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Abstract Background Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO and genome-wide association studies (GWAS) have highlighted the polygenicity of this adverse drug reaction. Polygenic scores (PGS), which integrate information from multiple genetic variants across the genome, offer a promising tool for the identification of individuals who are at higher risk for CIO. Integrating large-scale hearing loss GWAS data with single cell omics data holds potential to overcome limitations related to small sample sizes associated with CIO studies, enabling the creation of PGSs to predict CIO risk. Results We utilized a large-scale hearing loss GWAS and murine inner ear single nuclei RNA-sequencing (snRNA-seq) data to develop two polygenic scores: a hearing loss PGS (PGSHL) and a biologically informed PGS for CIO (PGSCIO). The PGSCIO included only variants which mapped to genes that were differentially expressed within cochlear cells that showed differential abundance in the murine snRNA-seq data post-cisplatin treatment. Evaluation of the association of these PGSs with CIO in our target CIO cohort revealed that PGSCIO demonstrated superior performance (P = 5.54 × 10− 5) relative to PGSHL (P = 2.93 × 10− 3). PGSCIO was also associated with CIO in our test cohort (P = 0.04), while the PGSHL did not show a significant association with CIO (P = 0.52). Conclusion This study developed the first PGS for CIO using a large-scale hearing loss dataset and a biologically informed filter generated from cisplatin-treated murine inner ear snRNA-seq data. This innovative approach offers new avenues for developing PGSs for pharmacogenomic traits, which could contribute to the implementation of tailored therapeutic interventions. Further, our approach facilitated the identification of specific cochlear cells that may play critical roles in CIO. These novel insights will guide future research aimed at developing targeted therapeutic strategies to prevent CIO.

Abstract A significant consequence of climate change is the rising incidence of wildfires. When wildfires occur close to wine grape (Vitis vinifera) production areas, smoke-derived volatile phenolic compounds can be taken up by the grape berries, negatively affecting the flavor and aroma profile of the resulting wine and compromising the production value of entire vineyards. Evidence for the permeation of smoke-associated compounds into grape berries has been provided through metabolomics; however, the basis for grapevines’ response to smoke at the gene expression level has not been investigated in detail. To address this knowledge gap, we employed time-course RNA sequencing to observe gene expression-level changes in grape berries in response to smoke exposure. Significant increases in gene expression (and enrichment of gene ontologies) associated with detoxification of reactive compounds, maintenance of redox homeostasis, and cell wall fortification were observed in response to smoke. These findings suggest that the accumulation of volatile phenols from smoke exposure activates mechanisms that render smoke-derived compounds less reactive while simultaneously fortifying intracellular defense mechanisms. The results of this work lend a better understanding of the molecular basis for grapevines’ response to smoke and provide insight into the origins of smoke-taint-associated flavor and aroma attributes in wine produced from smoke-exposed grapes.

ABSTRACT Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been reported, including mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and increased copies of plasmepsin II/III (pm2/3). We generated a cross between a Cambodia-derived multidrug-resistant KEL1/PLA1 lineage isolate (KH004) and a drug-susceptible Malawian parasite (Mal31). Mal31 harbors a wild-type (3D7-like) pfcrt allele and a single copy of pm2/3, while KH004 has a chloroquine-resistant (Dd2-like) pfcrt allele with an additional G367C substitution and multiple copies of pm2/3. We recovered 104 unique recombinant parasites and examined a targeted set of progeny representing all possible combinations of variants at pfcrt and pm2/3. We performed a detailed analysis of competitive fitness and a range of PPQ susceptibility phenotypes with these progenies, including PPQ survival assay, area under the dose response curve, and a limited point IC50. We find that inheritance of the KH004 pfcrt allele is required for reduced PPQ sensitivity, whereas copy number variation in pm2/3 further decreases susceptibility but does not confer resistance in the absence of additional mutations in pfcrt. A deep investigation of genotype-phenotype relationships demonstrates that progeny clones from experimental crosses can be used to understand the relative contributions of pfcrt, pm2/3, and parasite genetic background to a range of PPQ-related traits. Additionally, we find that the resistance phenotype associated with parasites inheriting the G367C substitution in pfcrt is consistent with previously validated PPQ resistance mutations in this transporter.IMPORTANCEResistance to piperaquine, used in combination with dihydroartemisinin, has emerged in Cambodia and threatens to spread to other malaria-endemic regions. Understanding the causal mutations of drug resistance and their impact on parasite fitness is critical for surveillance and intervention and can also reveal new avenues to limiting the evolution and spread of drug resistance. An experimental genetic cross is a powerful tool for pinpointing the genetic determinants of key drug resistance and fitness phenotypes and has the distinct advantage of quantifying the effects of naturally evolved genetic variation. Our study was strengthened since the full range of copies of KH004 pm2/3 was inherited among the progeny clones, allowing us to directly test the role of the pm2/3 copy number on resistance-related phenotypes in the context of a unique pfcrt allele. Our multigene model suggests an important role for both loci in the evolution of this multidrug-resistant parasite lineage.

Introduction: Older adults often have multiple comorbidities; therefore, they are at high risk for adverse events after discharge. The 4Ms framework—what matters, medications, mentation, mobility—has been used in acute and ambulatory care settings to identify risk factors for adverse events in older adults, although it has not been used in the emergency department (ED). We aimed to determine whether 1) use of the 4Ms worksheet would help emergency clinicians understand older adult patients’ goals of care and 2) use of the worksheet was feasible in the ED. Methods: We conducted a qualitative, descriptive study among patients aged ≥60 years and emergency clinicians from January–June 2022. Patients were asked to fill out a 4Ms worksheet; following this, semi-structured interviews were conducted with patients and clinicians separately. We analysed data to create codes, which were divided into categories and sub-categories. Results: A total of 20 older patients and 19 emergency clinicians were interviewed. We identified two categories based on our aims: understanding patient goals of care (sub-categories: clinician/ patient concordance; understanding underlying goals of care; underlying goals of care discrepancy) and use of 4Ms Worksheet (sub-categories: worksheet to discussion discrepancy; challenges using worksheet; challenge completing worksheet before discharge). Rates of concordance between patient and clinician on main concern/goal of care and underlying goals of care were 82.4% and 15.4%, respectively. Conclusion: We found that most patients and emergency clinicians agreed on the main goal of care, although clinicians often failed to elicit patients’ underlying goal(s) of care. Additionally, many patients preferred to have the interviewer fill out the worksheet for them. There was often discrepancy between what was written and what was discussed with the interviewer. More research is needed to determine the best way to integrate the 4Ms framework within emergency care.

BackgroundResearch has shown that heterosexual African American male individuals aged 18-24 years have a higher prevalence of sexually transmitted infections (STIs) and are more likely to engage in risky sexual behavior. There is a critical need to promote sexual reproductive health (SRH) services among this population, especially in urban settings. Young African American male individuals use social media platforms to access health information, showcasing the potential of social media and web-based links as tools to leverage electronic engagement with this population to promote SRH care. ObjectiveThis study aims to explore electronic engagement with young African American male individuals in discussions about SRH care. This paper focuses on the recruitment and social media marketing methods used to recruit young, heterosexual African American male individuals aged 18-24 years for the Stay Safe Project, a larger study that aims to promote SRH services among this population in Detroit, Michigan. We investigate the use of TinyURL, a URL shortener and customized tool, and culturally informed social media marketing strategies to promote electronic engagement within this population. MethodsParticipants were recruited between December 2021 and February 2022 through various modes, including email listserves, Mailchimp, the UMHealthResearch website, X (formerly Twitter), Facebook, and Instagram. Images and vector graphics of African American male individuals were used to create social media advertisements that directed participants to click on a TinyURL that led to a recruitment survey for the study. ResultsTinyURL metrics were used to monitor demographic and user data, analyzing the top countries, browsers, operating systems, and devices of individuals who engaged with the customized TinyURL links and the total human and unique clicks from various social media platforms. Mailchimp was the most successful platform for electronic engagement with human and unique clicks on the custom TinyURL link, followed by Instagram and Facebook. In contrast, X, traditional email, and research recruiting websites had the least engagement among our population. Success was determined based on the type of user and follower for each platform, whether gained in the community through sign-ups or promoted at peak user time and embedded and spotlighted on nontraditional media (eg, social media sites, blogs, and podcasts) for the user. Low engagement (eg, traditional email) from the target population, limited visibility, and fewer followers contributed to decreased engagement. ConclusionsThis study provides insight into leveraging customized, shortened URLs, TinyURL metrics, and social media platforms to improve electronic engagement with young African American male individuals seeking information and resources about SRH care. The results of this study have been used to develop a pilot intervention for this population that will contribute to strategies for encouraging sexual well-being, clinic use, and appropriate linkage to SRH care services among young, heterosexual African American male individuals.

Abstract Background Potassium regulation in the body is primarily done in the kidney. In addition to this, hyperkalemia, occurs in approximately 10% of individuals with chronic kidney disease (CKD) and is associated with elevated all-cause mortality. Individuals with CKD are often told to restrict dietary potassium (K), however, this recommendation is based on low quality evidence. Reduced quality of life, limited dietary choices and nutritional deficiencies are all potential negative outcomes that may occur when restricting dietary K in CKD patients. There is a need for randomized controlled trials investigating the impact of dietary K modification on serum K concentrations in people with CKD. Methods A randomized 2-period crossover design comparing a liberalized K fruit and vegetable diet where participants will be required to consume ~ 3500 mg of dietary K daily, to a standard K restricted diet where participants will be required to consume

Abstract Background Bipolar spectrum disorders (BSDs) are associated with a heightened sensitivity to rewards and elevated reward-related brain function in cortico-striatal circuitry. A separate literature documents social and circadian rhythm disruption in BSDs. Recently, integrated reward-circadian models of BSDs have been proposed. These models draw on work indicating that the two systems influence each other and interact to affect mood functioning. When dysregulated, reward and circadian system signaling may combine to form a positive feedback loop, whereby dysregulation in one system exacerbates dysregulation in the other. Project CREST (Circadian, Reward, and Emotion Systems in Teens) provides a first systematic test of reward-circadian dysregulation as a synergistic and dynamic vulnerability for first onset of BSD and increases in bipolar symptoms during adolescence. Methods This NIMH-funded R01 study is a 3-year prospective, longitudinal investigation of approximately 320 community adolescents from the broader Philadelphia area, United States of America. Eligible participants must be 13–16 years old, fluent in English, and without a prior BSD or hypomanic episode. They are being selected along the entire dimension of self-reported reward responsiveness, with oversampling at the high tail of the dimension in order to increase the likelihood of BSD onsets. At Times 1–6, every 6 months, participants will complete assessments of reward-relevant and social rhythm disruption life events and self-report and diagnostic assessments of bipolar symptoms and episodes. Yearly, at Times 1, 3, and 5, participants also will complete self-report measures of circadian chronotype (morningness-eveningness) and social rhythm regularity, a salivary dim light melatonin onset (DLMO) procedure to assess circadian phase, self-report, behavioral, and neural (fMRI) assessments of monetary and social reward responsiveness, and a 7-day ecological momentary assessment (EMA) period. During each EMA period, participants will complete continuous measures of sleep/wake and activity (actigraphy), a daily sleep diary, and three within-day (morning, afternoon, evening) measures of life events coded for reward-relevance and social rhythm disruption, monetary and social reward responsiveness, positive and negative affect, and hypo/manic and depressive symptoms. The fMRI scan will occur on the day before and the DLMO procedure will occur on the first evening of the 7-day EMA period. Discussion This study is an innovative integration of research on multi-organ systems involved in reward and circadian signaling in understanding first onset of BSD in adolescence. It has the potential to facilitate novel pharmacological, neural, and behavioral interventions to treat, and ideally prevent, bipolar conditions.

Abstract Infertility or subfertility is a critical barrier to sustainable cattle production, including in heifers. The development of heifers that do not produce a calf within an optimum window of time is a critical factor for the profitability and sustainability of the cattle industry. In parallel, heifers are an excellent biomedical model for understanding the underlying etiology of infertility because well-nourished heifers can still be infertile, mostly because of inherent physiological and genetic causes. Using a high-density single nucleotide polymorphism (SNP) chip, we collected genotypic data, which were analyzed using an association analysis in PLINK with Fisher’s exact test. We also produced quantitative transcriptome data and proteome data. Transcriptome data were analyzed using the quasi-likelihood test followed by the Wald’s test, and the likelihood test and proteome data were analyzed using a generalized mixed model and Student’s t-test. We identified two SNPs significantly associated with heifer fertility (rs110918927, chr12: 85648422, P = 6.7 × 10−7; and rs109366560, chr11:37666527, P = 2.6 × 10−5). We identified two genes with differential transcript abundance (eFDR ≤ 0.002) between the two groups (Fertile and Sub-Fertile): Adipocyte Plasma Membrane Associated Protein (APMAP, 1.16 greater abundance in the Fertile group) and Dynein Axonemal Intermediate Chain 7 (DNAI7, 1.23 greater abundance in the Sub-Fertile group). Our analysis revealed that the protein Alpha-ketoglutarate-dependent dioxygenase FTO was more abundant in the plasma collected from Fertile heifers relative to their Sub-Fertile counterparts (FDR < 0.05). Lastly, an integrative analysis of the three datasets identified a series of molecular features (SNPs, gene transcripts, and proteins) that discriminated 21 out of 22 heifers correctly based on their fertility category. Our multi-omics analyses confirm the complex nature of female fertility. Very importantly, our results also highlight differences in the molecular profile of heifers associated with fertility that transcend the constraints of breed-specific genetic background.

In undergraduate life sciences education, open educational resources (OERs) increase accessibility and retention for students, reduce costs, and save instructors time and effort. Despite increasing awareness and utilization of these resources, OERs are not centrally located, and many undergraduate instructors describe challenges in locating relevant materials for use in their classes. To address this challenge, we have designed a resource collection (referred to as Open Resources for Biology Education, ORBE) with 89 unique resources that are primarily relevant to undergraduate life sciences education. To identify the resources in ORBE, we asked undergraduate life sciences instructors to list what OERs they use in their teaching and curated their responses. Here, we summarize the contents of the ORBE and describe how educators can use this resource as a tool to identify suitable materials to use in their classroom context. By highlighting the breadth of unique resources openly available for undergraduate biology education, we intend for the ORBE to increase instructors' awareness and use of OERs.

OBJECTIVES/GOALS: Social isolation/loneliness is a public health crisis and one that is unlikely to be solved through pharmacology. Nonpharmacological approaches, such as dance, are needed. The objective of this study is to investigate the physiological correlates of dance-induced improvements in social connection. METHODS/STUDY POPULATION: Participants were randomly assigned to participate for 4 weeks (2 times per week, 90-minute sessions) in either 1) improvisational dance training (experimental group; n=7); or a 2) dance movie watching experience (control group; n=7). Before and after the intervention, using mobile brain-body imaging techniques, participants and their instructor had their brain (via electroencephalography) and body physiology (via photoplethysmography) recorded during a series of verbal and nonverbal interactive experiences. Participants were also video recorded via 4 surrounding cameras for later motion capture analysis. Neuropsychological assessments were also conducted before and after the intervention. RESULTS/ANTICIPATED RESULTS: We found that dance significantly increased social skills including empathy, interpersonal skills, emotional regulation, mindfulness, and attention. Additionally, we found that dance significantly increased interbrain synchrony during nonverbal experiences including theta (4-8 Hz), beta (12-35 Hz), and gamma (35-45 Hz) frequencies in the occipital lobe. Increases in interbrain synchrony were also positively correlated with increases in empathy. Additionally, intercardiac synchrony between the participant and instructor showed a significant correlation at post-intervention only. Future investigations will focus on the relationship between interbrain, intercardiac, and movement synchrony. DISCUSSION/SIGNIFICANCE: Our findings support the idea that dance increases interpersonal synchrony at the level of the brain, heart, and behavior. Understanding the neural and somatic mechanisms of social behaviors will help promote understanding and development of interventions for the critical problem of social isolation and loneliness.

Abstract Introduction Prior studies have demonstrated an association between time to revision total knee arthroplasty (rTKA) and indication; however, the impact of early versus late revision on post-operative outcomes has not been reported. Materials and methods A retrospective, observational study examined patients who underwent unilateral, aseptic rTKA at an academic orthopedic hospital between 6/2011 and 4/2020 with > 1-year of follow-up. Patients were early revisions if they were revised within 2 years of primary TKA (pTKA) or late revisions if revised after greater than 2 years. Patient demographics, surgical factors, and post-operative outcomes were compared. Results 470 rTKA were included (199 early, 271 late). Early rTKA patients were younger by 2.5 years (p = 0.002). The predominant indications for early rTKA were instability (28.6%) and arthrofibrosis/stiffness (26.6%), and the predominant indications for late rTKA were aseptic loosening (45.8%) and instability (26.2%; p

Aims: Revision total knee arthroplasty (rTKA) is a technically challenging and costly procedure. It is well-documented that primary TKA (pTKA) have better survivorship than rTKA; however, we were unable to identify any studies explicitly investigating previous rTKA as a risk factor for failure following rTKA. The purpose of this study is to compare the outcomes following rTKA between patients undergoing index rTKA and those who had been previously revised. Methods: This retrospective, observational study reviewed patients who underwent unilateral, aseptic rTKA at an academic orthopaedic speciality hospital between June 2011 and April 2020 with > one-year of follow-up. Patients were dichotomized based on whether this was their first revision procedure or not. Patient demographics, surgical factors, postoperative outcomes, and re-revision rates were compared between the groups. Results: A total of 663 cases were identified (486 index rTKAs and 177 multiply revised TKAs). There were no differences in demographics, rTKA type, or indication for revision. Multiply revised patients had significantly longer rTKA operative times (p < 0.001), and were more likely to be discharged to an acute rehabilitation centre (6.2% vs 4.5%) or skilled nursing facility (29.9% vs 17.5%; p = 0.003). Patients who had been multiply revised were also significantly more likely to have subsequent reoperation (18.1% vs 9.5%; p = 0.004) and re-revision (27.1% vs 18.1%; p = 0.013). The number of previous revisions did not correlate with the number of subsequent reoperations (r = 0.038; p = 0.670) or re-revisions (r = −0.102; p = 0.251). Conclusion: Multiply revised TKA had worse outcomes, with higher rates of facility discharge, longer operative times, and greater reoperation and re-revision rates compared to index rTKA. Cite this article: Bone Jt Open 2023;4(5):393–398.

Abstract Background A gap currently exists between genetic variants and the underlying cell and tissue biology of a trait, and expression quantitative trait loci (eQTL) studies provide important information to help close that gap. However, two concerns that arise with eQTL analyses using RNA-sequencing data are normalization of data across samples and the data not following a normal distribution. Multiple pipelines have been suggested to address this. For instance, the most recent analysis of the human and farm Genotype-Tissue Expression (GTEx) project proposes using trimmed means of M-values (TMM) to normalize the data followed by an inverse normal transformation. Results In this study, we reasoned that eQTL analysis could be carried out using the same framework used for differential gene expression (DGE), which uses a negative binomial model, a statistical test feasible for count data. Using the GTEx framework, we identified 35 significant eQTLs (P

AbstractCancer is a devastating health problem with inadequate treatment options. Many conventional treatments for solid-tumor cancers lack tumor specificity, which results in low efficacy and off-target damage to healthy tissues. Nanoparticle (NP)-mediated photothermal therapy (PTT) is a promising minimally invasive treatment for solid-tumor cancers that has entered clinical trials. Traditionally, NPs used for PTT are coated with passivating agents and/or targeting ligands, but alternative coatings are being explored to enhance tumor specific delivery. In particular, cell-derived membranes have emerged as promising coatings that improve the biointerfacing of photoactive NPs, which reduces their immune recognition, prolongs their systemic circulation and increases their tumor accumulation, allowing for more effective PTT. To maximize treatment success, membrane-wrapped nanoparticles (MWNPs) that enable dual tumor imaging and PTT are being explored. These multifunctional theranostic NPs can be used to enhance tumor detection and/or ensure a sufficient quantity of NPs that have arrived in the tumor prior to laser irradiation. This review summarizes the current state-of-the-art in engineering MWNPs for combination cancer imaging and PTT and discusses considerations for the path toward clinical translation.

Background: Dysmenorrhea (painful menstrual cramps) is one of the most common gynecological complaints in women and girls. Dysmenorrhea may be a condition itself or a result of another medical condition, including endometriosis and chronic pelvic pain. Research examining the relationship between menstrual pain ratings and catastrophizing has produced mixed results. Objective: To review and meta-analyze the relationship between catastrophizing and pain ratings of chronic cyclical pelvic pain. Design: Cross-sectional, longitudinal, and intervention studies that reported the relationship between menstrual/pelvic pain and catastrophizing were included. Study populations had to include healthy menstruating persons or persons with a condition associated with cyclical pelvic pain including primary dysmenorrhea, endometriosis, and/or chronic pelvic pain. Data sources and methods: A systematic search of articles published since 2012 on PubMed, PsychInfo, CINHAL, and Medline was conducted in January and rerun in November of 2022. Search terms included cyclical pelvic pain, dysmenorrhea, endometriosis, pelvic pain, and catastrophizing. Data extraction was completed independently by two extractors and cross-checked for errors. A random-effects meta-regression was used to synthesize the data using restricted maximum likelihood. Results: Twenty-five studies examining 4,540 participants were included. A random effects model found a meta-correlation between catastrophizing and pain of r = .31 (95% confidence interval: .23–.40) p

Abstract Background Tonsillar carcinomas are rarely reported in dogs. Information on outcome after treatment is sparse and prognosis is guarded to poor. Hypothesis/Objectives Assess treatment outcome and potential prognostic factors in a population of dogs with cytological or histopathological diagnosis of tonsillar carcinoma. Animals A total of 123 client‐owned dogs with diagnosis of tonsillar carcinoma confirmed by cytology or histopathology. Methods Retrospective, multi‐institutional study. Medical records of 12 institutions were reviewed from 2012 to 2021. Results Treatment included surgery, chemotherapy (conventional, tyrosine kinase inhibitors or metronomic chemotherapy), radiotherapy, nonsteroidal anti‐inflammatory drugs (NSAIDs) or a combination of these. Surgery was performed in 68 cases, chemotherapy was administered in association with NSAIDs in 64 cases, NSAIDs were used alone in 14 cases and in association with surgery in 21 cases, whereas radiotherapy was used alone or in combination with surgery or chemotherapy in 20 cases. Overall survival time (OST) was 126 days (95% confidence interval [CI], 88‐164). Significantly longer survival (P

Background: Fully porous acetabular shells are an appealing choice for patients with extensive acetabular defects undergoing revision total hip arthroplasty (rTHA). This study reports on the early outcomes of a novel 3-D printed fully porous titanium acetabular shell in revision acetabular reconstruction. Methods: A multicenter retrospective study of patients who received a fully porous titanium acetabular shell for rTHA with a minimum of 2 years of follow-up was conducted. The primary outcome was rate of acetabular revision. Results: The final study cohort comprised 68 patients with a mean age of 67.6 years (standard deviation 10.4) and body mass index of 29.5 kg/m2 (standard deviation 5.9). Ninety-four percent had a preoperative Paprosky defect grade of 2A or higher. The average follow-up duration was 3.0 years (range 2.0-5.1). Revision-free survivorship at 2 years was 81% for all causes, 88% for acetabular revisions, and 90% for acetabular revision for aseptic acetabular shell failure. Eight shells were explanted within 2 years (12%): 3 for failure of osseointegration/aseptic loosening (4%) after 15, 17, and 20 months; 3 for infection (4%) after 1, 3, and 6 months; and 2 for instability (3%). At the latest postoperative follow-up, all unrevised shells showed radiographic signs of osseointegration, and none had migrated. Conclusions: This novel 3-D printed fully porous titanium shell in rTHA demonstrated good survivorship and osseointegration when used in complex acetabular reconstruction at a minimum of 2 years. Level of evidence: IV, case series.

Abstract Background Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is an effective, but highly resource intensive salvage treatment option in COVID patients with acute respiratory distress syndrome (ARDS). Right ventricular (RV) dysfunction is a known sequelae of COVID-19 induced ARDS, yet there is a paucity of data on the incidence and determinants of RV dysfunction on VV ECMO. We retrospectively examined the determining factors leading to RV failure and means of early identification of this phenomenon in patients on VV ECMO. Methods The data was extracted from March 2020 to March 2021 from the regional University of Washington Extracorporeal Life Support database. The inclusion criteria included patients > 18 years of age with diagnosis of COVID-19. All had already been intubated and mechanically ventilated prior to VV ECMO deployment. Univariate analysis was performed to identify risk factors and surrogate markers for RV dysfunction. In addition, we compared outcomes between those with and without RV dysfunction. Results Of the 33 patients that met inclusion criteria, 14 (42%) had echocardiographic evidence of RV dysfunction, 3 of whom were placed on right ventricular assist device support. Chronic lung disease was an independent risk factor for RV dysfunction (p = 0.0002). RV dysfunction was associated with a six-fold increase in troponin I (0.07 ng/ml vs. 0.44 ng/ml, p = 0.039) and four-fold increase in brain natriuretic peptide (BNP) (158 pg/ml vs. 662 pg/ml, p = 0.037). Deep vein thrombosis (DVT, 21% vs. 43%, p = 0.005) and pulmonary embolism (PE, 11% vs. 21%, p = 0.045) were found to be nearly twice as common in the RV dysfunction group. Total survival rate to hospital discharge was 39%. Data trended towards shorter duration of hospital stay (47 vs. 65.6 days, p = 0.15), shorter duration of ECMO support (21 days vs. 36 days, p = 0.06) and improved survival rate to hospital discharge (42.1% vs. 35.7%, p = 0.47) for those with intact RV function compared to the RV dysfunction group. Conclusions RV dysfunction in critically ill patients with COVID-19 pneumonia in common. Trends of troponin I and BNP may be important surrogates for monitoring RV function in patients on VV ECMO. We recommend echocardiographic assessment of the RV on such patients.

Abstract Cancer is a global health problem that needs effective treatment strategies. Conventional treatments for solid-tumor cancers are unsatisfactory because they cause unintended harm to healthy tissues and are susceptible to cancer cell resistance. Nanoparticle-mediated photothermal therapy is a minimally invasive treatment for solid-tumor cancers that has immense promise as a standalone therapy or adjuvant to other treatments like chemotherapy, immunotherapy, or radiotherapy. To maximize the success of photothermal therapy, light-responsive nanoparticles can be camouflaged with cell membranes to endow them with unique biointerfacing capabilities that reduce opsonization, prolong systemic circulation, and improve tumor delivery through enhanced passive accumulation or homotypic targeting. This ensures a sufficient dose of photoresponsive nanoparticles arrives at tumor sites to enable their complete thermal ablation. This review summarizes the state-of-the-art in cell membrane camouflaged nanoparticles for photothermal cancer therapy and provides insights to the path forward for clinical translation.

Abstract Background Cytoplasmic and nuclear maturation of oocytes, as well as interaction with the surrounding cumulus cells, are important features relevant to the acquisition of developmental competence. Methods Here, we utilized Brilliant cresyl blue (BCB) to distinguish cattle oocytes with low activity of the enzyme Glucose-6-Phosphate Dehydrogenase, and thus separated fully grown (BCB positive) oocytes from those in the growing phase (BCB negative). We then analyzed the developmental potential of these oocytes, mitochondrial DNA (mtDNA) copy number in single oocytes, and investigated the transcriptome of single oocytes and their surrounding cumulus cells of BCB positive versus BCB negative oocytes. Results The BCB positive oocytes were twice as likely to produce a blastocyst in vitro compared to BCB- oocytes (P

Background: Glioblastoma is the most aggressive and common primary brain tumor. Patients usually present with a short clinical history that often includes focal neurological deficits. Historically 1- and 5-year survival of patients with this disease has been low. There are now increasing reports of patients living longer, making it important to understand the clinical progression of the disease to predict patient needs. Methods: Patients ≥ 18 years who were enrolled in the central nervous system (CNS) tumor registry at HonorHealth in Scottsdale, Arizona between April 7, 2017 and February 5, 2020 were included. Demographic data and data on adverse events were collected from the CNS tumor registry. The data was analyzed and reported as means and standard deviations. Results: 12 male and 7 female patients were included in the study. The average time to follow-up was 15.12 months and patients experienced the onset of psychiatric/neurological adverse events an average of 3.29 months after surgery, cardiovascular/respiratory adverse events 3.42 months after surgery, and general adverse events 3.71 months after surgery. Additionally, 63.2% of patients experienced a seizure with an average time to onset of 6.75 months after surgery. Conclusions: Patients with glioblastoma experience psychiatric/neurological adverse events first, followed by cardiovascular/respiratory adverse events, and finally followed by general adverse events. Most patients will experience at least one seizure.

The COVID -19 pandemic allowed for widespread implementation of telehealth as a delivery method for occupational therapy (OT) services. The purpose of this study was to investigate the perceptions of novice telehealth OT practitioners regarding telehealth as a delivery method for OT services. Quantitative data was collected through a modified version of the Telehealth Usability Questionnaire and analyzed via descriptive statistics. Qualitative data was collected by open-ended questions and analyzed via thematic analysis. OT practitioners’ responses revealed four major themes: logistics of telehealth practice, role of client champions, capacity of the OT practitioner, and styles and approaches. The study revealed that OT sessions delivered via telehealth increased access to clients and continuity of services. Client champion engagement, effective coaching strategies, and practitioner flexibility supported the success of OT telehealth sessions.

We investigate the spatiotemporal evolution of high-degree acoustic-mode frequencies of the Sun and surface magnetic activity over the course of multiple solar cycles, to improve our understanding of the connection between the solar interior and atmosphere. We focus on high-degree p -modes due to their ability to characterize conditions in the shear layer just below the solar surface, and analyze 22 yr of oscillation frequencies obtained from the Global Oscillation Network Group. Considering 10.7 cm radio flux measurements, the sunspot number, and the local magnetic activity index as solar-activity proxies, we find strong correlation between the mode frequencies and each activity index. We further investigate the hemispheric asymmetry associated with oscillation frequencies and magnetic activity proxies, and find that both were dominant in the southern hemisphere during the descending phase of cycle 23, while in cycle 24 these quantities fluctuated between northern and southern hemispheres. Analyzing the frequencies at different latitudes with the progression of solar cycles, we observe that the variations at midlatitudes were dominant in the southern hemisphere during the maximum-activity period of cycle 24, but the values overlap as the cycle advances toward the minimum phase. The mode frequencies at the beginning of cycle 25 are found to be dominant in the southern hemisphere following the pattern of magnetic activity. The analysis provides added evidence that the variability in oscillation frequencies is caused by both strong and weak magnetic fields.

Abstract Introduction Surgeons can improve their practice by understanding potentially avoidable reasons for early revision total knee arthroplasty (rTKA). The purpose of this study is to describe potentially avoidable indications for rTKA within 5 years of the index procedure. Methods This retrospective observational analysis utilized the rTKA database at a large, academic orthopedic specialty hospital to identify 167 consecutive rTKA from 2014 to 2019 performed within 5 years after primary TKA (pTKA). Two fellowship-trained arthroplasty surgeons reviewed the cases to classify them as potentially avoidable or unavoidable. Unavoidable indications for rTKA included infection/wound complication, arthrofibrosis, instability due to underlying collagen disease or significant weight loss, and any traumatic event leading to pTKA failure. Potentially avoidable indications included atraumatic instability, intraoperative fracture, metal allergy, and atraumatic patellar instability or maltracking. Aseptic loosening was considered avoidable if it occurred in the presence of component malpositioning or poor cementation technique. Results There were 112 (67.1%) unavoidable cases and 55 avoidable cases (32.9%). Of the unavoidable cases, there were 68 rTKA for infection or wound complications (60.7%), 23 for arthrofibrosis (20.5%), 6 for instability (5.4%), 6 for postoperative fracture (5.4%), 6 for aseptic loosening (5.4%), and 3 for extensor mechanism pathology following trauma (2.6%). Of the potentially avoidable rTKA, 24 were for aseptic loosening (43.7%), 23 for atraumatic instability (41.8%), 6 for atraumatic extensor mechanism pathology (10.9%), 1 for nickel allergy (1.8%), and 1 for intraoperative fracture (1.8%). Conclusion These findings indicate that over 30% of early rTKA are potentially avoidable. Interventions should focus on addressing potentially avoidable causes such as short-term aseptic loosening and instability to reduce the need for costly and resource-intensive rTKA. Level of evidence III, retrospective observational analysis

IntroductionRare neurodevelopmental disorders, including inherited white matter disorders or leukodystrophies, often present a diagnostic challenge on a genetic level given the large number of causal genes associated with a range of disease subtypes. This study aims to demonstrate the challenges and lessons learned in the genetic investigations of leukodystrophies through presentation of a series of cases solved using exome or genome sequencing.MethodsEach of the six patients had a leukodystrophy associated with hypomyelination or delayed myelination on MRI, and inconclusive clinical diagnostic genetic testing results. We performed next generation sequencing (case-based exome or genome sequencing) to further investigate the genetic cause of disease.ResultsFollowing different lines of investigation, molecular diagnoses were obtained for each case, with patients harboring pathogenic variants in a range of genes including TMEM106B, GJA1, AGA, POLR3A, and TUBB4A. We describe the lessons learned in reaching the genetic diagnosis, including the importance of (a) utilizing proper multi-gene panels in clinical testing, (b) assessing the reliability of biochemical assays in supporting diagnoses, and (c) understanding the limitations of exome sequencing methods in regard to CNV detection and region coverage in GC-rich areas.DiscussionThis study illustrates the importance of applying a collaborative diagnostic approach by combining detailed phenotyping data and metabolic results from the clinical environment with advanced next generation sequencing analysis techniques from the research environment to increase the diagnostic yield in patients with genetically unresolved leukodystrophies.

Abstract Background The cyclical nature of gene expression in the intraerythrocytic development cycle (IDC) of the malaria parasite, Plasmodium falciparum, confounds the accurate detection of specific transcriptional differences, e.g. as provoked by the development of drug resistance. In lab-based studies, P. falciparum cultures are synchronized to remove this confounding factor, but the rapid detection of emerging resistance to artemisinin therapies requires rapid analysis of transcriptomes extracted directly from clinical samples. Here we propose the use of cyclical regression covariates (CRC) to eliminate the major confounding effect of developmentally driven transcriptional changes in clinical samples. We show that elimination of this confounding factor reduces both Type I and Type II errors and demonstrate the effectiveness of this approach using a published dataset of 1043 transcriptomes extracted directly from patient blood samples with different patient clearance times after treatment with artemisinin. Results We apply this method to two publicly available datasets and demonstrate its ability to reduce the confounding of differences in transcript levels due to misaligned intraerythrocytic development time. Adjusting the clinical 1043 transcriptomes dataset with CRC results in detection of fewer functional categories than previously reported from the same data set adjusted using other methods. We also detect mostly the same functional categories, but observe fewer genes within these categories. Finally, the CRC method identifies genes in a functional category that was absent from the results when the dataset was adjusted using other methods. Analysis of differential gene expression in the clinical data samples that vary broadly for developmental stage resulted in the detection of far fewer transcripts in fewer functional categories while, at the same time, identifying genes in two functional categories not present in the unadjusted data analysis. These differences are consistent with the expectation that CRC reduces both false positives and false negatives with the largest effect on datasets from samples with greater variance in developmental stage. Conclusions Cyclical regression covariates have immediate application to parasite transcriptome sequencing directly from clinical blood samples and to cost-constrained in vitro experiments.

This scoping review fills the gap on key characteristics of interventions and trainings for direct support workforce (DSW) of adults across disabilities and aging adults. We included quantitative and qualitative studies examining the impact of interventions in home and community-based settings in the United States or internationally and published in English since 1990. We initially identified 2,551 titles and completed final data extraction on 65 articles. Most of the studies were quantitative. The interventions reviewed were diverse, including Active support, Positive Behavior Support, and DSW stress reduction. We concluded that there is a need to conduct high-quality research focused on DSW well-being and their feeling of being valued to inform the field on how to best select and retain them.

Immunopanning is an efficient and reliable method for isolating primary cells from rodent brain tissue, making it a valuable tool for researchers interested in in vitro glial models. Here, we present an immunopanning protocol optimized for the isolation of Platelet-Derived Growth Factor Receptor Alpha positive (PDGFRα+) oligodendrocyte precursor cells (OPCs) from mouse brain tissue that results in a high yield of pure OPCs from minimal quantities of starting tissue. • The protocol presented here is optimized for a PDGFRα-dependent selection of mouse OPCs using a commercial antibody, accounting for the relatively weaker adhesion of OPCs to the anti-PDGFRα plate as compared to other oligodendrocyte lineage markers (e.g., MOG). • A modified papain digestion step, with 95% O2/5% CO2 gas that is humidified prior to perfusion, significantly enhances the yield of dissociated cells and final yield of OPCs. • Isolating OPCs at the PDGFRα+ stage permits the expansion of cells in culture, facilitating studies using transgenic mice, and enables studies on the development of the oligodendrocyte lineage without the spatial and temporal complexity of in vivo studies.

Community-based participatory research (CBPR) approaches are being leveraged more and more in efforts to improve health equity. Informing the building of community-academic partnerships, CBPR draws on the community’s expressed needs and engages stakeholders in future intervention development. To date, however, little has been published on such efforts targeting the health of young Black men (ages 18-24), despite this population’s disproportionate need. In this paper, we describe the formation of a community-academic partnership in a federally qualified health center, with the goal of improving the health of young Black men in Detroit, Michigan. After conducting a needs assessment, we built upon existing networks to form a Community Advisory Board (CAB). We held three community forums during which CAB members highlighted key health issues in their community and described how they could be addressed. We developed a plan for future research and community engagement based on community input. Finally, we provide insights on community engagement strategies, forum structure, setting boundaries, trust-building, and valuable information in addressing the inequities in health that affect young Black men.

Simulation has been recognized for its ability to develop competency-level skills and as a replacement for some introductory fieldwork (FW) hours. This study explored how occupational therapy competency-related skills developed over sequential in-person simulations across health practice contexts during Level 1 FW. Entry-to-practice occupational therapy students (N = 66) participated in six sequential, formative, Level 1 FW simulations. The first three sequential simulations (the same patient case evolves in each successive interaction) included a trained simulated patient in a community mental health context and the following three engaged a trained simulated inpatient in a physical health context. Evaluation rubric variables included selected Competencies for Occupational Therapists in Canada (2021) scaffolded to performance expectations at an introductory Level 1 FW placement level. Quantitative pre-post comparison design with secondary data analysis was analyzed using Wilcoxon signed-rank test and ordered logistic regression. Each additional simulation demonstrated significant increases in the odds of improved performance in clinical skills, clinical decision making, responding to evolving patient's needs and priorities, identifying their own strengths and weaknesses, articulating clinical reasoning, and receiving constructive criticism. However, students' skills in the physical health context for decision-making and responding to the patient's needs and priorities did not demonstrate the same improvement trajectories as the mental health context. Sequential simulations are an effective modality for developing Level 1 competency related skills in different practice contexts. Depending on the competency-related practice skill and context, three or more formative unfolding simulations in that context may be needed for a significant improvement.

Spanish is the second most spoken language in the United States and the most taught additional language (L2) in elementary-level schools. However, the amount and type of access differs according to the resources available. Rural settings, which comprise a third of all schools in the US, often have fewer resources and support for the development and maintenance of exposure-track L2 programs, which meet once per week with the goal of, as the name suggests, providing exposure to the L2, rather than a focus on cumulative language development. Given that there are immediate and long-term benefits of even low levels of early bilingualism, ensuring access to quality L2 education is a matter of equity. This paper centers on the first year of a longitudinal collaboration between an exposure-track Spanish language teacher in a rural elementary school, and the research team who created a task-based program tailored for the school following a needs analysis. We analyze the first year of the grant-funded program based on task effectiveness, student enjoyment, and teacher perspectives. We contextualize results within the rural community and offer initial longitudinal data on US exposure-track Spanish. We detail how we adjusted the program for the second year, are freely sharing the materials on the Task Bank (tblt.indiana.edu) and have transferred the program to the teacher's autonomy. Finally, we highlight that the success of this program was and is due to the collaborative nature of the partnership between the teacher, the researchers, and the administrators.

Thalamocortical network dysfunction contributes to seizures and sleep deficits in Dravet syndrome (DS), an infantile epileptic encephalopathy, but the underlying molecular and cellular mechanisms remain elusive. DS is primarily caused by mutations in the SCN1A gene encoding the voltage-gated sodium channel NaV1.1, which is highly expressed in GABAergic reticular thalamus (nRT) neurons as well as glutamatergic thalamocortical neurons. We hypothesized that NaV1.1 haploinsufficiency alters somatosensory corticothalamic circuit function through both intrinsic and synaptic mechanisms in nRT and thalamocortical neurons. Using Scn1a heterozygous mice of both sexes aged P25-P30, we discovered reduced excitability of nRT neurons and thalamocortical neurons in the ventral posterolateral (VPL) thalamus, while thalamocortical ventral posteromedial (VPM) neurons exhibited enhanced excitability. NaV1.1 haploinsufficiency enhanced GABAergic synaptic input and reduced glutamatergic input to VPL neurons, but not VPM neurons. In addition, glutamatergic input to nRT neurons was reduced in Scn1a heterozygous mice. These findings introduce alterations in glutamatergic synapse function and aberrant glutamatergic neuron excitability in the thalamus as disease mechanisms in DS, which has been widely considered a disease of GABAergic neurons. This work reveals additional complexity that expands current models of thalamic dysfunction in DS and identifies new components of corticothalamic circuitry as potential therapeutic targets.

Studies investigating autistic community research priorities indicate a mismatch between what autism research focuses on and what autistic people want to see researched. Furthermore, there has not been a research priority-setting exercise specifically with autistic people in Scotland, where there are unique cultural, political and social contexts. Using a community-based participatory design, we aimed to identify the research priorities of autistic adults living in Scotland. Autistic and non-autistic researchers designed and conducted a survey where 225 autistic adults rated and ranked research topics in order of importance and provided qualitative feedback on issues and questions important to them. The top five research priorities were mental health/well-being, identification and diagnosis of autistic people, support services, knowledge and attitudes towards autistic people and issues impacting autistic women. There were differences in priorities according to different intersections of identity, and qualitative responses indicated a desire for research to focus on support and understanding. The bottom three priorities concerned genetics, treatments and interventions and causes. These findings emphasise the need to address the gap between what autism research focuses on and the everyday lives of autistic people.

Initial teacher education programs have been criticised for their failure to deliver classroom-ready graduates. Problems of concern for preservice teachers (PSTs) identified in the literature are insufficient time in the classroom, lack of confidence, inadequate pedagogical knowledge and a theory practice divide. This research examines a school-university partnership approach to science teacher education from the perspective of PSTs, school students, teachers and teacher educators where university tutorials were conducted in a school environment. This research is underpinned by practice architectures theory, it follows collaborative participatory action research methodology using mixed methods of data collection including surveys, interviews and focus groups. The research findings revealed how the program built on PSTs' pedagogical knowledge and confidence and connected theory with practice. Teachers observed high level student engagement and students building on their prior science knowledge in innovative science lessons. The research provides rich data that illuminate aspects in this school-university partnership approach from a range of perspectives.

Abstract Bolbophorus damnificus (Digenea: Bolbophoridae) causes significant losses in US catfish aquaculture. Little is known regarding the prevalence of infected snail hosts during outbreaks. To assess prevalence of snails observed shedding Bolbophorus spp. cercariae, as well as snails that were infected but not observed shedding cercariae, Planorbella trivolvis (n = 8,159) were collected from 14 catfish production ponds with B. damnificus activity in Mississippi, USA. Individual snails were placed in 10 ml of filtered (20 μm) reservoir pond water and observed for 48 hr for cercariae release. Identification of B. damnificus or Bolbophorus sp. type II cercariae was confirmed by duplex PCR. Genomic DNA was isolated from ~100 non‐shedding snails from each pond and the PCR assay used to identify the presence of B. damnificus or Bolbophorus sp. type II infected snails. The prevalence of snails shedding B. damnificus ranged from 0.23 to 13.6%. Observation of cercariae shedding underestimated true B. damnificus and Bolbophorus sp. type II prevalence in 42.9 and 64.3% of sampled ponds, respectively. Prevalence of B. damnificus infected snails was typically

Abstract Background Like in many settings, implementation of evidence-based practices often fall short in pediatric intensive care units (PICU). Very few prior studies have applied implementation science frameworks to understand how best to improve practices in this unique environment. We used the relatively new integrated Promoting Action on Research Implementation in Health Services (iPARIHS) framework to assess practice improvement in the PICU and to explore the utility of the framework itself for that purpose. Methods We used the iPARIHS framework to guide development of a semi-structured interview tool to examine barriers, facilitators, and the process of change in the PICU. A framework approach to qualitative analysis, developed around iPARIHS constructs and subconstructs, helped identify patterns and themes in provider interviews. We assessed the utility of iPARIHS to inform PICU practice change. Results Fifty multi-professional providers working in 8 U.S. PICUs completed interviews. iPARIHS constructs shaped the development of a process model for change that consisted of phases that include planning, a decision to adopt change, implementation and facilitation, and sustainability; the PICU environment shaped each phase. Large, complex multi-professional teams, and high-stakes work at near-capacity impaired receptivity to change. While the unit leaders made decisions to pursue change, providers’ willingness to accept change was based on the evidence for the change, and provider’s experiences, beliefs, and capacity to integrate change into a demanding workflow. Limited analytic structures and resources frustrated attempts to monitor changes’ impacts. Variable provider engagement, time allocated to work on changes, and limited collaboration impacted facilitation. iPARIHS constructs were useful in exploring implementation; however, we identified inter-relation of subconstructs, unique concepts not captured by the framework, and a need for subconstructs to further describe facilitation. Conclusions The PICU environment significantly shaped the implementation. The described process model for implementation may be useful to guide efforts to integrate changes and select implementation strategies. iPARIHS was adequate to identify barriers and facilitators of change; however, further elaboration of subconstructs for facilitation would be helpful to operationalize the framework. Trial registration Not applicable, as no health care intervention was performed.