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Background: Interviewer-assisted administration of International Prostate Symptoms Score (IPSS) and Internal Index of Erectile Function-5 (IIEF-5) questionnaires in men with lower urinary tract symptoms (LUTS) due to benign prostate enlargement (BPE) may generate inconsistent outcomes. Objectives: To assess the correlation between the scores from interviewer-assisted administration of the IPSS questionnaire and the IIEF-5 questionnaire in men with uncomplicated LUTS due to BPE. Materials and Methods: The IPPS and the IIEF-5 questionnaires were administered with interviewer assistance to a cross-section of men presenting to the hospital with symptoms of LUTS due to uncomplicated BPE. The demographics were ascertained, and the association between IPPS and IIEF-5 scores was determined using linear correlation. Results: There were 211 participants in 18 months with a mean age of 66.5 ± 9.5years. The mean prostate volume, prostate-specific antigen, peak flow rate, and post-void residual volume were 55.2 ± 10.1 mL, 3.1 ± 0.7 ng/mL, 20.8 ± 8.2 mL/s, and 38.1 ± 21.5 mL, respectively. One hundred and eighty-six participants (88.2%) attained post-primary level of formal education. Moderate LUTS was reported in 51.7% (n = 109), while severe LUTS was reported in 10.4% (n = 22) participants. The mean storage LUTS (sLUTS) score was 6.25 ± 2.84, the mean voiding LUTS (vLUTS) score was 4.27 ± 4.56, and the mean IPSS was 10.38 ± 6.44. The mean IIEF-5 score was 15.17 ± 6.09. There was a poor correlation between IIEF-5 and sLUTS (Spearman rho –0.02; P = 0.77), vLUTS (Spearman rho –0.058; P = 0.403), IPSS scores (Spearman rho –0.048; P = 0.49), as well as with quality of life (QoL) preferences (F 1.722; P = 0.117). Conclusions: Interviewer-assisted IIEF-5 scores do not relate with sLUTS, vLUTS IPSS, and QoL due to LUTS, as is the case with reports on self-administered IIEF-5 scores.

Many patients with cancer experience cancer-related cognitive decline (CRCD). Previous studies have shown that elevated S100β, a calcium-binding protein commonly found in glial cells, can exhibit neurotoxic effects, including disruption of the blood-brain barrier (BBB). We studied changes in S100β levels in patients with breast cancer receiving chemotherapy, and the relationship to changes in cognitive function. A total of 505 women with breast cancer (mean (sd) age; 53.4 (53.6)) and 336 age-matched controls without cancer (52.8 (10.3)) were included from a nationwide study as part of the National Cancer Institute Community Oncology Research Program (NCORP). Both groups provided blood samples and completed neurocognitive assessments within 7 days before the patients with breast cancer received their first chemotherapy dose (pre-chemotherapy; T1) and within 1 month of their last chemotherapy administration (post-chemotherapy; T2). Utilizing a linear mixed model, multivariate linear regressions, and Spearman rank correlations (rs), we investigated longitudinal changes in serum S100β concentrations and their relationships to changes in neurocognitive outcomes over time. We observed an increase in S100β for patients with breast cancer (p = 0.002), but not for controls without cancer over time (p = 0.683). Additionally, we identified subtle relationships between increases in serum S100β and worsening in cognitive performance on the Backward Counting test (rs = 0.11, p = 0.041) and self-reported FACT-Cog Perceived Cognitive Abilities (rs = −0.10, p = 0.025). Regression analyses adjusted for age, race, body-mass index (BMI), education, menopausal status, anxiety, and depression revealed a trend remained for the relationship of S100β with Backward Counting. In conclusion, we found that patients with breast cancer experience a significant increase in concentration of serum S100β over the course of chemotherapy. This increase is correlated with worsening in some neurocognitive outcomes from pre-to post-chemotherapy, with trending results remaining following adjustment for covariates.

This article is about a framework for determining the degree of realism of any given passenger ride motion discomfort measurement formula. After providing some context and reviewing evidence of deficiency in currently popular ride motion discomfort measurement formulas, the article outlines the research program that needs to be carried out in order to establish such a framework. The research begins with gathering recordings of uncomfortable ride motion episodes encountered in a chosen type of passenger transport service. It then has test subjects compare the episodes via a ride motion simulator and adjust their amplitudes pair wise until they cause equal discomfort. It explains how to take the pair wise amplitude adjustments and determine amplitude adjustments that bring all of the motion episode recordings to a common level of discomfort so that they form a normalized set. Then, the lower the scatter of the scores assigned by any given discomfort measurement formula to the members of that set, the more realistic that formula will be for the chosen service.

Summary: Immunophenotyping of out-of-hospital cardiac arrest (OHCA) patients is of increasing interest but has challenges. Here, we describe steps for the design of the clinical cohort, planning patient enrollment and sample collection, and ethical review of the study protocol. We detail procedures for blood sample collection and cryopreservation of peripheral blood mononuclear cells (PBMCs). We detail steps to modulate immune checkpoints in OHCA PBMC ex vivo. This protocol also has relevance for immunophenotyping other types of critical illness.For complete details on the use and execution of this protocol, please refer to Tamura et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Objectives To examine racial and ethnic disparities in postoperative opioid prescribing. Data sources Electronic health records (EHR) data across 24 hospitals from a healthcare delivery system in Northern California from January 1, 2015 to February 2, 2020 (study period). Study design Cross-sectional, secondary data analyses were conducted to examine differences by race and ethnicity in opioid prescribing, measured as morphine milligram equivalents (MME), among patients who underwent select, but commonly performed, surgical procedures. Linear regression models included adjustment for factors that would likely influence prescribing decisions and race and ethnicity-specific propensity weights. Opioid prescribing, overall and by race and ethnicity, was also compared to postoperative opioid guidelines. Data extraction Data were extracted from the EHR on adult patients undergoing a procedure during the study period, discharged to home with an opioid prescription. Principal findings Among 61,564 patients, on adjusted regression analysis, non-Hispanic Black (NHB) patients received prescriptions with higher mean MME than non-Hispanic white (NHW) patients (+ 6.4% [95% confidence interval: 4.4%, 8.3%]), whereas Hispanic and non-Hispanic Asian patients received lower mean MME (-4.2% [-5.1%, -3.2%] and − 3.6% [-4.8%, -2.3%], respectively). Nevertheless, 72.8% of all patients received prescriptions above guidelines, ranging from 71.0 to 80.3% by race and ethnicity. Disparities in prescribing were eliminated among Hispanic and NHB patients versus NHW patients when prescriptions were written within guideline recommendations. Conclusions Racial and ethnic disparities in opioid prescribing exist in the postoperative setting, yet all groups received prescriptions above guideline recommendations. Policies encouraging guideline-based prescribing may reduce disparities and overall excess prescribing.

Abstract The literature shows that investor attention to customer–supplier disclosure increases when suppliers’ information arrival is anticipated. Due to the widespread of city lockdowns in China and the implementation of social distancing to control the COVID-19 pandemic, investor attention to potential disruption of the supply chain spikes, leading to a price devaluation for firms with high supplier concentration risk. We find that a higher degree of supplier concentration is related to more serious stock price declines over the short-term and medium-term windows right after the Wuhan lockdown. This result lends support to the argument that the concentration risk of suppliers is a significant consideration for China stock market investors, especially under the potential financial distress at the firm level induced by the COVID-19 crisis.

Abstract Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate different aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess GBM invasiveness based on detecting tumor-specific anti-luciferase staining in brain slices, we found that U251-RedFLuc cells are more invasive than U87-luc2 cells. Lastly, we determined expression levels of ABC transporters in both models. Our findings indicate that U87-luc2 and U251-RedFLuc GBM models recapitulate different aspects of GBM heterogeneity that need to be considered in preclinical research.

The COVID-19 pandemic caused tremendous upheaval in schooling. In addition to devasting effects on students, these disruptions had consequences for researchers conducting studies on education programs and policies. Given the likelihood of future large-scale disruptions, it is important for researchers to plan resilient studies and think critically about adaptations when such turbulence arises. In this article, we utilize qualitative analysis of interviews with research study leaders to illuminate practical and methodological challenges, as well as promising practices that arose during the pandemic period. We find that researchers made pivots to address practical challenges and protect the feasibility of their studies. We also find that researchers took precautions, where possible, to understand and bolster internal validity. However, these pivots frequently surfaced additional threats to construct and external validity. We conclude with recommendations for future studies conducted in times of prolonged unplanned school closures or other large-scale disruptions.

Abstract Background Gene ontology (GO) enrichment analysis is frequently undertaken during exploration of various -omics data sets. Despite the wide array of tools available to biologists to perform this analysis, meaningful visualisation of the overrepresented GO in a manner which is easy to interpret is still lacking. Results Monash Gene Ontology (MonaGO) is a novel web-based visualisation system that provides an intuitive, interactive and responsive interface for performing GO enrichment analysis and visualising the results. MonaGO supports gene lists as well as GO terms as inputs. Visualisation results can be exported as high-resolution images or restored in new sessions, allowing reproducibility of the analysis. An extensive comparison between MonaGO and 11 state-of-the-art GO enrichment visualisation tools based on 9 features revealed that MonaGO is a unique platform that simultaneously allows interactive visualisation within one single output page, directly accessible through a web browser with customisable display options. Conclusion MonaGO combines dynamic clustering and interactive visualisation as well as customisation options to assist biologists in obtaining meaningful representation of overrepresented GO terms, producing simplified outputs in an unbiased manner. MonaGO will facilitate the interpretation of GO analysis and will assist the biologists into the representation of the results.

Introduction Surgical patients are commonly prescribed more opioids at discharge than needed to manage their postoperative pain. These excess opioids increase the risks of new persistent opioid use, opioid-induced ventilatory impairment and opioid diversion. This study tests the effectiveness of two behavioural nudges, one based on peer behaviour and one based on best practice guidelines, in reducing excessive postoperative opioid prescriptions.Methods and analysis The study will be conducted at 19 hospitals within a large healthcare delivery system in northern California, USA. Three surgical specialties (general surgery, orthopaedic surgery and obstetric/gynaecological surgery) at each hospital will be randomised either to a control group or to one of two active intervention arms. One intervention is grounded in the theory of injunctive norms, and provides feedback to surgeons on their postoperative opioid prescribing relative to prescribing guidelines endorsed by their institution. The other intervention draws from the theory of descriptive norms, and provides feedback similar to the first intervention but using peers’ behaviour rather than guidelines as the benchmark for the surgeon’s prescribing behaviour. The interventions will be delivered by a monthly email. Both interventions will be active for twelve months. The effects of each intervention relative to the control group and to each other will be tested using a four-level hierarchical model adjusted for multiple hypothesis testing.Ethics and dissemination Using behavioural nudges rather than rigid policy changes allows us to target excessive prescribing without preventing clinicians from using their clinical judgement to address patient pain. All study activities have been approved by the RAND Human Subjects Protection Committee (ID 2018-0988). Findings will be disseminated through conference presentations, peer-reviewed publications and social media accounts.Trial registration number NCT05070338.

Abstract Background To review retrospectively the outcomes of management of Fournier’s gangrene (FG) and to assess for possible seasonal variations in clinical presentations of FG to a referral hospital in a tropical African country. Methods The medical records of patients who presented with FG from February 2012 to December 2019 were reviewed. Of interest were age of patient, vital signs at presentation, site of gangrene, duration of hospital admission, and management interventions deployed. Analysis was with SPSS® version 21. Results Twenty-three of 28 medical records could be analyzed. Median Fournier’s Gangrene Severity Index (FGSI) was 5 (IQR:3–10), the median Uludag-FGSI (UFGSI) was 7 (IQR:4–14). In 82.6%, the scrotum was the site of onset; in 8.7%, the lesion had spread beyond the pelvis. Diabetes mellitus (30.4%), HIV infection (13.0%) and nephropathy (17.4%) were identified co-morbidities. There were 2.4 ± 1.0 debridement sessions and 1.5 ± 1.3 transfused units of blood per patient. In 60.9%, the wound edges were undermined and apposed; in 17.4%, split skin grafting or fascio-cutaneous flap cover was deployed. In 17.4%, satisfactory wound closure needed more than 1 theater session. Mean duration of hospital admission was 51.4 ± 19.4 days. No mortality was recorded. Majority (91.2%) presented in hot, dry months of October through March with peak in December. No case presented in the wet months of May through September. Conclusion Meager resources notwithstanding, FG management outcomes are generally satisfactory. Furthermore, FG is observed to present mostly in the hot, dry months of the year in the 8 years under review.

Abstract Many species use dormant stages for habitat selection by tying recovery to informative external cues. Other species have an undiscerning strategy in which they recover randomly despite having advanced sensory systems. We investigated whether elements of a species' habitat structure and life history can bar it from developing a discerning recovery strategy. The nematode Caenorhabditis elegans has a dormant stage called the dauer larva that disperses between habitat patches. On one hand, C. elegans colonization success is profoundly influenced by the bacteria found in its habitat patches, so we might expect this to select for a discerning strategy. On the other hand, C. elegans' habitat structure and life history suggest that there is no fitness benefit to varying recovery, which might select for an undiscerning strategy. We exposed dauers of three genotypes to a range of bacteria acquired from the worms' natural habitat. We found that C. elegans dauers recover in all conditions but increase recovery on certain bacteria depending on the worm's genotype, suggesting a combination of undiscerning and discerning strategies. Additionally, the worms' responses did not match the bacteria's objective quality, suggesting that their decision is based on other characteristics.

Summary: During the COVID-19 pandemic, US states developed Crisis Standards of Care (CSC) algorithms to triage allocation of scarce resources to maximize population-wide benefit. While CSC algorithms were developed by ethical debate, this protocol guides their quantitative assessment. For CSC algorithms, this protocol addresses (1) adapting algorithms for empirical study, (2) quantifying predictive accuracy, and (3) simulating clinical decision-making. This protocol provides a framework for healthcare systems and governments to test the performance of CSC algorithms to ensure they meet their stated ethical goals.For complete details on the use and execution of this protocol, please refer to Jezmir et al. (2021).

Background: Pathogenic variants in SCN1B, the gene encoding voltage-gated sodium channel b1/b1B subunits are associated with a spectrum of epileptic disorders. This study describes a child with early myoclonic encephalopathy and a compound heterozygous variant in the SCN1B gene (p.Arg85Cys and c.3G>C/p.Met1), along with the child’s clinical response to anti-seizure medications (ASMs) and the ketogenic diet. We reviewed the current clinical literature pertinent to SCN1B-related epilepsy. Methods: We described the evaluation and management of a patient with SCN1B-related developmental and epileptic encephalopathy (DEE). We used the Medline and Pubmed databases to review the various neurological manifestations associated with SCN1B genetic variants, and summarize the functional studies performed on SCN1B variants. Results: We identified 20 families and six individuals (including the index case described herein) reported to have SCN1B-related epilepsy. Individuals with monoallelic pathogenic variants in SCN1B often present with genetic epilepsy with febrile seizures plus (GEFS+), while those with biallelic pathogenic variants may present with developmental and epileptic encephalopathy (DEE). Individuals with DEE present with seizures of various semiologies (commonly myoclonic seizures) and status epilepticus at early infancy and are treated with various antiseizure medications. In our index case, adjunctive fenfluramine was started at 8 months of age at 0.2 mg/kg/day with gradual incremental increases to the final dose of 0.7 mg/kg/day over 5 weeks. Fenfluramine was effective in the treatment of seizures, resulting in a 50% reduction in myoclonic seizures, status epilepticus, and generalized tonic-clonic seizures, as well as a 70–90% reduction in focal seizures, with no significant adverse effects. Following the initiation of fenfluramine at eight months of age, there was also a 50% reduction in the rate of hospitalizations. Conclusions: SCN1B pathogenic variants cause epilepsy and neurodevelopmental impairment with variable expressivity and incomplete penetrance. The severity of disease is associated with the zygosity of the pathogenic variants. Biallelic variants in SCN1B can result in early myoclonic encephalopathy, and adjunctive treatment with fenfluramine may be an effective treatment for SCN1B-related DEE. Further research on the efficacy and safety of using newer ASMs, such as fenfluramine in patients under the age of 2 years is needed.

Summary: Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.

Abstract Background There is paucity of information on the community-based prevalence and severity of lower urinary tract symptoms (LUTS) in men who are 40 years and older in the southeast region of Nigeria. This study seeks to determine the community-based prevalence of LUTS and the relationship between LUTS, and body mass index (BMI) and mid-abdominal circumference (MAC) in men. Methods An interviewer-administered, questionnaire-based survey. Three of nine settlement clusters were randomly selected while systematic random sampling of 1 in 3 eligible subjects was used to select participants. Analysis was done using SPSS® version 20. Results One thousand three hundred and nineteen duly completed questionnaires were analyzed. The respondents are within ages 40-92 years with mean age 54.2 ± 10.2 years, mean BMI 25.97 ± 4.18Kg/m2 and mean MAC 89.80 ± 12.43 cm. Overall prevalence of LUTS is 20.2%. Nocturia at a prevalence of 19.2% is the most prevalent lower urinary tract symptom and also the earliest to manifest. LUTS prevalence and severity increases with increasing age. About 9.6% report moderate LUTS while 2.3% report severe LUTS. Storage LUTS are reported more frequently than voiding LUTS. LUTS did not vary significantly with BMI, MAC or Wealth-Index. Conclusion LUTS prevalence and severity vary with age, but not with BMI, MAC or Wealth-Index.

Summary: This protocol aids both new and experienced researchers in designing retrospective clinical and translational studies of acute respiratory decline in hospitalized patients. This protocol addresses (1) the basics of respiratory failure and electronic health record research, (2) defining patient cohorts as “mild, progressive, or severe” instead of “ICU versus non-ICU”, (3) adapting physiological indices, and (4) using biomarker trends. We apply these approaches to inflammatory biomarkers in COVID-19, but this protocol can be applied to any progressive respiratory failure study.For complete details on the use and execution of this protocol, please refer to Mueller et al. (2020).

mTORopathies are a heterogeneous group of neurological disorders characterized by malformations of cortical development (MCD), enhanced cellular mechanistic target of rapamycin (mTOR) signaling, and epilepsy that results from mutations in mTOR pathway regulatory genes. Homozygous mutations (del exon 9–13) in the pseudokinase STE20-related kinase adaptor alpha (STRAD-α; STRADA), an mTOR modulator, are associated with Pretzel Syndrome (PS), a neurodevelopmental disorder within the Old Order Mennonite Community characterized by megalencephaly, intellectual disability, and intractable epilepsy. To study the cellular mechanisms of STRADA loss, we generated CRISPR-edited Strada mouse N2a cells, a germline mouse Strada knockout (KO−/−) strain, and induced pluripotent stem cell (iPSC)-derived neurons from PS individuals harboring the STRADA founder mutation. Strada KO in vitro leads to enhanced mTOR signaling and iPSC-derived neurons from PS individuals exhibit enhanced cell size and mTOR signaling activation, as well as subtle alterations in electrical firing properties e.g., increased input resistance, a more depolarized resting membrane potential, and decreased threshold for action potential (AP) generation. Strada−/− mice exhibit high rates of perinatal mortality and out of more than 100 litters yielding both WT and heterozygous pups, only eight Strada−/− animals survived past P5. Strada−/− mice are hypotonic and tremulous. Histopathological examination (n = 5 mice) revealed normal gross brain organization and lamination but all had ventriculomegaly. Ectopic neurons were seen in all five Strada−/− brains within the subcortical white matter mirroring what is observed in human PS brain tissue. These distinct experimental platforms demonstrate that STRADA modulates mTOR signaling and is a key regulator of cell size, neuronal excitability, and cortical lamination.

Summary: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Most DS patients carry de novo variants in SCN1A, resulting in Nav1.1 haploinsufficiency. Because SCN1A is expressed in heart and in brain, we proposed that cardiac arrhythmia contributes to SUDEP in DS. We generated DS patient and control induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). We observed increased sodium current (INa) and spontaneous contraction rates in DS patient iPSC-CMs versus controls. For the subject with the largest increase in INa, cardiac abnormalities were revealed upon clinical evaluation. Generation of a CRISPR gene-edited heterozygous SCN1A deletion in control iPSCs increased INa density in iPSC-CMs similar to that seen in patient cells. Thus, the high risk of SUDEP in DS may result from a predisposition to cardiac arrhythmias in addition to seizures, reflecting expression of SCN1A in heart and brain. : In this article, Isom, Parent, and colleagues show that the high risk of SUDEP in the developmental and epileptic encephalopathy, Dravet syndrome, may result from a predisposition to cardiac arrhythmias in addition to neuronal hyperexcitability, reflecting haploinsufficiency of SCN1A in heart and brain causing potential compensatory overexpression of other sodium-channel genes in those tissues. Keywords: epilepsy, cardiac arrhythmia, sodium channel, SUDEP, induced pluripotent stem cell (iPSC), developmental and epileptic encephalopathy

Abstract Background A strong focus of the post-genomic era is mining of the non-coding regulatory genome in order to unravel the function of regulatory elements that coordinate gene expression (Nat 489:57–74, 2012; Nat 507:462–70, 2014; Nat 507:455–61, 2014; Nat 518:317–30, 2015). Whole-genome approaches based on next-generation sequencing (NGS) have provided insight into the genomic location of regulatory elements throughout different cell types, organs and organisms. These technologies are now widespread and commonly used in laboratories from various fields of research. This highlights the need for fast and user-friendly software tools dedicated to extracting cis-regulatory information contained in these regulatory regions; for instance transcription factor binding site (TFBS) composition. Ideally, such tools should not require prior programming knowledge to ensure they are accessible for all users. Results We present TrawlerWeb, a web-based version of the Trawler_standalone tool (Nat Methods 4:563–5, 2007; Nat Protoc 5:323–34, 2010), to allow for the identification of enriched motifs in DNA sequences obtained from next-generation sequencing experiments in order to predict their TFBS composition. TrawlerWeb is designed for online queries with standard options common to web-based motif discovery tools. In addition, TrawlerWeb provides three unique new features: 1) TrawlerWeb allows the input of BED files directly generated from NGS experiments, 2) it automatically generates an input-matched biologically relevant background, and 3) it displays resulting conservation scores for each instance of the motif found in the input sequences, which assists the researcher in prioritising the motifs to validate experimentally. Finally, to date, this web-based version of Trawler_standalone remains the fastest online de novo motif discovery tool compared to other popular web-based software, while generating predictions with high accuracy. Conclusions TrawlerWeb provides users with a fast, simple and easy-to-use web interface for de novo motif discovery. This will assist in rapidly analysing NGS datasets that are now being routinely generated. TrawlerWeb is freely available and accessible at: http://trawler.erc.monash.edu.au.

Abstract Background Immuno-oncotherapy has emerged as a promising means to target cancer. In particular, therapeutic manipulation of tumor-associated macrophages holds promise due to their various and sometimes opposing roles in tumor progression. It is established that M1-type macrophages suppress tumor progression while M2-types support it. Recently, Tie2-expressing macrophages (TEM) have been identified as a distinct sub-population influencing tumor angiogenesis and vascular remodeling as well as monocyte differentiation. Methods This study develops a modeling framework to evaluate macrophage interactions with the tumor microenvironment, enabling assessment of how these interactions may affect tumor progression. M1, M2, and Tie2 expressing variants are integrated into a model of tumor growth representing a metastatic lesion in a highly vascularized organ, such as the liver. Behaviors simulated include M1 release of nitric oxide (NO), M2 release of growth-promoting factors, and TEM facilitation of angiogenesis via Angiopoietin-2 and promotion of monocyte differentiation into M2 via IL-10. Results The results show that M2 presence leads to larger tumor growth regardless of TEM effects, implying that immunotherapeutic strategies that lead to TEM ablation may fail to restrain growth when the M2 represents a sizeable population. As TEM pro-tumor effects are less pronounced and on a longer time scale than M1-driven tumor inhibition, a more nuanced approach to influence monocyte differentiation taking into account the tumor state (e.g., under chemotherapy) may be desirable. Conclusions The results highlight the dynamic interaction of macrophages within a growing tumor, and, further, establish the initial feasibility of a mathematical framework that could longer term help to optimize cancer immunotherapy.

Specifically ablating genes in human induced pluripotent stem cells (iPSCs) allows for studies of gene function as well as disease mechanisms in disorders caused by loss-of-function (LOF) mutations. While techniques exist for engineering such lines, we have developed and rigorously validated a method of simultaneous iPSC reprogramming while generating CRISPR/Cas9-dependent insertions/deletions (indels). This approach allows for the efficient and rapid formation of genetic LOF human disease cell models with isogenic controls. The rate of mutagenized lines was strikingly consistent across experiments targeting four different human epileptic encephalopathy genes and a metabolic enzyme-encoding gene, and was more efficient and consistent than using CRISPR gene editing of established iPSC lines. The ability of our streamlined method to reproducibly generate heterozygous and homozygous LOF iPSC lines with passage-matched isogenic controls in a single step provides for the rapid development of LOF disease models with ideal control lines, even in the absence of patient tissue.

Abstract Although chemotherapy combined with radiofrequency exposure has shown promise in cancer treatment by coupling drug cytotoxicity with thermal ablation or thermally-induced cytotoxicity, limited access of the drug to tumor loci in hypo-vascularized lesions has hampered clinical application. We recently showed that high-intensity short-wave capacitively coupled radiofrequency (RF) electric-fields may reach inaccessible targets in vivo. This non-invasive RF combined with gemcitabine (Gem) chemotherapy enhanced drug uptake and effect in pancreatic adenocarcinoma (PDAC), notorious for having poor response and limited therapeutic options, but without inducing thermal injury. We hypothesize that the enhanced cytotoxicity derives from RF-facilitated drug transport in the tumor microenvironment. We propose an integrated experimental/computational approach to evaluate chemotherapeutic response combined with RF-induced phenotypic changes in tissue with impaired transport. Results show that RF facilitates diffusive transport in 3D cell cultures representing hypo-vascularized lesions, enhancing drug uptake and effect. Computational modeling evaluates drug vascular extravasation and diffusive transport as key RF-modulated parameters, with transport being dominant. Assessment of hypothetical schedules following current clinical protocol for Stage-IV PDAC suggests that unresponsive lesions may be growth-restrained when exposed to Gem plus RF. Comparison of these projections to experiments in vivo indicates that synergy may result from RF-induced cell phenotypic changes enhancing drug transport and cytotoxicity, thus providing a potential baseline for clinically-focused evaluation.

Myelodysplastic syndromes are a broad group of haematopoietic malignancies that often progress to acute myeloid leukaemia. Here, the authors show that linear and branched evolution occurs within myelodysplastic syndrome and these patterns can be impacted by treatment.

Objective: Existing research demonstrates that being mastery oriented is associated with several academic outcomes such as better engagement and achievement. To date, however, there is a dearth of research evidence on the emotional payoffs of mastery orientation. The current study explored the link between mastery orientation, subjective well-being (SWB), and the mediating functions of perseverance and adaptability. Method: The study used data from the PISA 2018 dataset and had 6,062 participants, of which 54.4% were female and 46.4% were male. The proposed model was tested using path analysis to determine if perseverance predicts SWB and to examine the mediating roles of perseverance and adaptation. Results: The results showed that students' SWB was positively predicted by mastery orientation. Perseverance and adaptability also predicted SWB and served as a partial mediator of between mastery orientation and SWB. Conclusions: The study advances knowledge of the psychological benefits of students embracing mastery orientation. The findings suggest that pupils who are mastery-oriented not only succeed academically but also report higher levels of subjective well-being. Perseverance and adaptability serve as underlying psychological mechanisms in this relationship.

Objective: The present research assessed the psychometric validity of the Implicit Theories of Intelligence Scale (ITIS). Also, the current study examined how growth mindset is associated with academic achievement and engagement. Methods: A sample of 538 Filipino undergraduate students with a mean age of 20.9 (SD = 2.2) took part in the study. Confirmatory factor analysis was used for the within-network construct validity while correlation analysis for the between-network construct validity. Structural equation modelling was utilised in analysing the influence of growth mindset on academic outcomes. Results: The results indicate that the scale had good within-network validity, supporting its two-dimensional structure. The between-network construct validation revealed that growth mindset was associated with failure-is-enhancing mindset while fixed mindset was correlated with failure-is-debilitating mindset. Then, structural equation modelling revealed growth mindset predicted higher self-reported achievement through engagement. Conversely, fixed mindset was not associated with engagement, but it had a negative effect on achievement. Conclusion: The present study provided evidence that the ITIS is a valid and reliable measure of implicit theories of intelligence among Filipino undergraduate students. Growth mindset also predicted greater achievement through engagement.

Therapies targeted to the immune system, such as immunotherapy, are currently shaping a new, rapidly developing branch of promising cancer treatments, offering the potential to change the prognosis of previously non-responding patients. Macrophages comprise the most abundant population of immune cells in the tumor microenvironment (TME) and can undergo differentiation into functional phenotypes depending on the local tissue environment. Based on these functional phenotypes, tumor-associated macrophages (TAMs) can either aid tumor progression (M2 phenotype) or inhibit it (M1 phenotype). Presence of M2 macrophages and a high ratio of M2/M1 macrophages in the TME are clinically associated with poor prognosis in many types of cancers. Herein, we evaluate the effect of macrophage phenotype on the transport and anti-cancer efficacy of albumin-bound paclitaxel (nAb-PTX) loaded into porous silicon multistage nanovectors (MSV). Studies in a coculture of breast cancer cells (3D-spheroid) with macrophages and in vivo models were conducted to evaluate the therapeutic efficacy of MSV-nAb-PTX as a function of macrophage phenotype. Association with MSV increased drug accumulation within the macrophages and the tumor spheroids, shifting the inflammation state of the TME toward the pro-inflammatory, anti-tumorigenic milieu. Additionally, the treatment increased macrophage motility toward cancer cells, promoting the active transport of therapeutic nanovectors into the tumor lesion. Consequently, apoptosis of cancer cells was increased and proliferation decreased in the MSV-nAb-PTX-treated group as compared to controls. The results also confirmed that the tested system shifts the macrophage differentiation toward an M1 phenotype, possessing an anti-proliferative effect toward the breast cancer cells. These factors were further incorporated into a mathematical model to help analyze the synergistic effect of the macrophage polarization state on the efficacy of MSV-nAb-PTX in alleviating hypovascularized tumor lesions. In conclusion, the ability of MSV-nAb-PTX to polarize TAM to the M1 phenotype, causing (1) enhanced penetration of the drug-carrying macrophages to the center of the tumor lesion and (2) increased toxicity to tumor cells may explain the increased anti-cancer efficacy of the system in comparison to nAb-PTX and other controls.

Systemically injected nanoparticle (NPs) targeting tumor vasculature offer a venue for anti-angiogenic therapies as well as cancer detection and imaging. Clinical application has been limited, however, due to the challenge of elucidating the complex interplay of nanotechnology, drug, and tumor parameters. A critical factor representing the likelihood of endothelial adhesion is the NP vascular affinity, a function of vascular receptor expression and NP size and surface-bound ligand density. We propose a theoretical framework to simulate the tumor response to vasculature-bound drug-loaded NPs and examine the interplay between NP distribution and accumulation as a function of NP vascular affinity, size, and drug loading and release characteristics. The results show that uniform spatial distribution coupled with high vascular affinity is achievable for smaller NPs but not for larger sizes. Consequently, small (100 nm) NPs with high vascular affinity are predicted to be more effective than larger (1000 nm) NPs with similar affinity, even though small NPs have lower drug loading and local drug release compared to the larger NPs. Medium vascular affinity coupled with medium or larger sized NPs is also effective due to a more uniform distribution with higher drug loading and release. Low vascular affinity hampered treatment efficacy regardless of NP size, with larger NPs additionally impeded by heterogeneous distribution and drug release. The results further show that increased drug diffusivity mainly benefits heterogeneously distributed NPs, and would negatively affect efficacy otherwise due to increased wash-out. This model system enables evaluation of efficacy for vascular-targeted drug-loaded NPs as a function of critical NP, drug, and tumor parameters.

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

Insoluble recombinant proteins are a major issue for both structural genomics and enzymology research. Greater than 30% of recombinant proteins expressed in Escherichia coli (E. coli) appear to be insoluble. The prevailing view is that insolubly expressed proteins cannot be easily solubilized, and are usually sequestered into inclusion bodies. However, we hypothesize that small molecules added during the cell lysis stage can yield soluble protein from insoluble protein previously screened without additives or ligands. We present a novel screening method that utilized 144 additive conditions to increase the solubility of recombinant proteins expressed in E. coli. These selected additives are natural ligands, detergents, salts, buffers, and chemicals that have been shown to increase the stability of proteins in vivo. We present the methods used for this additive solubility screen and detailed results for 41 potential drug target recombinant proteins from infectious organisms. Increased solubility was observed for 80% of the recombinant proteins during the primary and secondary screening of lysis with the additives; that is 33 of 41 target proteins had increased solubility compared with no additive controls. Eleven additives (trehalose, glycine betaine, mannitol, L-Arginine, potassium citrate, CuCl(2), proline, xylitol, NDSB 201, CTAB and K(2)PO(4)) solubilized more than one of the 41 proteins; these additives can be easily screened to increase protein solubility. Large-scale purifications were attempted for 15 of the proteins using the additives identified and eight (40%) were prepared for crystallization trials during the first purification attempt. Thus, this protocol allowed us to recover about a third of seemingly insoluble proteins for crystallography and structure determination. If recombinant proteins are required in smaller quantities or less purity, the final success rate may be even higher.

Previous studies have revealed that academic buoyancy, or everyday academic resilience, have become more important amidst the COVID-19 pandemic. The current study was conducted to ascertain if determination and passion for attaining long-term aspirations, or grit, would facilitate the academic buoyancy of Filipino undergraduate students who are engaged in distance learning. Through quota sampling, 114 Filipino college learners (57 males, 57 females) aged 18 and above were recruited to complete an online survey which included the Triarchic Model of Grit Scale (TMGS) and Academic Buoyancy Scale (ABS). Hierarchical regression analysis revealed that grit had a positive impact on academic buoyancy while controlling for demographic variables. It was also identified that the grit dimension of adaptability to situations was the most significant predictor of academic buoyancy and that the demographic characteristics of the participants were not associated with their capability to cope and stay afloat on a day-to-day basis. The results provide interesting insights about the relationship between the triarchic model of grit and academic buoyancy in the collectivist setting.

Objective: The present study aimed to: (1) to determine how the two dimensions of perfectionism -- perfectionistic strivings (PS) and evaluative concerns (EC) are associated with academic engagement; and (2) to determine if failure mindset mediates the relationship between perfectionism and academic engagement. Method: Four hundred and forty-eight Filipino undergraduate students with an average age of 20.91 SD = 2.37 participated in the survey. Results: The results indicate that PS is positively linked to academic engagement through failure-is-enhancing beliefs. In contrast, EC is associated with lower academic engagement through a reduced failure-is-enhancing mindset. Conclusion: This study provides evidence that believing that failure is essential rather than unhelpful is an important factor in predicting academic engagement among perfectionists. Specifically, it was found that having high PS promotes the belief that failures are important in learning, while the opposite pattern was observed among those high in EC. This supports the view that perfectionism has an adaptive and a maladaptive side.