bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of Pelvic Floor Therapy Videos on YouTube: Does Popularity Predict Reliability?
Authors: Shah Shanaya , Eggers Erica , Hunter Krystal , Lipetskaia Lioudmila
Published: March 2024

This study reviewed instructional videos on YouTube regarding pelvic floor physical therapy and assessed the association between the videos’ popularity and the reliability of the videos’ content. YouTube was searched using the terms relevant to pelvic floor muscle training. The first 100 videos for each search term were screened, and relevant metrics were collected for those meeting the inclusion criteria. Videos were assessed by 2 independent, trained health care professionals for reliability using the Medical Quality Video Evaluation (MQ-VET) tool, the modified DISCERN tool, the Journal of American Medical Association benchmark criteria, and the Global Quality Score. Popularity was assessed using the Video Power Index (VPI). Higher values for all scoring systems correlated with greater reliability and greater popularity, respectively. Five hundred videos were screened. Two hundred thirty-four videos were duplicates, and 99 did not meet the inclusion criteria. A total of 167 videos were reviewed. The median VPI and MQ-VET score was 201,114.76 (interquartile range, 7,194,020.29) and 48.00 (interquartile range, 12.75), respectively. Spearman’s R value was 0.292 (P < 0.001), demonstrating a weak positive correlation between MQ-VET scores and VPI. The interrater reliability of the MQ-VET was good, with an intraclass correlation coefficient of 0.86 (95% confidence interval, 0.71–0.92). In summary, we identified a statistically significant but weak positive correlation between the reliability and popularity of YouTube videos about pelvic floor physical therapy.
Characteristics Associated With Recurrent Urinary Tract Infections: A Case-Control Study
Authors: Chapman Hannah L. , Edwards Joseph T. , Hadikusumo Harsono Alfonsus Adrian , Baecher Kendall , Zhai Guihua , Meyer Isuzu , Richter Holly E.
Published: March 2024

Importance

Recurrent urinary tract infections (rUTIs) affect 2–10% of adult women and are associated with a significant effect on quality of life, daily activities, and mental health.

Objective

The aim of this study was to identify clinical characteristics associated with rUTIs among women seeking care for pelvic floor disorders at an academic tertiary urogynecology clinic.

Study Design

A retrospective case-control study of women presenting to an academic tertiary urogynecology clinic was conducted. Cases were women with rUTIs, defined as ≥2 UTIs in 6 months or ≥3 within 1 year. Controls were women with no culture documented UTIs. Cases were matched 2:1 to controls by age and body mass index. Demographic and clinical characteristics were compared between cases and controls, and bivariate characteristics with P values ≤0.2 were assessed for an independent association with rUTIs by multivariable logistic regression.

Results

A total of 285 cases with rUTIs were identified, and 150 matched controls had a mean (SD) age of 72 (11.8) years and a body mass index of 29.6 (6.7; calculated as weight in kilograms divided by height in meters squared). Multivariable analysis revealed that prolapse beyond the introitus (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.13–0.60), parity (OR, 1.33; 95% CI, 1.08–1.64), Charlson Comorbidity Index (OR, 1.66; 95% CI, 1.37–2.03), and postvoid residual volume ≥100 mL (OR, 4.05; 95% CI, 2.01, 8.18) were associated with rUTIs.

Conclusions

In this ambulatory urogynecologic population, prolapse through the introitus was negatively associated with rUTIs, whereas parity, increased medical comorbidities, and elevated postvoid residual volume were positively associated with rUTI. Future research should seek an increased understanding of these factors associated with rUTI to implement effective preventive strategies.
Comparing Impact of Overactive Bladder Therapies on Nocturia
Authors: Getaneh Feven W. , Kolm Paul , Awulachew Hailegeorgis , Iglesia Cheryl B. , Dieter Alexis A.
Published: March 2024

Importance

Nocturia is a significant symptom in overactive bladder with little data regarding the impact of overactive bladder treatments on nocturia.

Objectives

Compare the effect of anticholinergic (AC) medication, onabotulinum toxin A (BTX), and sacral neuromodulation (SNM) on nocturia.

Study Design

Secondary analysis of the ABC and ROSETTA trials using data from the National Institutes of Health Data and Specimen Hub database. Patients reporting mean ≥2 voids/night on 3-day diary were included and divided into cohorts by treatment: the ABC trial: (1) AC and (2) BTX 100 units, and the ROSETTA trial: (3) BTX 200 units and (4) SNM. Primary outcome was change in mean voids/night on 3-day diary from baseline to 6 months assessed by mixed-effects models for repeated-measures data with interaction between treatment cohort and time included in model.

Results

A total of 197 patients were included: 43 (22%) AC, 37 (19%) BTX 100 U, 63 (32%) BTX 200 U, and 54 (27%) SNM. There were no significant differences in baseline voids/night, demographics, or urodynamic values except for younger age in AC and BTX 100 U cohorts (P = 0.04). At 6 months, all cohorts demonstrated a mean 41% decrease in mean voids/night (2.7 ± 0.4 at baseline to 1.6 ± 0.5 at 6 months; P < 0.001), with no significant difference in change in mean voids/night between treatment cohorts (decrease of 44% in AC, 46% in 100 U BTX, 32% 200 in U BTX, and 33% in SNM; P > 0.05).

Conclusion

For women with nocturia ≥2/night, treatment with AC, BTX 100 or 200 units, or SNM led to a significant decrease in voids/night at 6 months.
Antibiotics for UTI Prevention After Intradetrusor OnabotulinumtoxinA Injections
Authors: Heuer Christopher W. , Gisseman Jordan D. , Vaccaro Christine M. , Olsen Cara H. , Galgano Alissa C. , Dengler Katherine L.
Published: March 2024

Importance

Urinary tract infections (UTIs) occur in 8.6% to 48.1% of patients after intradetrusor onabotulinumtoxinA injections.

Objective

The objective of this study was to evaluate both choice and duration of antibiotic prophylaxis on the incidence of UTI within 30 days after in-office onabotulinumtoxinA injections.

Study Design

We included a single-site, retrospective cohort of 305 patients with overactive bladder or bladder pain syndrome receiving postprocedure prophylactic antibiotics for in-office, 100-unit intradetrusor onabotulinumtoxinA injections from 2019 to 2023. Categories of antibiotic prophylaxis compared included (1) nitrofurantoin 100 mg twice daily for 3 days, (2) nitrofurantoin 100 mg twice daily for 5 days, (3) trimethoprim-sulfamethoxazole 160 mg/800 mg twice daily for 3 days, and (4) “other regimens.” Primary outcome was incidence of UTI within 30 days. Variables were compared via χ
2 test. Crude/adjusted odds were estimated using binary logistic regression.

Results

Incidence of UTI was 10.4% for 3-day nitrofurantoin, 20.5% for 5-day nitrofurantoin, 7.4% for 3-day trimethoprim-sulfamethoxazole, and 25.7% among “other regimens” (P = 0.023). Differences among primary regimens were substantial but not statistically significant: 3-day trimethoprim-sulfamethoxazole had 31% lower odds of UTI versus 3-day nitrofurantoin (odds ratio [OR], 0.689; P = 0.518). Compared with 3-day nitrofurantoin regimen, the 5-day nitrofurantoin regimen had twice the odds of UTI (OR, 2.22; P = 0.088). Those receiving “other regimens” had nearly 3 times the odds of UTI (OR, 2.98; P = 0.018). Results were similar adjusting for age and race. Overall urinary retention rate was 1.97%.

Conclusions

Prophylactic antibiotic choice and duration of treatment potentially affect UTI incidence after in-office, intradetrusor onabotulinumtoxinA injections. Nitrofurantoin and trimethoprim-sulfamethoxazole for 3 days have the lowest UTI incidence.
Reconstruction of Urethral Sphincter With Polyacrylamide Hydrogel
Authors: Clearwater Whitney L. , Panushka Katherine , Najor Anna , Laudano Melissa , Fleischmann Nicole
Published: March 2024

Importance

Urethral bulking is an alternative to synthetic midurethral sling for the treatment of stress urinary incontinence (SUI) in women. Urethral bulking agents, which are injected in the submucosal tissues of the proximal urethra/bladder neck, have demonstrated less adverse effects with similar satisfaction rates but lower subjective and objective cure rates when compared with midurethral sling. Cystoscopic Reconstruction of External Sphincter Technique (CREST) is a novel technique, which reinforces the natural closure mechanism of the external urinary sphincter (EUS).

Objective

The aim of the study was to provide safety and efficacy data for injecting polyacrylamide hydrogel (PAHG) in the components of the female EUS.

Study Design

This was a retrospective chart review of patients using CREST with PAHG as initial treatment for SUI by a single surgeon from January 2022 to October 2022. Exclusion criteria are as follows: younger than 18 years, prior SUI surgery, concomitant pelvic organ prolapse or reconstructive procedure, neurological conditions, or history of radiation. Subjective and objective cure rates were measured by patient-reported symptoms and cough stress test. Urinary retention, postoperative urinary infection, and de novo urinary urgency were assessed.

Results

One hundred and thirteen consecutive patients met inclusion criteria with median follow-up of 3 months. Eighty-five percent of participants reported subjective improvement, 69% reported subjective cure, and 69% demonstrated objective cure. Nine patients reported transient postoperative retention, 8 reported postoperative urinary tract infections, and 5 reported de novo urgency. There were no serious adverse events.

Conclusions

CREST is a novel technique for injection of PAHG, into the EUS to treat SUI. Our data suggest that this technique could improve urethral injection outcomes with minimal complications.
Retrospective Cohort Study of Recovery From Sacrocolpopexy Versus Nonmesh Prolapse Repair
Authors: Guanzon Anna , Hale Douglass , Hamner Jennifer , Heit Michael
Published: March 2024

Importance

Providing recovery expectations for prolapse surgery is an important part of patient counseling and aids in patient-centered decision making.

Objectives

The purpose of this study was to determine if postoperative recovery from minimally invasive sacrocolpopexy (MISCP) is noninferior to that of native tissue repair.

Study Design

Recovery at 2 and 6 weeks was quantified using the Postdischarge Surgical Recovery 13 scale, where higher scores indicate greater patient-perceived recovery. A 2:1 MISCP to native tissue repair ratio was used. The study population was created from 3 prior studies involving patients who underwent prolapse surgery between 2013 and 2021.

Independent-samples t test was used for normally distributed data, Mann-Whitney U tests for nonnormally distributed data, and the χ
2 test for population proportions. A parsimonious linear regression analysis was performed to determine if the surgical group independently predicted postdischarge surgical recovery at 2 and 6 weeks, after controlling for significant confounders identified during bivariate analysis.

Results

The study population included 476 patients: 352 underwent MISCP and 124 underwent native tissue repair.

Postdischarge Surgical Recovery 13 scores for patients who underwent MISCP compared with native tissue repair were higher at 2 weeks (mean, 58.4 ± 18.2 vs 54.4 ± 18.7; P = 0.04) and at 6 weeks postoperatively (mean, 77.2 ± 15.6 vs 73.7 ± 18.7; P = 0.1).

Conclusions

Our findings indicate that recovery after MISCP is noninferior to that of native tissue repair. This information is important for delivering patient-centered care during preoperative counseling.
Treatment of Cervical Cancer Complicated by Advanced Pelvic Organ Prolapse: A Case Report
Authors: Chapman Hannah L. , Dholakia Jhalak J. , Marcrom Samuel , Liang Maggie , Richter Holly E.
Published: March 2024

Concurrent cervical cancer with advanced pelvic organ prolapse is rare: there are no well-established treatment recommendations. It is hypothesized that chronic irritation, as with long-standing pelvic organ prolapse, may lead to dysplasia and human papillomavirus–independent carcinoma, which represents only 5% of cervical cancers. Two patients with complete uterine procidentia were referred to gynecologic oncology with cervical squamous cell carcinoma; both were clinically staged as International Federation of Gynaecology and Obstetrics IB3. Treatment planning was complicated by procidentia in both cases. Standard definitive treatment of locally advanced cervical cancer is radiation therapy and concurrent chemotherapy; however, the mobility and externalization of the target lesion raised concerns regarding anatomic reproducibility during radiation treatment. After multidisciplinary team discussion (gynecologic oncology, urogynecology, radiation oncology), surgical resection and co-management with gynecologic oncology and urogynecology were successfully performed for definitive management for both patients. Although rare, this case study demonstrates the importance of multidisciplinary coordination in these complex clinical scenarios.
Uncovering Surface Penetration by Enterococci From Urinary Tract Infection Patients
Authors: Sansone Stephanie , Ramos Yusibeska , Segal Saya , Asfaw Tirsit S. , Morales Diana K.
Published: March 2024

Importance

The relationship between Enterococcus faecalis vaginal colonization and urinary tract infections (UTIs) remains uncertain.

Objective

We aimed to evaluate the surface invasion capability of E faecalis isolates from patients with and without UTIs as a potential readout of pathogenicity.

Study Design

Participants were females from urogynecology clinics, comprising symptomatic UTI and asymptomatic non-UTI patients, categorized by the presence or absence of E faecalis–positive cultures identified via standard urine culture techniques. Vaginal and urine samples from patients were plated on enterococci selective medium, and E faecalis isolates detected in both cohorts were species specific identified using 16S rRNA sequencing. Clinical isolates were inoculated on semisolid media, and both external colonies and underneath colony prints formed by agar-penetrating enterococci were imaged. External growth and invasiveness were quantified by determining colony-forming units of the noninvading and agar-penetrating cells and compared with the E faecalis OG1RF.

Results

We selected E faecalis isolates from urine and vaginal samples of 4 patients with and 4 patients without UTIs. Assays demonstrated that most isolates formed similarly sized external colonies with comparable colony-forming unit. Surface invasion differed across patients and isolation sites compared with OG1RF. The vaginal isolate from UTI patient 1, who had the most recurrences, exhibited significantly greater agar-invading capacity compared with OG1RF.

Conclusions

Our pilot study indicates that ex vivo invasion assays may unveil virulence traits in E faecalis from UTI patients. Enhanced enterococcal surface penetration could increase urogenital invasion risk. Further research is needed to correlate penetration with disease severity in a larger patient group.
Pelvic Floor Physical Therapy Attendance Among High-Risk Postpartum Patients
Authors: Toal Coralee , Goodman Noa , Durst Rachel , Giugale Lauren
Published: March 2024

Importance

Limited data describe attendance to pelvic floor physical therapy (PFPT) in a postpartum patient population.

Objectives

The objective was describe attendance to PFPT in a cohort of postpartum women at high-risk of pelvic floor concerns. We secondarily compared attendance between patients with and without evaluation in a postpartum pelvic floor healing clinic (PPFHC).

Study Design

This was a retrospective cohort study of 2 convenience samples from an academic hospital. The PPFHC cohort comprised all postpartum vaginal delivery patients evaluated in the PPFHC from July 2021 to July 2022. The historical pre-PPFHC cohort comprised patients with third/fourth-degree obstetrical lacerations from December 2019 to January 2021. We abstracted attendance to PFPT, number of visits, Pelvic Floor Distress Inventory-20 (PFDI-20) scores, Pelvic Floor Impact Questionnaire (PFIQ) scores, and discharge status.

Results

Our cohort contained 464 patients, 195 (42.0%) from pre-PPFHC and 269 (58.0%) from PPFHC. Among all patients 302 (65.1%) were referred to PFPT and 170 (56.3%) attended at least 1 visit, 82 (48.2%) were discharged from PFPT with goals met, and the median number of visits was 6 (3–10). The majority of patients (97.0%, n = 261) seen in the PPFHC were referred to PFPT, compared with 22.0% (n = 41) of pre-PPFHC patients (P < 0.01). More patients in the pre-PPFHC cohort attended PFPT than in those the PPFHC cohort (75.6% vs 53.5%, P ≤ 0.01). Most patients exhibited improved PFDI and PFIQ scores after PFPT (n = 88, 80.0%, and n = 89, 81.7% respectively).

Conclusions

Patients attending postpartum PFPT demonstrated high therapy completion rates. A dedicated PPFHC had more referrals, however, lower PFPT attendance rates, when compared with a historical cohort.
Overactive Bladder Medication Access
Authors: Courbron Yanghee , Foust-Wright Caroline
Published: March 2024

Importance

The price range, insurance coverage, and side effect burden of overactive bladder medications is broad and varied. An internal quality improvement project was undertaken to improve patient ability to access and ultimately adhere to preferred medication therapy for treatment of overactive bladder.

Objective

Our objective was to increase the percentage of patients per month at an academic Urogynecology practice who receive their preferred overactive bladder medication from baseline 39.5% to 45%.

Study Design

Data were extracted via Epic report. Manual chart review and calls to patients and/or pharmacy were completed to obtain status of medication access and reasons why medications were not taken. A targeted intervention was implemented with creation of a written document to help guide patients with options to decrease prescription costs. After this document was embedded into Epic after visit summary documentation, a repeat analysis was performed.

Results

The most common barrier to medication access was cost; specifically, the medication was not covered and a prior authorization was not initiated. Before the intervention, more than 60% of patients did not persist with their initially prescribed overactive bladder medication at a 6-month follow-up interval from office visit. Following implementation of a cost-navigation guide, persistence increased to 45.5% at a 3-month follow-up interval.

Conclusions

A targeted intervention on cost navigation of prescriptions can have a positive effect on patient access and persistence of using overactive bladder medications. Our practice continues to use our prescription navigation handout.
Investigating Ethical Tradeoffs in Crisis Standards of Care through Simulation of Ventilator Allocation Protocols
Authors: Herington Jonathan , Shand Jessica , Holden-Wiltse Jeanne , Corbett Anthony , Dees Richard , Ching Chin-Lin , Shaw Margie , Cai Xueya , Zand Martin
Published: March 2024

Introduction

Arguments over the appropriate Crisis Standards of Care (CSC) for public health emergencies often assume that there is a tradeoff between saving the most lives, saving the most life-years, and preventing racial disparities. However, these assumptions have rarely been explored empirically. To quantitatively characterize possible ethical tradeoffs, we aimed to simulate the implementation of five proposed CSC protocols for rationing ventilators in the context of the COVID-19 pandemic.

Methods

A Monte Carlo simulation was used to estimate the number of lives saved and life-years saved by implementing clinical acuity-, comorbidity- and age-based CSC protocols under different shortage conditions. This model was populated with patient data from 3707 adult admissions requiring ventilator support in a New York hospital system between April 2020 and May 2021. To estimate lives and life-years saved by each protocol, we determined survival to discharge and estimated remaining life expectancy for each admission.

Results

The simulation demonstrated stronger performance for age- and comorbidity-sensitive protocols. For a capacity of 1 bed per 2 patients, ranking by age bands saves approximately 28.7 lives and 3408 life-years per thousand patients, while ranking by Sequential Organ Failure Assessment (SOFA) bands saved the fewest lives (13.2) and life-years (416). For all protocols, we observed a positive correlation between lives saved and life-years saved. For all protocols except lottery and the banded SOFA, significant disparities in lives saved and life-years saved were noted between White non-Hispanic, Black non-Hispanic, and Hispanic sub-populations.

Conclusion

While there is significant variance in the number of lives saved and life-years saved, we did not find a tradeoff between saving the most lives and saving the most life-years. Moreover, concerns about racial discrimination in triage protocols require thinking carefully about the tradeoff between enforcing equality of survival rates and maximizing the lives saved in each sub-population.
Armed Violent Conflict and Healthcare-Seeking Behavior for Maternal and Child Health in Sub-Saharan Africa: A Systematic Review
Authors: Adeyanju Gbadebo Collins , Elisabeth Schrage Pia Marie , Jalo Rabiu Ibrahim , Abreu Liliana , Schaub Max
Published: March 2024

Background

Over 630 million women and children worldwide face displacement due to conflict or resided dangerously close to conflicts zones. While the adverse effects of physical destruction on healthcare delivery are relatively well understood, the effects on healthcare-seeking behavior remain underexplored, especially in sub-Saharan Africa. This study aims at the interconnections and knowledge gaps between exposure to armed violent conflicts and healthcare-seeking behaviors for maternal and child health in Sub-Saharan Africa.

Methods

Five key electronic databases (PubMed, Scopus, Web of Science, PsycNET, and African Journals Online) weresearched for peer-reviewed publications between 2000 and 2022. The review was designed according to PRISMA-P statement and the protocol was registered with PROSPERO database. The methodological quality and risks of bias were appraised using GRADE. A data extraction instrument was modelled along the Cochrane Handbook for Systematic Reviews and the Centre for Reviews and Dissemination of Systematic Reviews.

Result

The search results yielded 1,148 publications. Only twenty-one studies met the eligibility criteria, reporting healthcare-seeking behaviors for maternal and child health. Among the twenty-one studies, seventeen (81.0%) reported behaviors for maternal health such as antenatal care, skilled birth attendance, postnatal care services, and family planning. Similarly, nine studies (42.8%) observed behaviors for child health such as vaccination uptake, case management for pneumonia, diarrhea, malnutrition, and cough. While conflict exposure is generally associated with less favorable healthcare-seeking behavior, in some of the studies, healthcare outcomes improved. Marital status, male partner’s attitude, education, income and poverty levels were associated with healthcare-seeking behavior.

Conclusion

There is need for multifaceted interventions to mitigate the repercussions of armed violent conflicts on healthcare-seeking behavior, given its mixed effects on child and maternal healthcare utilization. While armed violent conflict disproportionately affects child compared to maternal health, it is noteworthy that, exposure to such conflicts may unintentionally also lead to positive outcomes.

Prospero registration number

CRD42023484004.
Downregulation of NR4A3 during inactivity alters glucose metabolism and impairs translation in human skeletal muscle
Authors: Smith Jonathon A.B. , Gabriel Brendan M. , Abdelmoez Ahmed M. , Savikj Mladen , Wright Shane C. , Koutsilieri Stefania , Barrès Romain , Lauschke Volker M. , Krook Anna , Zierath Juleen R. , Pillon Nicolas J.
Published: March 2024

The transcription factor NR4A3 is regulated by exercise and a potent modulator of skeletal muscle metabolism. We report here that physical inactivity decreased skeletal muscle NR4A3 levels, concomitant with mitochondrial function and proteostasis pathways. Silencing of NR4A3 in myotubes decreased glucose oxidation and increased lactate production. This coincided with greater signalling downstream of AMPK and elevated rates of fatty acid oxidation. While NR4A3 silencing reduced protein synthesis, mTORC1 signalling, and ribosomal transcription, overexpression of the canonical NR4A3 protein isoform augmented translation and cellular protein content. Moreover, restoration of NR4A3 levels rescued glucose oxidation in NR4A3-silenced myotubes and restored phosphorylation of mTORC1 substrates. NR4A3 depletion reduced myotube area and altered the abundance of contractile elements. Thus, downregulation of NR4A3 has adverse effects on skeletal muscle metabolism, myotube size, and contractile apparatus by directing mTORC1 signalling and ribosomal biogenesis. Our data demonstrate that NR4A3 controls skeletal muscle atrophy associated with physical inactivity.
Type I interferon induces TCR-dependent and -independent antimicrobial responses in γδ intraepithelial lymphocytes
Authors: Fischer Matthew A. , Jia Luo , Edelblum Karen L.
Published: March 2024

Intraepithelial lymphocytes (IEL) expressing the γδ T cell receptor (TCR) survey the intestinal epithelium to limit the invasion of microbial pathogens. The production of type I interferon (IFN) is a central component of an antiviral immune response, yet how these pro-inflammatory cytokines contribute to γδ IEL effector function remains unclear. Based on the unique activation status of IELs, and their ability to bridge innate and adaptive immunity, we investigated the extent to which type I IFN signaling modulates γδ IEL function. Using anex vivoculture model, we find that type I IFN alone is unable to drive IFNγ production, yet low level TCR activation synergizes with type I IFN to induce IFNγ production in murine γδ IELs. Further investigation into the underlying molecular mechanisms of co-stimulation revealed that TCRγδ-mediated activation of NFAT and JNK is required for type I IFN to promote IFNγ expression in a STAT4- dependent manner. Whereas type I IFN rapidly upregulates antiviral gene expression independent of a basal TCRγδ signal, neither tonic TCR triggering nor the presence of a TCR agonist was sufficient to elicit type I IFN-induced IFNγ productionin vivo. However, bypassing proximal TCR signaling events synergized with IFNAR/STAT4 activation to induce γδ IEL IFNγ production. These findings indicate that γδ IELs contribute to host defense in response to type I IFN by mounting a rapid antimicrobial response independent of TCRγδ signaling, and under permissive conditions, produce IFNγ in a TCR-dependent manner.
Dynamic culture of cerebral organoids using a pillar/perfusion plate for the assessment of developmental neurotoxicity
Authors: Acharya Prabha , Shrestha Sunil , Joshi Pranav , Choi Na Young , Lekkala Vinod Kumar Reddy , Kang Soo-Yeon , Ni Gabriel , Lee Moo-Yeal
Published: March 2024

Despite the potential toxicity of commercial chemicals to the development of the nervous system (known as developmental neurotoxicity or DNT), conventionalin vitrocell models have primarily been employed for the assessment of acute neuronal toxicity. On the other hand, animal models used for the assessment of DNT are not physiologically relevant due to the heterogenic difference between humans and animals. In addition, animal models are low-throughput, time-consuming, expensive, and ethically questionable. Recently, human brain organoids have emerged as a promising alternative to assess the detrimental effects of chemicals on the developing brain. However, conventional organoid culture systems have several technical limitations including low throughput, lack of reproducibility, insufficient maturity of organoids, and the formation of the necrotic core due to limited diffusion of nutrients and oxygen. To address these issues and establish predictive DNT models, cerebral organoids were differentiated in a dynamic condition in a unique pillar/perfusion plate, which were exposed to test compounds to evaluate DNT potential. The pillar/perfusion plate facilitated uniform, dynamic culture of cerebral organoids with improved proliferation and maturity by rapid, bidirectional flow generated on a digital rocker. Day 9 cerebral organoids in the pillar/perfusion plate were exposed to ascorbic acid (DNT negative) and methylmercury (DNT positive) in a dynamic condition for 1 and 3 weeks, and changes in organoid morphology and neural gene expression were measured to determine DNT potential. As expected, ascorbic acid didn’t induce any changes in organoid morphology and neural gene expression. However, exposure of day 9 cerebral organoids to methylmercury resulted in significant changes in organoid morphology and neural gene expression. Interestingly, methylmercury did not induce adverse changes in cerebral organoids in a static condition, thus highlighting the importance of dynamic organoid culture in DNT assessment.
Nanoparticles alter the nature and strength of intraploidy and interploidy interactions in plants
Authors: Esser Elizabeth A. , Tan Jiaqi , Wei Na
Published: March 2024

Engineered nanoparticles have profound impacts on organisms, yet there is limited understanding of how nanoparticle exposure shapes species interactions that are key for natural community dynamics. By growing plants of the same (intraploidy) and different ploidy levels (interploidy) ofFragariain axenic microcosms, we examined the influence of nanoparticles on species interactions in polyploid and diploid plants. We found that, under copper oxide (CuO) nanoparticle exposure, polyploids experienced reduced competition when growing with polyploids (the effect of polyploids on polyploids, RII8x,8x), and a shift towards facilitation when growing with diploids (the effect of diploids on polyploids, RII8x,2x). This reduction in competitive interactions in polyploids, in line with the stress gradient hypothesis, was primarily caused by nanoscale effects, because the strength of competitive interactions (RII8x,8xand RII8x,2x) remained relatively unchanged under CuO bulk particles compared to control conditions. In contrast, diploids experienced a shift from facilitation (RII2x,2xand RII2x,8x) under control conditions to neutrality under CuO nanoparticles, with a similar reduction in facilitation observed with both nanoparticles and bulk particles. These findings underscore ploidy specific interaction dynamics and the need of considering species interactions when predicting organismal responses to nanoparticle pollution in ecological communities.
Enhancing patient representation learning from electronic health records through predicted family relations
Authors: Huang Xiayuan , Arora Jatin , Erzurumluoglu Abdullah Mesut , Lam Daniel ,   Boehringer Ingelheim – Global Computational Biology and Digital Sciences, Zhao Hongyu , Ding Zhihao , Wang Zuoheng , de Jong Johann
Published: March 2024

Artificial intelligence and machine learning are powerful tools in analyzing electronic health records (EHRs) for healthcare research. Despite the recognized importance of family health history, in healthcare research individual patients are often treated as independent samples, overlooking family relations. To address this gap, we present ALIGATEHR, which models predicted family relations in a graph attention network and integrates this information with a medical ontology representation. Taking disease risk prediction as a use case, we demonstrate that explicitly modeling family relations significantly improves predictions across the disease spectrum. We then show how ALIGATEHR’s attention mechanism, which links patients’ disease risk to their relatives’ clinical profiles, successfully captures genetic aspects of diseases using only EHR diagnosis data. Finally, we use ALIGATHER to successfully distinguish the two main inflammatory bowel disease subtypes (Crohn’s disease and ulcerative colitis), illustrating its great potential for improving patient representation learning for predictive and descriptive modeling of EHRs.
PICK1 links KIBRA and AMPA receptors in coiled-coil-driven supramolecular complexes
Authors: Shao Xin , Volk Lenora
Published: March 2024

The human memory-associated protein KIBRA regulates synaptic plasticity and trafficking of AMPA-type glutamate receptors, and is implicated in multiple neuropsychiatric and cognitive disorders. How KIBRA forms complexes with and regulates AMPA receptors remains unclear. Here, we show that KIBRA does not interact directly with the AMPA receptor subunit GluA2, but that PICK1, a key regulator of AMPA receptor trafficking, can serve as a bridge between KIBRA and GluA2. We identified structural determinants of KIBRA-PICK1-AMPAR complexes by investigating interactions and cellular expression patterns of different combinations of KIBRA and PICK1 domain mutants. We find that the PICK1 BAR domain, a coiled-coil structure, is sufficient for interaction with KIBRA, whereas mutation of the BAR domain disrupts KIBRA-PICK1-GluA2 complex formation. In addition, KIBRA recruits PICK1 into large supramolecular complexes, a process which requires KIBRA coiled-coil domains. These findings reveal molecular mechanisms by which KIBRA can organize key synaptic signaling complexes.
The gut contractile organoid: a novel model for studying the gut motility regulated by coordinating signals between interstitial cells of Cajal and smooth muscles
Authors: Yagasaki Rei , Nakamura Ryo , Shikaya Yuuki , Tadokoro Ryosuke , Hao Ruolin , Wang Zhe , Eiraku Mototsugu , Inaba Masafumi , Takahashi Yoshiko
Published: March 2024

The gut undergoes peristaltic movements regulated by intricate cellular interactions. However, they have poorly been explored due to a lack of model system. We here developed a novel contractile organoid that is derived from the muscle layer of chicken embryonic hindgut. The organoid contained smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs; pacemaker) with few enteric neurons, and underwent periodic contractions. The organoid formed by self-organization with morphological arrangements of ICCs (internal) and SMCs (peripheral), allowing identification of these cells in live. GCaMP-Ca2+imaging analyses revealed that Ca2+transients between ICC- ICC, SMC-SMC or SMC-ICC were markedly coordinated. Pharmacological studies further showed that gap junctions play a role in ICC-to-SMC signaling, and also possible feedback from SMC’s contraction to ICC’s pace-making activities. In addition, two organoids with different rhythm became synchronized when mediated by SMCs, unveiling a novel contribution of SMCs to ICC’s pace-making. The gut contractile organoid developed in this study offers a useful model to understand the mechanisms underlying the rhythm coordination between/among ICCs and SMCs during gut peristaltic movements.
Spatial Dynamics of the Developing Human Heart
Authors: Lázár Enikő , Mauron Raphaël , Andrusivová Žaneta , Foyer Julia , He Mengxiao , Larsson Ludvig , Shakari Nick , Salas Sergio Marco , Avenel Christophe , Sariyar Sanem , Hansen Jan N. , Vicari Marco , Czarnewski Paulo , Braun Emelie , Li Xiaofei , Bergmann Olaf , Sylvén Christer , Lundberg Emma , Linnarsson Sten , Nilsson Mats , Sundström Erik , Adameyko Igor , Lundeberg Joakim
Published: March 2024

Heart development relies on a topologically defined interplay between a diverse array of cardiac cells. We finely curated spatial and single-cell measurements with subcellular imaging-based transcriptomics validation to explore spatial dynamics during early human cardiogenesis. Analyzing almost 80,000 individual cells and 70,000 spatially barcoded tissue regions between the 5.5thand 14thpostconceptional weeks, we identified 31 coarse- and 72 fine-grained cell states and mapped them to highly resolved cardiac cellular niches. We provide novel insight into the development of the cardiac pacemaker-conduction system, heart valves, and atrial septum, and decipher heterogeneity of the hitherto elusive cardiac fibroblast population. Furthermore, we describe the formation of cardiac autonomic innervation and present the first spatial account of chromaffin cells in the fetal human heart. We support independent exploration of our datasets by an open-access, spatially centric interactive viewer. In summary, our study delineates the cellular and molecular landscape of the developing heart’s architecture, offering links to genetic causes of heart disease.
Anti-fungal recombinant psoriasin effectively inhibits Candida albicans growth on denture base
Authors: Lifshits Lucia Adriana , Brohnshtein Edward , Attias May , Breuer Yoav , Cohen Adi , Gabay Matan , Sova Marina , Weinberg Evgeny , Zenziper Eran , Bar Daniel Z. , Sterer Nir , Gal Maayan
Published: March 2024

Oral candidiasis leading to denture stomatitis is a fungal infection resulting from unregulated growth and adhesion mainly ofCandida albicansonto acrylic denture base. Once the biofilm is formed, it is immune resistant and mainstay treatments involve toxic chemical antifungal agents or mechanical cleaning techniques, both offer limited efficacy. Consequently, there is an urgent need for more effective and safer therapeutic approaches. While biological modalities are expanding in general medicine, the exploration of protein-based therapeutics in dental medicine remains limited. This research evaluates the inhibitory effect of recombinantly expressed psoriasin on the growth ofCandida albicanson polymethyl methacrylate denture bases. Psoriasin, also known as S100-A7, has shown promise in treating microbial skin infections, and its natural presence in saliva makes it a promising candidate for treating oral microbial infections. Our findings indicate that psoriasin exhibits a strong, dose-dependent inhibition ofCandida albicansgrowth. Further, we incubated a polymethyl methacrylate denture base within the psoriasin solution. Notably, immersing the denture base in the solution completely eradicated fungal growth. Our research utilizes natural antifungal proteins within biomedical devices like denture bases, suggesting psoriasin as a safe alternative to chemical antifungals in dental medicine.
Chemical modification of hyaluronan oligosaccharides differentially modulates hyaluronan- hyaladherin interactions
Authors: Dodd Rebecca J. , Blundell Charles D. , Sattelle Benedict M. , Enghild Jan J. , Milner Caroline M. , Day Anthony J.
Published: March 2024

The glycosaminoglycan hyaluronan (HA) is a ubiquitous, non-sulphated polysaccharide with diverse biological roles mediated through its interactions with HA-binding proteins (HABPs). Most HABPs belong to the Link module superfamily, including the major HA receptor, CD44, and secreted protein TSG-6, which catalyzes the covalent transfer of Heavy Chains (HC) from inter-a-inhibitor (IaI) onto HA. The structures of the HA-binding domains (HABD) of CD44 (HABD_CD44) and TSG-6 (Link_TSG6) have been determined and their interactions with HA extensively characterized. The mechanisms of binding are different, with Link_TSG6 interacting with HA primarily via ionic and CH−π interactions, whereas HABD_CD44 binds solely via hydrogen bonds and van der Waals forces. Here we exploit these differences to generate HA oligosaccharides, chemically modified at their reducing ends, that bind specifically and differentially to these target HABPs. Hexasaccharides (HA6AN) modified with 2- or 3-aminobenzoic acid or 2-amino-4-methoxybenzoic acid (HA6-2AA, HA6-3AA, HA6-2A4MBA, respectively) had increased affinities for Link_TSG6 compared to unmodified HA6AN. These modifications did not increase the affinity for CD44_HABD. A model of HA6-2AA (derived from the solution dynamic 3D structure of HA4-2AA) was docked into the Link_TSG6 structure, providing evidence that the 2AA-carboxyl forms a salt bridge with Arginine-81. These modeling results informed a 2ndseries of chemical modifications for HA oligosaccharides, which again showed differential binding to the two proteins. Several modifications to HA4and HA6were found to convert the oligosaccharide into substrates for HC-transfer, whereas unmodified HA4and HA6are not. This study has generated valuable research tools to further understand HA biology.
Contrast-enhanced ultrasound imaging detects anatomical and functional changes in rat cervical spine microvasculature with normal aging
Authors: Harmon Jennifer N. , Chandran Preeja , Chandrasekaran Abarajithan , Hyde Jeffrey E. , Hernandez Gustavo J. , Reed May J. , Bruce Matthew F. , Khaing Zin Z.
Published: March 2024

Normal aging is associated with significant deleterious cerebrovascular changes; these have been implicated in disease pathogenesis and increased susceptibility to ischemic injury. While these changes are well documented in the brain, few studies have been conducted in the spinal cord. Here, we utilize specialized contrast-enhanced ultrasound (CEUS) imaging to investigate age-related changes in cervical spinal vascular anatomy and hemodynamics in male Fisher 344 rats, a common strain in aging research. Aged rats (24-26 mo., N=6) exhibited significant tortuosity in the anterior spinal artery and elevated vascular resistance compared to adults (4-6 mo., N=6; tortuosity index 2.20±0.15 vs 4.74±0.45, p<0.05). Baseline blood volume was lower in both larger vessels and the microcirculation in the aged cohort, specifically in white matter (4.44e14±1.37e13 vs 3.66e14±2.64e13 CEUS bolus AUC, p<0.05). To elucidate functional differences, animals were exposed to a hypoxia challenge; whereas adult rats exhibited significant functional hyperemia in both gray and white matter (GM: 1.13±0.10-fold change from normoxia, p<0.05; WM: 1.16±0.13, p<0.05), aged rats showed no response. Immunohistochemistry revealed reduced pericyte coverage and activated microglia behavior in aged rats, which may partially explain the lack of vascular response. This study provides the firstin vivodescription of age-related hemodynamic differences in the cervical spinal cord.
Characterisation ofSkoliomonasgen. nov., a haloalkaliphilic anaerobe related to barthelonids (Metamonada)
Authors: Eglit Yana , Williams Shelby K. , Roger Andrew J. , Simpson Alastair G.B.
Published: March 2024

Metamonads are a large and exclusively anaerobic clade of protists. Additionally, metamonads are one of the three clades with a proposed ‘excavate’ ancestral cell morphology, characterised by a conspicuous ventral groove often accompanied by a posterior flagellum with a vane. Here, we characterise four isolates of an anaerobic bacterivorous flagellate from hypersaline and alkaline soda lake environments, which represents a novel clade. Small subunit ribosomal RNA (SSU rRNA) gene phylogenies support recent phylogenomic analyses in placing this clade as the sister group toBarthelonaspp., a lineage that is itself sister to or deeply branching within Fornicata (Metamonada). The cells have a distinctive morphology comprised of a hunchbacked cell body with a narrow twisting ventral groove ending in a large opening to a conspicuous cytopharynx curving up the dorsal side of the cell. The right margin of the groove is defined by a thin ‘lip’ that twists slightly to the left towards the posterior. The posterior of the cell ends in a spike up to half a cell body long. The posterior flagellum bears a wide ventral-facing vane. One isolate forms cysts with a complex wall and a single plug. The narrow ventral groove and elongate cytopharynx are shared with barthelonids. We describe one isolate asSkoliomonas litria, gen. et sp. nov. Further investigation of mitochondrial-related organelles (MRO) inSkoliomonasspp. and detailed ultrastructural studies would be important to understanding the evolution of adaptation to anaerobic conditions in Metamonads—especially fornicates—as well as the evolution of the ‘excavate’ groove.
Trends in using intraoperative parathyroid monitoring during parathyroidectomy: Protocol and rationale for a cross-sectional survey study of North American surgeons
Authors: Staibano Phillip , McKechnie Tyler , Thabane Alex , Xie Michael , Zhang Han , Gupta Michael K. , Au Michael , Pasternak Jesse D. , Parpia Sameer , (Ted) Young JEM , Bhandari Mohit
Published: March 2024

Introduction

Hyperparathyroidism is a common endocrine disorder that can be secondary to a single or multiple abnormal parathyroid glands and can occur in the context of chronic kidney disease (CKD). There are three types of hyperparathyroidism, and all are definitively managed via surgical extirpation of abnormal parathyroid gland tissue. Intraoperative parathyroid hormone (IOPTH) monitoring was introduced over three decades ago and has been shown to improve clinical outcomes in patients with primary hyperparathyroidism (PHPT). As the incidence of PHPT rises due to improving screening globally and the incidence of CKD rises, it will be important to optimize adoption and standardization of IOPTH within endocrine surgery centers around the world. We will perform a cross-sectional survey study of surgeon rationale, operational details, and barriers associated with IOPTH adoption across North America.

Methods and analysis

We will utilize a convenience sampling technique to distribute an online survey to head and neck surgeons and endocrine surgeons across North America. This survey will be distributed via email to three North American professional societies (i.e., Canadian Society for Otolaryngologists–Head and Neck Surgeons, American Head and Neck Society, and American Association of Endocrine Surgeons). The survey will consist of 30 multiple choice questions that are divided into three concepts: (1) participant demographics and training details, (2) details of surgical adjuncts during parathyroidectomy, and (3) barriers to adoption of IOPTH. Descriptive analyses and multiple logistic regression models will be used to evaluate the impact of demographic, institutional, and training variables on the use of IOPTH monitoring and barriers to IOPTH adoption.

Discussion

This study will explore IOPTH monitoring for guiding parathyroid surgeries in secondary and tertiary hyperparathyroidism. An ability to capture surgeon practices regarding IOPTH monitoring will inform trials aimed to help optimize IOPTH in challenging populations.

Ethics and dissemination

Ethics approval was obtained by the Hamilton Integrated Research Ethics Board (2024-17173-GRA). We do not expect any survey respondents to experience any harms because of participating in this study. We plan to present the results of this study at national and international conferences, and we will publish these findings in peer-reviewed surgical journals. We plan to use these study findings to advocate for adoption of IOPTH technologies and inform future studies and trials.