutional accountability and reckoning with the coloniality of epistemology and ontology. There is a great emotional toll for Black women who are confronting and resisting gendered anti-black racism with deep internal struggles and triumphs. The violent institutional practices seek to eclipse Black women’s ability to dream, imagine and create. Whiteness is centered in institutional infrastructure, serves as a distraction, and impedes our ability to conceptualize the world we desire. We deserve to have imagination in our work. This narrative is a reflection of the harm of whiteness, a guide for Black women academics, a manifesto for change, and a testament to our humanity.

Category: Ankle Arthritis; Ankle Introduction/Purpose: Polyethylene (PE) wear particles have been shown to be a contributing factor of osteolysis and aseptic loosening. The use of highly cross-linked polyethylene (HXLPE) liners has been proven to reduce wear rates in hip and knee arthroplasty. To date, no clinical study has investigated the in vivo wear rates of HXLPE in total ankle arthroplasty (TAA). Therefore, the purpose of our study was to evaluate mid- and long-term outcomes and HXLPE wear rates in primary TAA. Methods: We retrospectively identified 49 patients who underwent primary TAA with HXLPE liners at a minimum of 5-year follow up. The average age was 65 years, 57.1% female, and average body mass index was 28.7 kg/m 2 . Polyethylene wear rates at final follow up were assessed using anteroposterior ankle radiographs and a validated computer assisted software. In addition, overall implant survivorship and complications were recorded. Results: The average polyethylene linear wear rate was 0.073 mm/year (SD, +/- 0.027) at mean 7.6 year (range, 5.1 to 12.2) follow up. Further analysis of patients with greater than 10 year follow up (n=8) demonstrated a linear wear rate of 0.06 mm/year (SD, +/- 0.02) at mean 11.1 year (range, 10.0 to 12.2). There were no instances of linear fracture or dissociation. Survivorship was 98.0% with 1 patient requiring removal of hardware and revision TAA secondary to failure of distal tibial osteotomy which was performed at index procedure. The rate of reoperation was 12.2% (n=6) with the most common indication being symptomatic ankle impingement treated with peri-implant cyst excision, exostectomy, and debridement (n=4). Conclusion: Highly crosslinked polyethylene liners in primary TAA demonstrated low in vivo wear rates and no cases of liner mechanical failures. In addition, our cohort demonstrated low complication and reoperation rates and exceptional survivorship at mid to long-term follow up. Therefore, the use of HXLPE liners is a viable option for surgeons performing TAA.

Rationale: Significant racial disparities in maternal mortality and morbidity rates in the U.S. have persisted over time, with Black women disproportionately bearing the burden. Studies have documented how experiences of structural racism contributes the disparities we see. However, most of these studies have focused on how domains of racism operate simultaneously, yet little is known about how these domains are interconnected and adversely impact health during pregnancy for Black women. To address this gap in the literature, this study explored how various domains of racism interconnect to shape Black women's lived experience during pregnancy, with a particular focus on factors maternal hypertension. Methods: Using a Charmaz grounded theory approach, this study presents qualitative findings from focus groups with Black women living in Greater New Haven, Connecticut and conducted between August 2020 and October 2020. Results: We identified five domains of racism and four ways these domains interconnect. These findings highlight the multidimensional nature of structural racism and the ways interconnected marginalization across domains creates novel pathways that adversely impact health. Conclusions: Our results show how institutions interact at various levels to create distinct health barriers for Black women that need to be addressed through holistic policies and interventions. To truly dismantle structural racism, we must attend to the underlying ideologies that allow these inequities in resources and opportunities to continue, especially capitalism and white supremacy. As we continue to challenge these larger ideologies, policy is a key tool to mitigate the health harms caused by structural racism.

Abstract Background Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer’s disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes. Methods We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated. Results The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p

Abstract Objective To evaluate medical student and attending surgeon experiences with a novel interactive virtual Otolaryngology ‐ Head and Neck Surgery (OHNS) medical student elective during the COVID‐19 pandemic. Study Design A virtual OHNS elective was created, with three components: (1) interactive virtual operating room (OR) experience using live‐stream video‐conferencing, (2) telehealth clinic, (3) virtual didactics. Setting OHNS Department at the University of Pennsylvania (May 2020 to June 2020). Methods Six medical students from the University of Pennsylvania; five attending otolaryngologists. Two surveys were designed and distributed to participating medical students and attending surgeons. Surveys included 5‐point Likert scale items, with 1 indicating “not at all” and 5 indicating “very much so”. Results Response rate was 100% for both surveys. Students on average rated the educational value of the telehealth experience as 4.2 ± 1.2, and the virtual OR experience as 4.0 ± 0.6. Most students (n = 5, 83%) indicated that they had enough exposure to faculty they met on this rotation to ask for a letter of recommendation (LOR) for residency if needed, while attending surgeons had an average response of 3.0 ± 1.0 when asked how comfortable they would feel writing a LOR for a student they met through the rotation. A majority of students (n = 4, 67%) felt they connected enough with faculty during the rotation to ask for mentorship. Half the students (n = 5, 50%) indicated that the rotation allowed them to evaluate the department's culture either “extremely well” or “somewhat well”. Conclusions Overall, participating students described this innovative virtual surgical rotation as an educationally and professionally valuable experience. With the continued suspension of visiting student rotations due to the COVID‐19 pandemic, this virtual model may have continued relevance to medical education.

Quantum science and computing represent a vital intersection between science and technology, gaining increasing importance in modern society. There is a pressing need to incorporate these concepts into the K-12 curriculum, equipping new generations with the tools to navigate and thrive in an evolving technological landscape. This study explores the professional learning of K-12 teachers (n = 49) related to quantum concepts and pedagogy. We used open-ended surveys, field notes, workshop artifacts, and interviews to examine teachers’ perceptions of quantum and how they made connections between quantum and their curriculum. Our data reveal that most teachers were excited and interested in teaching quantum but were aware of potential barriers and concerns that might get in the way of teaching quantum. We found that teachers readily identified connections to math and science in their curriculum, but only a few made connections to computing. Enthusiasm for teaching quantum concepts was found in both elementary and secondary educators, suggesting a widespread recognition of its importance in preparing students for a future where quantum technology is a fundamental aspect of their lives and careers.

‘Candidatus Liberibacter’ is a group of bacterial species that are obligate intracellular plant pathogens and cause Huanglongbing disease of citrus trees and Zebra Chip in potatoes. Here, we examined the extent of intra- and interspecific genetic diversity across the genus using comparative genomics. Our approach examined a wide set of Liberibacter genome sequences including five pathogenic species and one species not known to cause disease. By performing comparative genomics analyses, we sought to understand the evolutionary history of this genus and to identify genes or genome regions that may affect pathogenicity. With a set of 52 genomes, we performed comparative genomics, measured genome rearrangement, and completed statistical tests of positive selection. We explored markers of genetic diversity across the genus, such as average nucleotide identity across the whole genome. These analyses revealed the highest intraspecific diversity amongst the ‘Ca. Liberibacter solanacearum’ species, which also has the largest plant host range. We identified sets of core and accessory genes across the genus and within each species and measured the ratio of nonsynonymous to synonymous mutations (dN/dS) across genes. We identified ten genes with evidence of a history of positive selection in the Liberibacter genus, including genes in the Tad complex, which have been previously implicated as being highly divergent in the ‘Ca. L. capsica’ species based on high values of dN.

Though long-sought, transformation of pain management practice and culture has yet to be realized. We propose both a likely cause—entrenchment in a biomedical model of care that is observed and then replicated by trainees—and a solution: deliberately leveraging the hidden curriculum to instead implement a sociopsychobiological (SPB) model of care. We make use of Implicit Bias Recognition and Management, a tool that helps teams to first recognize and “surface” whatever is implicit and to subsequently intervene to change whatever is found to be lacking. We describe how a practice might use iterations of recognition and intervention to move from a biomedical to a SPB model by providing examples from the Chronic Pain Wellness Center in the Phoenix Veterans Affairs Health Care System. As pain management practitioners and educators collectively leverage the hidden curriculum to provide care in the SPB model, we will not only positively transform our individual practices but also pain management as a whole.

This study aimed to describe nurses’ experiences with personal protective equipment while providing patient care during the first wave of the COVID-19 pandemic in the US. From May 2020 to September 2020, 100 individual interviews were conducted with nurses from diverse backgrounds and practice settings. Interviews were audio-recorded, transcribed, and verified for thematic analysis. Three key themes emerged related to personal protective equipment during COVID-19: (1) concerns with safety, (2) concerns with personal protective equipment supply, and (3) concerns with health care systems changing personal protective equipment policies. These findings support the importance of transparent and equitable institution-wide PPE standards in creating safe working environments. Clear communication around personal protective equipment policies and procedures, personal protective equipment education, and assurance of equitable access to equipment that can mitigate risk and disability while also reducing fear, confusion, and frustration among nurses. Maintaining clear and consistent personal protective equipment guidelines and communication regarding supplies and procedures enhances transparency during both routine and critical times de-escalating the inevitable strain concomitant with providing patient care during a global pandemic.

BackgroundThroughout US history, chronic and infectious diseases have severely impacted minority communities due to a lack of accessibility to quality healthcare and accurate information, as well as underlying racism. These fault lines in the care of minority communities in the US have been further exacerbated by the rise of the COVID-19 pandemic. This study examined the factors associated with COVID-19 vaccine hesitancy by race and ethnicity, particularly among African American and Latinx communities in Eastern Pennsylvania (PA).MethodsSurvey data was collected in July 2021 in Philadelphia, Scranton, Wilkes-Barre, and Hazleton, PA. The 203 participants (38.7% Black, 27.5% Latinx) completed the 28-question survey of COVID-19 vaccination attitudes in either English or Spanish.ResultOut of the 203 participants, 181 participants met all the inclusion criteria, including completed surveys; of these participants, over three-fifths (63.5%) were acceptant of the COVID-19 vaccine whereas the remainder (36.5%) were hesitant. Binary logistic regression results showed that age, concern for vaccine efficacy, race, knowledge on the vaccine, and belief that the COVID-19 virus is serious significantly influenced COVID-19 vaccine hesitancy. Minorities were more likely to be hesitant toward vaccination (OR: 2.8, 95% CI: 1.1, 6.8) than non-Hispanic whites. Those who believed the COVID-19 vaccine was ineffective (OR: 8.3, 95% CI: 3.8, 18.2), and that the virus is not serious (OR: 8.3, 95% CI: 1.1, 61.8) showed the greatest odds of hesitancy.ConclusionsMinority status, age less than 45 years, misinformation about seriousness of COVID-19 illness, and concern about vaccine efficacy were contributing factors of COVID-19 vaccine hesitancy. Therefore, understanding and addressing the barriers to COVID-19 vaccination in minority groups is essential to decreasing transmission and controlling this pandemic, and will provide lessons on how to implement public health measures in future pandemics.

We examine the accuracy and precision of parameter estimates for both the exponential and normal distributions when using only a collection of sample extremes. That is, we consider a collection of random variables, where each of the random variables is either the minimum or maximum of a sample of nj independent, identically distributed random variables drawn from a normal or exponential distribution with unknown parameters. Previous work derived estimators for the population parameters assuming the nj sample sizes are constant. Since sample sizes are often not constant in applications, we derive new unbiased estimators that take into account the varying sample sizes. We also perform simulations to assess how the previously derived estimators perform when the constant sample size is simply replaced with the average sample size. We explore how varying the mean, standard deviation, and probability distribution of the sample sizes affects the estimation error. Overall, our results demonstrate that using the average sample size in place of the constant sample size still results in reliable estimates for the population parameters, especially when the average sample size is large. Our estimation framework is applied to a biological example involving plant pollination.

The PD-1:PD-L1 axis is a binary interaction that delivers inhibitory signals to T cells, impeding both immune surveillance and response to immunotherapy. Here we analyzed a phenomenon whereby tumor-specific T cells induce PD-L1 upregulation in autologous MDS cells in short-term culture, through a mechanism that is cell-contact-independent and partially IFNγ-dependent. After investigating a panel of small-molecule inhibitors, we determined that PD-L1 upregulation was attributed to the PKR-like ER kinase (PERK) branch of the unfolded protein response. Interestingly, we found that the cytotoxic capacity of tumor-specific T cells was not impaired by the expression of PD-L1 on MDS target cells. These results highlight a little appreciated aspect of PD-1:PD-L1 regulation in hematologic cancers and indicate that this phenomenon, while likely to hinder autochthonous immune surveillance, may not be an obstacle to immunotherapies such as personalized adoptive T-cell therapy.

Membranous nephropathy (MN) is an immune kidney disease characterized by glomerular subepithelial immune complexes (ICs) containing antigen, IgG, and products of complement activation. Whereas proteinuria is caused by complement-mediated podocyte injury, the pathways of complement activation remain controversial due to the predominance of IgG4 in ICs, an IgG subclass considered unable to activate complement. THSD7A, a transmembrane protein expressed on podocytes, is the target autoantigen in ~3% of cases of primary MN. In this study, we analyzed sera from 16 patients with THSD7A-associated MN with regard to the anti-THSD7A IgG subclasses and their ability to fix complement in vitro. The serum concentration of anti-THSD7A IgG varied over two orders of magnitude (1.3-243 μg/mL). As a relative proportion of all IgG anti-THSD7A, IgG4 was by far the most abundant subclass (median 79%), followed by IgG1 (median 11%). IgG4 was the dominant subclass of anti-THSD7A antibodies in 14 sera, while IgG1 was dominant in one and co-dominant in another. One quarter of MN sera additionally contained low levels of anti-THSD7A IgA1. ICs formed by predominantly IgG4 anti-THSD7A autoantibodies with immobilized THSD7A were relatively weak activators of complement in vitro, compared to human IgG1 and IgG3 mAbs used as positive control. Complement deposition on THSD7A ICs was dose-dependent and occurred to a significant extent only at relatively high concentration of anti-THSD7A IgG. C3b fixation by THSD7A ICs was completely abolished in factor B-depleted sera, partially inhibited in C4-depleted sera, unchanged in C1q-depleted sera, and also occurred in Mg-EGTA buffer. These results imply that THSD7A ICs predominantly containing IgG4 activate complement at high IgG4 density, which strictly requires a functional alternative pathway, whereas the classical and lectin pathways are dispensable. These findings advance our understanding of how IgG4 antibodies activate complement.

Objective: Current guidelines for hypoglossal nerve stimulator (HGNS) implantation eligibility include drug-induced sleep endoscopy (DISE) findings and other patient characteristics but lead to highly variable rates of surgical success across institutions. Our objective was to determine whether additional factors seen on preoperative evaluation could be used as predictors of surgical success. Study design: Retrospective chart review. Setting: Single-institution academic tertiary care medical center. Subjects: and Methods:This study included patients with obstructive sleep apnea (OSA) who underwent HGNS implantation between 2015 and 2018. Surgical success was defined as a postoperative apnea-hypopnea index (AHI) of less than 20 events per hour and an AHI reduction of at least 50%. Preoperative polysomnogram (PSG) results, DISE findings, and physical parameters were compared between surgical successes and failures. Results: A total of 68 patients were included in the analysis. The overall surgical success rate was 79.4% (54/68). Elevated preoperative AHI was associated with an increased likelihood of treatment failure, with an AHI of (36.9 ± 16.8) events/hour in the success group compared to (49.4 ± 19.6) events/hour in the failure group (P = 0.05). Patients observed to have partial lateral oropharyngeal collapse on DISE was more frequently associated with the treatment failure group than in the success group (P = 0.04). Conclusion: Patients who underwent HGNS implantation overall had a very high treatment response rate at our institution. Factors that may predispose patients to surgical failure included the presence of lateral oropharyngeal collapse and a significantly elevated preoperative AHI. These should be considered when determining surgical candidacy for HGNS implantation.

Introduction The ongoing COVID-19 pandemic represents the largest contemporary challenge to the nursing workforce in the 21 st century given the high stress and prolonged strain it has created for both human and healthcare supply resources. Nurses on the frontlines providing patient care during COVID-19 have faced unrivaled psychological and physical demands. However, no known large-scale qualitative study has described the emotions experienced by nurses providing patient care during the first wave of the COVID-19 pandemic in the US. Objective: Therefore, the purpose of this study was to qualitatively describe the emotions experienced by US nurses during the initial COVID-19 pandemic response. Methods One hundred individual interviews were conducted with nurses across the United States from May to September of 2020 asking participants to describe how they felt taking care of COVID-19 patients. All interviews followed a semi-structured interview guide, were audio recorded, transcribed, verified, and coded by the research team. Results Participants narratives of the emotions they experienced providing patient care during COVID-19 unequivocally described (1) moral distress, and moral distress related (1.1) fear, (1.2) frustration, (1.3) powerlessness, and (1.4) guilt. In sum, the major emotional response of nurses across the US providing patient care during the pandemic was that of moral distress. Conclusion Investments in healthcare infrastructures that address moral distress in nurses may improve retention and reduce burnout in the US nursing workforce.

Purpose: This study investigated women’s perceived causes for orgasmic difficulty during partnered sex and their relation to orgasmic pleasure. Method: From a community sample of 1843 women, we investigated 814 women’s attributions for their orgasmic difficulty during partnered sex. Frequencies of 18 attributions were generated and subsequently reduced to eight principal variables through dimension reduction. Women with and without distress were compared across these eight principal variables. These variables, along with relevant covariates, were then used to predict orgasmic pleasure through regression analysis. Results: The most frequently endorsed reasons for orgasmic difficulty were, in descending order, general stress/anxiety, arousal difficulty, sex-specific anxiety and issues with the partner. Women reporting high distress were more likely to cite partner issues and less likely to report general stress/anxiety as reasons for their difficulty. Regression analysis, however, indicated that the reasons most frequently endorsed by women were not necessarily those accounting for the greater variance in orgasmic pleasure, such reasons including inhibition/lack of interest, insufficient experience and partner-related issues. Difficulty reaching orgasm during masturbation as well as relationship satisfaction also explained differences in orgasmic pleasure. Conclusion: Women cite various reasons for orgasmic difficulty, most commonly general anxiety/stress, inadequate arousal, sex-specific stress and partner issues. Women who were distressed by their condition more frequently cited partner issues. Variance in orgasmic pleasure was most related to partner issues, sexual inhibition/lack of interest and insufficient experience. Overall, partner issues and relationship satisfaction played important roles in attributions for both orgasmic difficulty and orgasmic pleasure.

Subglottic stenosis (SGS) is a recurrent, obstructive, fibroinflammatory disease of the upper airway resulting in severe dyspnea, dysphonia, as well as other potentially fatal complications. Although aberrant inflammation and wound-healing are commonly associated with pathogenesis, the mechanism through which such processes occur and recur in affected patients remains poorly studied. Here we report that transcriptomic profiling of laryngotracheal regions from minimally-invasive mucosal swabs of SGS patients reveals a distinctively pro-inflammatory gene signature. Surprisingly, comparative genomics between SGS patients and mice with direct laryngotracheal injury suggest that SGS patients bear more resemblance to the acute than chronic phase of injury. Furthermore, functional and regulatory network analyses identify neutrophilic involvement through hyper-activation of NF-κB and its downstream inflammasome as a potential master regulator. Interestingly, nitric oxide synthesis was found to be downregulated in SGS patients compared to healthy controls. Thus, SGS represents a state of immunodeficiency whereby defective immune clearance triggers recurrent, long-lasting production of pro-inflammatory cytokines.

The identification of the major target antigen phospholipase A2 receptor (PLA2R) in the majority of primary (idiopathic) cases of membranous nephropathy (MN) has been followed by the rapid identification of numerous minor antigens that appear to define phenotypically distinct forms of disease. This article serves to review all the known antigens that have been shown to localize to subepithelial deposits in MN, as well as the distinctive characteristics associated with each subtype of MN. We will also shed light on the novel proteomic approaches that have allowed identification of the most recent antigens. The paradigm of an antigen normally expressed on the podocyte cell surface leading to in-situ immune complex formation, complement activation, and subsequent podocyte injury will be discussed and challenged in light of the current repertoire of multiple MN antigens. Since disease phenotypes associated with each individual target antigens can often blur the distinction between primary and secondary disease, we encourage the use of antigen-based classification of membranous nephropathy.

Abstract: Recurrent mutations implicate several epigenetic regulators in the early molecular pathobiology of myelodysplastic syndromes (MDS). We hypothesized that MDS subtypes defined by DNA methylation (DNAm) patterns could enhance our understanding of MDS disease biology and identify patients with convergent epigenetic profiles. Bisulfite padlock probe sequencing was used to measure DNAm of ∼500 000 unique cytosine guanine dinucleotides covering 140 749 nonoverlapping regulatory regions across the genome in bone marrow DNA samples from 141 patients with MDS. Application of a nonnegative matrix factorization (NMF)–based decomposition of DNAm profiles identified 5 consensus clusters described by 5 NMF components as the most stable grouping solution. Each of the 5 NMF components identified by this approach correlated with specific genetic abnormalities and categorized patients into 5 distinct methylation clusters, each largely defined by a single NMF component. Methylation clusters displayed unique differentially methylated regulatory loci enriched for active and bivalent promoters and enhancers. Two clusters were enriched for samples with complex karyotypes, although only one had an increased number of TP53 mutations. Each of the 3 most frequently mutated splicing factors, SF3B1, U2AF1, and SRSF2, was enriched in different clusters. Mutations of ASXL1, EZH2, and RUNX1 were coenriched in the SRSF2-containing cluster. In multivariate analysis, methylation cluster membership remained independently associated with overall survival. Targeted DNAm profiles identify clinically relevant subtypes of MDS not otherwise distinguished by mutations or clinical features. Patients with diverse genetic lesions can converge on common DNAm states with shared pathogenic mechanisms and clinical outcomes.

Epistasis is caused by genetic interactions among mutations that affect fitness. To characterize properties and potential mechanisms of epistasis, we engineered eight double mutants that combined mutations from the rho and rpoB genes of Escherichia coli. The two genes encode essential functions for transcription, and the mutations in each gene were chosen because they were beneficial for adaptation to thermal stress (42.2 °C). The double mutants exhibited patterns of fitness epistasis that included diminishing returns epistasis at 42.2 °C, stronger diminishing returns between mutations with larger beneficial effects and both negative and positive (sign) epistasis across environments (20.0 °C and 37.0 °C). By assessing gene expression between single and double mutants, we detected hundreds of genes with gene expression epistasis. Previous work postulated that highly connected hub genes in coexpression networks have low epistasis, but we found the opposite: hub genes had high epistasis values in both coexpression and protein-protein interaction networks. We hypothesized that elevated epistasis in hub genes reflected that they were enriched for targets of Rho termination but that was not the case. Altogether, gene expression and coexpression analyses revealed that thermal adaptation occurred in modules, through modulation of ribonucleotide biosynthetic processes and ribosome assembly, the attenuation of expression in genes related to heat shock and stress responses, and with an overall trend toward restoring gene expression toward the unstressed state.

Introduction Recent endeavors from governing bodies such as the AAMC have formally recognized the importance of aseptic technique. AAMC guidelines include activities that all graduating physicians should be able to perform with minimum indirect supervision and were developed to recognize these needs. For example, the skills necessary for aseptic technique include daily safety habits and general physician procedures. Methods We developed a scrub training curriculum and evaluated the program through a quasi-experimental study with a pre- and posttest design. Questions were developed to examine students' perceived knowledge and skills as related to the objectives of the course and to their anxieties, concerns, and future training needs. Results Between February 2020 and March 2020, 44 students completed the curriculum. Students indicated that self-efficacy significantly increased in all aspects of the curricular goals following curriculum completion. Students identified understanding OR etiquette as the most anxiety-provoking element associated with scrub training. They felt that more time could be spent elucidating this etiquette. On the other hand, tasks such as surgical hand hygiene were the least anxiety-inducing. Discussion We share this multimodal scrub training curriculum, mapped to the AAMC's guidelines, to reduce variability in teaching strategies and skills acquisition through a standardized curriculum. Also, we effectively imparted these skills and instilled a sense of confidence in learners as they worked to provide their best in patient care and safety.

Objective: To understand the relation of musculoskeletal strength and function to postural stability in ambulatory adults with cerebral palsy (CP) who have already developed muscle atrophy and osteoporosis. Design: Two independent group comparison of adults with CP and those without it. Setting: Laboratory study. Participants: Thirteen adults with CP with sex (9 women: 4 men), age (21-62y), and Gross Motor Function Classification System I-III, and 13 sex-, age-, and body-weight-matched control participants completed our study (N=26). Intervention: Not applicable. Main Outcome Measure: Bone mineral density (BMD), structural or geometrical deformities (at the proximal region of the femur at the hip joint), and maximal muscular strength (forearm and thigh) were measured. The primary outcome measure was postural stability (balance measured using an automated balance system and a Berg Balance Test). Results: Femoral BMD was significantly lower in the CP group compared to the control group, whereas BMD at lumbar and forearm regions was similar between groups. Geometrical angles, lengths, and diameters at the proximal femur were significantly lower in the CP group. There was a direct relation between BMD in the femoral neck and knee extension peak torque in the control group with no relation in the CP group. Although the control group did not show a relation between muscular strength and balance test, the CP group showed a significant linear relation among improving postural stability with greater levels of muscular strength. Conclusion: There were structural differences at the proximal femur and muscular weakness in adults with CP. In adults with CP, balance appears to be more influenced by structural alterations at the femur than muscular strength compared to the control group.

Importance: The COVID-19 pandemic is characterized by high transmissibility from patients with prolonged minimally- or asymptomatic periods, with a particularly increased risk of spread during aerosol-generating procedures, including endotracheal intubation. Observations: All patients presenting with upper airway obstruction due to angioedema during this time should be carefully managed in a way that is safest for both patient and provider. Conclusions: For patients requiring emergent airway management during the COVID-19 pandemic, minimization of aerosols while taking the necessary precautions to protect healthcare workers should are critical principles for their management.

Abstract Background Metastasis is responsible for a significant number of breast cancer-related deaths. Hypoxia, a primary driving force of cancer metastasis, induces the expression of BHLHE40, a transcription regulator. This study aimed to elucidate the function of BHLHE40 in the metastatic process of breast cancer cells. Methods To define the role of BHLHE40 in breast cancer, BHLHE40 expression was knocked down by a lentiviral construct expressing a short hairpin RNA against BHLHE40 or knocked out by the CRISPR/Cas9 editing system. Orthotopic xenograft and experimental metastasis (tail vein injection) mouse models were used to analyze the role of BHLHE40 in lung metastasis of breast cancer. Global gene expression analysis and public database mining were performed to identify signaling pathways regulated by BHLHE40 in breast cancer. The action mechanism of BHLHE40 was examined by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (CoIP), exosome analysis, and cell-based assays for metastatic potential. Results BHLHE40 knockdown significantly reduced primary tumor growth and lung metastasis in orthotopic xenograft and experimental metastasis models of breast cancer. Gene expression analysis implicated a role of BHLHE40 in transcriptional activation of heparin-binding epidermal growth factor (HBEGF). ChIP and CoIP assays revealed that BHLHE40 induces HBEGF transcription by blocking DNA binding of histone deacetylases (HDAC)1 and HDAC2. Cell-based assays showed that HBEGF is secreted through exosomes and acts to promote cell survival and migration. Public databases provided evidence linking high expression of BHLHE40 and HBEGF to poor prognosis of triple-negative breast cancer. Conclusion This study reveals a novel role of BHLHE40 in promoting tumor cell survival and migration by regulating HBEGF secretion.